clozapine and Schizophrenia

Several augmentation strategies have been used to improve symptomatology in patients not adequately responding to clozapine. Several randomised controlled trials (RCTs) have evaluated the efficacy of different strategies to augment clozapine. This systematic review and meta-analysis reviewed the available RCTs that have evaluated the clinical efficacy of various pharmacological agents, non-pharmacological strategies (occupational therapy, cognitive behaviour therapy), and somatic treatment [electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, etc.)] as augmenting agents to clozapine.. Data were extracted using standard procedures, and risk of bias was evaluated. Effect sizes were computed for the individual studies.. Forty-five clinical trials were evaluated. The pooled effect size for various antipsychotic medications was 0.103 (95% CI: 0.288-0.493,. To conclude, based on the findings of the present systematic review and meta-analysis, it can be said that compared to other treatment strategies, clozapine non-responsive patients respond maximum to mirtazapine followed by ECT.

Topics: Antipsychotic Agents; Clozapine; Humans; Mirtazapine; Risperidone; Schizophrenia

To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS).. Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking.. We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93).. Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).

Topics: Antipsychotic Agents; Clozapine; Entropy; Humans; Memantine; Mirtazapine; Network Meta-Analysis; Schizophrenia

Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes.. We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine.. Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using "Downs and Black," and "Q-Coh" instruments.. The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study.. Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Nicotine; Observational Studies as Topic; Schizophrenia; Substance-Related Disorders

Previous research has investigated the efficacy of clozapine in reducing suicidality in patients with schizophrenia and schizoaffective disorder. We aimed to systematically review published evidence, including studies concerning clozapine administration to treat: (a) refractory suicidality in other mental disorders, including bipolar disorder and borderline and other personality disorders; and (b) refractory cases of non-suicidal self-injury.. We performed a PUBMED-search (last day: July 17, 2022) of English-language studies, combining the keywords "clozapine", "suicidality", and "suicide" with various psychopathological terms (e.g. "schizophrenia"). All duplications were eliminated.. Fifty-one studies were eligible for inclusion in the review. Most studies suggest a superior anti-suicide effect of clozapine in schizophrenia/schizoaffective disorder, compared to other antipsychotics, or no antipsychotic therapy, which is not due to the close monitoring of patients for blood dyscrasias. No consensus exists as to whether other antipsychotic drugs share this effect. Discontinuation of clozapine is associated with increases in suicidality. Reductions in refractory suicidality/NSSI are observed in clozapine-treated patients with bipolar disorder or borderline personality disorder, but the evidence is limited. Potential biological underpinnings of the anti-suicide effect of clozapine include its unique profile of modulation of brain neurotransmitters; its non-selectivity for neurotransmitter receptors; specific genetic and hormonal factors; effects on neuroinflammation; and ability to elicit epileptiform activity.. The superior anti-suicide effect of clozapine in schizophrenia/schizoaffective disorder patients is well established. It may have a role in severe and refractory cases of suicidality and non-suicidal self-injury in patients with bipolar disorder or borderline personality disorder, but the level and quality of supporting evidence is limited.

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Schizophrenia; Suicide

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Risk Factors; Schizophrenia

Insomnia commonly occurs in schizophrenia, and insomnia is associated with suicide risk. Clozapine has anti-suicidal properties and beneficial effects on sleep. We performed a meta-analysis of insomnia in randomized controlled trials (RCTs) of patients with schizophrenia treated with clozapine. We hypothesized that compared to clozapine there is an increased odds of insomnia in patients treated with other antipsychotics.. We systematically searched PubMed, PsycINFO, and Web of Science databases. We included RCTs, in English, with data on insomnia in patients with schizophrenia treated with clozapine versus other antipsychotics. Data were pooled using a random effects model.. Eight RCTs (1952 patients: 922 on clozapine and 1030 on other antipsychotics) met inclusion criteria. Patients treated with other antipsychotics versus clozapine had a significant increased odds of insomnia (22.3 % versus 12.4 %, OR = 2.20, 95 % CI = 1.64-2.94, p < 0.01). Olanzapine, quetiapine, risperidone, and ziprasidone were each associated with significant increased odds of insomnia compared to clozapine. In meta-regression analyses, clozapine dose, publication year, sex, trial duration, and study quality score were unrelated to the association; however, there was a significant association with age. The observed ORs for insomnia from RCTs were almost perfectly correlated with reported ORs from pharmacovigilance data.. Clozapine is associated with significantly less insomnia compared to other antipsychotics. Findings provide additional evidence for improvement in sleep as a potential pathway underlying clozapine's anti-suicidal properties. A greater mechanistic understanding of this association is needed.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Schizophrenia; Sleep Initiation and Maintenance Disorders

This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia.. The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored.. Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P = 0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation.. Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

Topics: Antipsychotic Agents; Clozapine; Double-Blind Method; Humans; Lurasidone Hydrochloride; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Schizophrenia is a major psychiatric disorder with unknown aetiology. Recent evidence suggests a potential role for cytokines in its pathophysiology and that antipsychotic medication may alter this. While the aetiology of schizophrenia remains only partly understood, an altered immune function representing an important avenue of further discovery. In this systematic review and meta-analysis we focus on the specific effects of second generation antipsychotics risperidone and clozapine on inflammatory cytokines.. A defined systematic search of PubMed and Web of Science databases was performed to identify relevant studies published between Jan 1900 and May 2022. After screening of 2969 papers, 43 studies (27 single-arm and 8 dual-arm) were included that consisted of a total of 1421 patients with schizophrenia in the systematic review. From these, twenty studies (4 dual-arm; 678 patients) had data available on which a meta-analysis could be carried out.. Our meta-analysis showed a significant reduction of pro-inflammatory cytokines post-risperidone treatment in the absence of a similar association with clozapine. Subgroup analyses (First episode v chronic) demonstrated that duration of illness influenced the extent of cytokine alteration; risperidone treatment produced significant cytokine changes (lowered IL-6 and TNF-α) in chronic patients but not in first-episode psychosis (FEP) patients.. Varying treatment effects on cytokines can be observed by the use of different antipsychotic drugs. The cytokine alterations post-treatment are influenced by the specific antipsychotic drugs and patient status. This may explain disease progression in certain patient groups and influence therapeutic choices in the future.

Topics: Anti-Inflammatory Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Cytokines; Humans; Olanzapine; Risperidone; Schizophrenia

Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate.. To personalize clozapine treatment, we investigated the efficacy of clozapine as first- or second-line treatment and investigated whether there are factors that were associated with efficacy and side effects.. We collected a unique cohort of over 800 clozapine users diagnosed with a schizophrenia spectrum disorder. We meta-analyzed factors that were associated with response during clozapine treatment. Additionally, we conducted genetic association analyses to investigate the relations between side effects and symptom severity during clozapinetreatment.. From our meta-analyses, we found that clozapine was more effective when used as a first- or second-line treatment. Furthermore, we found that younger age, less negative symptoms and the paranoid subtype of schizophreniawere associated with a better clozapine response. Several specific locations on genes (loci) were associated with clozapine-induced agranulocytosis and neutropenia, while polygenic risk scores were associated with symptom severity.. We found that clozapine could be effective earlier in treatment and identified factors that could aid the prediction of< response to clozapine treatment in the future. These finding could contribute to the start of a personalized clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Humans; Neutropenia; Precision Medicine; Schizophrenia

Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Psychiatry; Quality of Life; Schizophrenia; Schizophrenia, Treatment-Resistant

Although clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response.. Using individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice.. We conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response.. We included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223-558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine.. Clozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychiatric Status Rating Scales; ROC Curve; Schizophrenia

Although therapeutic drug monitoring of clozapine is recommended, its optimisation is often adjusted only on the basis of dosage. The aim of this study was to assess the link between clozapine plasma concentrations and clinical response by a meta-analysis of published studies and by an individual participant data meta-analysis.. We conducted a computerised search of bibliographic databases (EMBASE, PubMed, Clinical Trials, and Web of Science) to identify studies that assessed the relationship between clozapine serum or plasma concentrations and clinical efficacy. Using pooled data, we investigated the association between improvement of clinical outcome and clozapine or norclozapine plasma concentrations, the sum of clozapine and norclozapine plasma concentrations, and the coefficient of variation of clozapine plasma concentrations. Using available individual data, we assessed the relationship between clozapine plasma concentrations and clinical response (changes in the Brief Psychiatric Rating Scale score) and identified a threshold level for a favourable clinical response.. Fifteen studies satisfied inclusion criteria. Our meta-analysis showed that responders had clozapine plasma concentrations that were, on average, 117 ng/mL higher than non-responders. The patients with plasma clozapine concentrations above the thresholds identified in each study had a higher likelihood of responding (odds ratio = 2.94, p < 0.001). Norclozapine plasma concentrations were not associated with a clinical response. The meta-analysis of individual data supported this result and confirmed the link between clozapine concentrations and a change in the Brief Psychiatric Rating Scale score and/or the probability of clinical response. Finally, with the analysis of the coefficient of variation of clozapine plasma concentrations, we found that a greater inter-individual fluctuation in plasma concentrations was associated with a loss of clinical response.. Our work confirmed that, in contrast to clozapine doses, clozapine plasma concentrations were related to a favourable clinical response, with a mean difference between responders and non-responders of 117 ng/mL. A threshold for a treatment response of 407 ng/mL was determined, with a high discriminatory capacity, and a sensitivity and specificity of 71% and 89.1%, respectively.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Treatment Outcome

Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS). Although the evidence base for its wide-ranging, unique efficacy continues to expand, clozapine remains alarmingly underutilized in industrialized countries. Analyzing the causes and consequences of this problem is crucial for substantially improving the quality of care for TRS patients.. Clozapine is the most effective antipsychotic for reducing all-cause mortality in TRS. In most cases, treatment resistance emerges during the first psychotic episode. Delaying clozapine treatment has a negative impact on long-term outcome. Patients' experience with clozapine treatment is largely positive despite a comparatively high rate of side effects. Patients prefer clozapine, while psychiatrists regard it as a burden due to concerns regarding safety and side effect management. Shared decision-making (SDM), which increases the likelihood of a clozapine recommendation, is not routinely used, possibly due to stigmatization of TRS patients.. The mortality-reducing effects of clozapine alone warrant its regular use. Therefore, psychiatrists must not exclude patients from the decision regarding a clozapine trial by not even offering it. Rather, they have a clear obligation to align their actions more closely with the existing evidence and patients' needs and to facilitate the timely initiation of clozapine.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychiatry; Psychotic Disorders; Schizophrenia

Early non-response is a well-established prognostic marker but evidence-based and consistent recommendations to manage it are limited. The aim of this systematic review and meta-analysis was to generate evidence-based strategies for the management of schizophrenia patients with early non-response to 2 weeks of antipsychotic treatment.. We conducted a systematic review and meta-analysis of randomized trials comparing antipsychotic dose escalation, switch, augmentation and continuation in individuals with study-defined early antipsychotic treatment non-response. Eligibility criteria were (1) clinical trials of primary psychosis treating for at least 2 weeks with antipsychotic monotherapy with study-defined operationalized criteria for early non-response; and (2) randomization to at least two of the following treatment strategies: dose escalation, switch, augmentation, or treatment continuation. Information sources were Pubmed, PsycINFO, and EMBASE, and risk of bias was assessed using Jadad scores. Results were synthesized using random-effects meta-analysis, comparing each intervention with treatment continuation for total symptom change as the primary outcome, generating standardized mean differences (SMDs) and 95% confidence intervals (CIs). Studies meeting the selection criteria but providing insufficient data for a meta-analysis were presented separately.. We screened 454 records by 1 August 2022, of which 12 individual datasets met the inclusion criteria, representing 947 research participants. Of those studies, five provided data to include in the meta-analysis (four with early non-response at 2 weeks, one at 3 weeks). Early non-response was defined within a timeline of 2 weeks in eight datasets, with the remaining datasets ranging between 3 and 4 weeks. The rates of early non-response ranged between 72.0 and 24.1%, and the endpoint ranged within 4-24 weeks post randomization. Quality was good (i.e., Jadad score of ≥3) in 8 of the 12 datasets. Overall, three studies compared antipsychotic switch versus continuation and two compared antipsychotic switch versus augmentation, in both cases without significant pooled between-group differences for total symptom severity (n = 149, SMD 0.18, 95% CI -0.14 to 0.5). Individually, two relatively large studies for antipsychotic switch versus continuation found small advantages for switching antipsychotics for total symptom severity (n = 149, SMD -0.49, 95% CI -1.05 to -0.06). One relatively large study found an advantage for dose escalation, although this finding has not been replicated and was not included in the meta-analysis. None of the alternatives included antipsychotic switch to clozapine.. Despite robust accuracy of early antipsychotic non-response predicting ultimate response, the evidence for treatment strategies that should be used for early non-response after 2-3 weeks is limited. While meta-analytic findings were non-significant, some individual studies suggest advantages of antipsychotic switch or dose escalation. Therefore, any conclusions should be interpreted carefully, given the insufficient high-quality evidence.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Psychotic Disorders; Schizophrenia

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.

Topics: Antipsychotic Agents; Clozapine; Humans; Quality of Life; Schizophrenia

Schizophrenia, a serious psychiatric disorder, is among the top 10 global causes of disability and affects nearly 1% of the world population. Antipsychotics constitute the best treatment for patients with schizophrenia, however, this treatment class carries a high risk of metabolic syndrome, including lipid abnormalities. Indeed, the risk of metabolic syndrome would be increased in the population with schizophrenia compared to the general population. The objective is to summarize the prevalence, the mechanisms, and the potential treatments of antipsychotic-induced metabolic syndrome. This is a narrative review of the literature. We searched the electronic database Medline, accessed through PubMed, to find studies that investigated the prevalence and treatments of metabolic syndrome in the adult population using antipsychotics. The prevalence of metabolic syndrome in patients treated with antipsychotics ranges from 37% to 63%. Antipsychotic iatrogenic effects include weight gain/increased waist circumference, dyslipidemia, insulin resistance/type 2 diabetes, and hypertension. Clozapine and olanzapine are reported to precipitate the onset of metabolic syndrome features. In patients with metabolic syndrome, an antipsychotic with less metabolic side effects such as lurasidone, lumateperone, ziprasidone, and aripiprazole should be prioritized. Unlike medications, aerobic exercise and dietetic counseling were found to be efficient as the nonpharmacologic treatment of antipsychotic-induced metabolic syndrome. Few pharmacological treatments were proven effective against weight gain in this patient population. The risk of metabolic syndrome induced by antipsychotics should be early recognized and closely monitored. Primary and secondary prevention of metabolic syndrome or onset of its feature might help reduce the risk of death for patients using antipsychotics.

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hypertension; Metabolic Syndrome; Olanzapine; Schizophrenia; Weight Gain

According to current guidelines, clozapine should be used as a third step in treatment resistant schizophrenia (TRS). In everyday clinical practice, however, it is frequently used at a much later stage, which leads to a significant deterioration of prognosis. The first part of this narrative overview focuses on the most frequent side effects of clozapine, on the relevance of slow titration, and on specific aspects of therapeutic drug monitoring (TDM).. Medline, the Guideline for the use of clozapine 2013 of the Netherlands Clozapine Collaboration Group, and the S3 Guideline for Schizophrenia of the German Association for Psychiatry, Psychotherapy and Psychosomatics were searched for relevant literature, the last query dating from April 28th, 2023.. Despite its unique efficacy clozapine is underused in clinical practice and prescription varies between and within countries. Next to hematological, metabolic, and vegetative side effects, clozapine induced inflammation manifesting in the form of pneumonia or myocarditis, which is mainly associated with rapid titration, represents a major clinical challenge with CRP monitoring being of particular relevance. In this context, it also has to be noted that sex, smoking behavior, and ethnic origin impact clozapine metabolism, thus requiring personalized dosing.. Slow titration when possible, TDM, and CYP diagnostics when appropriate increase patient safety during treatment with clozapine and thus the likelihood of early prescription of this compound in TRS.. HINTERGRUND: Laut geltender Leitlinien sollte Clozapin als Mittel dritter Wahl bei therapieresistenten schizophrenen Störungen (TRS) Verwendung finden. Im klinischen Alltag erfolgt der Einsatz jedoch häufig zu einem wesentlich späteren Zeitpunkt, was zu einer deutlichen Verschlechterung der Krankheitsprognose führt. Der erste Teil dieser narrativen Übersicht beleuchtet häufige unerwünschte Arzneimittelwirkungen (UAW) von Clozapin, die Bedeutung einer langsamen Titration und spezifische Aspekte des Therapeutischen Drug Monitoring (TDM).. Die Datenbank Medline sowie die Guideline for the use of clozapine 2013 der Netherlands Clozapine Collaboration Group und die S3-Behandlungsleitlinie Schizophrenie der Deutschen Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde e.V. wurden nach relevanter Literatur untersucht, die letzte Abfrage erfolgte am 28.04.2023.. Trotz einzigartiger Wirksamkeit erfolgt die Verordnung von Clozapin im klinischen Alltag deutlich seltener als indiziert und variiert sowohl innerhalb als auch zwischen den Ländern. Neben hämatologischen, metabolischen und vegetativen UAW stellen die vor allem bei rascher Titration zu beobachtenden entzündlichen Erkrankungen in Form von Pneumonie oder Myokarditis wesentliche klinische Herausforderungen dar, so dass CRP-Kontrollen von besonderer Bedeutung sind. In diesem Zusammenhang muss insbesondere auch beachtet werden, dass Geschlecht, Rauchverhalten und ethnische Herkunft der Patient:innen den Clozapin-Stoffwechsel beeinflussen und daher eine individuelle Dosierung erforderlich machen.. Eine nach Möglichkeit langsame Titration, TDM und gegebenenfalls eine CYP-Diagnostik erhöhen die Patient:innensicherheit während einer Behandlung mit Clozapin und somit die Wahrscheinlichkeit einer frühzeitigen Verordnung dieser Substanz bei TRS.

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Psychiatry; Schizophrenia

Due to its unique efficacy in treatment-resistant schizophrenia, discontinuation of treatment with clozapine is frequently associated with a significant worsening of symptoms, but also with an increased risk of suicide. Based on the literature, this review aims at summarizing different monitoring recommendations in order to be able to continue this therapy despite the occurrence of side effects. In addition, we provide recommendations when rechallenge of a previously stopped treatment with clozapine can be considered and when a definite discontinuation must take place.. Medline, the Guideline for the use of clozapine 2013 of the Netherlands Clozapine Collaboration Group, and the S3 Guideline for Schizophrenia of the German Association of Psychiatry, Psychotherapy and Psychosomatics were searched for relevant literature, the last query dating from April 28th, 2023.. If agranulocytosis or cardiomyopathy develops, treatment with clozapine must be discontinued and should not be resumed thereafter. In contrast, treatment with clozapine which had to be discontinued due to myocarditis or prolongation of the QTc interval may be continued if left ventricular function is normal or after normalization of the QTc interval. Other side effects are usually not absolute contraindications for rechallenge but often require the adjunctive use of additional pharmacologic and non-pharmacologic measures.. Taking into consideration various monitoring recommendations, cessation of treatment with clozapine can often be prevented or treatment with clozapine that has been discontinued due to side effects can be resumed.. HINTERGRUND: Auf Grund seiner unvergleichbaren Wirksamkeit bei therapieresistenten schizophrenen Störungen ist der Abbruch einer Behandlung mit Clozapin häufig mit einer erheblichen Verschlechterung der Krankheitssymptomatik, aber auch mit einem erhöhten Suizidrisiko verbunden. Ziel der vorliegenden Übersichtsarbeit ist es, auf Basis aktueller Fachliteratur verschiedene Monitoring-Empfehlungen zusammen zu fassen, um diese Therapie gegebenenfalls trotz auftretender unerwünschter Arzneimittelwirkungen (UAW) fortsetzen zu können. Des Weiteren wird ausgearbeitet, wann eine unterbrochene Therapie mit Clozapin wieder aufgenommen werden kann (Rechallenge) und wann ein definitiver Behandlungsabbruch erfolgen muss.. Die Datenbank Medline sowie die Guideline for the use of clozapine 2013 der Netherlands Clozapine Collaboration Group und die S3-Behandlungsleitlinie Schizophrenie der Deutschen Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde e.V. wurden nach relevanter Literatur untersucht, die letzte Abfrage erfolgte am 28.04.2023.. Bei Entwicklung einer Agranulozytose oder einer Kardiomyopathie muss die Behandlung mit Clozapin beendet werden und sollte auch im weiteren Verlauf nicht wieder aufgenommen werden. Dem gegenüber kann eine auf Grund einer Myokarditis bzw. einer unter der Behandlung auftretenden Verlängerung der QTc-Zeit abgebrochene Behandlung mit Clozapin bei regelrechter linksventrikulärer Funktion bzw. nach Normalisierung der QTc-Zeit gegebenenfalls fortgesetzt werden. Andere UAW stellen in der Regel keine absolute Kontraindikation für eine Rechallenge dar, erfordern jedoch häufig den adjuvanten Einsatz zusätzlicher pharmakologischer und nicht-pharmakologischer Maßnahmen.. Unter Berücksichtigung verschiedener Monitoring-Empfehlungen kann die Beendigung einer Behandlung mit Clozapin häufig verhindert bzw. eine auf Grund von UAW abgebrochene Behandlung mit Clozapin wieder aufgenommen werden.

Topics: Antipsychotic Agents; Clozapine; Humans; Myocarditis; Psychotherapy; Schizophrenia

Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal.. CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included.. Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment.. Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.

Topics: Antipsychotic Agents; Catatonia; Cholinergic Agents; Clozapine; Humans; Schizophrenia; Substance Withdrawal Syndrome

Antipsychotic drug-induced myocarditis is a serious and potentially fatal adverse drug reaction characterized by inflammation of the heart muscle (myocardium) that typically develops within the first month after commencing an antipsychotic drug. Although the precise mechanism of this severe adverse drug reaction is unknown, multiple theories have been proposed with varying levels of support from cellular or animal studies. We conducted a systematic review, in accordance with PRISMA guidelines, of published preclinical and clinical studies investigating the cellular mechanism by which antipsychotic drugs induce myocarditis. A literature search including all studies available before December 10, 2022, yielded 15 studies that met our inclusion criteria. Antipsychotics examined in the included studies included clozapine (n = 13), ziprasidone (n = 1), amisulpride (n = 1), haloperidol (n = 1), levomepromazine (n = 1), olanzapine (n = 1), and sertindole (n = 1). The evidence suggests several overlapping mechanistic cascades involving: (1) increased levels of catecholamines, (2) increased proinflammatory cytokines, (3) increased reactive oxygen species (ROS), (4) reduced antioxidant levels and activity, and (5) mitochondrial damage. Notable limitations such as, a focus on clozapine, sample heterogeneity, and use of supratherapeutic doses will need to be addressed in future studies. Discovery of the mechanism by which antipsychotic drugs induce myocarditis will allow the development of clinically-useful biomarkers to identify those patients at increased risk prior to drug exposure. The development or repurposing of therapeutics to prevent or treat drug-induced myocarditis will also be possible and this will enable increased and safe use of antipsychotics for those patients in need.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Schizophrenia

Up to 30% of patients with a diagnosis of treatment-resistant psychosis remain symptomatic despite an optimal trial with the gold standard treatment, clozapine. Emerging evidence suggests the clinical utility of long-acting injections (LAI) in such clinical scenarios. In this study, we aimed to describe clozapine augmentation with LAIs in an inner London hospital and explore the literature on the clinical effectiveness of this treatment modality.. Patients prescribed clozapine, who were commenced on a LAI between 2007 and 2023 by the United Kingdom's largest mental health trust, were identified from electronic patient records. First, routine clinical data were used to describe the use, effectiveness, and safety of this augmentation strategy. Second, we conducted a literature search up to 1st June 2023 to identify published studies describing clinical outcomes after clozapine augmentation with a LAI. Clinical outcomes were collated and presented in a table, including hospitalisation rates and quantitative clinical assessments using validated scales.. Of the 1248 patients prescribed clozapine in SLaM, three patients (0.2%) received augmentation with the following LAIs: olanzapine embonate, paliperidone palmitate and pipotiazine palmitate. This treatment strategy was clinically effective and generally well tolerated in all three cases. Twelve published studies between 2010 and 2022 were included in the review. Eight distinct LAIs were reported (4 first and 4 second generation antipsychotics), with risperidone and paliperidone most widely studied. All the identified studies were observational including mirror-image studies, case series and case reports. Duration of follow up varied from 3 months to 3 years. There was evidence that the use of LAIs with clozapine can significantly reduce clinical symptoms, hospitalisation rates and bed days. No serious adverse effects were reported.. This preliminary evidence suggests clinical utility of LAIs in alleviating residual symptoms and subsequently reducing hospitalisation rates in patients optimised on clozapine treatment. The current study warrants further investigations including a randomised controlled study to establish the clinical efficacy, tolerability, and place in therapy of this treatment modality.

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Humans; Paliperidone Palmitate; Risperidone; Schizophrenia

Cognitive behavioural therapy for psychosis (CBTp), an effective treatment for people with schizophrenia, may have a role in clozapine refractory schizophrenia.. A systematic-review and meta-analysis on the impact of CBTp on psychotic symptoms in people on clozapine.. We searched PubMed, Embase, PsycInfo, CINAHL and Cochrane for randomised control trials of CBTp as augmentation in people with treatment-refractory schizophrenia on clozapine and conducted pair-wise meta-analyses.. Four studies met inclusion criteria. On pairwise meta-analyses, the primary outcome of total psychotic symptoms was not significantly altered by CBTp at either therapy endpoint or six to twelve months follow-up. Secondary outcomes showed that CBT improved positive symptoms at both therapy endpoint (SMD -0.33, 95%CI -0.50 to -0.16,. CBTp may lead to small benefits for positive symptoms refractory to clozapine. Given the low risks associated with CBTp, and the limited alternative options for clozapine refractory schizophrenia, this approach should be considered in this population.

Topics: Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Humans; Psychotic Disorders; Schizophrenia; Schizophrenia, Treatment-Resistant

The Dutch Clozapine Collaboration Group is frequently asked for advice about the management of clozapine-treated patients when infected with or vaccinated against SARS-CoV-2. We provide state of the art information about the risks of SARS-CoV-2 infection for patients on clozapine and we give advice on measures to be taken, especially in regard to the monitoring of clozapine plasma levels, WBC count and differentiation during COVID-19 and after vaccination. We present an overview of relevant editorials, observational studies, and case studies, in which COVID-19 was reported in patients on clozapine. Patients using clozapine may have a higher risk of infection than patients with schizophrenia spectrum disorders (SSD) using other antipsychotics. SARS-CoV-2 infection can result in a dangerous increase of clozapine plasma levels, and granulocytopenia and lymphocytopenia (generally mild and short-term) may also occur, usually not as a result of clozapine treatment. Clozapine intoxication, pneumonia and delirium are the main complications of COVID-19 in patients on clozapine. In order to prevent clozapine intoxication, reduction of the original dose by half is generally recommended in clozapine users who contract COVID-19. When a cytokine storm is suspected in an advanced stage of COVID-19, reduction by three quarters seems more appropriate. If COVID-19 patients on clozapine develop granulocytopenia, SARS-CoV-2, rather than clozapine, should be considered as the cause. Schizophrenia patients in general and clozapine users in particular belong to a high-risk group that warrants early vaccination on a medical indication.

Topics: Antipsychotic Agents; Clozapine; COVID-19; Humans; SARS-CoV-2; Schizophrenia

Antipsychotic pharmacotherapy is considered a first-line treatment in schizophrenia-related disorders and is associated with favorable prognosis and lower mortality rates. However, low adherence rates present a major clinical challenge. In this paper, we will review contemporary approaches to improve adherence to antipsychotic treatment, considering their mechanism of action, safety, tolerability and acceptability.. Novel pharmacological delivery methods included different routes of administration of registered medications (such as intramuscular clozapine preparation and transdermal asenapine), modifications of existing compounds (such as 3-monthly injectable formulation of paliperidone palmitate), and increased interest in oral long-acting medication formulations (such as with penfluridol). In addition, we reviewed innovative technology to monitor adherence, based on the use of electronic digital medicine systems and ingestible sensors.. All of these diverse approaches were clinically relevant in enhancing treatment adherence and found to be safe and tolerable. The place of each approach is predicated on a personalized approach in each patient, and future research could usefully use large comparative studies to establish robust treatment guidelines. The implementation of new and varied approaches to antipsychotic treatment adherence is welcomed and have the potential to make a significant impact on morbidity in this often difficult-to-treat population.

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Humans; Medication Adherence; Paliperidone Palmitate; Schizophrenia

The emergence of coronavirus SARS-CoV-2, and the subsequent global epidemic of COVID-19, brought with it innumerable new clinical experiences across all medical specialties, and psychiatry is no exception. Individuals with serious mental illness, in particular schizophrenia and related disorders, may be especially susceptible to coronavirus infection given the overlapping risk factors of vulnerable sociodemographic status, increased challenges with quarantining requirements, and limited compliance with "respiratory etiquette." The case presented here describes a patient with schizophrenia who was being managed on clozapine and who developed symptomatic COVID-19 infection. Special care was taken to ensure that potential interactions between clozapine and the associated COVID-19 treatments were safe for the patient's mental and physical wellbeing.. A 71-year-old schizophrenic Caucasian male is being managed with clozapine. While hospitalized, the patient was screened positive for COVID-19 and was admitted to the ICU due to his declining respiratory status. He was treated with both remdesivir and prednisone. He was able to fully recover from his COVID-19 infection.. The authors review the clinical characteristics of the case, highlighting both the overlapping synergistic effects and antagonistic influences of clozapine therapy in combination with COVID-19 and its associated treatments. A review of the literature offers an opportunity to examine various frameworks for individualized clinical decision-making while making the case for greater epidemiologic research into the optimal management of individuals with a psychotic disorder who are diagnosed with COVID-19 infection.

Topics: Aged; Clozapine; COVID-19; Humans; Male; Psychotic Disorders; SARS-CoV-2; Schizophrenia

Treatment-resistant schizophrenia (TRS) is associated with high levels of functional impairment, healthcare usage and societal costs. Cross-sectional studies may overestimate TRS rates because of selection bias.. We aimed to quantify TRS rates by using first-episode cohorts to improve resource allocation and clozapine access.. We undertook a systematic review of TRS rates among people with first-episode psychosis and schizophrenia, with a minimum follow-up of 8 weeks. We searched PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews, and meta-analysed TRS rates from included studies.. Twelve studies were included, totalling 11 958 participants; six studies were of high quality. The rate of TRS was 22.8% (95% CI 19.1-27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5-30.0%, P < 0.001) among first-episode schizophrenia cohorts. Subgroup sensitivity analyses by location of recruitment, TRS definition, study quality, time of data collection and retrospective versus prospective data collection did not lead to statistically significant differences in heterogeneity. In a meta-regression, duration of follow-up and percentage drop-out did not significantly affect the overall TRS rate. Men were 1.57 times more likely to develop TRS than women (95% CI 1.11-2.21, P = 0.010).. Almost a quarter of people with first-episode psychosis or schizophrenia will develop TRS in the early stages of treatment. When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third. These high rates of TRS highlight the need for improved access to clozapine and psychosocial supports.

Topics: Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Female; Humans; Male; Retrospective Studies; Schizophrenia; Schizophrenia, Treatment-Resistant

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain

Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics.

Topics: Alcohol Drinking; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Schizophrenia

Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective-with the exception of clozapine-against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D

Topics: Antipsychotic Agents; Clozapine; Dopamine; Drug Discovery; Humans; Schizophrenia

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant; Transcranial Direct Current Stimulation

Long-term institutionalization of the forensic psychiatry patient population places a psychological burden on patients and family members as well as a financial burden on the health care system at large. Although electroconvulsive therapy is a well-established tool for patients with treatment-resistant schizophrenia, it is infrequently used in the forensic setting. This review serves to demonstrate an example of electroconvulsive therapy in combination with clozapine as a means of reducing length of hospitalization in a forensic psychiatric patient. Furthermore, this review will discuss factors limiting the prescribing of electroconvulsive therapy to this patient population including ethical considerations and availability.

Topics: Antipsychotic Agents; Clozapine; Electroconvulsive Therapy; Forensic Psychiatry; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant

Although numerous studies reported some changes of cortical silent period (CSP), an indicator of gamma-aminobutyric acid (GABA) function in central nervous system, in schizophrenia patients, it has been unknown how the disease stage and antipsychotic medication affect CSP values.. The present study conducted a systematic review of previous literature comparing CSP between schizophrenia patients and healthy subjects, and then performed meta-analysis on the effects of (1) the disease stage and (2) antipsychotics on CSP.. (1) In the comparison of the disease stage comprising a total of 17 reports, there was no significant difference in CSP between patients under drug-naïve first-episode psychoses and healthy controls, or between patients with antipsychotic medication and healthy controls. (2) In the comparison of the antipsychotic class, patients treated with clozapine were longer in CSP compared to healthy controls. Patients treated with olanzapine/quetiapine or with other type of antipsychotics were not different from healthy controls. Regarding other type of antipsychotics, the iteration analysis after leaving out one literature showed that patients were shorter in CSP than healthy controls.

Topics: Antipsychotic Agents; Clozapine; gamma-Aminobutyric Acid; Humans; Neural Inhibition; Olanzapine; Quetiapine Fumarate; Receptors, GABA; Schizophrenia

Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation.. A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation* OR cease* OR withdraw* OR discontinu* OR halt* OR stop* OR switch*) AND (schizophreni* OR schizoaffective)).. A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group.. Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

Topics: Antipsychotic Agents; Clozapine; Humans; Olanzapine; Retrospective Studies; Schizophrenia

Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HT

Topics: Antipsychotic Agents; Clozapine; Humans; Receptors, Dopamine D2; Schizophrenia; Schizophrenia, Treatment-Resistant

Early-onset schizophrenia (EOS) - onset before age 18 - is linked with great disease burden and disability. Decision-making for EOS pharmacological treatment may be challenging due to conflicting information from evidence and guidelines and unidentified care needs may remain unmet.We searched for systematic reviews, meta-analyses and umbrella reviews of EOS pharmacological treatment published in PubMed over the past 10 years and selected five clinical guidelines from Europe, North-America and Australia. Based on predefined outcomes, we critically compared the evidence supporting EOS-approved drugs in Europe and/or North-America with guidelines recommendations. We also evaluated the coverage of these outcomes to identify unmet needs.One systematic review, nine meta-analyses and two umbrella reviews (k=203 trials, N=81,289 participants, including duplicated samples across selected articles) were retrieved. Evidence supported the efficacy of aripiprazole, clozapine, haloperidol, lurasidone, molindone, olanzapine, quetiapine, risperidone and paliperidone in EOS, all of which obtained approval for EOS either in Europe and/or in North-America. Cognition, functioning and quality of life, suicidal behaviour and mortality and services utilisation and cost-effectiveness were poorly covered/uncovered.Among the antipsychotics approved for EOS, aripiprazole, lurasidone, molindone, risperidone, paliperidone and quetiapine emerged as efficacious and comparably safe options. Olanzapine is known for a high risk of weight gain and haloperidol for extrapyramidal side-effects. Treatment-resistant patients should be offered clozapine. Future long-term trials looking at cognition, functioning, quality of life, suicidal behaviour, mortality, services utilisation and cost-effectiveness are warranted. Closer multi-agency collaboration may bridge the gap between evidence, guidelines and approved drugs.

Topics: Adolescent; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Haloperidol; Humans; Lurasidone Hydrochloride; Molindone; Olanzapine; Paliperidone Palmitate; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Systematic Reviews as Topic

Clozapine is the only licenced medication for treating treatment-resistant schizophrenia. Previous studies have suggested unequal rates of clozapine treatment by ethnicity among individuals with schizophrenia-spectrum disorders. One previous review has investigated this topic but was restricted to studies from the USA. This current review aims to synthesise the international literature regarding ethnic disparities in clozapine prescription amongst individuals with schizophrenia-spectrum disorders. We searched CINAHL, PubMed, Medline, Embase, APA PsycINFO and Open Grey and reviewed studies reporting on the proportion of service-users prescribed clozapine separately for different ethnic groups, in individuals with a primary diagnosis of schizophrenia or any schizophrenia-spectrum disorders. A narrative synthesis was conducted to integrate information from included studies. The review was registered in PROSPERO (Number: CRD42020221731). From 24 studies, there is strong, consistent evidence that Black and Hispanic service-users in the UK and the USA are significantly less likely to receive clozapine than White/Caucasian service-users after controlling for multiple demographic and clinical potential confounders. In New Zealand, Māori service-users were reported to be more likely to receive clozapine than those of White/European ethnicity. There is mixed evidence regarding Asian service-users in the UK. The mentioned disparities were observed in studies with TRS and non-TRS cohorts. The results imply that access to clozapine treatment varies among ethnic groups. These findings raise an ethical concern as they suggest a compromise of the standards of care in schizophrenia treatment practices. Interventions are needed to reduce clozapine prescribing disparities among ethnic communities.

Topics: Antipsychotic Agents; Clozapine; Ethnicity; Humans; Prescriptions; Schizophrenia

BACKGROUND Myocarditis is cardiac muscle inflammation caused by infectious or noninfectious agents. Rarely, clozapine, an atypical antipsychotic drug used to treat resistant schizophrenia, has been reported to cause myocarditis, as we report in this case. CASE REPORT A 29-year-old man, who was known to have schizophrenia and was on olanzapine therapy, presented in our Emergency Department with active psychosis, and was subsequently admitted to the psychiatric ward for refractory schizophrenia. He was started on clozapine, which was cross-titrated with olanzapine. On day 20 of being treated with clozapine, he developed a high-grade fever and chest pain. EKG demonstrated new-onset prolonged QT corrected for heart rate (QTc), premature ventricular contractions, ST-T wave changes with an increased ventricular rate, and ventricular bigeminy with elevated troponin and inflammatory markers. Echocardiography showed a reduced left ventricular ejection fraction. Coronary angiography showed normal coronary arteries, low cardiac output, and cardiac index consistent with cardiogenic shock was also observed. Other pertinent laboratory results included negative respiratory viral panel, including COVID-19 PCR, negative blood cultures, and negative stool screen for ova and parasite. Clozapine was discontinued and the patient received management for heart failure with reduced ejection fraction. He improved clinically with return of EKG to normal sinus rhythm and improved left ventricular ejection fraction on repeat echocardiogram. CONCLUSIONS Acute myocarditis can occur due to a myriad of causes, both infectious and noninfectious; thus, determining the lesser-known causes, such as drug-related etiology, is essential to provide appropriate treatment for patients.

Topics: Adult; Clozapine; COVID-19; Humans; Male; Myocarditis; Olanzapine; Schizophrenia; Schizophrenia, Treatment-Resistant; Stroke Volume; Ventricular Function, Left

Clozapine response varies widely from person to person, which may be due to inter-individual genetic variability. This umbrella review aims to summarize the current evidence on associations between pharmacodynamic genes and response to clozapine treatment.. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis methodology, a systematic literature search was conducted in the PubMed and EMBASE databases from inception to November 2021 to identify systematic reviews and meta-analyses of studies that examined genetic determinants of clozapine response. The quality of the reviews was assessed with the AMSTAR-2 tool.. From a total of 128 records, 10 studies representing nine systematic reviews and one meta-analysis met our inclusion criteria. The overall quality of the included studies was poor. All systematic reviews concluded that the results of primary studies were largely negative or conflicting. Most evidence was found for an association with clozapine response and rs6313 and rs6314 within HTR2A and rs1062613 within HTR3A in the serotonergic system.. Conclusive evidence for associations between genetic variants and clozapine response is still lacking. Hypothesis-generating genetic studies in large, well-characterized study populations are urgently needed to obtain more consistent and clinically informative results. Future studies may also include multi-omics approaches to identify novel genetic determinants associated with clozapine response.

Topics: Clozapine; Databases, Factual; Humans; Schizophrenia; Systematic Reviews as Topic

Treatment-resistant schizophrenia (TRS) comes with significant medical comorbidities, including heart disease, liver disease, and diabetes-all of which contribute to higher mortality rates and shortened life expectancy. Second-generation antipsychotic medications do not consistently alleviate psychotic symptoms, especially among patients with TRS. Clozapine, the gold standard of pharmacological treatment for TRS, offers only partial relief for many patients. Additional treatment approaches, which include cognitive behavioral therapy (CBT), are often necessary.. The aim of this integrative review was to assess the efficacy of CBT as an adjunctive treatment for TRS in various study populations.. The Johns Hopkins Nursing Evidence-Based Practice Model and Guidelines were used to guide the review. A literature search of PubMed, CINAHL, Scopus, and PsycInfo was conducted, and a total of 66 articles were identified. Strong inclusion and exclusion criteria were applied to ensure that only high-quality studies were included for analysis.. Of the eight studies that met the eligibility criteria, five indicated that CBT has statistically significant efficacy in reducing positive psychotic symptoms of TRS. There was also evidence that in implementing CBT, a follow-up period of at least six months helps to sustain improvements.. CBT can be a safe and effective adjunctive treatment for patients with this illness. We recommend that nurses who work in psychiatric settings, EDs, and home health or community care settings obtain training in CBT.

Topics: Clozapine; Cognitive Behavioral Therapy; Humans; Psychotic Disorders; Schizophrenia; Schizophrenia, Treatment-Resistant

Topics: Acetylcysteine; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Though clozapine is recommended for treatment of tardive dyskinesia (TD) relating to the use of antipsychotic medications, studies comprehensively investigating the treatment effect of clozapine on TD are still limited.. This review examines the effectiveness of clozapine as an intervention for tardive dyskinesia and dystonia in patients with all psychiatric conditions. Effectiveness of clozapine, duration to exert the effect and dosage used were also analysed.. A search in the PubMed, PsycINFO and clinicaltrials databases was performed, using the search terms "Clozapine" AND "dyskinesia" OR "dystonia". Full-text articles that reported the use of clozapine to treat abnormal involuntary movements and were written in English were included.. A total of 48 studies were identified, of which 13 were clinical trials and 35 were case reports. Significant improvement was seen in 86.7% of patients with schizophrenia spectrum disorders (average dose of clozapine = 355 mg/day) and 93% of patients with other psychiatric disorders (average dose of clozapine = 152.5 mg/day). Patients with other psychiatric diagnoses had faster improvement than the patients with schizophrenia spectrum disorders. Variation in improvements and dosage were also seen in the clinical trials.. Results suggested an overall effectiveness of clozapine in the treatment of TD for patients with a range of psychiatric conditions. Different response time and clozapine dosage were seen in patients with different psychiatric conditions, suggesting different treatment protocols are required for different conditions. Most of the studies identified are of inadequate qualities, highlighting the need for high quality studies to provide clearer evidence.

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Schizophrenia; Tardive Dyskinesia

Treatment resistant schizophrenia (TRS), the lack of response to at least two antipsychotics administered at adequate dose and duration, epitomizes in psychiatry one of the most difficult-to-treat pathologies, epidemiologically relevant (affecting one-third of schizophrenia patients) and with severe consequences for the patients in terms of overall functioning. After 50 years, only one drug is approved for TRS: clozapine. Furthermore, a few patients do not respond even to clozapine and are indicated as clozapine-resistant patients.. In this review and expert opinion, we have critically appraised the current literature, discussing the role of old and new agents in treating resistant schizophrenia.. The search for therapy against TRS, beyond clozapine or in addition to clozapine, has emerged over time, capturing mainly three types of strategies: 1. Add-on of a second-generation antipsychotic (i.e. amisulpride); 2. Add-on of a second antipsychotic with significantly different receptor profile compared to the older ones (e.g. aripiprazole and cariprazine); 3. Novel strategies beyond dopamine D2/D3 receptor occupancy (e.g. xanomeline + trospium, TAAR1-agonists, sodium benzoate, and D-amino acids). More high-quality clinical trials applying the current operationalized criteria for TRS and clozapine-resistance are required to evaluate the efficacy of alternative and add-on treatments.

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant

The Schizophrenia Exome Meta-Analysis (SCHEMA) consortium identified 10 genes in which loss-of-function (LoF) variants are highly associated with schizophrenia (SZ). In a well-characterized sample of 988 patients with psychotic disorders, we investigated whether patients bearing a SCHEMA variant presented with unusual or unique signs, symptoms, or course of illness. We identified 5 patients who carried a LoF variant in a SCHEMA gene, each in a different gene. None of the patients with a SCHEMA variant had unique symptoms. However, compared to the average of patients in the sample, all of the patients with a SCHEMA variant had earlier onset of any mental illness and more hospitalizations. Also, among SCHEMA carriers, 80 % were treated with clozapine, 60 % with ECT, all with either clozapine or ECT and 40 % with both clozapine and ECT, compared to only 2 % treated with clozapine and 18 % treated with ECT in the comparison group of patients without SCHEMA variants. All 5 patients with a SCHEMA variant had polysubstance abuse, and all had attempted suicide. Fewer than half had such presentations in the group without SCHEMA variants. In this small sample, SCHEMA variants appear to be associated with earlier onset, less favorable response to standard first-line treatments, and more severe illness, but not unique presentations of illness.

Topics: Antipsychotic Agents; Clozapine; Electroconvulsive Therapy; Humans; Psychotic Disorders; Schizophrenia; Treatment Outcome

Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host's eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018-2022) and identified twenty two eligible cases, restricted only to human patients' experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (

Topics: Antipsychotic Agents; Clozapine; Gastrointestinal Microbiome; Humans; Olanzapine; Prebiotics; Probiotics; Schizophrenia

The primary aim was to systematically review the literature regarding the effectiveness of clozapine in reducing symptoms of primary psychotic and bipolar disorders in older adults. The secondary aim was to describe other reported patient and caregiver outcomes of clozapine treatment in older adults.. MEDLINE, Embase, PsychINFO, ProQuest, and PubMed databases were searched according to PRISMA guidelines for original empirical research examining the effectiveness of clozapine in adults aged 65 years or more with primary psychotic and bipolar disorders. Identified studies were assessed for methodological quality using the QualSyst tool.. 1121 records were screened, of which 7 studies met the inclusion criteria. In total, 128 subjects participated in the included studies (111 of whom were from a single study), with an age range of 65-86 years, and diagnoses including schizophrenia, schizoaffective disorder, bipolar disorder, and delusional disorder. Indications for clozapine use included treatment resistance and inability to tolerate other treatments. While six out of seven studies reported some improvement on the primary measure of psychopathology after treatment with clozapine, the group effects were modest and based on low-level evidence. Additional reported outcomes included discharge destination, death, and relapse. Most of the included studies were only of adequate methodological quality, with significant risks of bias identified.. Clozapine may have positive effects for primary psychotic and bipolar illnesses in some older adults, but the group effects reported were modest and based on low-level evidence studies with methodological limitations. Based on these findings, clinical decision-making about whether or not to trial clozapine should involve an individualized analysis of potential benefits and risks in collaboration with patients and their families and caregivers.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Bipolar Disorder; Clozapine; Humans; Psychotic Disorders; Schizophrenia

Clozapine (CLZ) is the superior drug in treatment of schizophrenia. Serum concentration of CLZ is associated with clinical response and dose-dependents side effects, where generalized tonic-clonic seizures are most critical. Thus, therapeutic drug monitoring (TDM) of CLZ may guide individual dosing to reach target exposure and prevent dose-dependent side effects. However, current TDM methods are not capable of predicting the risk of agranulocytosis, which is a dose-. The article provides an overview of clinical, pharmacological, and toxicological aspects of CLZ, and the role of TDM as a tool for dose titration and follow-up in patients with TRS. Main focus is on current challenges and strategies in CLZ TDM, including future perspectives on potential identification/analysis of CLZ metabolite biomarkers reflecting the risk of granulocyte toxicity.. The association between CLZ serum concentration, clinical response and risk of seizures is indisputable. TDM should therefore always guide CLZ dose titration. Development of advanced TDM methods, including biomarkers predicting the risk of granulocyte toxicity might extend TDM to be a tool for deciding which patients that can be treated safely with CLZ, potentially increasing its utility beyond TRS.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance; Humans; Schizophrenia; Seizures

As the burden of treatment-resistant schizophrenia (TRS) on patients and society is high it is important to identify predictors of response to medications in TRS. The aim was to analyse whether baseline patient and study characteristics predict treatment response in TRS in drug trials.. A comprehensive search strategy completed in PubMed, Cochrane and Web of Science helped identify relevant studies. The studies had to meet the following criteria: English language clinical trial of pharmacological treatment of TRS, clear definition of TRS and response, percentage of response reported, at least one baseline characteristic presented, and total sample size of at least 15. Meta-regression techniques served to explore whether baseline characteristics predict response to medication in TRS.. 77 articles were included in the systematic review. The overall sample included 7546 patients, of which 41% achieved response. Higher positive symptom score at baseline predicted higher response percentage. None of the other baseline patient or study characteristics achieved statistical significance at predicting response. When analysed in groups divided by antipsychotic drugs, studies of clozapine and other atypical antipsychotics produced the highest response rate.. This meta-analytic review identified surprisingly few baseline characteristics that predicted treatment response. However, higher positive symptoms and the use of atypical antipsychotics - particularly clozapine -was associated with the greatest likelihood of response. The difficulty involved in the prediction of medication response in TRS necessitates careful monitoring and personalised medication management. There is a need for more investigations of the predictors of treatment response in TRS.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Tolerance; Female; Humans; Male; Schizophrenia

To summarize the current state of knowledge on antipsychotic treatment strategies for the acute phase and treatment resistance in schizophrenia, we conducted a systematic review of guidelines and algorithms.. We conducted a systematic literature search to identify clinical guidelines and algorithms on this topic using MEDLINE and Embase. We extracted information on recommendations for antipsychotic treatment strategies, including those for non-response (i.e., increasing antipsychotic dose and switching to another antipsychotic) and treatment resistance.. We identified a total of 17 guidelines/algorithms in various countries that were published after 2011. With respect to antipsychotic dose, most of the guidelines (N = 10/11) agreed starting with a low dose or the lowest licensed/effective dose and then titrating the dose upwards. Regarding antipsychotic treatment strategies for non-response, all of the guidelines (N = 9/9) recommended increasing antipsychotic dose towards the upper end of its approved dose range. Five guidelines suggested for increasing beyond the therapeutic dose range in exceptional cases, while overall 10 guidelines including them were negative about such strategy. The vast majority of guidelines (N = 16/17) recommended switching to another antipsychotic for non-response; however, some guidelines mentioned the lack of evidence for these strategies other than the use of clozapine. All the guidelines (N = 17/17) endorsed initiating clozapine after failure to respond to 2 different antipsychotics. Four guidelines endorsed an early use of clozapine, yet as the third antipsychotic.. The currently available guidelines and algorithms recommended increasing antipsychotic dose and switching to another antipsychotic, particularly clozapine for treatment-resistant schizophrenia, during the acute phase of schizophrenia for non-response.

Topics: Algorithms; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

A recent increase in the literature regarding the evidence base for clozapine has made it increasingly difficult for clinicians to judge "best evidence" for clozapine use. As such, we aimed at elucidating the state-of-the-art for clozapine with regard to efficacy, effectiveness, tolerability, and management of clozapine and clozapine-related adverse events in neuropsychiatric disorders. We conducted a systematic PRISMA-conforming quantitative meta-review of available meta-analytic evidence regarding clozapine use. Primary outcome effect sizes were extracted and transformed into relative risk ratios (RR) and standardized mean differences (SMD). The methodological quality of meta-analyses was assessed using the AMSTAR-2 checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to AMSTAR-2. Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in schizophrenia (treatment-resistant and non-treatment-resistant subpopulations) compared to first-generation antipsychotics (FGAs) and to pooled FGAs/second-generation antipsychotics (SGAs) in treatment-resistant schizophrenia (TRS). Despite an unfavorable metabolic and hematological adverse-event profile compared to other antipsychotics, hospitalization, mortality and all-cause discontinuation (ACD) rates of clozapine surprisingly show a pattern of superiority. Our meta-review outlines the superior overall efficacy of clozapine compared to FGAs and most other SGAs in schizophrenia and suggests beneficial efficacy outcomes in bipolar disorder and Parkinson's disease psychosis (PDP). More clinical studies and subsequent meta-analyses are needed beyond the application of clozapine in schizophrenia-spectrum disorders and future studies should be directed into multidimensional clozapine side-effect management to foster evidence and to inform future guidelines.

Topics: Antipsychotic Agents; Bipolar Disorder; Clozapine; Humans; Psychotic Disorders; Schizophrenia

Clozapine is underutilized due, in part, to concerns about rare but severe adverse drug reactions, including cardiac inflammation and injury (myocarditis). Risk factors for clozapine-induced myocarditis are limited and predictors for the successful rechallenge of clozapine after an episode of myocarditis are even more poorly understood. We conducted a systematic review, in accordance with the PRISMA recommendation, of published case reports to describe demographic and clinical characteristics of patients with clozapine-induced myocarditis and identify potential markers of clozapine rechallenge success. A total of 180 cases from 88 articles were evaluated. Male cases of clozapine-associated myocarditis were more frequently reported than female cases by a ratio of 6:1. Less than half of patients reported the presence of chest pain (35%) or flu-like symptoms (43%) but increases in troponin or C-reactive protein were present in 87% of cases. Clozapine rechallenge was carried out in 34 (2 female) cases, with successful reintroduction in 22 (2 female) cases (64.7%) and one fatality (2.9%). No demographic or clinical markers were significantly associated with rechallenge success after correction for multiple testing. Standardized reporting of clozapine-induced myocarditis cases is needed to facilitate the identification of factors associated with successful rechallenge.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Myocarditis; Schizophrenia

Treatment-resistant schizophrenia is prevalent and difficult to manage, as patients fail multiple antipsychotic trials before being considered as treatment-resistant. Currently clozapine is the only Food and Drug Administration-approved pharmacotherapy for treatment-resistant schizophrenia but remains under-prescribed. The purpose of this study is to investigate recent literature on clozapine in order to identify barriers to prescribing clozapine and categorize the recommended solutions.. We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Using free text and the medical subject headings, we searched MEDLINE/PubMed electronic bibliographic database from 2017 until 2020. Eligible studies included peer-reviewed English language articles with multiple methodologies aiming to identify clozapine barriers in treatment-resistant schizophrenia. We used search terms combining clozapine AND treatment OR treatment-resistant schizophrenia AND barriers AND prescribing OR prescription OR prescriber. We merged search results in a citation manager software, removed duplicates, and screened the remaining articles based on the study eligibility criteria.. We retrieved 123 studies, however, only 10 articles exclusively met the study inclusion criteria for full text review. These studies represented 20 countries; 6 were exclusively conducted in the US. The top barriers delineated by the studies include: providers' lack of knowledge and training (n = 7), concern about side effects (n = 8), and poor adherence (n = 7). All studies described more than 1 barrier. Other barriers included prescriber-perceived barriers (n = 4), administrative barriers (n = 5), and other healthcare systems-related barriers (n = 3). Top recommendations to overcome clozapine prescription barriers included improving prescriber clozapine education/training, utilizing interdisciplinary teams and providing integrated care via clozapine clinics, and simplifying blood test monitoring.. Clozapine remains under-prescribed for patients with treatment-resistant schizophrenia due to multiple barriers related to the individual prescriber, system of care, and technology. It is recommended that by improving prescriber knowledge and training, use of integrated care, and use of technology that can enable continuous, real-time blood test monitoring, these barriers may be overcome.

Topics: Antipsychotic Agents; Clozapine; Delivery of Health Care; Humans; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Postpartum Period; Pregnancy; Pregnancy Complications; Schizophrenia

Treatment-resistant schizophrenia, affecting approximately 20-30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly.

Topics: Antipsychotic Agents; Clozapine; Observational Studies as Topic; Prospective Studies; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile.. This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs.. Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded.. A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025).. Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Heart Rate; Humans; Pregnancy; Schizophrenia; Schizophrenic Psychology; Triglycerides; Weight Gain

The aim of this systematic review and meta-analysis was to characterize ultra-treatment-resistant Schizophrenia also known as clozapine-resistant schizophrenia (CRS) patients across clozapine combination and augmentation trials through demographic and clinical baseline data. Furthermore, we investigated the variability and consistency in CRS definitions between studies.. Systematic searches of articles indexed in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and PsycINFO were conducted in March 2020. 1541 randomized and non-randomized clinical trials investigating pharmacological and non-pharmacological clozapine add-on strategies were screened and a total of 71 studies were included. The primary outcome was the overall symptom score at baseline, measured with Positive and Negative Syndrome Scale (PANSS) total or Brief Psychiatric Rating Scale (BPRS) total scores.. Data from 2731 patients were extracted. Patients were overall moderately ill with a mean PANSS total score at baseline of 79.16 (±7.52), a mean duration of illness of 14.64 (±4.14) years with a mean clozapine dose of 436.94 (±87.47) mg/day. Illness severity data were relatively homogenous among patients independently of the augmentation strategy involved, although stark geographical differences were found. Overall, studies showed a large heterogeneity of CRS definitions and insufficient guidelines implementation.. This first meta-analysis characterizing CRS patients and comparing CRS definitions revealed a lack of consistent implementation of a CRS definition from guidelines into clinical trials, compromising the replicability of the results and their applicability in clinical practice. We offer a new score modeled on a best practice definition to help future trials increase their reliability.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Reproducibility of Results; Schizophrenia

The long-term treatment of patients with schizophrenia often involves the management of relapses for most patients and the development of treatment resistance in some patients. To stabilize the clinical course and allow as many patients as possible to recover, clinicians need to recognize dopamine supersensitivity, which can be provoked by administration of high dosages of antipsychotics, and deal with it properly. However, no treatment guidelines have addressed this issue. The present review summarized the characteristics of long-acting injectable antipsychotics, dopamine partial agonists, and clozapine in relation to dopamine supersensitivity from the viewpoints of receptor profiles and pharmacokinetics. The potential merits and limitations of these medicines are discussed, as well as the risks of treating patients with established dopamine supersensitivity with these classes of drugs. Finally, the review discussed the biological influence of antipsychotic treatment on the human brain based on findings regarding the relationship between the hippocampus and antipsychotics.

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Dopamine Agonists; Humans; Psychoses, Substance-Induced; Schizophrenia

Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06-0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.

Topics: Antipsychotic Agents; Clozapine; Demography; Hospitalization; Humans; Outcome Assessment, Health Care; Schizophrenia; Treatment Outcome

Schizophrenia is a severe neuropsychiatric disorder characterized by a diverse range of symptoms that can have profound impacts on the lives of patients. Currently available antipsychotics target dopamine receptors, and while they are useful for ameliorating the positive symptoms of the disorder, this approach often does not significantly improve negative and cognitive symptoms. Excitingly, preclinical and clinical research suggests that targeting specific muscarinic acetylcholine receptor subtypes could provide more comprehensive symptomatic relief with the potential to ameliorate numerous symptom domains. Mechanistic studies reveal that M1, M4, and M5 receptor subtypes can modulate the specific brain circuits and physiology that are disrupted in schizophrenia and are thought to underlie positive, negative, and cognitive symptoms. Novel therapeutic strategies for targeting these receptors are now advancing in clinical and preclinical development and expand upon the promise of these new treatment strategies to potentially provide more comprehensive relief than currently available antipsychotics.

Topics: Animals; Antipsychotic Agents; Clozapine; Cognitive Dysfunction; Humans; Muscarinic Agonists; Pyridines; Receptors, Muscarinic; Schizophrenia; Thiadiazoles

Schizophrenia is a serious long-term disorder in which the metabolic complications and abnormalities of the brain-derived neurotrophic factor (BDNF) can be found. In this study, we conducted a systematic review of the relationship between BDNF, metabolic syndrome (MetS) and its components in schizophrenic patients.. Data were collected mainly from PubMed, Google Scholar, Scopus, and ProQuest databases. The keywords related to the BDNF, MetS, schizophrenia were searched. Two reviewers independently screened 1061 abstracts. And eventually, a total of 7 studies (6 observational and 1 interventional) was included in the systematic reviews.. Four of the 7 study ascertained statistically significant inverse relationship between serum BDNF levels and MetS in schizophrenic patients. While in the other two studies, there was no inverse relationship. In the last selected study, the researchers found a weak association between the Val66Met polymorphism in BDNF Gene and clozapine-induced MetS.. Although this relationship could not be determined but BDNF levels appear to be reduced in schizophrenic patients with MetS and factors such as sex and antipsychotic class differentiation, sampling and methodology and episodes of illness could play a role in the results and outcomes.

Topics: Antipsychotic Agents; Brain-Derived Neurotrophic Factor; Chronic Disease; Clinical Trials as Topic; Clozapine; Comorbidity; Diet; Fasting; Female; Genetic Predisposition to Disease; Humans; Hypertriglyceridemia; Life Style; Male; Metabolic Syndrome; Mutation, Missense; Observational Studies as Topic; Polymorphism, Single Nucleotide; Prevalence; Schizophrenia; Sex Factors

The purpose of this study was to assess the risk factors for clozapine-induced central nervous system (CNS) abnormalities (i.e., electroencephalogram [EEG] abnormalities, myoclonus, and seizures). We retrospectively analyzed data from 106 patients with schizophrenia who received clozapine treatment through our hospital. A review of the EEG recordings showed that 71 of these patients (67.0 %) developed CNS abnormalities after initiating clozapine treatment. EEG abnormalities, myoclonus, and seizures occurred in 53.8 %, 38.7 %, and 8.5 % of the patients, respectively. Multivariate logistic regression analysis showed that the risk factors for clozapine-induced CNS abnormalities were concomitant lithium usage (odds ratio, 4.560; 95 % confidence interval, 1.750-11.900) and shorter illness durations before clozapine initiation (odds ratio, 0.796; 95 % confidence interval, 0.649-0.976). However, plasma clozapine levels and the usage of antiepileptics did not exhibit associations with the risks of CNS abnormalities. Clinicians should monitor their patients for incident CNS abnormalities when administering lithium in combination with clozapine regardless of plasma clozapine levels or the usage of antiepileptics. This is especially true for patients with short illness durations.

Topics: Antipsychotic Agents; Clozapine; Electroencephalography; Humans; Japan; Nervous System Malformations; Retrospective Studies; Risk Factors; Schizophrenia

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction.. Aim was to review reports of clozapine-related reactions fulfilling the registry of severe cutaneous adverse reaction (RegiSCAR) criteria for DRESS syndrome reported as such or otherwise, to provide a descriptive overview of demographic patterns, clinical manifestations, and DRESS course and investigate associations between demographic, DRESS parameters, and clinical outcomes.. This review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines and registered with PROSPERO (registration number CRD42020156385). We searched PubMed/Embase/PsychInfo/Cochrane for reports of clozapine-related reactions meeting RegiSCAR criteria. Associations between RegiSCAR scores and time-to-recovery with demographic/clinical variables were assessed. Demographic/clinical characteristics of patients with versus without reported DRESS were compared using non-parametrical tests.. Clozapine-related DRESS may be rare, but also underreported. Clinicians need to be aware of it even in patients under clozapine-monotherapy or without skin rash.

Topics: Antipsychotic Agents; Clozapine; Drug Hypersensitivity Syndrome; Female; Humans; Male; Schizophrenia; Sex Distribution

Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.

Topics: Antipsychotic Agents; Clozapine; Epigenesis, Genetic; Humans; Precision Medicine; Risperidone; Schizophrenia

Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN).. A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC).. The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10. The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

Topics: Antipsychotic Agents; Clozapine; Genome-Wide Association Study; Humans; Neutropenia; Schizophrenia

The use of ketamine for depression has increased rapidly in the past decades. Ketamine is often prescribed as an add-on to other drugs used in psychiatric patients, but clear information on drug-drug interactions is lacking. With this review, we aim to provide an overview of the pharmacodynamic interactions between ketamine and mood stabilizers, benzodiazepines, monoamine oxidase-inhibitors, antipsychotics, and psychostimulants.. MEDLINE and Web of Science were searched.. Twenty-four studies were included. For lithium, no significant interactions with ketamine were reported. Two out of 5 studies on lamotrigine indicated that the effects of ketamine were attenuated. Benzodiazepines were repeatedly shown to reduce the duration of ketamine's antidepressant effect. For the monoamine oxidase-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent S-ketamine use. One paper indicated an interaction between ketamine and haloperidol, 2 other studies did not. Four papers investigated risperidone, including 3 neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. Clozapine significantly blunted ketamine-induced positive symptoms in patients with schizophrenia but not in healthy participants. One paper reported no effect of olanzapine on ketamine's acute psychotomimetic effects.. Current literature shows that benzodiazepines and probably lamotrigine reduce ketamine's treatment outcome, which should be taken into account when considering ketamine treatment. There is evidence for an interaction between ketamine and clozapine, haloperidol, and risperidone. Due to small sample sizes, different subject groups and various outcome parameters, the evidence is of low quality. More studies are needed to provide insight into pharmacodynamic interactions with ketamine.

Topics: Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Depression; Drug Interactions; Female; Haloperidol; Humans; Ketamine; Lithium; Male; Olanzapine; Psychotropic Drugs; Risperidone; Schizophrenia; Treatment Outcome

Clozapine is superior to other antipsychotics as a therapy for treatment-resistant schizophrenia and schizoaffective disorder with increased risk of suicidal behavior. This drug has also been used in the off-label treatment of bipolar disorder, major depressive disorder (MDD), and Parkinson's disease (PD). Although usually reserved for severe and treatment-refractory cases, it is interesting that electroconvulsive therapy (ECT) has also been used in the treatment of these psychiatric disorders, suggesting some common or related mechanisms. A literature review on the applications of clozapine and electroconvulsive therapy (ECT) to the disorders mentioned above was undertaken, and this narrative review was prepared. Although both treatments have multiple actions, evidence to date suggests that the ability to elicit epileptiform activity and alter EEG activity, to increase neuroplasticity and elevate brain levels of neurotrophic factors, to affect imbalances in the relationship between glutamate and γ-aminobutyric acid (GABA), and to reduce inflammation through effects on neuron-glia interactions are common underlying mechanisms of these two treatments. This evidence may explain why clozapine is effective in a range of neuropsychiatric disorders. Future increased investigations into epigenetic and connectomic changes produced by clozapine and ECT should provide valuable information about these two treatments and the disorders they are used to treat.

Topics: Antipsychotic Agents; Bipolar Disorder; Clozapine; Depressive Disorder, Major; Electroconvulsive Therapy; Humans; Parkinson Disease; Schizophrenia

Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between individuals. We therefore systematically reviewed and meta-analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels.. We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta-analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta-regression by study duration was conducted.. Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40-3.67, p < 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85-2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00-0.49, p = 0.05), and lower rates of relapse (SMD -0.72, 95% CI -1.26 to -0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome.. Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavourable risk-benefit ratio.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Schizophrenia

Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia. Despite its superior efficacy profile as compared with other antipsychotics, clozapine remains underutilized. Clozapine monitoring systems clearly describe the proposed management of clozapine-induced neutropenia; however, no specific mention is made of how to interpret neutrophilic leukocytosis, despite that being a relatively frequent finding. Prescribers unfamiliar with this molecule may misjudge its clinical significance, potentially leading to untimely treatment interruption. Here, we systematically review the literature on the risk of neutrophilic leukocytosis during clozapine treatment, and describe eight additional cases among our patient cohort.. We performed a systematic review of the literature on PubMed and Embase using the PRISMA 2020 guidelines, and selected all original reports describing either (1) the prevalence of neutrophilic leukocytosis during clozapine treatment, or (2) the clinical significance of neutrophilic leukocytosis. We described eight additional cases of neutrophilic leukocytosis during clozapine treatment while attending an outpatient psychiatric clinic.. Our research ultimately yielded the selection of 13 articles included in this systematic review. The case series highlighted the presence of stable and clinically unremarkable neutrophilia during a follow-up ranging from one to ten years.. Existing evidence indicates that leukocytosis associated with clozapine treatment can be considered as an asymptomatic and benign condition, suggesting that no change in clozapine treatment is needed upon its detection.

Topics: Antipsychotic Agents; Clozapine; Humans; Leukocytosis; Prevalence; Schizophrenia

Clozapine is the only approved strategy for treatment-resistant schizophrenia, although it is highly underutilized. We aim to generate practical and actionable evidence-based recommendations for the use of this drug considering prescription barriers.. Narrative review.. A consistent body of evidence supports the efficacy of clozapine reducing morbidity and mortality in schizophrenia. The main obstacles to its use are the lack of experience by prescribers and perceived treatment burden. Systematic screening of eligibility, utilization of available resources for consultation, developing a professional network with other stakeholders, as well as optimizing how clozapine is presented to patients is discussed. Furthermore, specific evidence-based recommendations for initiation, maintenance, and safety monitoring with clozapine are provided.. Clozapine prescription is one of the areas in psychiatry with the greatest mismatch between efficacy and utilization in clinical practice. Although multiple barriers to the use of clozapine exist, some of these may be overcome by updates of routine clinical practice.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as "clozapineresistant", "ultra-treatment-resistant", or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials. Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia. This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.

Topics: Antioxidants; Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sodium Benzoate

Schizophrenia is a neuropsychiatric disorder that chronically affects 21 million people worldwide. Second-generation antipsychotics (SGAs) are the cornerstone in the management of schizophrenia. However, despite their efficacy in counteracting both positive and negative symptomatology of schizophrenia, recent clinical observations have described an increase in the prevalence of metabolic disturbances in patients treated with SGAs, including abnormal weight gain, hyperglycemia and dyslipidemia. While the molecular mechanisms responsible for these side-effects remain poorly understood, increasing evidence points to a link between SGAs and adipose tissue depots of white, brown and beige adipocytes. In this review, we survey the present knowledge in this area, with a particular focus on the molecular aspects of adipocyte biology including differentiation, lipid metabolism, thermogenic function and the browning/beiging process.

Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue; Antipsychotic Agents; Cell Differentiation; Clozapine; Female; Humans; Lipid Metabolism; Male; Mesenchymal Stem Cells; Metabolic Syndrome; Prevalence; Schizophrenia; Sex Factors; Thermogenesis

Topics: Antipsychotic Agents; Clozapine; Cognition; Drug Monitoring; Humans; Schizophrenia

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

Schizophrenia is a severe psychiatric disorder with variable therapeutic responses, the etiology and pathophysiology of which require further elucidation.. To review which pharmacological options are effective and safe and for which treatment goals in schizophrenia.. Narrative review of the pharmacological therapy of adults diagnosed with schizophrenia.. Despite heterogeneous therapeutic responses, to date only dopamine antagonists or partial agonists are approved for the treatment of schizophrenia. The efficacy of antipsychotic agents differs only gradually, with the exception of clozapine for treatment-resistant schizophrenia, whereas undesired adverse effects are more variable. Those antipsychotic agents that show gradual efficacy advantages in meta-analyses of acute and maintenance treatment (clozapine, amisulpride, olanzapine, risperidone) are also those where at least one undesired adverse effect is most severely expressed. Antipsychotic adverse effects occur in subgroups of patients and are generally tolerable or treatable, whereas the "side effect" of untreated schizophrenia affects almost all patients, including relapses, psychosocial deterioration, secondary treatment resistance and increased mortality. Therefore, in patients with a confirmed diagnosis of schizophrenia, a lifelong continuous therapy is currently most likely indicated, ideally with antipsychotic agents for which adherence is directly measurable and improved. In the case of treatment resistant clozapine is the agent of choice, followed by electroconvulsive therapy, which also has the best evidence as augmentation treatment in cases of clozapine resistance.. New therapeutic agents with improved efficacy and tolerability as well as effectiveness for negative symptoms and cognitive disturbance are needed.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Olanzapine; Risperidone; Schizophrenia

Clozapine has been used in treatment-resistant patients with schizophrenia. However, only 40% of patients with treatment-resistant schizophrenia have response to clozapine. Many augmentation strategies have been proposed to treat those clozapine-resistant patients, but the results are inconclusive. In this review, we intended to review papers dealing with the augmentation strategies in the treatment of clozapineresistant patients with schizophrenia.. We reviewed randomized, double-blind, placebo- or sham-controlled trials (RCT) for clozapine-resistant patients with schizophrenia in Embase, PsycINFO, Cochrane, and PubMed database from January 1990 to June 2019.. Antipsychotics, antidepressants, mood stabilizers, brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation, and other strategies, were used as an augmentation in clozapine-resistant patients with schizophrenia. Except for better evidence in memantine with 2 RCTs and cognitive behavior therapy in 2 studies to support its effectiveness, we found that all the other effective augmentations, including sulpiride, ziprasidone, duloxetine, mirtazapine, ECT, sodium benzoate, ginkgo biloba, and minocycline, had only one RCT with limited sample size.. In this review, no definite effective augmentation strategy was found for clozapine-resistant patients. Some potential strategies with beneficial effects on psychopathology need further studies with a larger sample size to support their efficacy.

Topics: Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Schizophrenia

Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit.. Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data.. A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI -0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine.. The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use.

Topics: Aging; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Clozapine (CLZ) is prescribed to (relatively) treatment-resistant patients with schizophrenia spectrum disorders. Currently, it is unknown what factors predict response to CLZ. Therefore, we performed meta-analyses to identify predictors of CLZ response, hence aiming to facilitate timely and efficient prescribing of CLZ.. A systematic search was performed in 'Pubmed' and 'Embase' until 1 January 2019. Articles were eligible if they provided data on predictors of CLZ response measured demographic and clinical factors at baseline or biochemical factors at follow-up in schizophrenia spectrum disorder patients.. A total of 34 articles, total number of participants = 9386; N unique = 2094, were eligible. Factors significantly associated with better CLZ response were: lower age, lower PANSS negative score and paranoid schizophrenia subtype.. The results of our meta-analyses suggest that three baseline demographic and clinical features are associated with better clozapine response, i.e. relatively young age, few negative symptoms and paranoid schizophrenia subtype. These variables may be taken into account by clinicians who consider treating a specific patient with CLZ.

Topics: Antipsychotic Agents; Clozapine; Humans; Outcome Assessment, Health Care; Schizophrenia

Clozapine is a second-generation antipsychotic drug that is considered the most effective treatment for refractory schizophrenia. Several clozapine population pharmacokinetic models have been introduced in the last decades. Thus, a systematic review was performed (i) to compare published pharmacokinetics models and (ii) to summarize and explore identified covariates influencing the clozapine pharmacokinetics models.. A search of publications for population pharmacokinetic analyses of clozapine either in healthy volunteers or patients from inception to April 2019 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded.. Twelve studies were included in this review. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. Significant interindividual variations of clozapine pharmacokinetic parameters were found in most of the included studies. Age, sex, smoking status, and cytochrome P450 1A2 were found to be the most common identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models.. Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Female; Humans; Male; Middle Aged; Models, Biological; Schizophrenia

It is not uncommon to find obsessive-compulsive symptoms (OCS) in patients treated with clozapine. These symptoms are attributed to anti-serotonergic effects of clozapine. The objective of this study was to conduct a systematic review of reported cases of clozapine-associated OCS to better understand the nature and management of these symptoms.. MEDLINE, Embase, and PsycINFO databases were searched with no publication year or language restrictions. Studies reporting cases of clozapine-associated OCS, either de novo or exacerbation of preexisting OCS, were included. The final search date was July 11, 2019.. Fifty-seven studies, involving 107 cases (75 de novo, 32 exacerbated OCS), were included. Clozapine triggered moderate-severe OCS at varying doses (100-900 mg/day) and treatment durations (median 6 months, interquartile range 2-24 months). Higher severity was significantly associated with preexisting OCS, poorer insight into OCS, and active psychosis at the time of OCS. Common strategies to treat clozapine-associated OCS included adding selective serotonin reuptake inhibitors, clomipramine, or aripiprazole, often accompanied by clozapine dose reduction. The rate of response to antidepressants was 49% (29/59), where younger age, shorter duration of underlying illness, shorter cloza-pine treatment duration, better insight into OCS, and presence of taboo thoughts were significantly associated with antidepressant response. Subsequent clozapine dose reduction was effective in many non-responders, where aripiprazole was simultaneously added in 50% (8/16).. Clozapine can trigger severe OCS. Adding aripiprazole with/without clozapine dose reduction may be a good alternative to antidepressants for managing clozapine-associated OCS. Clinicians should be more vigilant about these adverse effects and administer appropriate treatments.

Topics: Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Clozapine; Humans; Obsessive-Compulsive Disorder; Schizophrenia

To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge.. Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Re-challenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5-24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT.. Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.

Topics: Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Humans; Myocarditis; Schizophrenia

This narrative review on clozapine blood levels or therapeutic drug monitoring (TDM) includes sections focused on drug clearance and TDM, personalized dosing with TDM, clinical applications of TDM in Asians, and areas needing further study. Asian patients need half the clozapine dose (D) used in the United States to get the same blood concentrations (C). The concentration-to-dose (C/D) ratio measures drug clearance. In the United States, the average clozapine patient usually needs from 300 to 600 mg/day to reach 350 ng/mL. US male smokers reach this therapeutic C with a D of 600 mg/day (C/D ratio of 0.60 = 600/350), whereas US female nonsmokers usually need a D of 300 mg/day (C/D ratio of 1.17 = 300/350). While in the United States, average CLO C/D ratios typically are 0.6-1.2 ng/mL per mg/day, in Asian populations they range from 1.20 in male smokers to 2.40 in female smokers, requiring Ds of 300 to 150 mg/day to obtain 350 ng/mL. Asian patients can become clozapine poor metabolizers (PMs), needing very low Ds (50-150 mg/day) to get therapeutic Cs, by taking inhibitors (fluvoxamine, oral contraceptives and valproic acid), due to obesity, or during inflammations with systemic effects. In 573 Asian patients from five samples, around 1% were PMs due to taking inhibitors, 1% due to inflammation, 1% due to obesity, and 7% were potential genetic PMs. The potential genetic PMs ranged between 3% and 13%, but this prevalence will have to be better established in future studies including genetic testing for possible CYP1A2 mutations, which may explain PM status.

Topics: Adult; Antipsychotic Agents; Asian People; Clozapine; Drug Monitoring; Female; Humans; Male; Precision Medicine; Schizophrenia

Increasing users' knowledge about the expected benefits and risks of clozapine may contribute to the initiation and maintenance of clozapine in persons with treatment-resistant schizophrenia (TRS). The objective was to identify the educational needs of clozapine users and the interventions aimed at addressing these needs.. We systematically searched multiple electronic databases for articles: (i) exploring educational needs of clozapine users and of their relatives; and (ii) reporting educational interventions aimed at addressing these needs. Data were synthesized narratively.. A total of 30 articles published from 1990 to 2019 in 8 countries fulfilled our inclusion criteria. As most studies on educational needs (n = 18) were carried out in persons already taking clozapine, educational needs of TRS patients who were candidates for clozapine treatment are not well documented. Users' level of knowledge about clozapine was often poor, especially about adverse effects or interactions with other substances, with a poor retention of information delivered at treatment initiation. Among 12 studies reporting educational interventions in clozapine users, five provided quantitative outcomes. Their findings suggest that structured educational programmes may contribute to promote clozapine initiation and to improve users' knowledge about this drug.. The literature is sparse on structured educational interventions about clozapine, and only one randomized controlled trial was identified. A promising strategy emerging from this review may be staging educational interventions according to the evolving needs of persons with TRS before clozapine use, at initiation and during maintenance treatment.

Topics: Clozapine; Humans; Patient Education as Topic; Risk Assessment; Schizophrenia

Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level.

Topics: Antipsychotic Agents; Asian People; Clozapine; Coronavirus Infections; COVID-19; Drug Labeling; Humans; Pandemics; Pneumonia; Pneumonia, Viral; Psychiatry; Schizophrenia

Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.

Topics: Antipsychotic Agents; Clozapine; Humans; Neutropenia; Schizophrenia

The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe, multiorganic, and potentially life-threatening drug-induced hypersensitivity reaction, linked to several common drugs, including antiepileptics, antibiotics, and several psychotropic drugs, including clozapine. Due to the importance of clozapine in the management of treatment-resistant schizophrenia, a systematic review and characterization of clozapine-related DRESS syndrome is long overdue.. This systematic review was conducted following PRISMA guidelines. PubMed, Embase, PsychINFO, and the Cochrane Library databases were independently reviewed up to 1 November 2019 for articles reporting clozapine-related DRESS syndrome cases. The RegiSCAR score system was applied to systematically characterize the clinical presentations of selected studies.. Clozapine-related DRESS syndrome was reported in six patients from four articles. Five patients received polypharmacy. Skin rash and liver involvement with elevated liver enzymes were very common. No fatal cases were found. Treatment mainly included clozapine discontinuation and immunosuppression. The mismatch between incidences of DRESS with other responsible drugs, the common misdiagnosis of this syndrome, and the fact that an extensive literature search only identified six cases suggests that clozapine-related DRESS may be overlooked. It is, therefore, necessary to optimize diagnostic strategies to identify immune-related side effects of clozapine.

Topics: Antipsychotic Agents; Clozapine; Drug Hypersensitivity Syndrome; Humans; Polypharmacy; Schizophrenia

The COVID-19 pandemic is a particularly relevant threat to mentally ill patients, and it constitutes a new challenge for health care providers. To the best of our knowledge, there is not any embracing published review about the use of psychotropic drugs during the COVID-19 pandemic.. Non-systematic literature review. A search in the PubMed database was performed, with the terms 'psychotropic drugs', 'COVID-19', 'psychiatry' and 'pandemic'. Consensus and clinical guidelines about psychotropic drugs and COVID-19 approach, published by scientific societies, governmental entities and drug regulatory agencies were included.. We present the recommendations about the use of psychotropic drugs during the COVID-19 pandemic, in the outpatient and inpatient settings. The treatment of affective bipolar disorder and schizophrenia have now added increased difficulties. Some psychotropic drugs interfere with the pathophysiology of the novel coronavirus infection and they could interact with the drugs used in the treatment of COVID-19. Some patients will need pharmacological interventions due to the presence of delirium. Smoking cessation changes the serum levels of some psychotropic drugs and may influence their use.. The COVID-19 pandemic has created new challenges in clinical practice. Psychiatric patients are a vulnerable population and often a careful clinical, laboratorial and electrocardiographic evaluation may be needed, particularly in those diagnosed with COVID-19. The regular treatment of mentally ill patients with COVID-19 presents increased complexity.. Introdução: A pandemia de COVID-19 constitui uma ameaça particularmente relevante para os portadores de doença mental e um novo desafio para os profissionais que os acompanham. Até à data, tanto quanto sabemos, não existe qualquer revisão abrangente publicada relativamente à utilização de fármacos psicotrópicos durante a pandemia COVID-19. Material e Métodos: Revisão não sistemática da literatura. A pesquisa na PubMed foi realizada com os termos ‘psychotropic drugs’, ‘COVID-19’, ‘psychiatry’ e ‘pandemic’. Foram incluídos os consensos e as normas publicadas pelas sociedades científicas, entidades governamentais e agências regulamentares de medicamentos. Resultados e Discussão: Apresentam-se recomendações relativamente à utilização de psicofármacos durante a pandemia COVID-19, em contexto de ambulatório e de internamento. O tratamento da perturbação afetiva bipolar e da esquizofrenia tem agora dificuldades acrescidas. Alguns psicofármacos interferem com os mecanismos fisiopatológicos envolvidos na infeção pelo novo coronavírus e têm interações com os fármacos utilizados no tratamento da COVID-19. Em doentes com COVID-19 e com delirium, a utilização de psicofármacos poderá ser necessária. A cessação tabágica altera os níveis séricos de alguns psicofármacos e pode condicionar a sua utilização. Conclusão: A pandemia de COVID-19 coloca novos desafios na prática clínica. Os doentes psiquiátricos constituem uma população vulnerável, sendo frequentemente necessária uma avaliação clínica, laboratorial e eletrocardiográfica cuidadosa, naqueles com o diagnóstico de COVID-19. Os doentes mentais com COVID-19 apresentam uma complexidade acrescida na gestão da sua terapêutica habitual.

Topics: Antiviral Agents; Benzodiazepines; Betacoronavirus; Bipolar Disorder; Body Temperature Regulation; Buprenorphine; Clozapine; Coronavirus Infections; COVID-19; Delayed-Action Preparations; Drug Interactions; Hospitalization; Humans; Lithium Compounds; Mental Disorders; Methadone; Narcotic Antagonists; Pandemics; Pneumonia, Viral; Psychotropic Drugs; SARS-CoV-2; Schizophrenia; Smoking Cessation Agents; Valproic Acid

A systematic review of association studies on the role of single nucleotide variants (SNVs) of the dopaminergic system genes on the effectiveness of clozapine in schizophrenia has been perfromed. A search of literature was conducted in PubMed, MedLine, Web of Science Core Collection (Clarivate Analytics), Web of Science, Russian Science Citation Index, Scopus, Scientific Research, Google Scholar, Oxford Press, e-Library from 1995-2019. Association studies of 53 SNPs of genes encoding dopamine receptor isoforms (. Систематизированы результаты исследований роли носительства однонуклеотидных вариантов (ОНВ) генов дофаминергической системы у пациентов, страдающих шизофренией, и его влияния на эффективность клозапина. Проведен анализ англо- и русскоязычной литературы (1995—2019 гг., глубина поиска 24 года). Использовались следующие базы данных: PubMed, MedLine, Web of Science Core Collection (Clarivate Analytics), Web of Science, Russian Science Citation Index, Scopus, Scientific Research, Google Scholar, Oxford Press, e-Library. Проанализированы ассоциативные исследования 53 ОНВ генов, кодирующих изоформы дофаминового рецептора (

Topics: Catechol O-Methyltransferase; Clozapine; Dopamine; Genotype; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Russia; Schizophrenia

Antipsychotic polypharmacy (APP), defined as the use of more than one antipsychotic, is common in schizophrenia. However, current guidelines consider that the level of evidence to support APP is weak and mostly recommend monotherapy.. Meta-analyses of randomized controlled trials (RCTs) on the efficacy and tolerability of APP, effectiveness studies on its use in clinical practice, as well as theoretical models liable to legitimate this use are reviewed and discussed on the basis of a systematic literature search (PubMed) ranging from 1995 to 2020.. There is now increasing evidence from both efficacy and effectiveness studies, that APP may be beneficial for some schizophrenia patients. The most evidence seems to be for the combination of clozapine and aripiprazole. The choice of this combination may fit in well with the dopamine supersensitivity hypothesis in schizophrenia. Guidelines should be revised, but further studies are needed to confirm the efficacy/effectiveness of this combination, especially in the case of first-episode schizophrenia.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Humans; Models, Theoretical; Polypharmacy; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Schizophrenia

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization's (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Connexin 43; Humans; Pneumonia; Schizophrenia; Seizures; Signal Transduction; Treatment Outcome

In recent years, there is a new optimism in schizophrenia therapeutics with the emergence of immunomodulation as a potential treatment approach. Current evidence points to various immunological abnormalities in schizophrenia, including cell-mediated processes, acute phase proteins, cytokines, and intracellular mediators. Trait- and state-related immune dysfunction appears to exist, and a strong case can therefore be made for immunomodulation therapies in the prevention, treatment, and/or moderating the course of schizophrenia.Immunomodulation approaches include use of nonsteroidal anti-inflammatory agents to stop or moderate an over-activated inflammatory process, anti-oxidants, nutrients, vitamins, herbal products, and other neuroprotection agents that inhibit pro-inflammatory processes, optimal use of antipsychotic drugs (APDs) that may have anti-inflammatory actions or in certain cases such as clozapine may enhance blunted inflammatory responses, and biological agents to antagonize specific immune mediators such as the cytokines. A combination of two or more of the above approaches is also worthy of consideration.In this chapter, the available data for each of the above approaches is reviewed and discussed. Strengths and limitations of current studies are identified, and suggestions are made for future studies. For example, identifying patients with high levels of specific biomarkers such as C-Reactive Protein, IL-6, IFN-γ, TNF-α, and genetic polymorphisms of cytokines, and match them with clinical subgroups such as prodromal, first episode psychosis, chronic psychosis, and negative symptoms with the aim of developing targeted treatment approaches and more personalized medicine. Meanwhile, since the science and trial data are not advanced enough to make definitive recommendations, clinicians should stay up to date with the literature, obtain detailed immunological histories, and review the risk-benefit ratio of adding available immune modulating agents to standard therapies, to provide optimal and state-of-the-art care to patients.

Topics: Anti-Inflammatory Agents; Antipsychotic Agents; Clozapine; Cytokines; Humans; Inflammation; Schizophrenia

Because women are often perceived as having better outcomes than men in psychotic illnesses such as schizophrenia - women are less often in hospital, have a lower suicide rate, are less often involved with the law, enjoy better relationships with family and friends - the question arises as to whether or not this apparent advantage is attributable to a gender difference in antipsychotic response.. The aim of this paper is to critically review the quantitative and qualitative literature on gender difference in antipsychotic response sourced mainly from medical databases of the last ten years.. There are theoretical reasons why women's effective doses of antipsychotics might need to be lower than guidelines recommend for men, especially as regards olanzapine and clozapine, but, because there are so many variables that impinge on antipsychotic response, it is difficult to provide definitive guidance. What is evident is that some antipsychotic side effects, weight gain for instance, are more worrisome for women than for men. It is also evident that, after menopause, women need an increase in their antipsychotic dose; other reproductive stages in women's lives require special prescribing considerations as well.. There is a science, and an art, to prescribing antipsychotics, which needs to take gender into account. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Olanzapine; Psychoses, Substance-Induced; Psychotic Disorders; Risperidone; Schizophrenia; Sex Factors

By combining knowledge of pharmacogenetics, therapeutic drug monitoring (TDM) and drug-drug interactions (DDIs) the author developed a model for personalizing antipsychotic dosing, which is applied to risperidone, 9-hydroxyrisperidone or paliperidone, and clozapine. Drugs are approved using an average dose for an ideal average patient, but pharmacologists have described outliers: genetic poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Environmental and personal variables can also make patients behave as PMs or UMs. Drug clearance is represented by the concentration-to-dose (C/D) ratio under steady-state and trough conditions. A very low C/D ratio indicates a UM, while a very high C/D ratio indicates a PM. Total risperidone C/D ratio for the oral formulation is around 7 ng/ml per mg/day and can be influenced by CYP2D6 polymorphism, DDIs with inducers and inhibitors, and renal function. Oral paliperidone has low availability; its C/D ratio is around 4.1 ng/ml per mg/d and can be influenced by inducers and renal impairment. Once-a-month long-acting paliperidone provides a C/D ratio around 7.7 ng/ml per mg/day at steady state, which is expected to be in the 8th month (before the 9th injection). TDM is particularly important for long-acting paliperidone formulations that may accumulate once steady state is reached (after years for the 3- and 6-month formulations). In the US, clozapine C/D ratios typically range from 0.6 (male smokers) to 1.2 (female non-smokers) ng/ml per mg/day. East Asians' clozapine C/D ratios appear to be twice as high. Inhibitors (including fluvoxamine and oral contraceptives) and inflammation can also increase clozapine C/D ratios. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Routes; Drug Monitoring; Humans; Paliperidone Palmitate; Pharmacogenetics; Precision Medicine; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia

Clozapine is one of the most widely used antipsychotics for treating psychiatric illnesses such as schizophrenia and bipolar disorder. This drug, however, is associated with adverse effects such as weight gain, metabolic syndrome, and blood dyscrasias. The manifestations of mental illness may differ between men and women. Yet, there is little evidence on the influence of sex on treatment response or the occurrence of AEs. To fill this gap of knowledge, we carried out a systematic review of the literature on sex differences in the effectiveness and adverse effects of clozapine. Scant evidence has been published on differences in effectiveness of clozapine between men and women. Indeed, to the best of our knowledge, this issue has only been addressed in a published study. Regarding adverse effects, males have been reported to be more likely to develop metabolic abnormalities such as cholesterol or triglycerides, hypertension, and cardiovascular risk, while females are at a higher risk for gaining weight, developing diabetes, and needing laxatives. Nevertheless, given the scarcity of sex-based studies on this drug, further studies are needed to explore sex-based differences, as the results obtained may be crucial to clinical practice and help improve the quality of life of patients.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cohort Studies; Female; Humans; Male; Metabolic Syndrome; Quality of Life; Schizophrenia; Sex Characteristics; Treatment Outcome; Weight Gain

Mortality from cardiovascular disease is increased in people with mental health disorders in general and schizophrenia in particular. The causes are multifactorial, but it is known that antipsychotic medication can cause cardiac side-effects beyond the traditional coronary risk factors. Schizophrenia itself is a contributor to an increased risk of cardiovascular mortality via cardiac autonomic dysfunction and a higher prevalence of metabolic syndrome, both contributing to a reduced life expectancy. The pro-arrhythmic impact of traditional antipsychotics, especially via the hERG-potassium channel, has been known for several years. Newer antipsychotics have a reduced pro-arrhythmic profile but might contribute to higher cardiac death rates by worsening the metabolic profile. Clozapine-induced cardiomyopathy, which is dose independent, is a further concern and continuous monitoring of these patients is required. Prophylaxis with angiotensin-converting enzyme inhibitors is currently under review. Overall, management of cardiovascular risk within this population group must be multifaceted and nuanced to allow the most effective treatment of serious mental illness to be conducted within acceptable parameters of cardiovascular risk; some practical measures are presented for the clinical cardiologist.

Topics: Antipsychotic Agents; Autonomic Nervous System Diseases; Cardiovascular Diseases; Clozapine; Humans; Metabolic Syndrome; Risk Assessment; Schizophrenia

Patients with schizophrenia have an elevated mortality risk compared to the general population, with cardiovascular-related deaths being the leading cause. The role of clozapine use in the long-term mortality risk is unclear. While clozapine treatment may increase the risk for cardiovascular mortality, it may have protective effects regarding suicidal behavior.. We systematically searched EMBASE, MEDLINE, and PsycINFO and reviewed studies that used a long-term follow-up (ie, >52 weeks) and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders who had received clozapine treatment.. Altogether, 24 studies reported on 1327 deaths from any causes during 217691 patient years in patients treated with clozapine. The unadjusted mortality rate in 22 unique samples during a follow-up of 1.1-12.5 (median = 5.4) years was 6.7 (95% confidence interval [CI] = 5.4-7.9) per 1000 patient years. Long-term, crude mortality rate ratios were not significantly lower in patients ever treated with clozapine during follow-up, but significantly lower in patients continuously treated with clozapine compared to patients with other antipsychotics (mortality rate ratio = 0.56, 95% CI = 0.36-0.85, P-value = .007). Few studies reported on rates of long-term cause-specific mortality (suicide and ischemic heart disease), which showed no significant difference in patients using clozapine compared to patients using other antipsychotics. Statistical heterogeneity was high in all analyses.. Continuous clozapine treatment in schizophrenia patients was associated with a significantly lower long-term all-cause mortality rate compared to other antipsychotic use. These findings, combined with the known efficacy of clozapine, give reason to re-evaluate the hesitancy to prescribe clozapine in regular care settings.. PROSPERO CRD42017069390.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Since the serendipitous discovery of the first antipsychotic (AP) drug in the 1950s, APs remain the cornerstone of treatment for schizophrenia. A shift over the past two decades away from first-generation, conventional APs to so-called "atypical" (or 2nd/3rd generation) APs parallels acknowledgment of serious metabolic side-effects associated in particular with these newer agents. As will be reviewed, AP drugs and type 2 diabetes are now inextricably linked, contributing to the three- to fivefold increased risk of type 2 diabetes observed in schizophrenia. However, this association is not straightforward. Biological and lifestyle-related illness factors contribute to the association between type 2 diabetes and metabolic disease independently of AP treatment. In addition, APs have a well-established weight gain propensity which could also account for elevated risk of insulin resistance and type 2 diabetes. However, compelling preclinical and clinical evidence now suggests that these drugs can rapidly and directly influence pathways of glucose metabolism independently of weight gain and even in absence of psychiatric illness. Mechanisms of these direct effects remain poorly elucidated but may involve central and peripheral antagonism of neurotransmitters implicated not only in the therapeutic effects of APs but also in glucose homeostasis, possibly via effects on the autonomic nervous system. The clinical relevance of studying "direct" effects of these drugs on glucose metabolism is underscored by the widespread use of these medications, both on and off label, for a growing number of mental illnesses, extending safety concerns well beyond schizophrenia.

Topics: Animals; Antipsychotic Agents; Autonomic Nervous System; Clozapine; Diabetes Mellitus, Type 2; Glucose; Glucose Clamp Technique; Humans; Insulin Resistance; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Weight Gain

Schizophrenia is a debilitating condition with three main symptom domains: positive, negative, and cognitive. Approximately one-third of persons with schizophrenia will fail to respond to treatment. Growing evidence suggests that treatment-resistant (refractory) schizophrenia (TRS) may be a distinct condition from treatment-respondent schizophrenia. There is limited evidence on effective treatments for TRS, and a lack of standardized diagnostic criteria for TRS has hampered research. Areas covered: A literature search was conducted using Pubmed.gov and the EMBASE literature database. The authors discuss the pragmatic definitions of TRS and review treatments consisting of antipsychotic monotherapy and augmentation strategies. Expert opinion: Currently available first-line antipsychotic medications are generally effective at treating the positive symptoms of schizophrenia, leaving residual negative and cognitive symptoms. Before diagnosing TRS, rule out any pharmacodynamic or pharmacokinetic failures. Most evidence supports clozapine as having the most efficacy for TRS. If clozapine is used, it should be optimized, and serum levels should be at least 350-420 ng/ml. If clozapine is unable to be tolerated, some evidence suggests olanzapine at dosages up to 40mg/day can be useful. Augmentation strategies have weak evidence. Tailoring treatment to the specific domain is the preferred approach, and the use of a structured assessment/outcome measure is encouraged.

Topics: Antipsychotic Agents; Clozapine; Humans; Olanzapine; Schizophrenia; Treatment Outcome

A fair amount of subjects with schizophrenia do not respond to clozapine and are defined 'ultra-resistant'. In this systematic review and meta-analysis, we tested the efficacy of adjunctive second-generation antipsychotics (SGAs) for main symptom domains (positive, negative, and depressive symptoms) in individuals with clozapine-resistant schizophrenia. We searched main electronic databases till December 2017. We included twelve double-blind, randomized, placebo-controlled trials (RCTs), evaluating the efficacy of SGAs for clozapine non/partial responders. We did not find any difference between SGAs and placebo (standardized mean difference, SMD = -0.21; p = 0.170; I

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology

Recovery rates in schizophrenia remain suboptimal with up to one-third resistant to standard treatments, a population prevalence of 0.2%. Clozapine is the only evidenced-based treatment for treatment resistant schizophrenia (TRS), yet there are significant delays in its use or it may not be trialled, potentially impacting the chance of recovery. Better outcomes with earlier use of clozapine may be possible. There is emerging evidence that early treatment resistance is not uncommon from the earliest stages of psychosis. In this review, we provide an update on TRS, its epidemiology and its management, with a specific focus on the optimal use and timing of clozapine and augmentation strategies for the one-third of patients who do not respond to clozapine.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Drug Resistance; Electroconvulsive Therapy; Female; Humans; Male; Mental Health Recovery; Patient Care Management; Prevalence; Psychotic Disorders; Schizophrenia; Secondary Prevention; Young Adult

There are many psychotropic drugs available for treatment of schizophrenia. The clinician's choice of the most effective first-line antipsychotic treatment for patients with schizophrenia should balance considerations of differential efficacy of antipsychotics against the relative risk of different side effects.. We reviewed recent studies using meta-analytic techniques and additional studies of new antipsychotics which quantitatively evaluate the efficacy of side effects of first- and second-generation antipsychotics and studies of the efficacy on add-on secondary medications. We present an integrated summary of these results to guide a clinician's decision-making.. Recent meta-analyses have suggested that antipsychotics are not equivalent in efficacy. Clozapine (effect size [SMD] 0.88 vs. placebo), amisulpride (effect size 0.6 vs placebo), olanzapine (effect size 0.59 vs. placebo), and risperidone (effect size 0.56 vs placebo) show small but statistically significant differences compared to a number of other antipsychotics on measures of overall efficacy (effect sizes 0.33-0.50). However, increasing placebo response remains a concern in interpreting these data. Amisulpride (effect size 0.47 vs placebo) and cariprazine (effect size in one trial compared to risperidone 0.29) have the strongest evidence indicating greater efficacy for treating primary negative symptoms relative to other antipsychotics. In terms of side effects, clozapine and olanzapine have among the highest weight gain potential and sertindole and amisulpride have more effects on QTc prolongation than other commonly used antipsychotics. Prolactin elevation is highest with paliperidone, risperidone, and amisulpride. Adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who also have severe depressive or negative symptoms. For multi-episode patients with an inadequate response to an adequate dose and duration of the initial antipsychotic choice, switching to another antipsychotic, with a different receptor profile, may improve response, although evidence is very limited. In first-episode patients, a recent study on switching to another antipsychotic, with a different receptor profile after 4 weeks demonstrated no beneficial effects. There is little evidence to support using doses above the therapeutic range other than in exceptional circumstances.. Our review of recent studies using meta-analytic techniques has provided evidence that all antipsychotics are not equal in the severity of different side effects and in some measures of clinical efficacy. Comparative analysis and rankings from network meta-analyses can provide guidance to clinicians in choosing the most appropriate antipsychotic for first-line treatment, if used in conjunction with available information of the patient's history of previous clinical response or higher risks for specific side effects.

Topics: Amisulpride; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea.. We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm.. 19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies = 6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52-3.73; number needed to treat [NNT] 3, 95% CI 1.9-2.7), diphenhydramine (studies = 5, RR 3.09, 95% CI 2.36-4.03; NNT 2, 95% CI 1.5-2.0), chlorpheniramine (studies = 2, RR 2.37, 95% CI 1.59-3.55; NNT 3, 95% CI 1.6-3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03-15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2-204.1).. Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.

Topics: Antidepressive Agents; Antipsychotic Agents; Clozapine; Histamine Antagonists; Humans; Medicine, Chinese Traditional; Muscarinic Antagonists; Randomized Controlled Trials as Topic; Salivation; Schizophrenia; Sialorrhea

Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genetic Association Studies; Genotype; HLA-B Antigens; HLA-DQ beta-Chains; Humans; Neutropenia; Schizophrenia; Solute Carrier Organic Anion Transporter Family Member 1B3

Topics: Antipsychotic Agents; Clozapine; Health Personnel; Humans; Monitoring, Physiologic; Primary Health Care; Professional Role; Schizophrenia

This review will aim to summarize the current body of epidemiological, clinical and therapeutic knowledge concerning specific co-occurrence of obsessive-compulsive symptoms (OCSs) and schizophrenia spectrum disorder.. Almost 30% of the patients with schizophrenia display OCS, and three main contexts of emergence are identified: prodromal symptoms of schizophrenia, co-occurrence of OCS and schizophrenia and antipsychotics-induced OCS. Recent clinical studies show that patients with SZ and OCS have more severe psychotic and depressive symptoms, higher suicidality and lower social functioning. A recent cognitive investigation found that OCS and delusions share specific metacognitive profiles, particularly through a heightened need to control thoughts. Finally, a recent cross-sectional study of clozapine-induced OCS found a dose-response relationship between clozapine and OCS. OCS appeared reliably as linked to poorer outcomes among patients with schizophrenia. However, the specific clinical value of OCS among other prodromal symptoms of schizophrenia remains unknown.

Topics: Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Humans; Obsessive-Compulsive Disorder; Prodromal Symptoms; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Transcranial Magnetic Stimulation; Treatment Failure

It is commonly recommended that a switch to clozapine be implemented in the face of tardive dyskinesia, even if current treatment involves another "atypical" agent. However, reports do indicate clozapine carries a liability for tardive dyskinesia.. This review sought to evaluate clozapine in relation to tardive dyskinesia in the context of available evidence.. Medline, Embase, and PsycINFO databases were searched for studies published in English, using the keywords:. In total, 513 unique citations were identified and 29 reports met the inclusion criteria. Thirteen studies suggest clozapine reduces dyskinetic symptoms over time (. Research to date supports switching to clozapine for the purpose of reducing tardive dyskinesia risk and/or treating existing tardive dyskinesia, but prospective randomized controlled trials are necessary if we are to substantiate existing recommendations.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Schizophrenia

Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice.. To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies.. Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018.. Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder.. Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data.. Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies.. Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90).. In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Schizophrenia

To identify the clinical determinants of fever in clozapine users and their impact on management of clozapine treatment.. Articles published in English or French identified with a MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search, from inception through February 2019, using the term "clozapine" in combination with "fever" OR "hyperthermia" OR "body temperature" OR "pyrexia" OR "febrile" OR "heat" OR "thermoregulation". Information extracted for each medical condition were frequency, time to onset after initiation of clozapine treatment, characteristics of fever, associated symptoms, laboratory tests used for diagnosis, course, lethality, discontinuation of clozapine. Data were synthesized narratively.. Our search yielded 394 unique hits published from 1993 to 2018. We included 73 articles in the review: two meta-analyses, 14 reviews, six epidemiological studies, 11 clinical studies and 40 case reports. During clozapine initiation, fever is most frequently benign and transient but should be closely monitored as it may be the first stage of potentially life-threatening adverse drug reactions (ADR) (agranulocytosis, neuroleptic malignant syndrome myocarditis, hepatitis, pancreatitis, nephritis, colitis, etc.). Other ADR associated with fever are independent of duration of exposure to clozapine (heat stroke, pneumonia, pulmonary embolism, necrotizing colitis). If fever is due to intercurrent infection, therapeutic drug monitoring is recommended to adjust clozapine daily dosage.. Benign causes of fever are much more frequent than life-threatening ADR during clozapine treatment. Discontinuation should not be considered as automatic in the event of fever, especially during the early phase of clozapine initiation.

Topics: Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Colitis; Dose-Response Relationship, Drug; Drug Monitoring; Fever; Hepatitis; Humans; Infections; Lupus Erythematosus, Systemic; Myocarditis; Nephritis; Neuroleptic Malignant Syndrome; Pancreatitis; Pneumonia; Pulmonary Embolism; Schizophrenia; Serositis

Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, clozapine levels and adverse events is complex and multi-factorial. Monitoring of clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.

Topics: Antipsychotic Agents; Clozapine; Humans; Infections; Schizophrenia

Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system.

Topics: Aggression; Antipsychotic Agents; Clozapine; Criminal Law; Criminals; Humans; Schizophrenia; Violence

Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200-600mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users.

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Humans; Schizophrenia; Substance-Related Disorders

Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI.. To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse.. On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers).. We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data.. We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach.. We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving th. There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Dual (Psychiatry); Humans; Mental Disorders; Olanzapine; Patient Dropouts; Perphenazine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Substance-Related Disorders; Thiazoles

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Substance-Related Disorders; Suicide

Clozapine is the first second generation antipsychotic with different receptor profile of action. Clozapine is the most efficacious drug for the treatment of psychotic disorder and is the drug of choice in treatment resistant schizophrenia. Clozapine is used in elderly patients infrequently owing to its adverse effects profile and tolerability. There is paucity of literature with respect to clozapine use in late life. In this narrative review, we discuss clozapine use in elderly and challenges associated with its use.

Topics: Aged; Aging; Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Cognitive Dysfunction; Humans; Metabolic Diseases; Schizophrenia; Seizures

The use of clozapine requires monitoring the absolute neutrophil count because of the risk of agranulocytosis, but other potentially fatal adverse events associated with clozapine (specifically, myocarditis and cardiomyopathy) do not have mandatory procedures. We performed a systematic review of English-language articles to synthesize an evidence-based approach for myocarditis and cardiomyopathy monitoring. Articles published from January 1988 through February 2017 were identified through a search of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Google Scholar. Selected articles were required to relate to myocarditis or cardiomyopathy in humans from exposure to clozapine. A total of 144 articles were included. Recommendations varied widely. Some authors recommended baseline laboratory monitoring, with or without follow-up testing, for C-reactive protein, creatine kinase MB, and troponin. Electrocardiography was commonly recommended, and echocardiography was less commonly recommended. The expense of monitoring was a consideration. A unanimous recommendation was to stop the use of clozapine and seek a cardiovascular consultation if myocarditis or cardiomyopathy is suspected. Although there is general agreement on which tests to perform for confirming myocarditis and cardiomyopathy, preemptive screening for these clozapine-induced conditions is controversial, and cost and barriers for the use of clozapine are concerns. For asymptomatic patients receiving clozapine, testing could include baseline electrocardiography, echocardiography as part of a cardiac consultation if patients have cardiac disease or risk factors, and monitoring of C-reactive protein and troponin as indicated.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Monitoring, Physiologic; Myocarditis; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Outcome Assessment, Health Care; Practice Guidelines as Topic; Schizophrenia; Time-to-Treatment

Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies.. We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses.. On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Electroconvulsive Therapy; Humans; Schizophrenia

As clozapine is under-prescribed in persons with treatment-resistant schizophrenia (TRS), it is necessary to better identify the determinants of health inequalities in access to clozapine use.. To identify mental health professionals' characteristics or attitudes and institutional characteristics facilitating or limiting clozapine prescribing.. We systematically searched multiple electronic databases for articles reporting: (i) mental health professionals' attitudes and characteristics favoring or limiting clozapine prescribing; (ii) institutional characteristics associated with variations in clozapine prescribing; (iii) interventions aimed at enhancing clozapine prescribing. Data were synthesized narratively.. A total of 31 articles reporting findings of 29 studies published from 1993 to 2017 in 11 countries fulfilled our inclusion criteria. The main prescriber-related barriers to clozapine prescribing are lack of personal prescribing experience and concern with pharmacological characteristics of clozapine (blood monitoring and adverse effects). Lack of knowledge about the effectiveness of clozapine does not appear as a major determinant of under-prescription. Institutional-related characteristics favoring clozapine prescribing are prescribers' adherence to evidence-based medicine principles and learning by modelling from experienced clozapine prescribers.. Effective strategies to increase access to clozapine in persons with TRS include implementation of integrated clozapine clinics, simplification of blood monitoring, education for prescribers and contact with experienced prescribers. Programs addressing barriers in clozapine prescription need to be disseminated more broadly to ensure persons with TRS have access to evidenced based treatments such as clozapine. Inequality in access to clozapine care should be more systematically handled by mental health facilities and health regulatory agencies.

Topics: Antipsychotic Agents; Attitude of Health Personnel; Clozapine; Drug Resistance; Healthcare Disparities; Humans; Schizophrenia

The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in symptoms severity, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Design; Humans; Molecular Targeted Therapy; Precision Medicine; Psychology, Clinical; Receptors, Cholinergic; Receptors, Dopamine; Receptors, Glutamate; Receptors, Histamine; Receptors, Serotonin; Schizophrenia

To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis.. Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1.22-3.64], 1.7x risk (95% CI 1.13-2.59), and 2.15x risk (95% CI 1.3-3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1-4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120 bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03-0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results.. Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Glycine Plasma Membrane Transport Proteins; Humans; Hypothalamo-Hypophyseal System; Membrane Glycoproteins; Pharmacogenetics; Pituitary-Adrenal System; Receptor, trkB; Receptors, Glucocorticoid; Schizophrenia; Tacrolimus Binding Proteins

Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine-the only antipsychotic with an indication for TR-SCZ-is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline

Topics: Antipsychotic Agents; Clozapine; Humans; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Time-to-Treatment; Treatment Outcome

Treatment-resistant schizophrenia (TRS) is common and debilitating. A subgroup of patients even has clozapine-resistant schizophrenia (CRS). We aimed to evaluate the efficacy and safety of electroconvulsive therapy (ECT) augmentation of clozapine for CRS. Systematic literature search of randomized controlled trials (RCTs) reporting on ECT augmentation of clozapine in CRS. Co-primary outcomes included symptomatic improvement at post-ECT assessment and study endpoint. Eighteen RCTs (n = 1769) with 20 active treatment arms were identified and meta-analyzed. Adjunctive ECT was superior to clozapine regarding symptomatic improvement at post-ECT assessment (Standardized Mean Difference (SMD) = -0.88, 95% Confidence Interval (CI): -1.33 to -0.44; I. CRD42018089959.

Topics: Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Schizophrenia

Clozapine has unique efficacy for symptoms in treatment-resistant schizophrenia; however, symptomatic remission is not necessary nor sufficient for functional improvement. No study has pooled the effect of clozapine on psychosocial function across clinical trials.. We conducted a systematic review and meta-analysis to compare the effects of clozapine with other antipsychotics on psychosocial function, and described the predictors of functional outcome.. We searched MEDLINE/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Central Register of controlled trials and clinical trial registries till April 2018, with no language limits. Eligible studies were randomised controlled trials of clozapine vs. typical or atypical antipsychotics among adults with treatment-resistant schizophrenia. We included studies with flexible or fixed doses of antipsychotics within the therapeutic range to reflect naturalistic care. Effect sizes of studies were pooled using generic inverse variance and random-effects models and presented as standard mean differences. Study quality was assessed in accordance with the Cochrane Collaboration guideline, and subgroup analyses were carried out to identify potential moderators and methodological biases.. Nine studies with 1279 participants (69.7% male) were included. Clozapine showed beneficial effects on psychosocial function, but both short-term trials [n = 3; comparing 99 people taking clozapine with 97 controls (standardised mean difference = 0.04; 95% confidence interval - 0.24, 0.32; p = 0.77; I. Clozapine does not appear superior to other antipsychotics for improvement of psychosocial function. Standardisation of psychosocial function measurement is needed to improve the quality of evidence. Further exploration of the predictors of good psychosocial outcomes with clozapine treatment may improve personalisation of care.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Humans; Schizophrenia; Schizophrenic Psychology

There is conflicting evidence on the association between antipsychotic polypharmacy and metabolic syndrome in schizophrenia. We conducted a review of published systematic reviews to evaluate evidence on the association between metabolic syndrome (diabetes, hypertension, and hyperlipidaemia) and exposure to antipsychotic polypharmacy in schizophrenia.. We searched five electronic databases, complemented by reference screening, to find systematic reviews that investigated the association of antipsychotic polypharmacy in schizophrenia with hypertension, diabetes, or hyperlipidaemia. Selection of reviews, data extraction and review quality were conducted independently by two people and disagreements resolved by discussion. Results were synthesised narratively.. We included 12 systematic reviews, which reported heterogeneous results, mostly with narrative syntheses and without pooled data. The evidence was rated as low quality. There was some indication of a possible protective effect of drug combinations including aripiprazole for diabetes and hyperlipidaemias, compared to other combinations and/or monotherapy. Only one review reported the association between APP and hypertension. The most frequently reported combinations of medication included clozapine, possibly representing a sample of patients with treatment resistant illness. No included review reported results separately by setting (primary or secondary care).. Further robust studies are needed to elucidate the possible protective effect of aripiprazole. Long-term prospective studies are required for accurate appraisal of diabetes risk, hypertension and hyperlipidaemia in patients exposed to antipsychotic polypharmacy.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Polypharmacy; Prospective Studies; Schizophrenia; Systematic Reviews as Topic

No consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta-analysis therefore focus on the use of clozapine as first-line or second-line treatment in non-treatment-resistant patients.. Articles were eligible if they investigated clozapine compared to another antipsychotic as a first- or second-line treatment in non-treatment-resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random-effects meta-analyses.. Fifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta-analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges' g = 0.220, P = 0.026, 95% CI = 0.026-0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges' g = 0.274, P = 0.030, 95% CI = 0.027-0.521).. The few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first- or second-line treatment. Only large clinical trials may comprehensively probe disease stage-dependent superiority of clozapine and investigate overall tolerability.

Topics: Antipsychotic Agents; Clozapine; Humans; Outcome Assessment, Health Care; Schizophrenia

Tardive dyskinesia (TD) is an antipsychotic-induced movement disorder that typically occurs after long-term exposure to antipsychotic drugs. There is evidence that switching to clozapine reduces TD. This meta-analysis reviews the effect of switching to clozapine on the severity of TD.. The PubMed, PsycINFO, and Embase databases were searched for clozapine, tardive dyskinesia, and related keywords. The search was restricted to articles written in English and Dutch, and it was last updated on October 13, 2015.. Sixteen studies were included in the meta-analysis. Inclusion criteria were a diagnosis of schizophrenia or a related disorder, a switch to clozapine monotherapy, and reports of scores on a TD rating scale before and after the switch to clozapine.. Two independent investigators extracted the data. Data were converted to standardized mean change scores and analyzed in a random-effects model.. A random-effects model showed that the overall effect of switching to clozapine was a significant reduction in TD (npatients = 1,060, d = -0.40, P < .01), especially in the 4 studies that investigated the severity of TD as a primary outcome (npatients = 48, d = -2.56, P = .02).. The overall results show that clozapine treatment can yield a slight reduction in TD. The severity of TD was reduced greatly in patients with moderate to severe TD. In patients with minimal to mild TD, switching to clozapine seldom worsens TD and a trend toward reduction is seen. These results support that a switch to clozapine should be considered for patients with moderate to severe TD and/or patients who experience substantial discomfort due to TD.

Topics: Antipsychotic Agents; Clozapine; Drug Substitution; Humans; Schizophrenia; Severity of Illness Index; Tardive Dyskinesia

The sleep architecture (or sleep kinetics) of schizophrenia is different from that of other mental illnesses, including major depressive disorder. However, clinicians rarely consider these parameters in clinical settings during treatment. This article discusses the use of polysomnography to characterize the sleeping patterns of patients diagnosed with schizophrenia and the positive influence of clozapine on sleep in patients with schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Humans; Polysomnography; Schizophrenia; Schizophrenic Psychology; Sleep; Sleep Stages

Between 40% and 70% of people with treatment-resistant schizophrenia do not respond to clozapine, despite adequate blood levels. For these people, a number of treatment strategies have emerged, including the prescription of a second anti-psychotic drug in combination with clozapine.. To determine the clinical effects of various clozapine combination strategies with antipsychotic drugs in people with treatment-resistant schizophrenia both in terms of efficacy and tolerability.. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (to 28 August 2015) and MEDLINE (November 2008). We checked the reference lists of all identified randomised controlled trials (RCT). For the first version of the review, we also contacted pharmaceutical companies to identify further trials.. We included only RCTs recruiting people of both sexes, aged 18 years or more, with a diagnosis of treatment-resistant schizophrenia (or related disorders) and comparing clozapine plus another antipsychotic drug with clozapine plus a different antipsychotic drug.. We extracted data independently. For dichotomous data, we calculated risk ratios (RRs) and 95% confidence intervals (CI) on an intention-to-treat basis using a random-effects meta-analysis. For continuous data, we calculated mean differences (MD) and 95% CIs. We used GRADE to create 'Summary of findings' tables and assessed risk of bias for included studies.. We identified two further studies with 169 participants that met our inclusion criteria. This review now includes five studies with 309 participants. The quality of evidence was low, and, due to the high degree of heterogeneity between studies, we were unable to undertake a formal meta-analysis to increase the statistical power.For this update, we specified seven main outcomes of interest: clinical response in mental state (clinically significant response, mean score/change in mental state), clinical response in global state (mean score/change in global state), weight gain, leaving the study early (acceptability of treatment), service utilisation outcomes (hospital days or admissions to hospital) and quality of life.We found some significant differences between clozapine combination strategies for global and mental state (clinically significant response and change), and there were data for leaving the study early and weight gain. We found no data for service utilisation and quality of life. Clozapine plus aripiprazole versus clozapine plus haloperidolThere was no long-term significant difference between aripiprazole and haloperidol combination strategies in change of mental state (1 RCT, n = 105, MD 0.90, 95% CI -4.38 to 6.18, low quality evidence). There were no adverse effect data for weight gain but there was a benefit of aripiprazole for adverse effects measured by the LUNSERS at 12 weeks (1 RCT, n = 105, MD -4.90, 95% CI -8.48 to -1.32) and 24 weeks (1 RCT, n = 105, MD -4.90, 95% CI -8.25 to -1.55), but not 52 weeks (1 RCT, n = 105, MD -4.80, 95% CI -9.79 to 0.19). Similar numbers of participants from each group left the study early (1 RCT, n = 106, RR 1.27, 95% CI 0.72 to 2.22, very low quality evidence). Clozapine plus amisulpride versus clozapine plus quetiapine One study showed a significant benefit of amisulpride over quetiapine in the short term, for both change in global state (Clinical Global Impression (CGI): 1 RCT, n = 50, MD -0.90, 95% CI -1.38 to -0.42, very low quality evidence) and mental state (Brief Psychiatric Rating Scale (BPRS): 1 RCT, n = 50, MD -4.00, 95% CI -5.86 to -2.14, low quality evidence). Similar numbers of participants from each group left the study early (1 RCT, n = 56, RR 0.20, 95% CI 0.02 to 1.60, very low quality evidence) Clozapine plus risperidone versus clozapine plus sulpirideThere was no difference between risperidone and sulpiride for clinically significant response, defined by the study as 20% to 50% reduction. The reliability of results from this review is limited, evidence is of low or very low quality. Furthermore, due to the limited number of included studies, we were unable to undertake formal meta-analyses. As a consequence, any conclusions drawn from these findings are based on single, small-sized RCTs with high risk of type II error. Properly conducted and adequately powered RCTs are required. Future trialists should seek to measure patient-important outcomes such as quality of life, as well as clinical response and adverse effects.

Topics: Adult; Amisulpride; Antipsychotic Agents; Aripiprazole; Clozapine; Dibenzothiazepines; Drug Resistance; Drug Therapy, Combination; Female; Haloperidol; Humans; Male; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride; Thiazoles; Weight Gain

To meta-analyze randomized controlled trials (RCTs) for the efficacy and safety of adjunctive antiepileptic drugs (AEDs) to augment clozapine therapy for treatment-resistant schizophrenia.. The search included databases in English (PubMed, PsycINFO, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register) and in Chinese (China Journal Net [CJN], WanFang, and China Biology Medicine [CBM]) and references from retrieved articles. The databases were searched using dates inclusive from their onset until January 1, 2016, for terms reflecting (a) schizophrenia, (b) clozapine, and (c) adjunctive drugs.. From 1,969 potentially relevant articles, 21 articles describing 22 RCTs were selected.. Two independent investigators extracted data for a random-effects meta-analysis and assessed the quality of the studies using risk of bias and the Jadad scale. Standard mean difference, risk ratio (RR) ± 95% confidence intervals (CIs), and the number needed to harm (NNH) were used.. A total of 22 RCTs (N = 1,227) with 4 AEDs (topiramate [5 RCTs, n = 270], lamotrigine [8 RCTs, n = 299], sodium valproate [6 RCTs, n = 430], and magnesium valproate [3 RCTs, n = 228]) were analyzed. The means weighted by sample size were 12.1 weeks for treatment duration, 36.2 years for age, and 61% for male frequency. Significant superiority in total psychopathology was observed for topiramate (P < .0001), lamotrigine (P = .05), and sodium valproate (P = .002), compared to clozapine monotherapy. After removing outliers, the positive effect of sodium valproate remained, but the positive effect of lamotrigine disappeared (P = .40). Significantly improved efficacy in positive and general symptom severity was observed for topiramate (P = .04 and P = .02, respectively) and sodium valproate (P = .009 and P = .003, respectively). There were no significant differences regarding adverse drug reactions and all-cause discontinuations except for topiramate, which was associated with more all-cause discontinuations (RR = 1.99; 95% CI, 1.16 to 3.39; P = .01; I² = 0%; NNH = 7).. Sodium valproate augmentation was efficacious and safe. Topiramate augmentation had a too-high discontinuation rate. High-quality RCTs are needed to inform clinical recommendations.

Topics: Adult; Anticonvulsants; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology

Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; HLA Antigens; Humans; Schizophrenia

Schizophrenia and related disorders such as schizophreniform and schizoaffective disorder are serious mental illnesses characterised by profound disruptions in thinking and speech, emotional processes, behaviour and sense of self. Clozapine is useful in the treatment of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms (such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what dose of clozapine is most effective with the least side effects.. To compare the efficacy and tolerability of clozapine at different doses and to identify the optimal dose of clozapine in the treatment of schizophrenia, schizophreniform and schizoaffective disorders.. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (August 2011 and 8 December 2016).. All relevant randomised controlled trials (RCTs), irrespective of blinding status or language, that compared the effects of clozapine at different doses in people with schizophrenia and related disorders, diagnosed by any criteria.. We independently inspected citations from the searches, identified relevant abstracts, obtained full articles of relevant abstracts, and classified trials as included or excluded. We included trials that met our inclusion criteria and reported useable data. For dichotomous data, we calculated the relative risk (RR) and the 95% confidence interval (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) again based on a random-effects model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.. We identified five studies that could be included. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). Four of the five included studies were based on a small number of participants. We rated all the evidence reported for the main outcomes of interest as low or very low quality. No data were available for the main outcomes of global state, service use or quality of life. Very low dose compared to low doseWe found no evidence of effect on mental state between low and very low doses of clozapine in terms of average Brief Psychiatric Rating Scale-Anchored (BPRS-A) endpoint score (1 RCT, n = 31, MD 3.55, 95% CI -4.50 to 11.60, very low quality evidence). One study found no difference between groups in body mass index (BMI) in the short term (1 RCT, n = 59, MD -0.10, 95% CI -0.95 to 0.75, low-quality evidence). Very low dose compared to standard doseWe found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS-A endpoint score (1 RCT, n = 31, MD 6.67, 95% CI -2.09 to 15.43, very low quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI -0.76 to 0.96, low-quality evidence) Low dose compared to standard doseWe found no evidence of effect on mental state between low doses and standard doses of clozapine in terms of both clinician-assessed clinical improvement (2 RCTs, n = 141, RR 0.76, 95% CI 0.36 to 1.61, medium-quality evidence) and clinically important response as more than 30% change in BPRS score (1 RCT, n = 176, RR 0.93, 95% CI 0.78 to 1.10, medium-quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 57, MD 0.20, 95% CI -0.84 to 1.24, low-quality evidence).We found some evidence of effect for other adverse effect outcomes; however, the data were again limited. Very low dose compared to low doseThere was limited evidence that serum triglycerides were lower at low-dose clozapine compared to very low dose in the short term (1 RCT, n = 59, MD 1.00, 95% CI 0.51 to 1.49). Low dose compared to standard doseWeight gain was lower at very low dose compared to standard dose (1 RCT, n = 27, MD -2.70, 95% CI -5.38 to -0.02). Glucose level one hour after meal was also lower at very lose dose (1 RCT, n = 58, MD -1.60, 95% CI -2.90 to -0.30). Total cholesterol levels were higher at very low c. We found no evidence of effect on mental state between standard, low and very low dose regimes, but we did not identify any trials on high or very high doses of clozapine. BMI measurements were similar between groups in the short term, although weight gain was less at very low dose compared to standard dose in one study. There was limited evidence that the incidence of some adverse effects was greater at standard dose compared to lower dose regimes. We found very little useful data and the evidence available is generally of low or very low quality. More studies are needed to validate our findings and report on outcomes such as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life. There is a particular lack of medium- or long-term outcome data, and on dose regimes above the standard rate.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Schizophrenia

Second generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation linked to the use of SGAs. The aims of this article are to present patients with a history of psychotic disorders and of severe metabolic diabetic ketoacidosis, possibly associated with the use of antipsychotics, and to review the current literature on the topic of antipsychotic-induced DKA.. PubMed/Medline and EBSCO databases were searched using the keywords: diabetic ketoacidosis, antipsychotics, atypical antipsychotics, second generation antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpride and haloperidol. Case reports, case series and reviews of case series were included in the review.. The majority of patients who developed DKA following treatment with antipsychotics were treated with olanzapine and clozapine in monotherapy or in combination with other antipsychotics. DKA mostly occurred in the first six months of antipsychotic treatment. Other risk factors included insulin resistance prior to antipsychotic treatment, male gender and middle age.. Clinicians should consider the risk of DKA when starting treatment with SGAs. Preventive measures for patients with psychotic disorders using antipsychotics should include regular assessment of risk factors and screening for diabetes before and after administering antipsychotics, especially in the first months of treatment. Whenever possible, polypharmacy should be avoided.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Haloperidol; Humans; Insulin; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

Schizophrenia is a devastating illness that affects up to 1% of the population; it is characterized by a combination of positive symptoms, negative symptoms, and cognitive impairment. Currently, treatment consists of one class of medications known as antipsychotics, which include typical (first-generation) and atypical (second-generation) agents. Unfortunately, antipsychotic medications have limited efficacy, with up to a third of patients lacking a full response. Clozapine, the first atypical antipsychotic developed, is the only medication shown to be superior to all other antipsychotics. However, owing to several life-threatening side effects and required enrollment in a registry with routine blood monitoring, clozapine is greatly underutilized in the US. Developing a medication as efficacious as clozapine with limited side effects would likely become the first-line therapy for schizophrenia and related disorders. In this review, we discuss the history of clozapine, landmark studies, and its clinical advantages and disadvantages. We further discuss the hypotheses for clozapine's superior efficacy based on neuroreceptor binding, and the limitations of a receptor-based approach to antipsychotic development. We highlight some of the advances from pharmacogenetic studies on clozapine and then focus on studies of clozapine using unbiased approaches such as pharmacogenomics and gene expression profiling. Finally, we examine how these approaches could provide insights into clozapine's mechanism of action and side-effect profile, and lead to novel and improved therapeutics.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Clozapine is the most effective antipsychotic for the 25% to 33% of people with schizophrenia who are treatment resistant, but not all people achieve response. Using data from a previously published clozapine systematic review and meta-analysis, we explored the proportion of people who achieved response and examined the absolute and percentage change in Positive and Negative Syndrome Scale (PANSS) scores. Overall, 40.1% (95% confidence interval [CI], 36.8%-43.4%) responded, with a mean reduction in PANSS of 22.0 points (95% CI, 20.9-23.1), a reduction of 25.8% (95% CI, 24.7%-26.9%) from baseline. These reductions are clinically meaningful. A 40% response rate to clozapine suggests that 12% to 20% of people with schizophrenia will be ultra-resistant.

Topics: Antipsychotic Agents; Clozapine; Humans; Outcome Assessment, Health Care; Schizophrenia

Many people with schizophrenia do not achieve a satisfactory treatment response with their initial antipsychotic drug treatment. Sometimes a second antipsychotic, in combination with the first, is used in these situations.. To examine whether:1. treatment with antipsychotic combinations is effective for schizophrenia; and2. treatment with antipsychotic combinations is safe for the same illness.. We searched the Cochrane Schizophrenia Group's register which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran searches in September 2010, August 2012 and January 2016. We checked for additional trials in the reference lists of included trials.. We included all randomised and quasi-randomised controlled trials comparing antipsychotic combinations with antipsychotic monotherapy for the treatment of schizophrenia and/or schizophrenia-like psychoses.. We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CIs. For the meta-analysis we used a random-effects model. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for included studies.. Sixty-two studies are included in the review, 31 of these compared clozapine monotherapy with clozapine combination. We considered the risk of bias in the included studies to be moderate to high. The majority of trials had unclear allocation concealment, method of randomisation and blinding, and were not free of selective reporting.There is some limited evidence that combination therapy is superior to monotherapy in improving clinical response (RR 0.73, 95% CI 0.63 to 0.85; participants = 2364; studies = 29, very low-quality evidence), although subgroup analyses show that the positive result was due to the studies with clozapine in both the monotherapy and combination groups (RR 0.66, 95% CI 0.53 to 0.83; participants = 1127; studies = 17). Few studies reported on rate of relapse, most likely due to the short length of the studies. Overall, a combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in preventing relapse (RR 0.63, 95% CI 0.31 to 1.29; participants = 512; studies = 3, very low-quality evidence), but the pooled data showed high heterogeneity (I² = 82%). A combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in reducing the number of participants discontinuing treatment early (RR 0.89, 95% CI 0.73 to 1.07; participants = 3103; studies = 43, low-quality evidence). No difference was found between treatment groups in the number of participants hospitalised (RR 0.96, 95% CI 0.36 to 2.55; participants = 202; studies = 3, low-quality evidence) . We did not find evidence of a difference between treatment groups in serious adverse events or those requiring discontinuation (RR 1.05, 95% CI 0.65 to 1.69; participants = 2398; studies = 30, very low-quality evidence). There is as lack of evidence on clinically important change in quality of life, with only four studies reporting average endpoint or change data for this outcome on three different scales, none of which showed a difference between treatment groups.. Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials, limiting the assessment of long-term efficacy and safety. We found very low-quality evidence that a combination of antipsychotics may improve the clinical response. We also found low-quality evidence that a combination of antipsychotics is may make no difference at preventing participants from leaving the study early, preventing relapse and/or causing more serious adverse events than monotherapy.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Patient Dropouts; Quality of Life; Randomized Controlled Trials as Topic; Recurrence; Schizophrenia; Treatment Outcome

Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine.. Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context.. A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocyte-colony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported.. Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.

Topics: Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia; Schizophrenia

Clozapine is the gold standard medication for treatment refractory schizophrenia, but unfortunately, its use is also associated with many adverse metabolic side effects. There may be a strong genetic component to the development of these adverse effects. We undertook a systematic review to examine the evidence for genetic variation being associated with secondary metabolic outcomes in patients with schizophrenia on clozapine, under both longitudinal and cross-sectional study designs. We limited studies to those examining patients definitely taking clozapine, unlike prior reviews that have examined metabolic effects of patients taking a range of antipsychotic medications. We found associations with outcomes such as increases in BMI and metabolic syndrome for variants in genes such as LEP and HTR2C. Meta-analysis of rs381328 in HTR2C revealed that the presence of the T allele led to a 0.63 kg/m

Topics: Adult; Alleles; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Female; Genetic Variation; Genotype; Humans; Male; Metabolic Syndrome; Schizophrenia

Gastrointestinal hypomotility (GIH) is an under-reported but highly prevalent and potentially dangerous side effect of clozapine. In a comprehensive meta-analysis of clozapine-treated patients, the prevalence of GIH was 32%. In general, GIH has consistently been reported to have a negative impact on quality of life, and there is no reason to believe this will be different in clozapine-treated patients with therapy-resistant schizophrenia. GIH is dangerous; in a comparative review of lethal side effects of clozapine, the mortality of agranulocytosis was 2.2-4.2% compared with 15.0-27.5% for GIH. The mortality rate in our review of all published case reports of ileus was 43.7%. (Co-)Prescription of anticholinergic drugs in patients treated with clozapine should be avoided as anticholinergics are associated with increased incidence and fatality of ileus. Prevention of GIH can best be obtained by frequent and targeted questioning by the mental healthcare providers of the patients' defecation pattern and this is therefore strongly recommended for timely detection and treatment of treatment-emergent GIH throughout clozapine treatment. Treatment approaches can be either preventive laxative prescription with every clozapine prescription in all clozapine-treated patients or targeted treatment of treatment-emergent GIH. First-line treatments of GIH are the osmotic laxative macrogol, stool softener docusate and bowel stimulant senna. As the occurrence of severe cases of GIH is not restricted to a certain treatment duration, alertness for and/or treatment of GIH is required for the whole duration of clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Incidence; Prevalence; Quality of Life; Schizophrenia

Although a minority of persons with schizophrenia (SCZ) commits violent acts, SCZ remains a risk factor for violence. Here, we present a broad overview of evidence-based treatments for violence in SCZ, including biological and psychosocial interventions.. We conducted MEDLINE and PsychINFO literature searches to retrieve articles relating to treatments for violent, hostile, or aggressive behaviours in SCZ.. Clozapine shows the strongest evidence for treating the acute violence of SCZ. Other atypical antipsychotics also possess antiaggressive effects, although the evidence is not as robust as that for clozapine. Psychosocial treatments can be useful adjuncts to pharmacotherapy once patients' positive symptoms have stabilized. Cognitive behavioural therapy for psychosis and cognitive remediation are 2 psychosocial interventions that have demonstrated positive outcomes for violence in SCZ. Most psychosocial studies that examined violence as an outcome were conducted in forensic psychiatric settings.. Effective treatments exist for persons with SCZ who pose a risk for violent and aggressive behaviour, although the overall evidence base remains relatively weak. More randomized controlled trials of programs showing evidence for reduction of violence in SCZ are required. Further research should delineate which patients could benefit from multimodal treatment and where and when such treatments are optimally delivered.

Topics: Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Cognitive Remediation; Humans; Schizophrenia; Violence

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10

Topics: Carrier Proteins; Case-Control Studies; Clozapine; Exome; Female; Genome-Wide Association Study; HLA-DQ beta-Chains; Humans; Male; Neutropenia; Odds Ratio; Schizophrenia; Solute Carrier Organic Anion Transporter Family Member 1B3

Clozapine is an antipsychotic used in the management of treatment-resistant schizophrenia. However, little is known about clozapine use during pregnancy and lactation, or its impact on the mother, foetus, and infant. This review aims to summarize the available literature on the safety of clozapine use during the perinatal period. EMBASE, PsycINFO, and MEDLINE were searched from their inceptions through June 2016. The review encompasses 21 studies that have examined clozapine use during pregnancy and lactation. The limited available data do not support an increased risk of congenital malformations in foetuses exposed to clozapine during pregnancy, though rates of gestational diabetes are twice as high in pregnant women using clozapine. Clozapine accumulation in foetal serum possibly contributes to increased rates of floppy infant syndrome at delivery, decreased foetal heart rate variability, and seizures in infancy. Clozapine crosses the placenta and also accumulates in breast milk, which may increase the risk of agranulocytosis in infants and may necessitate infant testing. The majority of these data come from case reports and case series, making it unclear if the published risks associated with clozapine are due to mental illness, lifestyle factors, or co-treatment with other psychotropic medications. While the available literature on clozapine use during the perinatal period is very limited, the risks of clozapine use during pregnancy and the postpartum period should be discussed with women and weighed against those associated with other treatments and partially or untreated schizophrenia.

Topics: Antipsychotic Agents; Breast Feeding; Clozapine; Female; Humans; Infant; Lactation; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Schizophrenia

Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: GCLM, ZNF652, and GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia.

Topics: Antipsychotic Agents; Autopsy; Brain; Clozapine; Databases, Bibliographic; Female; Gene Expression; Humans; Male; Schizophrenia; Signal Transduction

Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes.. A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics).. Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons.. Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Humans; Prospective Studies; Schizophrenia; Treatment Outcome

Patients with schizophrenia die on average 25 years earlier than the general population, and this gap appears to be increasing. Most of the excess mortality is due to premature cardiovascular deaths rather than suicide. Many psychotropic agents are orexigenic and can increase weight and promote dyslipidaemia. Traditional cardiac risk factors are undertreated among patients with schizophrenia, and they are less likely to receive cardiac revascularisation than those without a mental illness. Clozapine is an atypical antipsychotic medication effective for treatment of refractory schizophrenia, but is associated with the risk of myocarditis and cardiomyopathy. Established protocols in Australia screen for myocarditis for patients who are initiating clozapine therapy and for long term monitoring for cardiomyopathy with echocardiography. Coordinated care between tertiary providers, general practitioners and primary health care professionals should monitor the physical health of people with psychosis or schizophrenia at least annually and treatment should be offered accordingly.

Topics: Antipsychotic Agents; Australia; Cardiomyopathies; Cardiovascular Diseases; Clozapine; Delivery of Health Care; Echocardiography; Humans; Mass Screening; Mental Health Services; Metabolic Syndrome; Myocarditis; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Australia; Clozapine; Cost-Benefit Analysis; Drug Utilization; Echocardiography; Female; Health Care Costs; Humans; Male; Myocarditis; Practice Patterns, Physicians'; Risk Assessment; Schizophrenia; Severity of Illness Index; Unnecessary Procedures

Clozapine is currently the ultimate effective therapy for otherwise treatment-refractory schizophrenia. However, the drug is also associated with many adverse effects, some of them potentially fatal. Thus, there is an unmet need to predict clinical response to clozapine. As the pharmacokinetics of clozapine vary considerably between and within individuals, there may be an association between genetic polymorphisms and clozapine plasma concentration and consequently, clinical response. We have reviewed studies that have investigated the association between clozapine metabolic pathways related to genes polymorphisms in relation to plasma clozapine concentration and clinical response. Overall, most of the studies reported negative results. The only gene polymorphism that has been found to be associated with clozapine plasma concentration and response was the ABCB1 gene, which codes for transmembrane transporters expressed in the bowel mucosa, blood-brain barrier, kidney and liver. More prospective longitudinal studies are needed to elucidate the possible role of the ABCB1 polymorphism and transmembrane transporters in clozapine pharmacokinetics and clinical response.

Topics: Animals; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B; Clozapine; Cytochrome P-450 Enzyme System; Humans; Polymorphism, Genetic; Schizophrenia

Schizophrenia is an incurable neuropsychiatric disorder managed mostly by treatment of the patients with antipsychotics. However, the efficacy of these drugs has remained only low to moderate despite intensive research efforts since the early 1950s when chlorpromazine, the first antipsychotic, was synthesized. In addition, antipsychotic treatment can produce often undesired severe side effects in the patients and addressing these remains a large unmet clinical need. One of the reasons for the low effectiveness of these drugs is the limited knowledge about the molecular mechanisms of schizophrenia, which impairs the development of new and more effective treatments. Recently, proteomic studies of clinical and preclinical samples have identified changes in the levels of specific proteins in response to antipsychotic treatment, which have converged on molecular pathways such as cell communication and signaling, inflammation and cellular growth, and maintenance. The findings of these studies are summarized and discussed in this review and we suggest that this provides validation of proteomics as a useful tool for mining drug mechanisms of action and potentially for pinpointing novel molecular targets that may enable development of more effective medications.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Brain; Chlorpromazine; Clozapine; Disease Models, Animal; Gene Expression Regulation; Glycolysis; Humans; Mitochondrial Proteins; Nerve Tissue Proteins; Oxidative Phosphorylation; Proteome; Proteomics; Schizophrenia; Treatment Outcome

The primary aim of this systematic review and meta-analysis was to assess the proportion of patients with Treatment Resistant Schizophrenia (TRS) that respond to ECT augmentation of clozapine (C+ECT). We searched major electronic databases from 1980 to July 2015. We conducted a random effects meta-analysis reporting the proportion of responders to C+ECT in RCTs and open-label trials. Five clinical trials met our eligibility criteria, allowing us to pool data from 71 people with TRS who underwent C+ ECT across 4 open label trials (n=32) and 1 RCT (n=39). The overall pooled proportion of response to C+ECT was 54%, (95% CI: 21.8-83.6%) with some heterogeneity evident (I(2)=69%). With data from retrospective chart reviews, case series and case reports, 192 people treated with C+ECT were included. All studies together demonstrated an overall response to C+ECT of 66% (95% CI: 57.5-74.3%) (83 out of 126 patients responded to C+ECT). The mean number of ECT treatments used to augment clozapine was 11.3. 32% of cases (20 out of 62 patients) with follow up data (range of follow up: 3-468weeks) relapsed following cessation of ECT. Adverse events were reported in 14% of identified cases (24 out of 166 patients). There is a paucity of controlled studies in the literature, with only one single blinded randomised controlled study located, and the predominance of open label trials used in the meta-analysis is a limitation. The data suggests that ECT may be an effective and safe clozapine augmentation strategy in TRS. A higher number of ECT treatments may be required than is standard for other clinical indications. Further research is needed before ECT can be included in standard TRS treatment algorithms.

Topics: Antipsychotic Agents; Clozapine; Electroconvulsive Therapy; Humans; Schizophrenia

In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published.. To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis.. MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014.. At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo.. At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration's risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting.. The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events.. Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs.. Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

Topics: Adult; Antipsychotic Agents; Bayes Theorem; Benzodiazepines; Clozapine; Double-Blind Method; Drug Resistance; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Patient Acceptance of Health Care; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Single-Blind Method; Treatment Outcome

Clozapine remains the drug of choice for treatment-resistant schizophrenia. As a consequence of its long history and complex pharmacology, we suspected wide variation in the regulations of clozapine use across different countries. The summaries of product characteristics (SPCs) from clozapine manufacturers, as well as local and national guidelines in the following selected countries, were reviewed: China, Denmark, Ireland, Japan, The Netherlands, New Zealand, Romania, the UK and the US. Clozapine is available as tablets in all countries, as an oral suspension in all included countries, with the exception of Japan and Romania, as orally disintegrating tablets in the US and China, and as an injectable in The Netherlands. General practitioner prescribing is only available in The Netherlands, New Zealand, the UK and the US, although with some restrictions in some of the countries. In Ireland and China, clozapine is only dispensed through hospital pharmacies. Hematological monitoring is mandatory in all countries but varies substantially in frequency, e.g. in Denmark hematologic monitoring is mandatory weekly for 18 weeks, followed by monthly monitoring, compared with Japan where blood work is required weekly for 26 weeks, followed by biweekly hematologic monitoring thereafter. In most included countries, with the exception of Denmark, Romania and The Netherlands, the manufacturer provides a mandatory hematological monitoring database, and dispensing of clozapine is not permissible without acceptable white blood count and absolute neutrophil count results. Local guidelines in New Zealand recommend echocardiography and routine troponin during the initial phases of treatment with clozapine. Regulations of clozapine vary widely with regard to rules of prescribing and monitoring. A worldwide update and harmonization of these regulations is recommended.

Topics: Antipsychotic Agents; Clozapine; Drug and Narcotic Control; Drug Monitoring; Drug Resistance; Drugs, Generic; Humans; Internationality; Schizophrenia

The need for chemotherapy treatment in a cancer patient who uses clozapine raises a clinical dilemma because both therapies can cause agranulocytosis. A 45-year-old male diagnosed with schizophrenia used clozapine together with zuclopenthixol for more than 15 years. Non-Hodgkin's lymphoma was treated with chemotherapy twice, and clozapine was continued during both courses of chemotherapy. Agranulocytosis did not occur during the first treatment. During the second treatment, agranulocytosis occurred, but was attributed to chemotherapy, and blood counts recovered spontaneously. Successful concomitant use of clozapine and cancer chemotherapy is based on a limited number of case reports. However, two case reports describe persistent neutropenia or agranulocytosis, possibly related to this combination.. Clozapine should only be continued during cancer chemotherapy if favoured by the risk-to-benefit ratio.

Topics: Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Clozapine; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Schizophrenia; Treatment Outcome

Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. One of the adverse effects is neutropenia. This dysplasia is a rare but major side effect which leads to a discontinuation and constitutes further contraindication. Thereafter, therapeutic options decrease dramatically. Mechanisms involved are not well known at this time and can be combined. A toxic hypothesis may be more likely than an immune-allergic one.. We have reviewed publications on Medline describing procedures that allowed clozapine rechallenge after blood dyscrasia in refractory schizophrenia. Three different procedures were found: simple rechallenge, rechallenge with lithium and rechallenge with Granulocyte - colony stimulating factor (G-CSF). Rechallenge could be simple or multiple.. These past years, clozapine have been rechallenged successfully after neutropenia thanks to different procedures, the different options being simple rechallenge, rechallenge with lithium and/or rechallenge with G-CSF. Lithium as G-CSF are used to increase neutrophil blood rate and prevent neutropenia recurrence after clozapine rechallenge. G-CSF was first used within the context of chemotherapy and extends now to clozapine-induced neutropenia. Both for lithium and G-CSF, numerous procedures are reviewed and cannot be compared.. Publications are limited but increasing, and they point out that a careful rechallenge can be successful. However, interesting data can be extracted. First, clozapine is more likely to be incriminated in neutropenia when patients receive many drugs, but a careful study could prevent some discontinuation. Indeed, other drugs or a hematologic disease could be involved. Moreover, several contributing factors have been found such as HLA group and drug interaction. Ethnic origin also affects neutrophil rate. That is why, in Great Britain, a subgroup of patients "benign ethnic neutropenia" has been introduced to enlarge threshold and allow these patients to access clozapine despite lower blood counts. Then, rechallenge choice has to be done on a case-by-case basis and only after considering the benefits and risks of such a treatment. Most of the time, clinical advice of rechallenge arises from the inefficiency of other antipsychotics and even sismotherapy failure. Patients and sometimes families have to be informed and give their consent. Preventive measures have been found such as taking a hematologic recommendation and doing twice-a-week blood sample monitoring. With regards lithium and G-CSF, some efficient doses are assumed (lithium: 0,4-1,1 mEq/L and G-CSF>0,3 mg/week). Lithium as G-CSF may have other adverse effects which need to be considered. There is no successful rechallenge reported after agranulocytosis. Some publications highlight that if neutropenia occurs on rechallenge, it will do so more quickly and more severe than at the time of initial trial of clozapine.. There is emerging evidence of successful clozapine rechallenging. However, further investigations are required as randomized controlled trials to reassess guidelines and establish the safety and effectiveness of the different procedures. Because of the practical and ethical difficulties of designing such studies, referral hospitals could be elected, and common background writing proposed in order to ease data comparison.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Neutropenia; Psychotic Disorders; Schizophrenia

High violence prevalence is a common concern for forensic psychiatric settings. Categorizing underlying drivers of violence has helped to direct treatment and management efforts toward psychotic, predatory, and impulsively violent psychopathology. This article describes a series of cases in which clozapine provided adequate control of psychosis in women suffering schizophrenia-spectrum disorders. Nevertheless, impulsive violence remained problematic. Add-on methylphenidate was found to be safe and effective in curbing impulsive violent behavior in this select group of patients.

Topics: Adult; Antipsychotic Agents; Central Nervous System Stimulants; Clozapine; Drug Therapy, Combination; Female; Humans; Impulsive Behavior; Methylphenidate; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Violence

Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring.. An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates.. Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Resistance; Humans; Neutropenia; Schizophrenia

Although treatment-resistant schizophrenia (TRS) was described 50 years ago and has a gold standard treatment with clozapine based on well-defined criteria, there is still a matter of great interest and controversy. In terms of the underlying mechanisms of the development of TRS, progress has been made for the elucidation of the neurochemical mechanisms. Structural neuroimaging studies have shown that patients with TRS have significant reduction of the prefrontal cortex volume when compared with non- TRS. This article updates and enhances our previous review with new evidence mainly derived from new studies, clinical trials, systematic reviews, and meta-analyses.

Topics: Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Drug Resistance; Electroconvulsive Therapy; Humans; Neuroimaging; Prefrontal Cortex; Risk Factors; Schizophrenia; Transcranial Magnetic Stimulation; Treatment Outcome

Constipation is a frequently overlooked side effect of clozapine treatment that can prove fatal. We conducted a systematic review and meta-analysis to estimate the prevalence and risk factors for clozapine-associated constipation. Two authors performed a systematic search of major electronic databases from January 1990 to March 2016 for articles reporting the prevalence of constipation in adults treated with clozapine. A random effects meta-analysis was conducted. A total of 32 studies were meta-analyzed, establishing a pooled prevalence of clozapine-associated constipation of 31.2% (95% CI: 25.6-37.4) (n = 2013). People taking clozapine were significantly more likely to be constipated versus other antipsychotics (OR 3.02 (CI: 1.91-4.77), p < 0.001, n = 11 studies). Meta-regression identified two significant study-level factors associated with constipation prevalence: significantly higher (p = 0.02) rates of constipation were observed for those treated in inpatient versus outpatient or mixed settings and for those studies in which constipation was a primary or secondary outcome measure (36.9%) compared to studies in which constipation was not a specified outcome measure (24.8%, p = 0.048). Clozapine-associated constipation is common and approximately three times more likely than with other antipsychotics. Screening and preventative strategies should be established and appropriate symptomatic treatment applied when required.

Topics: Antipsychotic Agents; Clozapine; Constipation; Humans; Odds Ratio; Prevalence; Schizophrenia; Serotonin Antagonists

Clozapine is an efficacious treatment for treatment-resistant schizophrenia; however its use can be limited by side effect intolerability. Sinus tachycardia is a common adverse event associated with clozapine treatment. Various pharmacological treatments are used to control heart rate increase due to clozapine use and can include a decreased rate of clozapine titration, a switch to a different antipsychotic, or treatment with negative chronotropic drugs.. To assess the clinical effects and efficacy of pharmacological interventions for clozapine-induced sinus tachycardia.To systematically review the adverse events associated with pharmacological interventions for clozapine-induced sinus tachycardia.. On 23 March 2015, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and registries of clinical trials. There are no language, date, document type or publication status limitations for inclusion of records in the register.. Randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced tachycardia.. We independently screened and assessed studies for inclusion using pre-specified inclusion criteria.. The electronic searches located three references. However, we did not identify any studies that met our inclusion criteria.. With no studies meeting the inclusion criteria, it is not possible to arrive at definitive conclusions. There are currently insufficient data to confidently inform clinical practice. We cannot, therefore, conclude whether specific interventions, such as beta-blockers, are less effective or more effective than standard courses of alternative treatments for tachycardia. This lack of evidence for the treatment of clozapine-induced tachycardia has implications for research and practice. Well-planned, conducted and reported randomised trials are indicated. One trial is currently underway. Current practice outside of well-designed randomised trials should be clearly justified.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Tachycardia, Sinus

This meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of the combination of electroconvulsive therapy (ECT) and antipsychotic medication (except for clozapine) versus the same antipsychotic monotherapy for treatment-resistant schizophrenia (TRS). Two independent investigators extracted data for a random effects meta-analysis and pre-specified subgroup and meta-regression analyses. Weighted and standard mean difference (WMD/SMD), risk ratio (RR) ±95% confidence intervals (CIs), number needed to treat (NNT), and number needed to harm (NNH) were calculated. Eleven studies (n = 818, duration = 10.2±5.5 weeks) were identified for meta-analysis. Adjunctive ECT was superior to antipsychotic monotherapy regarding (1) symptomatic improvement at last-observation endpoint with an SMD of -0.67 (p<0.00001; I2 = 62%), separating the two groups as early as weeks 1–2 with an SMD of -0.58 (p<0.00001; I2 = 0%); (2) study-defined response (RR = 1.48, p<0.0001) with an NNT of 6 (CI = 4–9) and remission rate (RR = 2.18, p = 0.0002) with an NNT of 8 (CI = 6–16); (3) PANSS positive and general symptom sub-scores at endpoint with a WMD between -3.48 to -1.32 (P = 0.01 to 0.009). Subgroup analyses were conducted comparing double blind/rater-masked vs. open RCTs, those with and without randomization details, and high quality (Jadad≥adadup analyses were Jadad<3) studies. The ECT-antipsychotic combination caused more headache (p = 0.02) with an NNH of 6 (CI = 4–11) and memory impairment (p = 0.001) with an NNH of 3 (CI = 2–5). The use of ECT to augment antipsychotic treatment (clozapine excepted) can be an effective treatment option for TRS, with increased frequency of self-reported memory impairment and headache.. CRD42014006689 (PROSPERO).

Topics: Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Drug Resistance; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine's impact on glucagon-like peptide (GLP-1). There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine.. We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group's trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers.. Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg) and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2). Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results.. Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered.. PROSPERO registration number: CRD42015029723.

Topics: Antipsychotic Agents; Blood Glucose; Body Mass Index; Body Weight; Clozapine; Fasting; Humans; Hypoglycemic Agents; Metabolic Syndrome; Metformin; Obesity; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; Triglycerides; Waist Circumference; Weight Gain

A substantial proportion (40-70%) of patients with treatment-resistant schizophrenia experience persistent symptoms despite an adequate clozapine trial. Brain stimulation techniques (BST) such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) have shown promise in medication-refractory schizophrenia. However, their co-administration with clozapine raises some safety concerns.. We conducted a systematic literature search through Pubmed and cross-references for relevant publications evaluating the safety and efficacy of combining BST with clozapine. Expert commentary: Evidence from a randomized controlled trial and open-label trials suggest that ECT is an effective intervention in clozapine-refractory schizophrenia. There is limited evidence that the combination is safe. However, until sufficient data accumulate, it would be prudent to be vigilant against adverse effects related to lowered seizure threshold, cognitive impairment, and cardiovascular events. Both high frequency rTMS over the dorsolateral prefrontal cortex and low frequency rTMS over the temporoparietal cortex have been safely administered in patients receiving clozapine. However, rTMS efficacy in clozapine-refractory patients remains uncertain. The evidence for tDCS-clozapine combination is in the form of case reports and needs to be evaluated in controlled trials. Newer methods of brain stimulation and refinement of existing BSTs hold promise for the future.

Topics: Antipsychotic Agents; Brain; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Transcranial Direct Current Stimulation; Transcranial Magnetic Stimulation; Treatment Outcome

Although clozapine is the 'gold standard' for treatment-refractory schizophrenia, meta-analyses of clozapine for this condition are lacking.. We conducted a systematic review and meta-analysis of clozapine treatment for people with treatment-refractory schizophrenia.. We searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of clozapine for treatment-refractory schizophrenia.. Twenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for clozapine in a meta-regression.. Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Preclinical Research After the identification of the schizophrenia as an illness over a century ago, treatment of affected individuals included unspecific, mostly very robust methods including deep insulin coma and lobectomy/leucotomy. The first relatively specific treatment of schizophrenia started about 60 years ago with the antipsychotic chlorpromazine. All currently approved antipsychotic drugs block dopamine receptors, indicating that manipulation of dopaminergic function is fundamental to a therapeutic response in psychosis. Despite refinements in their mechanism of action, the therapeutic effects of subsequent generations of antipsychotics are insufficient in claiming superiority over the first generation, with the possible exception of clozapine. Dopamine receptor blockade is necessary but not always sufficient for antipsychotic response and improvements have been reported with molecules acting on other receptors (glutamate, glycine, cannabidiol, estrogen), intracellular signaling proteins, or products of identified risk genes. Here, we review the current status of drugs under investigation. In addition, we emphasize that the development of the novel compounds to target the underlying cognitive dysfunction and negative symptom dimension of full blown schizophrenia, or attenuated psychosis syndrome and specific endophenotypes related to the increased risk of psychosis in the general population, alongside efforts to deconstruct the concept of schizophrenia(s), represent the best way to meet patient needs for better therapies and more favorable outcomes. Drug Dev Res 77 : 357-367, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Antipsychotic Agents; Chlorpromazine; Clozapine; Cognitive Dysfunction; Dopamine Antagonists; Drug Design; Humans; Schizophrenia

Modern antipsychotic drugs are employed increasingly in the treatment of mood disorders as well as psychoses, stimulating interest in their possible contributions to altering suicidal risk. Clozapine remains the only treatment with an FDA-recognized indication for reducing suicidal risk (in schizophrenia). We carried out a systematic, computerized search for reports of studies involving antipsychotic drug treatment and suicidal behaviors. A total of 19 reports provide data with preliminary support for potential suicide risk-reducing effects of olanzapine, quetiapine, ziprasidone, aripiprazole, and asenapine in addition to clozapine, and provide some support for antipsychotic drug treatment in general. These preliminary findings encourage further testing of antipsychotics for effects on suicidal behavior, making use of explicit, pre-planned assessments of suicidal behavior.

Topics: Antipsychotic Agents; Clozapine; Humans; Risk Factors; Schizophrenia; Suicide Prevention

Clozapine is considered to be the most effective antipsychotic drug for patients with treatment resistant schizophrenia, but up to a third of the patients do not respond to this treatment. Various strategies have been tried to augment the effect of clozapine in non-responders, one of these strategies being electroconvulsive therapy. However, its efficacy and safety are not yet clear. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 55 studies, among them six randomized controlled trials addressing clozapine-resistant schizophrenia. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded electroconvulsive therapy probably augments response to clozapine in patients with treatment resistant schizophrenia, but it is not possible to determine if it leads to cognitive adverse effects because the certainty of the evidence is very low.

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Drug Resistance; Electroconvulsive Therapy; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Persistent violence not due to acute psychosis or mania can be managed only after appropriate characterization of the aggressive episodes (psychotic, impulsive, or predatory/planned/instrumental). The type of violence combined with the psychiatric diagnosis dictates the evidence-based pharmacologic approaches for psychotically motivated and impulsive aggression, whereas instrumental violence mandates forensic/behavioral strategies. For nonacute inpatients, schizophrenia spectrum disorders, traumatic brain injury, and dementia comprise the majority of individuals who are persistently aggressive, with impulsive actions the most common form of violence across all diagnoses. Neurobiological considerations combined with empirical data provide a comprehensive framework for systematic medication trials to manage persistently aggressive patients.

Topics: Aggression; Antimanic Agents; Antipsychotic Agents; Brain Injuries, Traumatic; Carbamazepine; Clozapine; Dementia; Humans; Impulsive Behavior; Neurobiology; Psychopharmacology; Psychotic Disorders; Schizophrenia; Violence

Psychotic disorders can lead some people to become agitated. Characterised by restlessness, excitability and irritability, this can result in verbal and physically aggressive behaviour - and both can be prolonged. Aggression within the psychiatric setting imposes a significant challenge to clinicians and risk to service users; it is a frequent cause for admission to inpatient facilities. If people continue to be aggressive it can lengthen hospitalisation. Haloperidol is used to treat people with long-term aggression.. To examine whether haloperidol alone, administered orally, intramuscularly or intravenously, is an effective treatment for long-term/persistent aggression in psychosis.. We searched the Cochrane Schizophrenia Group Trials Register (July 2011 and April 2015).. We included randomised controlled trials (RCT) or double blind trials (implying randomisation) with useable data comparing haloperidol with another drug or placebo for people with psychosis and long-term/persistent aggression.. One review author (AK) extracted data. For dichotomous data, one review author (AK) calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a fixed-effect model. One review author (AK) assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.. We have no good-quality evidence of the absolute effectiveness of haloperidol for people with long-term aggression. One study randomising 110 chronically aggressive people to three different antipsychotic drugs met the inclusion criteria. When haloperidol was compared with olanzapine or clozapine, skewed data (n=83) at high risk of bias suggested some advantage in terms of scale scores of unclear clinical meaning for olanzapine/clozapine for 'total aggression'. Data were available for only one other outcome, leaving the study early. When compared with other antipsychotic drugs, people allocated to haloperidol were no more likely to leave the study (1 RCT, n=110, RR 1.37, CI 0.84 to 2.24, low-quality evidence). Although there were some data for the outcomes listed above, there were no data on most of the binary outcomes and none on service outcomes (use of hospital/police), satisfaction with treatment, acceptance of treatment, quality of life or economics.. Only one study could be included and most data were heavily skewed, almost impossible to interpret and oflow quality. There were also some limitations in the study design with unclear description of allocation concealment and high risk of bias for selective reporting, so no firm conclusions can be made. This review shows how trials in this group of people are possible - albeit difficult. Further relevant trials are needed to evaluate use of haloperidol in treatment of long-term/persistent aggression in people living with psychosis.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Haloperidol; Humans; Middle Aged; Olanzapine; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia

Clozapine constitutes the treatment of choice in patients with schizophrenia with persisting symptoms despite antipsychotics at adequate dose and treatment duration. However, an important proportion does not respond to optimal doses of clozapine, so the addition of a second antipsychotic might increase clinical response. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 17 systematic reviews comprising 62 studies addressing the question of this article, including 26 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded adding a second antipsychotic to clozapine in patients with refractory schizophrenia probably leads to little or no difference in clinical response, and increases adverse effects.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Disease Models, Animal; gamma-Aminobutyric Acid; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission

Limited options are available for clozapine-resistant schizophrenia and intolerable side effects of clozapine. We conducted a systematic review of randomized-controlled trials (RCTs) to determine the efficacy and safety of aripiprazole augmentation of clozapine for schizophrenia. Electronic databases searched included PubMed, Scopus, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. This review synthesized the data of four short-term (8-24 weeks), placebo-controlled trials (N = 347). The overall relative risk (RR, 95% confidence interval) of discontinuation rates was not significantly different between groups (RR = 1.41, 95% CI = 0.78 to 2.56). The pooled standardized mean differences (SMDs, 95% CIs) (Z-test; number of study; I(2)-index) suggested trends of aripiprazole augmentation benefits on overall psychotic [-0.40 (-0.87 to 0.07) (n = 3; Z = 1.68, p = 0.09; I(2) = 68%)], positive [-1.05 (-2.39 to 0.29) (n = 3; Z = 1.54, p = 0.12; I(2) = 94%)], and negative [-0.36 (-0.77 to 0.05) (n = 3; Z = 1.74, p = 0.08; I(2) = 54%)] symptoms. Despite of no benefit on three cardiometabolic indices (i.e., fasting plasma glucose, triglyceride, and high-density lipoprotein), aripiprazole augmentation was superior for weight change with a mean difference (95% CI) of -1.36 kg (-2.35 to -0.36) (n = 3; Z = 2.67, p = 0.008; I(2) = 39%) and LDL-cholesterol with a mean difference of -11.06 mg/dL (-18.25 to -3.87) (n = 3; Z = 3.02, p = 0.003; I(2) = 31%). Aripiprazole augmentation was not correlated with headache and insomnia but significantly associated with agitation/akathesia (RR = 7.59, 95% CI = 1.43 to 40.18) (n = 3; Z = 2.38, p = 0.02; I(2) = 0%) and anxiety (RR = 2.70, 95% CI = 1.02 to 7.15) (n = 1; Z = 2.00, p = 0.05). The limited short-term data suggested that aripiprazole augmentation of clozapine can minimize the cardiometabolic risk, causes agitation/akathesia, and may be effective in attenuating psychotic symptoms.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Drug Synergism; Humans; Randomized Controlled Trials as Topic; Schizophrenia

Clozapine is an antipsychotic drug with superior efficacy in treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side-effects but a high propensity to induce weight gain and general metabolic dysregulation. Various pharmacological and behavioral treatment approaches for reducing clozapine-associated weight gain exist in the literature; however, there are currently no clear clinical guidelines as to which method is preferred. The aim of the current review is to systematically summarize studies that have studied both pharmacological and non-pharmacological interventions to attenuate or reverse clozapine-associated weight gain.. A systematic review of EMBASE and MEDLINE databases of all articles published prior to January 2014 was conducted. Seventeen studies were identified as meeting inclusion criteria and included in the review.. Aripiprazole, fluvoxamine, metformin, and topiramate appear to be beneficial; however, available data are limited to between one and three randomized controlled trials per intervention. Orlistat shows beneficial effects, but in males only. Behavioral and nutritional interventions also show modest effects on decreasing clozapine-associated weight gain, although only a small number of such studies exist.. While a number of pharmacological interventions can produce modest weight loss, each may be associated with negative side effects, which should be considered before beginning treatment. Given the pressing need to improve cardiometabolic health in most clozapine-treated patients, substantially more research is needed to develop sound clinical practice guidelines for the treatment of clozapine-associated weight gain.

Topics: Antipsychotic Agents; Clozapine; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain

This study was conducted to review systematically adjunctive treatments for weight reduction in patients with schizophrenia and compare efficacies of clinical trials through meta-analysis, so as to provide effective clinical guideline regarding weight control for patients taking atypical antipsychotics.. Candidate clinical trials were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO. Fourteen randomized clinical trials were included for systematic review and meta-analysis from 132 potential trials. The Comprehensive Meta-Analysis version 2 was used for meta-analysis.. Difference in means and significances from meta-analyses regarding weight control by adjunctive treatments showed that topiramate, aripiprazole, or sibutramine was more effective than metformin or reboxetine. Psychiatric evaluations did not show statistically significant changes between treatment groups and placebo groups except topiramate adjunctive treatments. Adverse effects regarding adjunctive therapies were tolerable and showed statistically no significances compared to control groups.. Though having several reports related to exacerbation of psychiatric symptoms, topiramate and aripiprazole are more efficacious than other medications in regard to weight reduction and less burden of critical adverse effects as well as being beneficial for clinical improvement.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Therapy, Combination; Humans; Obesity; Olanzapine; Schizophrenia

This paper aims to review the available evidence for the use of clozapine and electroconvulsive therapy (ECT) in combination.. Electronic searches were carried out to identify reports describing the combined use of clozapine and ECT.. Forty reports including 208 patients were identified. The majority of reports were in the form of case reports and case series, with few retrospective and open-label studies. The majority of patients were aged between 18 and 65 years and diagnosed with schizophrenia or schizoaffective disorder. Most of the patients refractory to clozapine were started on ECT as an augmentation therapy; however, in some reports, both ECT and clozapine were started concurrently, and in few cases clozapine was started after ECT. In terms of effectiveness, 37.5-100% patients improved in short-term, and sustained long-term improvement (3 weeks to 24 months) was described in few studies. In terms of the side-effect profile, five patients each had delirium and tachycardia and only four patients were described to have prolonged seizures. Overall, the combination was considered effective and safe.. There is evidence for the effectiveness and safety of the clozapine-ECT combination and it should be used in patients with treatment-resistant schizophrenia who do not respond to clozapine.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Schizophrenia; Young Adult

This article reviews the recent evidence for therapeutic strategies for patients with treatment-resistant schizophrenia (TRS) not responding to or only partially responding to clozapine.. A number of pharmacological and nonpharmacological biological approaches for clozapine-resistant TRS have been evaluated in clinical trials. Among these, the evidence supporting clozapine augmentation by pharmacological approaches is weak and the reported benefits were modest at best. However, the results of a recent randomized trial suggest that electroconvulsive therapy (ECT) may be efficacious for the short-term treatment of patients with clozapine-resistant TRS.. There is currently insufficient evidence for efficacy of pharmacological augmentation strategies to clozapine. ECT may be a promising option, but further research is necessary to confirm its long-term effects. Moreover, further controlled studies are warranted to clarify the potential of other biological and psychosocial approaches to serve as adjuvant treatments in patients with clozapine-resistant TRS.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Electroconvulsive Therapy; Humans; Schizophrenia; Treatment Outcome

Clozapine was approved by the US Food and Drug Administration in 1989 for the management of treatment-resistant schizophrenia, and has since proven to reduce symptom burden and suicide risk, increase quality of life, and reduce substance use in individuals with psychotic disorders. Nevertheless, clozapine's psychiatric benefits have been matched by its adverse effect profile. Because they are likely to encounter medical complications of clozapine during admissions or consultations for other services, hospitalists are compelled to maintain an appreciation for these iatrogenic conditions. The authors outline common (eg, constipation, sialorrhea, weight gain) and serious (eg, agranulocytosis, seizures, myocarditis) medical complications of clozapine treatment, with internist-targeted recommendations for management, including indications for clozapine discontinuation.

Topics: Adult; Antipsychotic Agents; Clozapine; Disease Management; Female; Gastrointestinal Diseases; Heart Diseases; Humans; Internal Medicine; Male; Middle Aged; Practice Guidelines as Topic; Schizophrenia

Neuroleptic malignant syndrome (NMS) requires emergency treatment and can be fatal. Combined aripiprazole and clozapine therapy is rarely used in clinical settings, and NMS related this combination still lacks evaluation. Herein, we present two cases of atypical NMS treated with aripiprazole and clozapine.. Case 1 was a schizophrenic male with a history of NMS under treatment with aripiprazole 20 mg. He was hospitalized and maintained with aripiprazole 5 mg and clozapine 225 mg. On the 25th day, atypical NMS occurred with rigidity, elevated creatine kinase, and stupor, which subsided with supportive therapy. He was discharged under treatment with aripiprazole 15 mg and fluoxetine 60 mg. Case 2 was a female with schizoaffective disorder without a history of NMS. She was hospitalized and maintained with clozapine 50 mg and aripirazole 30 mg. On the 11th day, atypical NMS occurred with mild fever, delirium, and rigidity, which subsided under supportive therapy.. Our cases highlight the atypical features of NMS in patients being treated with combined ari-piprazole and clozapine. Consciousness change, modest elevation of creatine kinase, and leukocytosis were the most consistent findings; hyperthermia accounts for only some of the cases. This is a reminder of the importance of earlier detection of the soft signs and atypical features of NMS under this combined treatment.

Topics: Adult; Aripiprazole; Clozapine; Creatine Kinase; Dose-Response Relationship, Drug; Drug Substitution; Drug Therapy, Combination; Female; Fluoxetine; Hospitalization; Humans; Injections, Intramuscular; Male; Middle Aged; Neuroleptic Malignant Syndrome; Piperazines; Psychotic Disorders; Quinolones; Schizophrenia; Schizophrenic Psychology

Groups of nonrefractory patients with schizophrenia, taking antipsychotics other than clozapine, show distinct trajectories of treatment response over time. Whether similar patterns of response occur with clozapine-treated patients remains uncertain.. We used a cluster analysis approach for longitudinal data (k-means longitudinal) to analyze individual patient data from 2 pivotal studies of clozapine, compared with chlorpromazine. Trajectories and symptom severity were examined in a younger, less chronic, mixed-sample (study 16, n=100) and in treatment-refractory (study 30, n=257) patients.. Early-good and delayed-partial trajectory groups were observed, with the early-good trajectory group comprised of 73/100 (73.0%) from the mixed patient study, and 147/257 (57.2%) refractory patients. In the mixed patient sample, the distribution of clozapine and chlorpromazine treatments did not differ between the early-good and delayed-partial trajectory groups; in refractory patients proportionately more clozapine treatment was present in the early-good (87/147, 59.2%), compared with the delayed-partial (35/110, 31.8%), trajectory group. In the early-good trajectory group, improvement in mean symptom severity was 63% in mixed-study patients. Clozapine resistance appeared to be present in 10/50 (20.0%) mixed-study patients, and in 35/122 (28.9%) refractory patients.. Early-good and delayed-partial response trajectories are seen in clozapine studies. The advantage of clozapine over chlorpromazine is seen most clearly in previous refractory patients, within the early-good trajectory group. Good and partial or poor responders to clozapine may merit further investigation.

Topics: Adult; Antipsychotic Agents; Chlorpromazine; Clozapine; Humans; Outcome Assessment, Health Care; Schizophrenia

Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders.. Recent meta-analyses of antipsychotic efficacy and tolerability have been included in this review, along with key papers on antipsychotic use in schizophrenia and other psychotic illnesses.. The heterogeneity in terms of individuals' response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment choice. Clozapine is the only effective medication for treatment-resistant schizophrenia.. There are a significant number of side effects associated with antipsychotic use. With a reduction in the frequency of extrapyramidal side effects with the use of second-generation antipsychotics, there has been a significant shift in the side effect burden, with an increase in the risk of cardiometabolic dysfunction.. There exist small and robust efficacy differences between medications (other than clozapine), and response and tolerability to each antipsychotic drug vary, with there being no first-line antipsychotic drug that is suitable for all patients.. A focus on the different symptom domains of schizophrenia may lead to endophenotypic markers being identified, e.g. for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote the development of novel therapeutics, which will rationally target cellular and molecular targets, rather than just the dopamine 2 receptor. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets and will utilize personalized medicine techniques, such as pharmacogenetic variants and biomarkers allowing for a tailored and safer use of antipsychotics.

Topics: Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Substitution; Humans; Medication Adherence; Schizophrenia

Previous association results between dopamine D1 receptor (DRD1) rs4532 polymorphism and antipsychotic treatment response in schizophrenia and schizoaffective subjects have been conflicting. Thus, we have conducted a systematic review followed by a meta-analysis. Our results indicated no association between DRD1 rs4532 polymorphism and overall antipsychotic response or clozapine monotherapy response.

Topics: Antipsychotic Agents; Clozapine; Female; Genetic Predisposition to Disease; Humans; Male; Polymorphism, Single Nucleotide; Receptors, Dopamine D1; Schizophrenia; Treatment Outcome

Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment.. This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein.. Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset.

Topics: Antipsychotic Agents; Clozapine; Genome-Wide Association Study; Humans; Pharmacogenetics; Precision Medicine; Schizophrenia

The use of antipsychotic therapy has been proven to have an association with the incidence of diabetes mellitus. The use of atypical antipsychotics is shown to have a higher association, in contrast with typical antipsychotics. Olanzapine and Clozapine appear to have the highest rates of diabetes mellitus incidence, due to their tendency to affect glucose metabolism compared with other antipsychotic drugs. In this research the main goal is to understand which antipsychotic drugs are the most diabetogenic and to show the mechanisms involved in the glucose metabolism dysregulations with special focus on Olanzapine considering it is a very commonly prescribed and used drug especially among patients with schizophrenia.. Our study is a literature based research. For our research we reviewed 41 Pubmed published articles from 2005 to 2015.. According to most of the literature, from all the antipsychotics, Clozapine followed by Olanzapine appear to be the atypical neuroleptics that most relate to metabolic syndrome and Diabetes. The basis for this metabolic dysregulations appears to be multifactorial in origin and a result of the drugs, environment and genes interaction.

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Female; Humans; Male; Olanzapine; Risk Assessment; Schizophrenia

The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack of clarity about its risk benefit ratio. This review synthesises and evaluates available evidence regarding the efficacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making.. We conducted a systematic review of the primary literature on the clinical efficacy and adverse drug reactions (ADRs) observed during CLZ treatment in EOS. We also identified relevant practice guidelines and summarised current guidance.. CLZ showed superior efficacy than other antipsychotics in treating refractory EOS patients; short-term clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported. Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specific EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes in blood pressure. Neutropenia was reported in 6-15% of cases but was usually transient while agranulocytosis was rare (<0.1%). Seizures were also uncommon (<3%). Metabolic changes were relatively common (8-22%) but emergent diabetes was not frequently observed (<6%). Overall the rate of discontinuation was low (3-6%). Current guidelines recommend the use of CLZ in EOS patients who have failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment.. Available data although limited in terms of number of studies are consistent in demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided patients are regularly monitored.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Early Diagnosis; Humans; Schizophrenia

Schizophrenia is a severe disorder that significantly affects the quality of life and total functioning of patients and their caregivers. Clozapine is the first atypical antipsychotic with fewer adverse effects and established efficacy. As a rule of thumb, risperidone is one of the most reliable and effective antipsychotics for newly diagnosed and chronic schizophrenics. Pharmacogenetic studies have identified genomic variants of candidate genes that seem to be important in the way a patient responds to treatment. The recent progress made in pharmacogenomics will improve the quality of treatment, since drug doses will be tailored to the special needs of each patient. In this article, we review the available literature attempting to delineate the role of genomic variations in clozapine and risperidone response in schizophrenic patients of various ethnicities. We conclude that pharmacogenomics for these two drugs is still not ready for implementation in the clinic.

Topics: Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Precision Medicine; Risperidone; Schizophrenia; Treatment Outcome

Clozapine, an atypical antipsychotic with documented efficacy in the management of treatment-resistant schizophrenia, is associated with the risk of adverse hematological outcomes. Of particular concern are reductions in white blood cells (WBC) and absolute neutrophil counts (ANC). Individuals who display moderate leukopenia (3000/mm(3) > WBC ≥ 2000/mm) upon initiation of clozapine therapy are at increased risk of developing agranulocytosis, defined as an ANC less than 500/mm. Complications of agranulocytosis can be severe and include increased risk of infection and mortality.. The primary objective of this study was to examine data on clozapine recipients who experienced adverse drug reactions (ADRs) related to decreases in WBC or ANC and ascertain whether other drugs and/or drug interactions had played a role. The analysis included multiple classes of medications.. A retrospective chart review was performed of open and closed medical records of all inpatient recipients of clozapine at a state psychiatric center between January 1, 2004 and June 30, 2011. Laboratory records of patients prescribed clozapine were examined for abnormal WBC counts or ANC. A hematological ADR was considered to have occurred if there was a substantial drop in either WBC or ANC or mild or moderate leukopenia or granulocytopenia. Each episode was analyzed for medications that might have contributed to the ADR. Data were collected for all scheduled and STAT medications started at any point during the clozapine patient's hospitalization. The following seven medication groups, based on the Therapeutic Classification System of the American Hospital Formulary System (AHFS), were chosen for analysis because they were consistently used in the majority of the patient population: antihistamines, anti-infectives, autonomic agents, cardiovascular agents, antipsychotics, vitamins, and gastrointestinal agents. Pearson correlation coefficients were calculated to identify associations between the presence of hematological ADRs and medications administered concomitantly with clozapine.. The following significant correlation coefficients were found between the use of a class of medications and the occurrence of a hematological ADR: antiinfective agents 0.409 (p < 0.01), gastrointestinal agents 0.329 (p < 0.01), and autonomic agents 0.309 (p < 0.01). In the subset of patients who were prescribed a proton-pump inhibitor or ranitidine concomitantly with clozapine, 24/26 (96%) experienced a hematological ADR.. Autonomic agents, anti-infective agents, and proton pump inhibitors and other gastrointestinal agents were all associated with hematological ADRs when co-prescribed with clozapine. Medications from these classes should be initiated cautiously in patients being treated with clozapine to avoid precipitous drops in ANC or WBC that may increase the risk of agranulocytosis.

Topics: Antipsychotic Agents; Clozapine; Female; Hematologic Diseases; Humans; Male; Middle Aged; Polypharmacy; Schizophrenia

To clarify the effects of smoking on the disposition of two commonly used antipsychotics, olanzapine and clozapine, and to create standards to adjust the doses of these drugs in clinical practice based on the smoking status.. A meta-analysis was conducted by searching MEDLINE, Scopus and the Cochrane Library for relevant prospective and retrospective studies.. We included the studies that investigated the effects of smoking on the concentration to dose (C/D) ratio of olanzapine or clozapine.. The weighted mean difference was calculated using a DerSimonian-Laird random effects model, along with 95% CI.. Seven association studies, comprising 1094 patients (652 smokers and 442 non-smokers) with schizophrenia or other psychiatric disorders, were included in the meta-analysis of olanzapine. The C/D ratio was significantly lower in smokers than in non-smokers (p<0.00001), and the mean difference was -0.75 (ng/mL)/(mg/day) (95% CI -0.89 to -0.61). Therefore, it was estimated that if 10 and 20 mg/day of olanzapine would be administered to smokers, about 7 and 14 mg/day, respectively, should be administered to non-smokers in order to obtain the equivalent olanzapine concentration. Four association studies of clozapine were included in the meta-analysis of clozapine, comprising 196 patients (120 smokers and 76 non-smokers) with schizophrenia or other psychiatric disorders. The C/D ratio was significantly lower in smokers than in non-smokers (p<0.00001), and the mean difference was -1.11 (ng/mL)/(mg/day) (95% CI -1.53 to -0.70). Therefore, it was estimated that if 200 and 400 mg/day of clozapine would be administered to smokers, about 100 and 200 mg/day, respectively, should be administered to non-smokers.. We suggest that the doses of olanzapine and clozapine should be reduced by 30% and 50%, respectively, in non-smokers compared with smokers in order to obtain an equivalent olanzapine or clozapine concentration.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Olanzapine; Schizophrenia; Smoking

Clozapine effectiveness in the treatment of refractory schizophrenia has been sustained by published evidence in the last two decades, despite the introduction of safer options.. Current clinical practice guidelines have strongly recommended the use of clozapine in treatment-resistant schizophrenia, but prescribing trends do not appear to have followed such recommendations. Clozapine is still underutilized especially in patients at risk of suicide. It seems that physicians are hesitant in prescribing clozapine due to concerns about serious adverse effects. Recent reports have highlighted the need to inform health professionals about the benefits of treating patients with clozapine and have voiced concerns about the underutilization of clozapine especially in patients at risk of suicide.. Guidelines and prescribing patterns reported in various countries worldwide are discussed. Suggestions on how to optimize clozapine utilization have been published but more efforts are needed to properly inform and support prescribers' practices.

Topics: Antipsychotic Agents; Clozapine; Drug Prescriptions; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia

Clozapine is effective for treatment-refractory schizophrenia, but it shows several severe and potentially life-threatening side effects such as agranulocytosis, myocarditis, and cardiomyopathy. Therefore, it is necessary to minimize the risk of clozapine and maximize its effectiveness by monitoring of safety. White blood cell monitoring is mandatory in many countries, but the clozaril patient monitoring service (CPMS) in Japan additionally requires blood sugar monitoring for adverse metabolic events. Aside from the side effects described above, clozapine can cause various adverse events including constipation, paralytic ileus, seizure, orthostatic hypotension, syncope, hypersalivation, aspiration pneumonia, and oversedation. Consequently, it is important to conduct safety monitoring other than CPMS-based in routine clinical settings. Regarding CPMS as one model for safety monitoring, herein we discuss how to monitor the side effects induced by psychotropic agents. Although the choice of monitoring method depends on which drug is used, routine monitoring of parameters such as serum drug concentration, full blood count, biochemistry test, ECG, EEG, chest and abdominal X-P, body weight, body temperature, pulse, and blood pressure is necessary for early detection and prevention of severe adverse events. Further examinations are necessary to reach consensus on how often monitoring is required. Psychiatrists must devote more attention not only to multidimensional psychiatric symptoms but also to physical conditions. Psychiatrists can show themselves at their best in holistic medical care only by administering balanced psychiatric and physical examinations.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Japan; Psychotropic Drugs; Schizophrenia

Schizophrenia is a chronic psychiatric disease, which is treated by antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists and have extrapyramidal side effects depending on the D2 antagonistic effect. Recently admitted antipsychotic drugs also have systemic side effects. Clozapine, which has the strongest antipsychotic effect, can cause neutropenia. A problem in the treatment of schizophrenia is poor patient compliance leading to the recurrence of psychotic symptoms.. A search was carried out in Medline using the following terms: antipsychotic drugs, antipsychotic effect, risperidone, olanzapine, clozapine, ziprasidone, aripiprazol, asenapine, questiapine, cariprazine, lurasidone, arrythmia, diabetes mellitus, weight gain, epileptic activity, extrapyramidal symptoms, sexual activity, clinical trials and tolerability.. Most clinical trials describe a good antipsychotic effect of the currently used antipsychotic drugs. The efficacy and safety of the antipsychotic drugs also depend on the form of schizophrenia, for example, the chronic recurrent form of schizophrenia. Clozapine and olanzapine have the safest therapeutic effect, while the side effect of neutropenia must be controlled by 3 weekly blood controls. If schizophrenia has remitted and if patients show a good compliance, the adverse effects can be controlled. The pharmacological treatment should be combined with social therapies and psychoeducation in order to reach a good therapeutic outcome.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dopamine D2 Receptor Antagonists; Humans; Medication Adherence; Olanzapine; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with first- and second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Receptors, Dopamine D2; Schizophrenia

Clozapine is an efficacious antipsychotic drug for patients with treatment-resistant schizophrenia, but does not sufficiently improve these symptoms in a substantial proportion of this population. There is no convincing evidence for the efficacy of any clozapine augmentation strategy. New evidence suggests that glutamate receptors are a candidate target for therapeutic effects in schizophrenia. We present an overview of studies assessing the potential clinical utility of adding glutamatergic agents to clozapine. We conducted 3 metaanalyses of data on positive, negative and overall symptoms of schizophrenia, analysing results from 3 studies on clozapine augmentation with glycine, 6 studies on lamotrigine add-on therapy to clozapine and 4 studies on topiramate addition to clozapine.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Synergism; Excitatory Amino Acid Agents; Glutamic Acid; Humans; Schizophrenia

We discuss the relevance of the glutamate hypothesis in explaining cognitive disturbances and negative symptoms in schizophrenia. 4 lines of evidence support the hypothesis that glutamate deregulation, mainly through dysfunction of the N-methyl-D-aspartate (NMDA) receptor, is an important underlying mechanism of schizophrenia. Glutamate pathways are promising sites for intervention. Glutamate agonists combined with non-clozapine antipsychotics and glutamate antagonists augmented to clozapine show interesting clinical benefits in refractory schizophrenia. We illustrate how unique properties of the NMDA receptor antagonist memantine in addition to clozapine, may cause improvement of positive, negative and cognitive symptoms of schizophrenia.

Topics: Clozapine; Drug Delivery Systems; Drug Therapy, Combination; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Memantine; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Schizophrenia for many patients is a lifelong mental disorder with significant consequences on most functional domains. One fifth to one third of patients with schizophrenia experience persistent psychotic symptoms despite adequate trials of antipsychotic treatment, and are considered to have treatment-resistant schizophrenia (TRS). Clozapine is the only medication to demonstrate efficacy for psychotic symptoms in such patients. However, clozapine is not effective in 40%-70% of patients with TRS and it has significant limitations in terms of potentially life-threatening side effects and the associated monitoring. Accordingly, a number of pharmacological and non-pharmacological biological approaches for clozapine-resistant TRS have emerged. This article provides a brief updated critical review of recent therapeutic strategies for TRS, particularly for clozapine-resistant TRS, which include pharmacotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Transcranial Direct Current Stimulation; Transcranial Magnetic Stimulation

Persistent negative symptoms and cognitive impairment are major clinical problems in the treatment of schizophrenia. There is no convincing evidence regarding the efficacy of augmentation of clozapine with a second antipsychotic, ethyl eicosapentaenoic acid (E-EPA), an antidepressant, a mood stabilizer or extract of Ginkgo biloba in clozapine-resistant schizophrenia. We present an overview of studies in which the potential clinical utility of the addition of non-glutamatergic agents to clozapine is assessed. We performed a meta-analysis on the efficacy of both risperidone and aripiprazole compared to placebo. We compared the effects of the addition of a second antipsychotic or an antidepressant to clozapine on positive, negative, overall and affective symptoms of schizophrenia in double-blind placebo-controlled trials.

Topics: Antidepressive Agents; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Eicosapentaenoic Acid; Ginkgo biloba; Humans; Plant Preparations; Randomized Controlled Trials as Topic; Schizophrenia

To conduct meta-analyses of all published association studies on the HTR2C -759C/T (rs3813829) polymorphism and olanzapine-induced weight gain in schizophrenia patients and on the HTR2C -759C/T, -697G/C (rs518147) and rs1414334:C> G polymorphisms and olanzapine/clozapine/risperidone-induced metabolic syndrome in schizophrenia patients.. Eligible studies were identified by searching PubMed and Web of Science databases. Meta-analyses were performed using Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI).. Our meta-analyses revealed both a significant positive association between the rs1414334 C allele and olanzapine/clozapine/risperidone-induced metabolic syndrome and a marginally significant positive association between the -697C allele and the induced metabolic syndrome in schizophrenia patients, but no significant association between the -759C/T polymorphism and the induced metabolic syndrome in schizophrenia patients. Our analysis further revealed a pronounced trend toward a significant negative association between the -759T allele and high olanzapine-induced weight gain and a trend toward a significant positive association between the -759C allele and high olanzapine-induced weight gain in Caucasian schizophrenia patients.. Our results support that HTR2C polymorphisms play a role in antipsychotic-induced metabolic disturbance. More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance.

Topics: Alleles; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genetic Association Studies; Humans; Male; Metabolic Syndrome; Olanzapine; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Risperidone; Schizophrenia; Weight Gain

A significant proportion of patients with schizophrenia receiving clozapine remain with partial response. In this group of patients findings regarding addition of various psychotropics to ongoing clozapine treatment for augmentation are controversial. In this review, literature regarding the efficacy and safety of adjunctive agents in clozapine resistant schizophrenic patients is examined. Augmentation agents added to clozapine in treatment resistant schizophrenic patients consist of antipsychotics, antidepressants, mood stabilizers, other agents (eg. omega 3 fatty acids and glutamatergic agents) and electroconvulsive therapy (ECT) in this review. The number of controlled studies evaluating augmentation of clozapine in schizophrenia patients are highest for risperidone and lamotrigine add on treatments. However, the results of recent meta-analyses studies do not support any benefit of either agent as adjunct to clozapine treatment. Some evidence regarding the success of clozapine augmentation with amisulpride, aripiprazole, mirtazapine, omega 3 fatty acids and ECT have been obtained which needs further clinical investigation. Current findings from relevant clinical studies point that theses studies have limitations of small sample size, variable definitions of clozapine resistance, heterogenity of outcome measures and methodological designs and that sufficient evidence does not yet exist regarding the success of various adjunctive treatments for clozapine resistant patients.

Topics: Antipsychotic Agents; Chemotherapy, Adjuvant; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Electroconvulsive Therapy; Humans; Schizophrenia; Treatment Outcome

Schizophrenia is a common serious mental health condition which has significant morbidity and financial consequences. The mainstay of treatment has been antipsychotic medication but one third of people will have a 'treatment resistant' and most disabling and costly illness. The aim of this survey was to produce a broad overview of available randomised evidence for interventions for people whose schizophrenic illness has been designated 'treatment resistant'.. We searched the Cochrane Schizophrenia Group's comprehensive Trials Register, selected all relevant randomised trials and, taking care not to double count, extracted the number of people randomised within each study. Finally we sought relevant reviews on the Cochrane Library and investigated how data on this subgroup of people had been presented.. We identified 542 relevant papers based on 268 trials (Average size 64.8 SD 61.6, range 7-526, median 56 IQR 47.3, mode 60). The most studied intervention is clozapine with 82 studies (total n = 6299) comparing it against other anti-psychotic medications. Cognitive behavioural therapy (CBT), electroconvulsive therapy (ECT), or transcranial magnetic stimulation (TMS) supplementing a standard care and risperidone supplementation of clozapine has also been extensively evaluated within trials. Many approaches, however, were clearly under researched. There were only four studies investigating combinations of non-clozapine antipsychotics. Only two psychological approaches (CBT and Family Rehabilitation Training) had more than two studies. Cochrane reviews rarely presented data specific to this important clinical sub-group.. This survey provides a broad taxonomy of how much evaluative research has been carried out investigating interventions for people with treatment resistant schizophrenia. Over 280 trials have been undertaken but, with a few exceptions, most treatment approaches--and some in common use--have only one or two relevant but small trials. Too infrequently the leading reviews fail to highlight the paucity of evidence in this area--as these reviews are maintained this shortcoming should be addressed.

Topics: Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Humans; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Treatment Failure

Although clozapine (CLZ) is considered the best evidence-based therapeutic option for treatment of resistant schizophrenia patients, a significant proportion of CLZ-treated patients show a partial or inadequate response to treatment, leading to increased healthcare cost and poor quality of life for affected individuals.. This paper comprises a review of main research in CLZ augmentation strategies for treatment-refractory schizophrenia, with a focus on research conducted between 1990 and 2014. Databases that were searched include: PubMed, CINAHL, EMBASE PsychINFO, AgeLine and Cochrane Database of Systematic Reviews. Primary search terms were 'clozapine augmentation', 'clozapine and add-on' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. We reviewed the available evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents.. Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. More research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and more well-designed trials are required to establish true efficacy and safety of CLZ augmentation strategies.

Topics: Affect; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Drug Therapy, Combination; Electroconvulsive Therapy; Health Care Costs; Humans; Quality of Life; Schizophrenia; Schizophrenic Psychology; Treatment Failure

Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens.

Topics: Antipsychotic Agents; Aripiprazole; Clinical Trials as Topic; Clozapine; Humans; Piperazines; Polypharmacy; Practice Patterns, Physicians'; Quinolones; Schizophrenia

The addition of fluvoxamine to clozapine induces a rise of plasma concentrations of clozapine. This enables the prescription of a lower number of clozapine tablets, yet it attains sufficient clozapine plasma concentrations, and facilitates treatment adherence.. Providing practical advice for the practical implementation of the addition of fluvoxamine to clozapine.. A review of the literature with Ovid Medline and the presentation of a case series (N=7).. Addition of 25 or 50 mg fluvoxamine induces a mean rise of plasma concentrations of clozapine with a factor 2-3, probably even higher with the addition of 100 mg. However, the range of this factor varies considerably between individuals. The use of clozapine and fluvoxamine at the same time possibly has a favourable impact on the metabolic side-effects of clozapine.. Addition of fluvoxamine to clozapine can lead to a dangerous rise of clozapine plasma concentrations. However, it can also be used to prescribe a lower number of clozapine tablets and to facilitate treatment adherence. A sufficient safety margin should be taken and regular control of clozapine plasma concentrations is mandatory.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug Synergism; Fluvoxamine; Humans; Schizophrenia

Olanzapine is one of the SGAs (second-generation antipsychotics) which have been used for the treatment of patients with schizophrenia and bipolar disorder in Japan. Olanzapine has various affinities for multiple receptors, including dopamine D2 receptor, serotonin 5-HT2A, 5-HT2C, 5-HT6 receptors, and adrenaline alpha1, histamine H1, muscarine M1-M5 receptors as well. Therefore, olanzapine is known as MARTA(multi-acting receptor targeted antipsychotics). Numerous studies have been conducted to compare the effectiveness of olanzapine between SGAs and FGAs (first-generation antipsychotics). According to the head-to-head meta-analysis and large-scale studies like CATIE and EUFEST, olanzapine seems to have not only higher efficacy but also less discontinuation comparing to other anti-psychotics.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome

Clozapine is a drug used in the management of treatment-resistant schizophrenia. Numerous clinical trials, including randomized double-blind clinical trials and large cohort studies, have revealed that clozapine is more effective than any other antipsychotic drugs. However, the same studies have also shown that this drug has several adverse effects such as an agranulocytosis. Therefore, in Japan, clozapine is approved for administration to only patients with treatment-resistant schizophrenia in whom treatment with other antipsychotic drugs was ineffective. Clozapine is prescribed only at approved institutes that are under the registration called Clozaril Patient Monitoring Service (CPMS), and white blood cell counts and prescription dosage of clozapine are strictly monitored under this service.

Topics: Agranulocytosis; Antipsychotic Agents; Brain Waves; Clozapine; Humans; Japan; Leukocyte Count; Schizophrenia

Neuroleptic malignant syndrome (NMS) is the most dangerous life-threatening complication of antipsychotic medication. It's development is connected with the blockade of dopaminergic transmission (D2 receptors) in the nigrostriatal system of the brain. Fever is one of the main symptoms of this syndrome and it's elevation is due to the activation of the immune system. Numerous studies report that treatment with clozapine (doses 37.5-600 mg) or olanzapine (doses 10-25 mg) or the use of these drugs in polytherapy cause pyrexia between 37.8-40.6 °C. Additionally, levels of proinflammatory interleukins such as IL-6, IL-1,TNF-α were increased. The aim of this article is to describe how olanzapine and clozapine influence fever development in NMS, in relation to the dose of the drug taken by schizophrenic patients including changes in immunological system.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Fever; Humans; Inflammation Mediators; Interleukins; Neuroleptic Malignant Syndrome; Olanzapine; Schizophrenia

The aim of this clinical review was to investigate the effectiveness and safety of the practice of antipsychotic poly-pharmacy (AP) in the long-term management of hospitalised patients with insufficient response to antipsychotic monotherapy.. The databases Medline, PsycINFO, Embase and Scopus were searched. Studies were required to include inpatients with long-term, treatment-resistant schizophrenia on maintenance AP. The search was restricted to systematic review studies.. The review yielded four studies of interest that showed no categorical advantage for maintenance AP for the population of interest. However, clozapine combination faired marginally well. Particular weaknesses of the present literature are low number of participants, and inadequate monitoring of potential adverse effects. The evidence on the risks and benefits of maintenance AP is not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry.. This review provides a synthesis of the evidence on the maintenance use of AP for hospitalised patients with long-term, treatment-resistant schizophrenia. The results show both no support for AP with some marginal benefit for clozapine combination therapy, and methodological weaknesses of the included studies. These findings have clinical implications for treatment decisions and suggest that sufficiently powered studies are needed.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Long-Term Care; Polypharmacy; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Drug Resistance; Drug Therapy, Combination; Electroconvulsive Therapy; Humans; Patient Compliance; Schizophrenia; Schizophrenic Psychology; Transcranial Magnetic Stimulation

To examine whether prescribing Clozapine was delayed in Treatment Resistant Schizophrenia (TRS), and elucidate possible reasons for this.. A retrospective Case note review was done. The main outcome measured was the mean maximum theoretical delay in starting Clozapine. In analyses, mean values were compared using an unpaired, 2-sided Student t-test. The association between duration of illness and theoretical delay was analysed by scatterplot and Pearson correlation coefficient.. 42 case notes were reviewed. Mean age of subjects was 40.1 years. The mean maximum theoretical delay in all patients was 5 years. A statistically significant longer delay was found in patients over 30 years, patients diagnosed with TRS before 1991,and for patients before the introduction of Risperidone. Delay was significantly shorter for patients admitted to a psychiatric hospital more than once a year.. There is a strong indication that Clozapine was not introduced at the earliest opportunity. Factors contributing to the delay include the patient's age, using sequential antipsychotic trials, and the failure to identify TRS. The use of Clozapine appears to have been adopted more in recent years, with a delay of five years to Clozapine for those diagnosed pre-1991, reducing to two years for those diagnosed pre-2003.. Mean average delay of prescribing clozapine was 5 years. Statistically significant delays in patients over 30 years of age.. There was no evaluation of: Reasons for co-prescribing of antipsychotics. Reasons for delay in prescribing Clozapine, e.g. prescriber inexperience, patient choice, risk of non-compliance etc. Evidence of treatment resistance, and whether primary or secondary in onset.

Topics: Adult; Age Factors; Antipsychotic Agents; Clozapine; Drug Prescriptions; Humans; Retrospective Studies; Schizophrenia; Time Factors

The efficacy of antipsychotic use in children and adolescents with psychosis has been shown in an increasing number of randomized controlled trials. Chronic use of second-generation and third-generation antipsychotics has the potential for significant side effects, especially metabolic syndrome. A review of the literature on side effect profiles of antipsychotic medications used in children and adolescents is provided to help clinicians develop treatment plans for their patients. Clozapine has the best efficacy of all antipsychotic medications in adults as well as children and adolescents who are treatment resistant. Guidance is provided for the management of clozapine side effects.

Topics: Adolescent; Age Factors; Age of Onset; Antipsychotic Agents; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Polypharmacy; Psychopharmacology; Psychotic Disorders; Randomized Controlled Trials as Topic; Risk Factors; Schizophrenia; Secondary Prevention; Treatment Outcome

Clozapine was the first true breakthrough in schizophrenia treatment since the discovery of chlorpromazine in 1950, effectively treating positive, negative, and some cognitive symptoms, as well as possessing unprecedented efficacy in treatment-resistant patients. Despite over 30 years of intense study, the precise molecular underpinnings that account for clozapine's unique efficacy remain elusive. In this Viewpoint, we will showcase the history and importance of clozapine to neuroscience in general, as well as for the treatment of schizophrenia, and review the synthesis, pharmacology, drug metabolism, and adverse events of clozapine.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Treatment Outcome

There is an argument that the superiority of second-generation antipsychotics (SGA) over first-generation antipsychotics (FGA) was established in part by the inappropriate use of FGA. When comparison was made with a proper FGA other than haloperidol or a low dose of FGA, the superiority of SGA disappeared in some studies. It would be too optimistic to regard the use of SGA itself as providing substantial progress in the level of treatment. However, with the introduction of SGA, the more effective and proper use of antipsychotics has prevailed. It is of clinical significance to pay more attention to the quality of life and rehabilitation of patients. At present, evidence indicates that clozapine is the most efficacious in treatment-resistant patients, despite its high-risk profile. The proper use of the drug is an important clinical issue.

Topics: Antipsychotic Agents; Clozapine; Humans; Practice Guidelines as Topic; Schizophrenia; Treatment Outcome

Clozapine is a uniquely efficacious antipsychotic drug in treatment-resistant schizophrenia. Its use is restricted due to adverse effects including a rare but dangerous reduction in neutrophils (agranulocytosis) and the mandatory hematological monitoring this entails in many countries. We review the statistical, ethical and legal issues arising from a hypothetical pharmacogenetic test for clozapine, using the UK as an exemplary case for consideration. Our key findings include: a consideration of the probabilistic results that a pharmacogenetic test may return; the impact on drug licensing; and the potential for pharmacogenetic tests for clozapine being used without consent under the UK's legal framework. We make recommendations regarding regulatory changes applicable to the special case of pharmacogenetic testing in clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Schizophrenia; United Kingdom

In many countries, second-generation ('atypical') antipsychotic drugs have become the first-line drug treatment for people with schizophrenia. It is not clear how the effects of the various second-generation antipsychotic drugs differ.. To evaluate the effects of quetiapine compared with other second-generation (atypical) antipsychotic drugs in the treatment of people with schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Group Trials Register (May 2010), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.. We included all randomised controlled trials (RCTs) comparing oral quetiapine with other oral forms of atypical antipsychotic medication in people with schizophrenia or schizophrenia-like psychoses.. We extracted data independently. For dichotomous data, we calculated risk ratios (RRs) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a random-effects model. We calculated number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For continuous data, we calculated mean differences (MDs), again based on a random-effects model.. Efficacy data tended to favour the control drugs over quetiapine (Positive and Negative Syndrome Scale (PANSS) total score vs olanzapine: 11 RCTs, n = 1486, mean quetiapine endpoint score 3.67 higher, CI 1.95 to 5.39, low quality; vs risperidone: 13 RCTs, n = 2155, mean quetiapine endpoint score 1.74 higher, CI 0.19 to 3.29, moderate quality; vs paliperidone: 1 RCT, n = 319, mean quetiapine endpoint score 6.30 higher, CI 2.77 to 9.83, moderate quality), but the clinical meaning of these data is unclear. No clear mental state differences were noted when quetiapine was compared with clozapine, aripiprazole or ziprasidone. Compared with olanzapine, quetiapine produced slightly fewer movement disorders (7 RCTs, n = 1127, RR use of antiparkinson medication 0.51, CI 0.32 to 0.81, moderate quality) and less weight gain (8 RCTs, n = 1667, RR 0.68, CI 0.51 to 0.92, moderate quality) and glucose elevation, but increased QTc prolongation (3 RCTs, n = 643, MD 4.81, CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (8 RCTs, n = 2163, RR use of antiparkinson medication 0.5, CI 0.36 to 0.69, moderate quality), less prolactin increase (7 RCTs, n = 1733, MD -35.25, CI -43.59 to -26.91) and some related adverse effects but greater cholesterol increase (6 RCTs, n = 1473, MD 8.57, CI 4.85 to 12.29). On the basis of limited data, compared with paliperidone, quetiapine induced fewer parkinsonian side effects (1 RCT, n = 319, RR use of antiparkinson medication 0.64, CI 0.45 to 0.91, moderate quality) and less prolactin increase (1 RCT, n = 319, MD -49.30, CI -57.80 to -40.80) and weight gain (1 RCT, n = 319, RR weight gain of 7% or more of total body weight 2.52, CI 0.5 to 12.78, moderate quality). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n = 522, RR use of antiparkinson medication 0.43, CI 0.2 to 0.93, moderate quality) and less prolactin increase. On the other hand, quetiapine was more sedating and led to greater weight gain (2 RCTs, n = 754, RR 2.22, CI 1.35 to 3.63, moderate quality) and cholesterol increase when compared with ziprasidone.. Available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks (around 60%). Comparisons with amisulpride, sertindole and zotepine do not exist. Although efficacy data favour olanzapine and risperidone compared with quetiapine, the clinical meaning of these data remains unclear. Quetiapine may produce fewer parkinsonian effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine. Quetiapine appears to have a similar weight gain profile to risperidone, as well as clozapine and aripiprazole (although data are very limited for the latter two comparators). Quetiapine may produce greater weight gain than ziprasidone and less weight gain than olanzapine and paliperidone. Most data that have been reported within existing comparisons are of very limited value because of assumptions and biases within them. Much scope is available for further research into the effects of this widely used drug.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Medication Adherence; Olanzapine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Thiazoles

Clozapine is considered the gold standard for the treatment of patients with treatment-resistant schizophrenia (TRS); however, randomized controlled trials (RCT) of olanzapine showed efficacy similar to clozapine in patients with TRS.. A systematic review was conducted comparing clozapine with olanzapine in patients with TRS. Meta-analyses were performed for single outcome measures. Response to treatment was measured by the percentage of responders, or mean change or endpoint values of psychotic symptoms scales. Effect sizes were shown as relative risks (RR), or standardized mean differences, with 95% confidence intervals.. Seven RCT were included, comprising 648 patients. Five meta-analyses were performed. Olanzapine and clozapine had similar effects on dropout rates (RR = 0.93, CI95% = 0.77-1.12), PANSS total endpoints (SMD = 0.21, CI95% = -0.04-0.46), and PANSS total mean changes (SMD = 0.08, CI95% = -0.01-0.027). Clozapine was superior to olanzapine for PANSS positive (SMD = 0.51, CI95% = 0.17-0.86) and negative (SMD = 0.50, CI95% = 0.16-0.85) subscales. There was a trend toward high doses of olanzapine producing higher effect sizes for this drug.. The results of this study suggest that clozapine is significantly more efficacious than olanzapine in improving positive and negative symptoms in TRS patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome

Clozapine is superior to other antipsychotic drugs for treatment of refractory schizophrenia. However, its use has been limited by its potentially serious adverse effects. There is little guidance on the management of patients who discontinue clozapine for reasons such as lack of response, intolerance, or noncompliance. The literature was searched for studies on the efficacy of antipsychotics that replaced clozapine in such patients. The search revealed 15 papers, which were evaluated in this article. Olanzapine was the most tested alternative to clozapine with most of the studies reporting positive outcome, especially in patients with less severe illness and those who stop clozapine for reasons other than poor response. Other antipsychotics were not adequately tested in this manner. We concluded that in patients who discontinue clozapine, considering a trial of olanzapine would be worthwhile.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Substitution; Evidence-Based Medicine; Humans; Olanzapine; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is the most effective antipsychotic medication for treatment-refractory schizophrenia and is also approved for suicidality in schizophrenia patients. However, it can cause significant medical morbidity and requires intensive medical monitoring once prescribed. Perhaps due to lack of familiarity with its use, it is underused in clinical practice and its initiation often delayed. This article reviews the literature on clozapine in order to measure its potential effectiveness against its adverse effects and ultimately aims to serve as a useful summary for clinicians in their everyday prescribing.

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Heart Diseases; Hematologic Diseases; Humans; Metabolic Diseases; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality of Life; Schizophrenia; Suicide Prevention; Venous Thromboembolism; Weight Gain

Less than half of patients with schizophrenia obtain full response to antipsychotic drugs and, while clozapine represents the treatment of choice for refractory psychosis, a significant number of individuals remain only partially responsive. Despite a need for augmentation in this subpopulation, to date clear choices have not been forthcoming. Because clozapine, along with the majority of second-generation agents (SGAs), are linked to metabolic disturbances, augmentation strategies that do not further exacerbate these side effects are needed. Topiramate, unlike other anticonvulsants used for augmentation purposes, has been associated with weight loss. This article reviews the safety and efficacy of topiramate in treatment-refractory schizophrenia, including effects on metabolic disturbances, which burden this population. While current evidence specifically examining improvements in psychopathology demonstrates small to moderate benefits with topiramate augmentation, a growing body of evidence suggests that topiramate may have beneficial effects on antipsychotic-induced weight gain. We conclude that topiramate's metabolic profile, taken together with a current lack of evidence supporting a particular augmentation strategy, argues for further well-controlled studies examining its potential as an augmentation strategy in schizophrenia.

Topics: Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Fructose; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Metabolic Diseases; Neuropsychological Tests; Schizophrenia; Schizophrenic Psychology; Topiramate; Weight Gain

Notwithstanding the considerable advances in the treatment options for schizophrenia, the cognitive symptoms in particular are not receptive to antipsychotic treatment and considered one of the main predictors for poor social and functional outcome of the disease. Recent findings in preclinical model systems indicate that epigenetic modulation might emerge as a promising target for the treatment of cognitive disorders. The aim of this review is to introduce some of the principles of chromatin biology to the reader and to discuss a possible role in the neurobiology and pathophysiology of schizophrenia. We will discuss potential epigenetic targets for drug therapy, including histone deacetylase inhibitors (HDACi). In a second part, conceptual and practical challenges associated with clinical trials of chromatin-modifying drugs in psychiatric patient populations are discussed, including safety profiles, the potential for adverse effects and general issues revolving around pharmacokinetics and pharmacodynamics. Additional investigations are required in order to fully evaluate the potential of HDACi and similar "epigenetic therapies" as novel treatment options for schizophrenia and other psychotic disease.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epigenesis, Genetic; gamma-Aminobutyric Acid; Histone Deacetylase Inhibitors; Histones; Humans; Protein Processing, Post-Translational; Schizophrenia; Valproic Acid

The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment.. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? What are the effects of drug treatments in people with schizophrenia who are resistant to standard antipsychotic drugs? What are the effects of interventions to improve adherence to antipsychotic medication in people with schizophrenia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amisulpride, chlorpromazine, clozapine, depot haloperidol decanoate, haloperidol, olanzapine, pimozide, quetiapine, risperidone, sulpiride, ziprasidone, zotepine, aripiprazole, sertindole, paliperidone, flupentixol, depot flupentixol decanoate, zuclopenthixol, depot zuclopenthixol decanoate, behavioural therapy, clozapine, compliance therapy, first-generation antipsychotic drugs in treatment-resistant people, multiple-session family interventions, psychoeducational interventions, and second-generation antipsychotic drugs in treatment-resistant people.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Humans; Risperidone; Schizophrenia; Treatment Outcome

When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder.. Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g).. Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.. Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

Topics: Antipsychotic Agents; Brief Psychiatric Rating Scale; Citalopram; Clozapine; Dioxoles; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Fructose; Humans; Lamotrigine; Piperidines; Psychiatric Status Rating Scales; Psychotropic Drugs; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Sulpiride; Topiramate; Treatment Outcome; Triazines

Despite the fact that many studies have addressed the use of ECT in schizophrenia questions on clinical use remain poorly answered and clinical application is largely based on data originating from depressed patients.. We review data on the use of ECT in schizophrenic patients drawn from original studies indicated by a Pubmed search and referenced in recent and older expert reviews with a specific focus on four issues: symptom response, technical application, continuation/maintenance ECT and combination with medication.. Catatonic patients are the most responsive. Positive symptoms such paranoid delusions and affective symptoms follow. There are indications that ECT may improve responsivity to medication. No particular technical features stand out in studies except lengthier courses, but not for catatonia. Combination with medication appears to be preferable over either treatment alone and effective combination particularly with clozapine is supported by data. Use of continuation and maintenance treatments in responders appears beneficial.. Certain schizophrenic patients may benefit significantly from the use of ECT. More specific research is required to address particular questions.

Topics: Antipsychotic Agents; Catatonia; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Schizophrenia

Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy.. In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis.. A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5).. 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct.. Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Risperidone; Schizophrenia

To examine using meta-analysis the effect of adding a second antipsychotic to established clozapine monotherapy.. A literature search was conducted in April 2011, and randomised placebo-controlled double-blind studies were identified. We performed a meta-analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel-plot analysis.. Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size -0.239 (95% CI: -0.452, -0.026); P = 0.028). Meta-regression of the effect of length of treatment on effect size showed no relationship (P = 0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR = 1.20, 95% CI 0.80-1.82). There was no evidence of publication bias.. Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation.

Topics: Antipsychotic Agents; Bibliometrics; Clozapine; Drug Synergism; Drug Therapy, Combination; Drug Tolerance; Humans; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Schizophrenia; Therapeutic Equivalency; Time Factors

Drug-receptor interactions are traditionally quantified in terms of affinity and efficacy, but there is increasing awareness that the drug-on-receptor residence time also affects clinical performance. While most interest has hitherto been focused on slow-dissociating drugs, D(2) dopamine receptor antagonists show less extrapyramidal side effects but still have excellent antipsychotic activity when they dissociate swiftly. Fast dissociation of clozapine, the prototype of the "atypical antipsychotics", has been evidenced by distinct radioligand binding approaches both on cell membranes and intact cells. The surmountable nature of clozapine in functional assays with fast-emerging responses like calcium transients is confirmatory. Potential advantages and pitfalls of the hitherto used techniques are discussed, and recommendations are given to obtain more precise dissociation rates for such drugs. Surmountable antagonism is necessary to allow sufficient D(2) receptor stimulation by endogenous dopamine in the striatum. Simulations are presented to find out whether this can be achieved during sub-second bursts in dopamine concentration or rather during much slower, activity-related increases thereof. While the antagonist's dissociation rate is important to distinguish between both mechanisms, this becomes much less so when contemplating time intervals between successive drug intakes, i.e., when pharmacokinetic considerations prevail. Attention is also drawn to the divergent residence times of hydrophobic antagonists like haloperidol when comparing radioligand binding data on cell membranes with those on intact cells and clinical data.

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Radioligand Assay; Receptors, Dopamine D2; Schizophrenia

Reducing the risk of violent and aggressive behaviour in patients with schizophrenia remains a clinical priority. There is emerging evidence to suggest that the second-generation antipsychotic, clozapine, is effective at reducing this risk in patients with schizophrenia and some evidence to suggest that it may be best in selected patients. We conducted a systematic literature search in March 2011 of all prospective and retrospective studies, which investigated clozapine's anti-aggressive effects in a variety of mental disorders. The review identified six animal studies, four randomized controlled trials, 12 prospective non-controlled studies and 22 retrospective studies, with four case studies. We found considerable evidence in support of clozapine's ability to reduce violent and aggressive behaviour. Clozapine's anti-aggressive effect was most commonly explored in patients with schizophrenia, with less evidence available for other psychiatric disorders, including borderline personality disorder, autistic spectrum disorders, post-traumatic stress disorder, bipolar disorder and learning disability. There was mixed evidence to address the question of whether or not clozapine was any more effective than other antipsychotics. In the case of schizophrenia, there was evidence to suggest that clozapine's anti-aggressive effect was more marked particularly in those with treatment-resistant illness. Its anti-aggressive effects appeared to be 'specific', being to some extent greater than both its more general antipsychotic and sedative effects. There were significant methodological inconsistencies in the studies we identified, particularly surrounding patient recruitment criteria, the definition and measurement of violence and the lack of randomized, controlled trials. Data on therapeutic monitoring were also limited. Clozapine can reduce violence and persistent aggression in patients with schizophrenia and other psychiatric disorders. It may offer an advantage over other antipsychotics, although perhaps exclusively in the case of traditionally defined 'treatment resistance' or more broadly defined 'complex cases' with co-morbidity. Larger, randomized, blinded, controlled studies with robust characterization of participants, and standardized measures of violence and aggression are, however, needed to fully understand this link and explore the possible mechanisms.

Topics: Adult; Aggression; Antipsychotic Agents; Child; Clozapine; Cross-Over Studies; Dose-Response Relationship, Drug; Humans; Randomized Controlled Trials as Topic; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Suicide; Violence

Antipsychotic polytherapy (APT) has evolved as a common treatment strategy at odds with recommendations from schizophrenia treatment guidelines. The literature on combinations with clozapine as a means to enhance efficacy and with aripiprazole to reduce side effects was reviewed. No solid evidence supporting antipsychotic combinations with clozapine for treatment-resistant patients with schizophrenia was identified. The reason for this may be that most combinations with clozapine increase the D(2)-receptor blockade, and this strategy is probably not efficient for patients with treatment-resistant schizophrenia. Some basic and clinical evidence for the addition of aripiprazole to lower prolactin levels was identified. In conclusion, there is very limited support in the evidence for the feasibility of rational APT.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Haloperidol; Humans; Piperazines; Prolactin; Quinolones; Schizophrenia

Contemporary analyses demonstrate an early response to antipsychotic treatment in non-refractory schizophrenia. The profile of response to clozapine is unknown. We used meta-analytic and statistical procedures to examine the response profile to clozapine. We identified 19 unique, randomized, double-blind controlled clinical trials with suitable time course data, representing 1745 subjects. Individual subject data were available for 419 subjects, obtained from two industry-sponsored trials. Symptom severity scores from the BPRS or the PANSS were entered into regression analyses to estimate linear and quadratic coefficients of the rate of change of symptom severity over 4 weeks. Both linear and quadratic regression coefficients for clozapine, and for comparator antipsychotics differed significantly from zero (p ≤ 0.001), indicating early response profiles. Compared with other antipsychotic arms, for clozapine the treatment response was greater (d = -0.578, p = 0.021), and the linear coefficient was steeper (d = -0.502, p = 0.042); the quadratic coefficients indicating attenuation did not differ. Analyses of 6-week data and individual subject data from non-refractory and refractory trials were consistent with the primary findings. Somewhat surprisingly, clozapine shows an early response profile, similar in pattern but somewhat larger in magnitude than other antipsychotic drugs.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Dose-Response Relationship, Drug; Drug Resistance; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Severity of Illness Index

Clozapine, an atypical antipsychotic, is a dibenzodiazepine derivative and its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. In accordance to several studies, it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia. Moreover, clozapine appears to be particularly beneficial in patients with schizophrenia who are suicidal and in those with comorbid substance use disorder. However, despite its efficacy, the general use of clozapine in clinical practice is somewhat limited because of the risk of several serious adverse effects such as agranulocytosis and thromboembolism. Clozapine may be associated with fatal myocarditis and cardiomyopathy in physically healthy young adults. Consequently, the FDA and the drug's manufacturer have strengthened warnings to include that a potentially fatal myocarditis may occur when taking clozapine. In the present paper the literature on clozapine-related myocardis will be reviewed and practical advice will be given concerning the diagnosis and management of such potentially fatal adverse effect.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug Labeling; Humans; Myocarditis; Schizophrenia; United States; United States Food and Drug Administration

Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine , a D(2)-5HT(2) antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death.. The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape.. Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.

Topics: Animals; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Resistance; Humans; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Suicide Prevention

Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets.

Topics: Animals; Antipsychotic Agents; Clozapine; Cytokines; Databases, Factual; Humans; Immune System; Schizophrenia

Patients with schizophrenia have a shorter life expectancy and their risk of dying from a cardiovascular disease is higher than the general population. Both facts have been attributed to the raised presence of metabolic syndrome. There is a big amount of scientific publications that deals with the relationship between schizophrenia, antipsychotic treatment, and the development of metabolic syndrome. There is also information about recommendations and clinical guides to achieve an adequate prevention, screening, and treatment of the disease. The aim of this review is to update the current information about this issue and to understand related etiologic factors, differences between antipsychotic drugs, and the current recommendations for patient's care.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cardiovascular Diseases; Clozapine; Comorbidity; Follow-Up Studies; Humans; Hypothalamus; Incidence; Life Expectancy; Lipid Metabolism; Metabolic Syndrome; Obesity, Abdominal; Olanzapine; Practice Guidelines as Topic; Schizophrenia; Weight Gain

Clozapine has been in use since 1975. It was withdrawn due to its toxic effects on granulocytes. It was reintroduced due to its positive effect on schizophrenia in patients who did not respond to two antipsychotic drugs. These patients suffer from a chronic debilitating disease, with numerous and sometimes chronic hospitalizations. Clozapine also has antiaggression and antisuicide effects, as well as specific effects on the negative symptoms of schizophrenia. There are severe side effects that may appear. These include suppression of granulocytes, cardiotoxic effect on the myocard, as well as cardiac conduction defects. It may also cause weight gain and early appearance of diabetis mellitus. All these side effects require strict and intensive monitoring. Clozapine blood Levels are needed for ascertaining the required dose. This article describes several reasons for the low level of use of clozapine in Israel. These include its side effect profile, tendency to use new medications, the demanding monitoring for side effects and the need for long term treatment to achieve clinical improvement.

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Schizophrenia; Schizophrenic Psychology; Time Factors

Main indication for antipsychotic medication is the treatment of schizophrenia and other psychotic disorders. Influential protocols in the treatment of schizophrenia recommend the use of antipsychotics in monotherapy. In case of therapy resistance, combination of antipsychotics is a feasible option. Applying antipsychotics in combination is common in clinical practice, although existing efficacy and safety data concerning antipsychotic combinations are scarce. Authors, after reviewing existing scientific data, make attempt to give recommendations for combined antipsychotic therapy in everyday clinical practice.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Haloperidol; Humans; Methotrimeprazine; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Clozapine is often referred to as the gold standard for the treatment of schizophrenia and yet has also been described as the most underutilized treatment for schizophrenia supported by solid evidence-based medicine. In 2008, it was used to treat only 4.4% of patients with schizophrenia in the U.S., which is ~10-20% of those with approved indications for clozapine for which there is no alternative of equal efficacy. Its use is much higher in Scandinavian countries and China. The primary indications for clozapine are: 1) treatment-resistant schizophrenia or schizoaffective disorder, defined as persistent moderate to severe delusions or hallucinations despite two or more clinical trials with other antipsychotic drugs; and, 2) patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Concerns over a number of safety considerations are responsible for much of the underutilization of clozapine: 1) agranulocytosis; 2) metabolic side effects; and, 3) myocarditis. These side effects can be detected, prevented, minimized and treated, but there will be a very small number of fatalities. Nevertheless, clozapine has been found in two large epidemiologic studies to have the lowest mortality of any antipsychotic drug, mainly due to its very large effect to reduce the risk for suicide. Other reasons for limited use of clozapine include the extra effort entailed in monitoring white blood cell counts to detect granulocytopenia or agranulocytosis and, possibly, minimal efforts to market it now that it is largely generic. Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Metabolic Diseases; Myocarditis; Risk Factors; Schizophrenia

Schizophrenia in children and adolescents is a rare and serious representation of adult schizophrenia that indicates phenotypic and neurobiological continuity with the adult version of the illness. Epidemiological, genetic, cognitive and imaging findings support the centrality of the neuro-developmental model in the etiology of the disease. The diagnostic criteria for schizophrenia in children and adolescents, and in adults are identical. However, many of the children suffering from schizophrenia display higher levels of impaired pre-morbid functionality than adults with schizophrenia, and have a worse prognosis. Similar to adult-schizophrenia, prognosis is further worsened by frequent co-morbidities. Currently, treatment mainly consists of anti-psychotic medications, including clozapine. However, there is little evidence as to its effectiveness and side-effects are common in younger age.

Topics: Adolescent; Adult; Age Factors; Age of Onset; Antipsychotic Agents; Child; Clozapine; Humans; Prognosis; Schizophrenia; Schizophrenic Psychology

Although the increased risk of violent behavior in individuals with schizophrenia is now well-established, there is considerable uncertainty in pharmacological strategies to reduce this risk. In this review, we performed a systematic search of three electronic databases from January 2000 to March 2010 of treatment research on the management of violence in schizophrenia. We identified eight randomized controlled trials. The main findings included the association of nonadherence to antipsychotic medication to violent outcomes, a specific anti-aggressive effect of clozapine and short-term benefits of adjunctive β-blockers. There was little evidence on the efficacy of adjunctive mood stabilizers, depot medication or electroconvulsive therapy. Future research should use validated outcomes, longer follow-up periods and investigate patients with comorbid substance misuse.

Topics: Adrenergic beta-Antagonists; Antipsychotic Agents; Clozapine; Comorbidity; Electroconvulsive Therapy; Female; Humans; Male; Medication Adherence; Randomized Controlled Trials as Topic; Schizophrenia; Substance-Related Disorders; Violence

In many countries of the industrialised world second-generation ("atypical") antipsychotics (SGAs) have become the first line drug treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs.. To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.. 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.2. Reference searching We inspected the references of all identified studies for more trials.3. Personal contact We contacted the first author of each included study for missing information.4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data.. We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.. We extracted data independently. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD), again based on a random-effects model.. The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with quetiapine, two with sertindole, three with ziprasidone and none with zotepine. Attrition from these studies was high (46.9%), leaving the interpretation of results problematic. Furthermore, 60% were industry sponsored, which can be a source of bias.There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard.Risperidone improved the general mental state (PANSS total score) slightly less than olanzapine (15 RCTs, n = 2390, MD 1.94 CI 0.58 to 3.31), but slightly more than quetiapine (9 RCTs, n = 1953, MD -3.09 CI -5.16 to -1.01) and ziprasidone (3 RCTs, n = 1016, MD -3.91 CI -7.55 to -0.27). The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same outcome.Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs (use of antiparkinson medication versus clozapine 6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48, NNH 6 CI 33 to 3; versus olanzapine 13 RCTs, n = 2599, RR 1.28 CI 1.06 to 1.55, NNH 17 CI 9 to 100; versus quetiapine 6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 100; versus ziprasidone 2 RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable; parkinsonism versus sertindole 1 RCT, n = 321, RR 4.11 CI 1.44 to 11.73, NNH 14 CI 100 to 8). Risperidone also increased prolactin levels clearly more than all comparators, except for amisulpride and sertindole for which no data were available.Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic problems than amisulpride (weight gain: 3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61), aripiprazole (cholesterol increase: 1 RCT, n = 83, MD 22.30 CI 4.91 to 39.69) and ziprasidone (cholesterol increase 2 RCTs, n = 767, MD 8.58 CI 1.11 to 16.04) but less than clozapine (weight gain 3 RCTs n = 373, MD -3.30 CI -5.65 to -0.95), olanzapine (weight gain 13 RCTs, n = 2116, MD -2.61 CI -3.74 to -1.48), quetiapine (ch. Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other SGAs. It may also differ from other compounds in efficacy and in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions. Further large trials, especially comparing risperidone with those other new drugs for which only a few RCTs are available, are needed.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride; Thiazoles

despite advances in pharmacotherapy of schizophrenia-spectrum disorders, a large percentage of persons with schizophrenia remain at least partially nonresponsive to treatment, leading to increased morbidity/mortality, increased healthcare cost, and poor quality of life for affected individuals.. this paper comprises a review of recent research in drug therapy for schizophrenia, particularly treatment-refractory schizophrenia, with a focus on research conducted between 2005 and June 2010. Databases that were searched include: Pubmed, CINAHL, Science Direct, Medline and Clinical Trials.gov. Primary search terms were 'treatment-refractory schizophrenia' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. An objective perspective on current trends in pharmacotherapy for treatment-refractory schizophrenia. We review the available evidence and discuss the strengths and weaknesses of published data in this field.. although there have been many advances in pharmacotherapy for schizophrenia, more well-designed trials are required to establish true efficacy and safety of current prescribing trends in clinical practice.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Resistance; Electroconvulsive Therapy; Health Care Costs; Humans; Quality of Life; Schizophrenia; Transcranial Magnetic Stimulation

Clozapine is the most powerful new‐generation antipsychotic. Although this drug leads to great therapeutic benefits, two types of undesirable conditions frequently occur with its use: side effects and resistance to treatment. Therapeutic drug monitoring of clozapine would be very useful to avoid both these situations. The necessity of monitoring the therapy is the result of a wide interindividual variability in the metabolism of clozapine. In this review, we highlight all the conditions underlying this variability, analyzing them one by one.. Relevant literature was identified through a search of MEDLINE and PubMed. In addition, the case of a treatment‐resistant patient with accelerated metabolism of clozapine is reported as representative of utility of therapeutic drug monitoring in terms of clozapine dose adjustment.. Genetic polymorphisms of cytochrome P450 enzymes and of neurotransmitter receptors; drug interactions; interactions of clozapine with other substances such as food and drink; smoking; and nonmodifiable variables such as age, ethnicity, and gender have been examined in relation to the existing scientific literature. The laboratory techniques that clinicians could use to identify these variables and adequate therapies are also reviewed.

Topics: Clozapine; Cytochrome P-450 CYP1A2; Humans; Individuality; Male; Schizophrenia; Treatment Outcome; Young Adult

Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side-effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed.. Studies of clozapine available in MEDLINE were reviewed.. A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350-420 ng/ml are necessary to determine non-response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine.. Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse.

Topics: Antipsychotic Agents; Calcium Channel Blockers; Central Nervous System Diseases; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Electroconvulsive Therapy; Heart Diseases; Humans; Lamotrigine; Schizophrenia; Treatment Outcome; Triazines

Since the development of clozapine, scores of antipsychotics have been introduced. These are, with one exception (aripiprazole), based on the pharmacological principle of 5-HT(2)/dopamine antagonism. Research on other treatment targets, which, in part, influence dopaminergic pathways directly or indirectly, is mounting. Managing psychotic symptoms is only one facet of successful treatment of schizophrenia. Effective remedies against negative symptoms and cognitive deficits are still an unmet clinical need.. With the focus on the topics mentioned above, the authors briefly review the latest clinical research organized on the basis of receptor systems and other drug targets, which are discussed to be involved in the pathophysiology of schizophrenia.. In conclusion, although clinicians will have to have considerable patience before truly novel anti-schizophrenia treatments become obtainable, a number of interesting leads with considerable theoretical potential are being explored. As yet, it is difficult to predict which of these mechanisms will effectively augment the currently available treatments.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Based on the glutamatergic NMDA receptor hypofunction theory of schizophrenia, NMDA receptor modulators (NMDARMs) may have therapeutic potential in the treatment of schizophrenia.. This meta-analysis aimed to evaluate the potential of modulators of the NMDA receptor as adjunctive therapy for schizophrenia, using the results from published trials.. A primary electronic search for controlled clinical trials using NMDARMs in schizophrenia was conducted on the PubMed, Cochrane Library, EMBASE, CINAHL® and PsycINFO databases. A secondary manual search of references from primary publications was also performed.. Inclusion criteria were the application of an established method of diagnosis, randomized case assignment, comparison of NMDARM add-on therapy with placebo, and double-blind assessment of symptoms in chronic schizophrenia using standardized rating scales. Results were based on a total sample size of 1253 cases from 29 trials that fulfilled the specified criteria.. Scores on rating scales or on their relevant subscales were obtained for all selected studies from published results for the minimum dataset to compute the difference between post- and pre-trial scores and their pooled standard deviation for NMDARM add-on therapy and placebo groups for negative, positive and total symptoms.. A negative standardized mean difference (SMD) indicates therapeutic benefit in favour of NMDARM add-on therapy and all SMD results mentioned here are statistically significant. The overall effect size for NMDARMs as a group was small for negative (SMD -0.27) and medium for total (SMD -0.40) symptoms of chronic schizophrenia. Subgroup analysis revealed medium effect sizes for D-serine and N-acetyl-cysteine (NAC) for negative (SMD -0.53 and -0.45, respectively) and total (SMD -0.40 and -0.64, respectively) symptoms, and for glycine (SMD -0.66) and sarcosine (SMD -0.41) for total symptoms. As adjuvants to non-clozapine antipsychotics, additional therapeutic benefits were observed for NMDARM as a group (SMD -0.14) and glycine (SMD -0.54) for positive symptoms; D-serine (SMD -0.54), NAC (SMD -0.45) and sarcosine (SMD -0.39) for negative symptoms; and NMDARM as a group (SMD -0.38), D-serine (SMD -0.40), glycine (SMD -1.12), NAC (SMD -0.64) and sarcosine (SMD -0.53) for total symptoms. When added to clozapine, none of the drugs demonstrated therapeutic potential, while addition of glycine (SMD +0.56) worsened positive symptoms.. Taking into consideration the number of trials and sample size in subgroup analyses, D-serine, NAC and sarcosine as adjuncts to non-clozapine antipsychotics have therapeutic benefit in the treatment of negative and total symptoms of chronic schizophrenia. While glycine improves positive and total symptoms as an adjuvant to non-clozapine antipsychotics, it worsens them when added to clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Glycine; Humans; Middle Aged; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Sarcosine; Schizophrenia; Treatment Outcome

Clozapine is the best treatment option in several clinical circumstances, including treatment-resistant schizophrenia, non treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. However, clozapine is associated with many serious side effects. Furthermore, monitoring requirements, i.e., frequent blood draws and frequent visits, discourage clozapine use. Therefore, the drug is underused. The only way to avoid the underuse of clozapine is full awareness of its side effects and competence to minimize them. The aim of the paper is reviewing the safety profile of clozapine and the suggested strategies in the management of its side effects, including neutropenia, eosinophilia, seizures, myocarditis, weight gain, diabetes, metabolic syndrome, hypersalivation, fever, constipation, ileus, urinary incontinence, sweating. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Movement Disorders; Psychotic Disorders; Schizophrenia

Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia.. To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia.. Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of metaregression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment.. Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0–76%).The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression – Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356).. Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early.More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Data Interpretation, Statistical; Drug Resistance; Female; Humans; Male; Models, Statistical; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Regression Analysis; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Time Factors; Treatment Outcome

Our aim in this article is 2-fold: first, to examine the mid-term to long-term data on efficacy, from controlled and naturalistic and other studies, in order to determine if they are consistent with the quantitative meta-analyses of mostly short-term, randomized controlled trials Our second (and most important) aim is to use these and other data to provide guidance about the potential relationship of these differences among antipsychotics to the individual patient's own experience with antipsychotic drugs in the process of shared decision-making with the patients and their significant others.. A search of PubMed, Embase, and PsychINFO was conducted for articles published in English between January 1, 1999, and April 2011, using the search terms double-blind AND randomized AND olanzapine AND (ziprasidone OR risperidone OR quetiapine OR haloperidol OR fluphenazine OR perphenazine OR aripiprazole).. Studies with a duration 3 months or longer, including patients with schizophrenia or schizoaffective disorder, reporting survival analysis for all-cause discontinuation and relapse or dropout due to poor efficacy were selected.. We extracted the number of patients relapsed due to poor efficacy and hazard rates for relapses.. Overall, the efficacy patterns of both controlled effectiveness and observational long-term studies closely parallel the efficacy observed in the short-term, controlled studies. The results of Phase 1 Clinical Antipsychotic Trials of Intervention Effectiveness are very similar to, but not identical with, the controlled short-term efficacy studies, the European First-Episode Schizophrenia Trial, and naturalistic studies. The mid-term and long-term data suggest that olanzapine is more effective than risperidone and that both of these are better than the other first- and second-generation antipsychotics except for clozapine, which is the most efficacious of all. Further large differences emerged regarding the specific mid-term and long-term safety profiles of individual antipsychotics.. Despite intraclass differences and the complexities of antipsychotic choice, the second-generation antipsychotics are important contributions not only to the acute phase but, more importantly, to the maintenance treatment of schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Combined Modality Therapy; Humans; Olanzapine; Patient Participation; Psychotherapy; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Time Factors; Treatment Outcome

Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently.. In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations.. A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost-effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated.. No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse.

Topics: Antipsychotic Agents; Clozapine; Humans; Reproducibility of Results; Schizophrenia; Treatment Outcome

D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n=758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies.

Topics: Adult; Amino Acid Substitution; Antipsychotic Agents; Black or African American; Clozapine; Female; Haplotypes; Humans; Linkage Disequilibrium; Male; Polymorphism, Single Nucleotide; Receptors, Dopamine D3; Schizophrenia; White People

Historically, schizophrenia has been associated with early-onset, persistent symptoms, and progressive decline accompanied by poor functional recovery. The advent of effective drugs in the 1950s improved symptom control, at least from the standpoint of positive features (e.g. hallucinations, delusions). However, even here the response was limited and efficacy in other symptom domains (cognitive, deficit/negative) was minimal. With clozapine as the prototype, the second-generation antipsychotics arrived in the 1990s with claims of improved tolerability, as well as greater and broader clinical efficacy, all of which was to translate to gains in functional outcome and quality of life. The capacity of these drugs to effect such changes has since been tempered, but it remains that the research and hope generated served as an impetus to redefine outcomes. A medical-based model, centred on pharmacotherapy and symptom resolution, has given way to a re-conceptualization of schizophrenia and treatment goals. There is a clearer distinction between clinical and functional outcomes, and, with this, greater attention has been given to these other symptom domains that curtail improvement in the latter. At the same time, a concerted shift to shared decision making has underscored quality-of-life issues that benefit from, but cannot be guaranteed by, either clinical or functional improvement. To this end, the field has now embraced a recovery model that is seen as a process, multidimensional and individualized, rather than dichotomous and symptom driven.

Topics: Antipsychotic Agents; Clozapine; Decision Making; Humans; Models, Biological; Patient Participation; Quality of Life; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Long-Term Care; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Sulpiride

In many countries of the industrialised world, second generation (atypical) antipsychotic drugs have become first line treatment for people with schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate. In this review we examined how the efficacy and tolerability of zotepine differs from that of other second generation antipsychotic drugs.. To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people with schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL CINAHL, EMBASE, MEDLINE and PsycINFO.. We included all randomised trials comparing oral zotepine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people with schizophrenia or schizophrenia-like psychoses.. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (MD) again based on a random effects model.. The review currently includes data from two short term, ill reported trials (total n=109). Both studies compared zotepine with clozapine. 34% of people left early but there was no significant difference between groups. Zotepine was less effective than clozapine (no clinically significant response: n=59, 1 RCT, RR 8.23 CI 1.14 to 59.17, NNH 3 CI 2 to 8; average score (BPRS total) at endpoint (n=59, 1 RCT, MD 6.00 CI 2.17 to 9.83). Zotepine induced more movement disorders than clozapine (use of antiparkinson medication: n=59, 1 RCT, RR 18.75 CI 1.17 to 301.08, NNH 3 CI 2 to 5) and higher prolactin levels (n=59, 1 RCT, MD 33.40 CI 14.87 to 51.93). Data on important other outcomes such as other adverse events, service use or satisfaction with care were not available.. Zotepine may be less effective than clozapine and associated with more movement disorders and higher prolactin levels, but the evidence base is too small and prone to bias, making any practical recommendations impossible. There is no randomised evidence on the effects of zotepine compared to second generation antipsychotic drugs other than clozapine. More studies are possible to justify.

Topics: Antipsychotic Agents; Clozapine; Dibenzothiepins; Humans; Randomized Controlled Trials as Topic; Schizophrenia

In many countries of the industrialised world second generation ('atypical') antipsychotic drugs have become the first line drug treatment for people with schizophrenia. It is not clear how the effects of the various second generation antipsychotic drugs differ.. To evaluate the effects of quetiapine compared with other second generation antipsychotic drugs for people with schizophrenia and schizophrenia-like psychosis.. We searched the Cochrane Schizophrenia Group Trials Register (April 2007), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.. We included all randomised control trials comparing oral quetiapine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random-effects model.. The review currently includes 21 randomised control trials (RCTs) with 4101 participants. These trials provided data on four comparisons - quetiapine versus clozapine, olanzapine, risperidone or ziprasidone.A major limitation to all findings is the high number of participants leaving studies prematurely (57.6%) and the substantial risk of biases in studies. Efficacy data favoured olanzapine and risperidone compared with quetiapine (PANSS total score versus olanzapine:10 RCTs, n=1449, WMD 3.66 CI 1.93 to 5.39; versus risperidone: 9 RCTs, n=1953, WMD 3.09 CI 1.01 to 5.16), but clinical meaning is unclear. There were no clear mental state differences when quetiapine was compared with clozapine or ziprasidone.Compared with olanzapine, quetiapine produced slightly fewer movement disorders (6 RCTs, n=1090, RR use of antiparkinson medication 0.49 CI 0.3 to 0.79, NNH 25 CI 14 to 100) and less weight gain (7 RCTs, n=1173, WMD -2.81 CI -4.38 to -1.24) and glucose elevation, but more QTc prolongation (3 RCTs, n=643, WMD 4.81 CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (6 RCTs, n=1715, RR use of antiparkinson medication 0.5 CI 0.3 to 0.86, NNH 20 CI 10 to 100), less prolactin increase (6 RCTs, n=1731, WMD -35.28 CI -44.36 to -26.19) and some related adverse effects, but more cholesterol increase (5 RCTs, n=1433, WMD 8.61 CI 4.66 to 12.56). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n=522, RR use of antiparkinson medication 0.43 CI 0.2 to 0.93, NNH not estimable) and prolactin increase. On the other hand quetiapine was more sedating and led to more weight gain (2 RCTs, n=754, RR 2.22 CI 1.35 to 3.63, NNH 13 CI 8 to 33) and cholesterol increase than ziprasidone.. Best available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks. Comparisons with amisulpride, aripiprazole, sertindole and zotepine do not exist. Most data that has been reported within existing comparisons are of very limited value because of assumptions and biases within them. There is much scope for further research into the effects of this widely used drug.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Medication Adherence; Olanzapine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Thiazoles

Sulpiride may be used in combination with other antipsychotic drugs in the hope of augmenting effectiveness - especially for those whose schizophrenia has proved resistant to treatment.. To evaluate the effects of sulpiride augmentation versus monotherapy for people with schizophrenia.. We searched the Cochrane Schizophrenia Group Trials Register (July 2009) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO.. All relevant randomised clinical trials (RCTs).. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a fixed-effect model. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model.. We included three short-term and one long-term trial (total N=221). All participants had schizophrenia that was either treatment-resistant or with prominent negative symptoms. All studies compared sulpiride plus clozapine with clozapine (+/- placebo), were small and at considerable risk of bias.Short-term data of 'no clinically significant response' in global state tended to favour sulpiride augmentation of clozapine compared with clozapine alone (n=193, 3 RCTs, RR 0.58 CI 0.3 to 1.09).People allocated to sulpiride plus clozapine had more movement disorders (n=70, 1 RCT, RR 48.24 CI 3.05 to 762.56) and an increase in serum prolactin (skewed data, 1 RCT), but less incidence of hypersalivation (n=162, 3 RCTs, RR 0.49 CI 0.29 to 0.83) and less weight gain (n=64, 1 RCT, RR 0.30 CI 0.09 to 0.99). The augmentation of clozapine by sulpiride also caused less appetite loss (n=70, 1 RCT, RR 0.09 CI 0.01 to 0.70, NNT 4 CI 4 to 12, Z=2.31, P=0.02) and less abdominal distension (n=70, 1 RCT, RR 0.10 CI 0.01 to 0.78, NNT 5 CI 4 to 19, Z=2.20, P=0.03).Long-term data showed no significant difference in global state (n=70, 1 RCT, RR 0.67 CI 0.42 to 1.08) and relapse (n=70, 1 RCT, RR 0.85 CI 0.5 to 1.3).. Sulpiride plus clozapine is probably more effective than clozapine alone in producing clinical improvement in some people whose illness has been resistant to other antipsychotic drugs including clozapine. However, much more robust data are needed.

Topics: Antipsychotic Agents; Clozapine; Drug Synergism; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Sulpiride

In many countries of the industrialised world second generation ("atypical") antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examined how the efficacy and tolerability of olanzapine differs from that of other second generation antipsychotics.. To evaluate the effects of olanzapine compared to other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.. 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.2. Reference searching We inspected the reference of all identified studies for more trials.3. Personal contact We contacted the first author of each included study for missing information.4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data.. We included all randomised trials that used at least single-blind (rater-blind) design, comparing oral olanzapine with oral forms of amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model.. The review currently includes 50 studies and 9476 participants which provided data for six comparisons (olanzapine compared to amisulpride, aripiprazole, clozapine, quetiapine, risperidone or ziprasidone). The overall attrition from the included studies was considerable (49.2%) leaving the interpretation of results problematic.Olanzapine improved the general mental state (PANSS total score) more than aripiprazole (2 RCTs, n=794, WMD -4.96 CI -8.06 to -1.85), quetiapine (10 RCTs, n=1449, WMD -3.66 CI -5.39 to -1.93), risperidone (15 RCTs, n=2390, WMD -1.94 CI -3.31 to -0.58) and ziprasidone (4 RCTs, n=1291, WMD -8.32 CI -10.99 to -5.64), but not more than amisulpride or clozapine. This somewhat better efficacy was confirmed by fewer participants in the olanzapine groups leaving the studies early due to inefficacy of treatment compared to quetiapine (8 RCTs, n=1563, RR 0.56 CI 0.44 to 0.70, NNT 11 CI 6 to 50), risperidone (14 RCTs, n=2744, RR 0.78 CI 0.62 to 0.98, NNT 50 CI 17 to 100) and ziprasidone (5 RCTs, n=1937, RR 0.64 CI 0.51 to 0.79, NNT 17, CI 11 to 33).Fewer participants in the olanzapine group than in the quetiapine (2 RCTs, n=876, RR 0.56 CI 0.41 to 0.77, NNT 11 CI 7 to 25) and ziprasidone (2 RCTs, n=766, RR 0.65 CI 0.45 to 0.93, NNT 17 CI 9 to 100) treatment groups, but not in the clozapine group (1 RCT, n=980, RR 1.28 CI 1.02 to 1.61, NNH not estimable), had to be re-hospitalised in the trials.Except for clozapine, all comparators induced less weight gain than olanzapine (olanzapine compared to amisulpride: 3 RCTs, n=671, WMD 2.11kg CI 1.29kg to 2.94kg; aripiprazole: 1 RCT, n=90, WMD 5.60kg CI 2.15kg to 9.05kg; quetiapine: 7 RCTs, n=1173, WMD 2.68kg CI 1.10kg to 4.26kg; risperidone: 13 RCTs, n=2116, WMD 2.61kg CI 1.48kg to 3.74kg; ziprasidone: 5 RCTs, n=1659, WMD 3.82kg CI 2.96kg to 4.69kg). Associated problems such as glucose and cholesterol increase were usually also more frequent in the olanzapine group.Other differences in adverse effects were less well documented. Nevertheless, olanzapine may be associated with slightly more extrapyramidal side effects than quetiapine (use of antiparkinson medication (6 RCTs, n=1090, RR 2.05 CI 1.26 to 3.32, NNH 25 CI 14 to 100), but less than risperidone (use of antiparkinson medication 13 RCTs, n=2599, RR 0.78 CI 0.65 to 0.95, NNH 17 CI 9 to 100) and ziprasidone (use of antiparkinson medication 4 RCTs, n=1732, RR 0.70 CI 0.50 to 0.97, NNH not estimable). It may also increase prolactin somewhat more than. Olanzapine may be a somewhat more efficacious drug than some other second generation antipsychotic drugs. This small superiority in efficacy needs to be weighed against a larger weight gain and associated metabolic problems than most other second generation antipsychotic drugs, except clozapine. These conclusions are tentative due to the large number of people leaving the studies early which possibly limits the validity of the findings. Further large, well-designed trials are necessary to establish the relative effects of different second generation antipsychotic drugs.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Sulpiride; Thiazoles

Clozapine is associated with various haematological adverse effects, including leukopenia, neutropenia, agarnulocytosis, leukocytosis, anaemia, eosinophilia, thrombocytopenia and thrombocythaemia. Recognition and treatment of clozapine-related seizures also will become increasingly important as clozapine use grows in the 1990s. The decision to stop clozapine as a result of haematological adverse effects or seizures is a frustrating one for the clinician, and frequently disastrous for the patient. Cessation of treatment results in relapse. In case that patient is unresponsive to other antipsychotic, restarting clozapine should be consider, despite the risk involved. As the risk of a second agranulocytosis is much higher in those patients, various methods of militating against repeat blood dyscrasias have been treated, including granulocyte colony-stimulating factor and lithium. The decision to restart clozapine should be taken on case-by-case basis and should take into account the likely risks and benefits of restarting. Prior response to clozapine and magnitude of patient deterioration on stopping treatment are important factors to take into this consideration. Clozapine-related seizures did not preclude successful treatment with clozapine. A strategy that has been proposed to reduce the occurrence of seizures is the addition of an anticonvulsant agent. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. With careful haematologyc control, the risk of agranulocytosis can be minimized and in case of clozapine related seizures recommendations include dose reduction, electroencephalogram (EEG), plasma-level monitoring and prophylactic antiepileptic treatment. Re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring.

Topics: Adult; Agranulocytosis; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Humans; Leukopenia; Lithium Carbonate; Psychotic Disorders; Recurrence; Risk Factors; Schizophrenia; Substance Withdrawal Syndrome; Thrombocytopenia

To comprehensively review the 2 recent and large antipsychotic effectiveness trials for treatment of schizophrenia: the United Kingdom's Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), and the National Institute of Mental Health-initiated Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial.. We present a review of the rationale, methodology, and findings to date from the CUtLASS and CATIE schizophrenia trials, including all primary and secondary outcomes.. The primary findings from both trials, CUtLASS and CATIE, suggest that first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) are equally effective in the treatment of schizophrenia. The exception is in treatment-resistant populations where clozapine exhibits superiority, compared with other SGAs. In the CATIE trial, there is a suggestion that olanzapine is superior in effectiveness, compared with other nonclozapine SGAs, although this seems to be mediated by past history of olanzapine use, and carries with it increased weight gain and metabolic adverse events. From a cost-effectiveness perspective, there is no evidence that SGAs are superior to FGAs, with findings suggesting the possibility that FGAs may be superior.. Past efficacy trials have strongly supported the position that SGAs are superior to FGAs in the treatment of schizophrenia and in side effect profile. Two large independent effectiveness trials, CUtLASS and CATIE, have offered a strong challenge to these claims. Both suggest that SGAs, except clozapine in the treatment-resistant population, offer little, if any, clinical benefits, and, moreover, harbour their own significant side effects.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cost-Benefit Analysis; Decision Making; Humans; National Institute of Mental Health (U.S.); Olanzapine; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; United Kingdom; United States

Polydipsia and episodic life-threatening water intoxication remain important clinical problems for a significant portion of persons with schizophrenia. The disorders are associated with increased morbidity and mortality from a number of causes. With a basic understanding of the pathophysiology, one can easily diagnose and assess the clinical conditions. We review here the scope and pathophysiology of disordered water imbalance, including both primary and secondary polydipsia and hyponatremia. Reversible factors and possible interventions are reviewed. Treatment options for preventing water intoxication have expanded from discontinuation of offending agents, targeted fluid restriction, and clozapine therapy to the addition of oral vasopressin antagonists. The latter, however, are extremely potent and must be carefully monitored.

Topics: Antidiuretic Hormone Receptor Antagonists; Antimanic Agents; Antipsychotic Agents; Benzazepines; Clozapine; Combined Modality Therapy; Diagnosis, Differential; Drinking; Humans; Hyponatremia; Lithium Carbonate; Randomized Controlled Trials as Topic; Receptors, Vasopressin; Risk Factors; Schizophrenia; Schizophrenic Psychology; Sodium Chloride Symporter Inhibitors; Tolvaptan; Water Deprivation; Water Intoxication; Water-Electrolyte Balance

The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine.. We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis.. We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine.. Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Cholesterol; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Sulpiride; Thiazoles; Weight Gain

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Drug Discovery; Drug Monitoring; Drug Resistance; Humans; Psychotic Disorders; Schizophrenia; Treatment Outcome

Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Long-Term Care; Metabolic Clearance Rate; Parkinsonian Disorders; Precision Medicine; Psychiatric Status Rating Scales; Research; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

In many parts of the world, particularly in industrialised countries, second generation (atypical) antipsychotic drugs have become first line treatment for people suffering from schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate.. To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people suffering from schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Group Trials Register (November 2009), inspected references of all identified studies for further trials and contacted authors of trials for additional information.. We included only randomised clinical controlled trials that compared zotepine with any forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people suffering from only schizophrenia or schizophrenia-like psychoses.. SS and KK extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model.. We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the comparison of zotepine and risperidone, mental state scoring found no significant difference between the groups (vs 4 mg: n=40, 1 RCT, MD average endpoint score (BPRS total, high=poor) 1.40 CI -9.82 to 12.62; vs 8 mg: n=40, 1 RCT, MD -1.30 CI -12.95 to 10.35) and use of antiparkinson medication was equivocal (vs 4 mg: n=40, 1 RCT, MD 1.80 CI -0.64 to 4.24; vs 8 mg: n=40, 1 RCT, MD 2.50 CI -0.05 to 5.05). Finally, when zotepine was compared with remoxipride, again no effect was found for mental state (n=58, 1 RCT, MD average endpoint score (BPRS total, high=poor) 5.70 CI -4.13 to 15.53) and there was no significant difference between the two groups in terms of use of antiparkinson medication (n=49, 1 RCT, RR 0.97 CI 0.41 to 2.29).Data on important other outcomes such as other adverse events, service use or satisfaction with care, quality of life were not available.. The evidence base around zotepine is insufficient to provide firm conclusions on its absolute or relative effects. This is despite it being in use in Austria, France, Germany, Japan and the UK.

Topics: Antipsychotic Agents; Clozapine; Dibenzothiepins; Humans; Randomized Controlled Trials as Topic; Remoxipride; Risperidone; Schizophrenia

To review clozapine's position in treatment algorithms for schizophrenia.. Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects.. The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials.. Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Drug Monitoring; Humans; North America; Schizophrenia; Treatment Outcome

Clozapine is an atypical antipsychotic demonstrated to be superior in the treatment of refractory schizophrenia which causes fewer movement disorders. Clozapine, however, entails a significant risk of serious blood disorders such as agranulocytosis which could be potentially fatal. Currently there are a number of newer antipsychotics which have been developed with the purpose to find both a better tolerability profile and a superior effectiveness.. To compare the clinical effects of clozapine with other atypical antipsychotics (such as amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) in the treatment of schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Groups Register (June 2007) and reference lists of all included randomised controlled trials. We also manually searched appropriate journals and conference proceedings relating to clozapine combination strategies and contacted relevant pharmaceutical companies.. All relevant randomised, at least single-blind trials, comparing clozapine with other atypical antipsychotics, any dose and oral formulations, for people with schizophrenia or related disorders.. We selected trials and extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD) again based on a random-effects model.. The review currently includes 27 blinded randomised controlled trials, which involved 3099 participants. Twelve randomised control trials compared clozapine with olanzapine, five with quetiapine, nine with risperidone, one with ziprasidone and two with zotepine. Attrition from these studies was high (overall 30.1%), leaving the interpretation of results problematic. Clozapine had a higher attrition rate due to adverse effects than olanzapine (9 RCTs, n=1674, RR 1.60 CI 1.07 to 2.40, NNT 25 CI 15 to 73) and risperidone (6 RCTs, n=627, RR 1.88 CI 1.11 to 3.21, NNT 16 CI 9 to 59). Fewer participants in the clozapine groups left the trials early due to inefficacy than risperidone (6 RCTs, n=627, RR 0.40 CI 0.23 to 0.70, NNT 11 CI 7 to 21), suggesting a certain higher efficacy of clozapine.Clozapine was more efficacious than zotepine in improving the participants general mental state (BPRS total score: 1 RCT, n=59, MD -6.00 CI -9.83 to -2.17), but not consistently more than olanzapine, quetiapine, risperidone and ziprasidone. There was no significant difference between clozapine and olanzapine or risperidone in terms of positive or negative symptoms of schizophrenia. According to two studies from China quetiapine was more efficacious for negative symptoms than clozapine (2 RCTs, n=142, MD 2.23 CI 0.99 to 3.48).Clozapine produced somewhat fewer extrapyramidal side-effects than risperidone (use of antiparkinson medication: 6 RCTs, n=304, RR 0.39 CI 0.22 to 0.68, NNT 7 CI 5 to 18) and zotepine (n=59, RR 0.05 CI 0.00 to 0.86, NNT 3 CI 2 to 5). More participants in the clozapine group showed decreased white blood cells than those taking olanzapine, more hypersalivation and sedation than those on olanzapine, risperidone and quetiapine and more seizures than people on olanzapine and risperidone. Also clozapine produced an important weight gain not seen with risperidone.Other differences in adverse effects were less documented and should be replicated, for example, clozapine did not alter prolactin levels whereas olanzapine, risperidone and zotepine did; compared with quetiapine, clozapine produced a higher incidence of electrocardiogram (ECG) alterations; and compared with quetiapine and risperidone clozapine produced a higher increase of triglyceride levels. Other findings that should be replicated were: clozapine improved social functioning less than risperidone and fewer participants in the clozapine group had to be hospitalised to avoid suicide attempts compared. Clozapine may be a little more efficacious than zotepine and risperidone but further trials are required to confirm this finding. Clozapine differs more clearly in adverse effects from other second generation antipsychotics and the side-effect profile could be key in the selection of treatment depending on the clinical situation and a patient's preferences. Data on other important outcomes such as cognitive functioning, quality of life, death or service use are currently largely missing, making further large and well-designed trials necessary. It is also important to take into account that the large number of people leaving the studies early limits the validity and interpretation of our findings.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Thiazoles

In a previous study, we found an association between 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) polymorphisms and the occurrence of the metabolic syndrome in patients using antipsychotics. In the current study, we set out to replicate our findings in another sample of patients and to explore in a pooled analysis of both samples the influence of the effect of individual antipsychotics. Data for this cross-sectional study came from 2 different samples, the original sample (n = 112) and the replication sample (n = 164). Primary end point was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the promoter region of the HTR2C gene [HTR2C:c.1-142948(GT)n, rs3813929 (-759 C/T), and rs518147 (-697 G/C)] and an intragenic polymorphism (rs1414334:C>G). The variants of HTR2C:c.1-142948(GT)n (odds ratio [OR], 1.69; 95% confidence interval [CI], 0.75-3.81) and rs1414334 (OR, 2.35; 95% CI, 0.96-5.77) were not significantly associated with the metabolic syndrome in the replication sample but did show significance in the pooled analysis (OR, 2.09; 95% CI, 1.12-3.91; and OR, 2.35; 95% CI, 1.19-4.62, respectively). The variant rs1414334 C allele was specifically associated with the metabolic syndrome in patients using clozapine (OR, 9.20; 95% CI, 1.95-43.45) or risperidone (OR, 5.35; 95% CI, 1.26-22.83). This study extends previous findings to a larger sample of patients and implicates specific antipsychotic drugs. The increased risk for the metabolic syndrome is particularly strong in carriers of the rs1414334 C allele using clozapine or risperidone.

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Female; Humans; Linkage Disequilibrium; Male; Metabolic Syndrome; Polymorphism, Genetic; Promoter Regions, Genetic; Receptor, Serotonin, 5-HT2C; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risperidone; Schizophrenia; Treatment Outcome

Long-term drug treatment of schizophrenia with typical antipsychotics has limitations: 25 to 33% of patients have illnesses that are treatment-resistant. Clozapine is an antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment.. To evaluate the effects of clozapine compared with typical antipsychotic drugs in people with schizophrenia.. For the current update of this review (March 2006) we searched the Cochrane Schizophrenia Group Trials Register.. All relevant randomised clinical trials (RCTs).. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model.. We have included 42 trials (3950 participants) in this review. Twenty-eight of the included studies are less than 13 weeks in duration, and, overall, trials were at significant risk of bias. We found no significant difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at the end of the study. Clinical improvements were seen more frequently in those taking clozapine (n=1119, 14 RCTs, RR 0.72 CI 0.7 to 0.8, NNT 6 CI 5 to 8). Also, participants given clozapine had fewer relapses than those on typical antipsychotic drugs (n=1303, RR 0.62 CI 0.5 to 0.8, NNT 21 CI 15 to 49). BPRS scores showed a greater reduction of symptoms in clozapine-treated patients, (n=1145, 16 RCTs, WMD -4.22 CI -5.4 to -3.1), although the data were heterogeneous (Chi(2) 0.0001, I(2) 66%). Short-term data from the SANS negative symptom scores favoured clozapine (n=196, 5 RCTs, WMD -5.92 CI -7.8 to -4.1). We found clozapine to be more acceptable in long-term treatment than conventional antipsychotic drugs (n=982, 16 RCTs, RR 0.60 CI 0.5 to 0.7, NNT 15 CI 12 to 20). Blood problems occurred more frequently in participants receiving clozapine (3.2%) compared with those given typical antipsychotics (0%) (n=1031, 13 RCTs, RR 7.09 CI 2.0 to 25.6). Clozapine participants experienced more drowsiness, hypersalivation, or temperature increase, than those given conventional neuroleptics. However, clozapine patients experienced fewer motor adverse effects (n=1433, 18 RCTs, RR 0.58 CI 0.5 to 0.7, NNT 5 CI 4 to 6).The clinical effects of clozapine were more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (n=370, 4 RCTs, RR 0.71 CI 0.6 to 0.8, NNT 4 CI 3 to 6) and symptom reduction. Thirty-four per cent of treatment-resistant participants had a clinical improvement with clozapine treatment.. Clozapine may be more effective in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse, than typical antipsychotic drugs - but data are weak and prone to bias. Participants were more satisfied with clozapine treatment than with typical neuroleptic treatment. The clinical effect of clozapine, however, is, at least in the short term, not reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The short-term benefits of clozapine have to be weighed against the risk of adverse effects. Within the context of trials, the potentially dangerous white blood cell decline seems to be more frequent in children and adolescents and in the elderly than in young adults or people of middle-age.The existing trials have largely neglected to assess the views of participants and their families on clozapine. More community-based long-term randomised trials are needed to evaluate the efficacy of clozapine on global and social functioning as trials in special groups such as people with learning disabilities.

Topics: Age Factors; Antipsychotic Agents; Clozapine; Humans; Randomized Controlled Trials as Topic; Schizophrenia

Clozapine is the drug of choice for patients with unsatisfactory response to routine antipsychotic treatment. Polypharmacy is widely used among patients having clozapine-resistant schizophrenia, although no solid evidence exists for any effective augmentation therapy for this patient population. We aimed to study the efficacy of lamotrigine in the treatment of clozapine-resistant schizophrenia.. We conducted electronic searches of the Cochrane PsiTri database, the Website of metaRegister of Controlled Trials, including NIH ClinicalTrials.gov, and a clinical trial register by the manufacturer of lamotrigine (GlaxoSmithKline). All randomized placebo-controlled studies on patients receiving clozapine were included in the analysis. The primary outcome measure was a total score for symptoms of psychosis, and the secondary outcome measures were scores for positive and negative symptoms of psychosis. For continuous and binary data, standardized mean differences (SMD), and odds ratios (OR) and the number needed to treat (NNT) were calculated, respectively.. Five trials with 10 to 24 weeks duration and total of 161 randomized clozapine patients were included in the meta-analysis. Lamotrigine was superior to placebo augmentation in both the primary outcome measure (SMD 0.57, 95%CI 0.25-0.89, p<0.001; OR 0.19, 95%CI 0.09-0.43, p<0.001; NNT 4, 95%CI 3-6) and secondary outcome measures (SMD 0.34, 95%CI 0.02-0.65 for positive symptoms, SMD 0.43, 95%CI 0.11-0.75 for negative symptoms).. This meta-analysis suggests that lamotrigine augmentation may be an effective treatment for patients with clozapine-resistant schizophrenia. A substantial proportion of these most severely ill patients appeared to obtain clinically meaningful benefit from this combination treatment.

Topics: Age Factors; Anticonvulsants; Antipsychotic Agents; Clozapine; Cognition Disorders; Drug Resistance; Drug Therapy, Combination; Humans; Lamotrigine; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triazines

Inadequate response to clozapine treatment is frequently encountered in practice and augmentation strategies have been developed in an attempt to improve response. Aims of the study were to evaluate the therapeutic effect of adding an antipsychotic drug to clozapine treatment.. Meta-analysis of randomized, placebo-controlled studies of antipsychotic augmentation of clozapine treatment.. Ten studies (including 522 subjects) met inclusion criteria. Antipsychotic augmentation showed significant benefit over the addition of placebo on only one outcome measure examined [mean effect size for rating scale score (BPRS/PANSS) -0.180, 95% CI -0.356 to -0.004]. Antipsychotic augmentation showed no advantage on withdrawals from trials (risk ratio 1.261, 95% CI 0.679-2.345) or on CGI scores (effect size -0.661, 95% CI -1.475 to 0.151). Duration of study was not associated with outcome (P = 0.95). There was no evidence of publication bias.. In studies lasting up to 16 weeks, the addition of an antipsychotic to clozapine treatment has marginal therapeutic benefit. Longer and larger trials are necessary to demonstrate the precise therapeutic utility of antipsychotic co-therapy with clozapine.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Placebos; Psychiatric Status Rating Scales; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

One in a hundred people will develop schizophrenia; about 75% of people have relapses and continued disability, and a third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment.. We conducted a systematic review and aimed to answer the following clinical questions: Which interventions reduce relapse; and improve adherence rates? Which interventions are effective in people resistant to standard antipsychotic drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review we present information relating to the effectiveness and safety of the following interventions: behavioural therapy, clozapine, cognitive behavioural therapy (CBT), compliance therapy, continuation of antipsychotic drugs (reduce relapse rates), first-generation antipsychotic drugs in treatment-resistant people, multiple-session family interventions, psychoeducational interventions, second-generation antipsychotic drugs in treatment-resistant people, and social-skills training.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Schizophrenia; Treatment Outcome

Although clozapine has been shown to be the treatment of choice in people with schizophrenia that are resistant to treatment, one third to two thirds of people still have persistent positive symptoms despite clozapine monotherapy of adequate dosage and duration. The need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine is the most common reason for simultaneously prescribing a second antipsychotic drug in combination with clozapine.. To determine the efficacy and tolerability of various clozapine combination strategies with antipsychotics in people with treatment resistant schizophrenia.. We searched the Cochrane Schizophrenia Group Trials Register (March 2008) and MEDLINE (up to November 2008). We checked reference lists of all identified randomised controlled trials and requested pharmaceutical companies marketing investigational products to provide relevant published and unpublished data.. We included only randomised controlled trials recruiting people of both sexes, aged 18 years or more, with a diagnosis of treatment-resistant schizophrenia (or related disorders) and comparing clozapine plus another antipsychotic drug with clozapine plus a different antipsychotic drug.. Two review authors independently extracted data and resolved disagreement by discussion with third member of the team. When insufficient data were provided, we contacted the study authors.. Three small (range of number of participants 28 to 60) randomised controlled trials were included in the review. Even though results from individual studies did not find that one combination strategy is better than the others, the methodological quality of included studies was too low to allow authors to use the collected data to answer the research question correctly.. In this review we considered the risk of bias too high because of the poor quality of the retrieved information (small sample size, heterogeneity of comparisons, flaws in the design, conduct and analysis). Although clinical guidelines recommend a second antipsychotic in addition to clozapine in partially responsive patients with schizophrenia, the present systematic review was not able to show if any particular combination strategy was superior to the others. New, properly conducted, randomised controlled trials independent from the pharmaceutical industry need to recruit many more patients to give a reliable estimate of effect or of no effect of antipsychotics as combination treatment with clozapine in patients who do not have an optimal response to clozapine monotherapy.

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride; Thiazoles

Topics: Antipsychotic Agents; Baclofen; Clozapine; Drug Resistance; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Humans; Schizophrenia; Smoking; Tobacco Use Disorder; Transcranial Magnetic Stimulation

In as many as one third of those afflicted with schizophrenia, the symptoms have emerged before adulthood. Early-onset schizophrenia is often a long-term illness with an unfavorable prognosis. Clozapine is more effective than other antipsychotic drugs in adults, but its use is limited by potential adverse effects, of which agranulocytosis is the most serious one. According to the treatment practice for adults, clozapine emerges inevitably as a drug option for difficult-to-manage schizophrenia in an under-aged person. The few studies conducted on the subject speak for the use of clozapine also in the under-aged.

Topics: Age of Onset; Antipsychotic Agents; Child; Clozapine; Humans; Schizophrenia

In many countries of the industrialised world second generation ('atypical') antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether, and if so how much, the effects of the various new generation antipsychotics differ is a matter of debate. In this review we examined how the efficacy and tolerability of ziprasidone differs from that of other second generation antipsychotics.. To evaluate the effects of ziprasidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Group Specialised Register (April 2007) and references of all identified studies for further trial citations. We contacted pharmaceutical companies and authors of trials for additional information.. We included all randomised, at least single-blind, controlled trials comparing oral ziprasidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone or zotepine in people with schizophrenia or schizophrenia-like psychoses.. We extracted data independently. For continuous data, we calculated weighted mean differences (MD) for dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate.. The review currently includes nine randomised controlled trials (RCTs) with 3361 participants. The overall rate of premature study discontinuation was very high (59.1%). Data for the comparisons of ziprasidone with amisulpride, clozapine, olanzapine, quetiapine and risperidone were available. Ziprasidone was a less acceptable treatment than olanzapine (leaving the studies early for any reason: 5 RCTs, n=1937, RR 1.26 CI 1.18 to 1.35, NNH 7 CI 5 to 10) and risperidone (3 RCTs, n=1029, RR 1.11 CI 1.02 to 1.20, NNH 14 CI 8 to 50), but not than the other second generation antipsychotic drugs. Ziprasidone was less efficacious than amisulpride (leaving the study early due to inefficacy: 1 RCT, n=123, RR 4.72 CI 1.06 to 20.98, NNH 8 CI 5 to 50) olanzapine (PANSS total score: 4 RCTs, n=1291, MD 8.32 CI 5.64 to 10.99) and risperidone (PANSS total score: 3 RCTs, n=1016, MD 3.91 CI 0.27 to 7.55). Based on limited data there were no significant differences in tolerability between ziprasidone and amisulpride or clozapine. Ziprasidone produced less weight gain than olanzapine (5 RCTs, n=1659, MD -3.82 CI -4.69 to -2.96), quetiapine (2 RCTs, n=754, RR 0.45 CI 0.28 to 0.74) or risperidone (3 RCTs, n=1063, RR 0.49 CI 0.33 to 0.74). It was associated with less cholesterol increase than olanzapine, quetiapine and risperidone. Conversely ziprasidone produced slightly more extrapyramidal side-effects than olanzapine (4 RCTs, n=1732, RR 1.43 CI 1.03 to 1.99, NNH not estimable) and more prolactin increase than quetiapine (2 RCTs, n=754, MD 4.77 CI 1.37 to 8.16), but less movement disorders (2 RCTs, n=822, RR 0.70 CI 0.51 to 0.97, NNT not estimable) and less prolactin increase (2 RCTs, n=767, MD -21.97 CI -27.34 to -16.60) than risperidone.. Ziprasidone may be a slightly less efficacious antipsychotic drug than amisulpride, olanzapine and risperidone. Its main advantage is the low propensity to induce weight gain and associated adverse effects. However, the high overall rate of participants leaving the studies early limits the validity of any findings.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride; Thiazoles

Poor treatment response in patients with schizophrenia is an important clinical problem, and one possible strategy is concurrent treatment with more than one antipsychotic (polypharmacy). We analyzed the evidence base for this strategy using a translational research model focused on clozapine-antipsychotic polypharmacy (CAP). We considered 3 aspects of the existing knowledge base and translational research: the link between basic science and clinical studies of efficacy, the evidence for effectiveness in clinical research and the implications of research for the health care delivery system. Although a rationale for CAP can be developed from receptor pharmacology, there is little available preclinical research testing these concepts in animal models. Randomized clinical trials of CAP show minimal or no benefit for overall severity of symptoms. Most studies at the level of health services are limited to estimates of CAP prevalence and some suggestion of increased costs. Increasing use of antipsychotic polypharmacy in general may be a factor contributing to the under-utilization of clozapine and long delays in initiating clozapine monotherapy. Translational research models can be applied to clinical questions such as the value of CAP. Better linkage between the components of translational research may improve the appropriate use of medications such as clozapine in psychiatric practice.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Therapy, Combination; Humans; Polypharmacy; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Treatment Failure; Treatment Outcome

Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

Topics: Animals; Antipsychotic Agents; Arousal; Autoreceptors; Avoidance Learning; Binding, Competitive; Brain; Clozapine; Cognition; Cognition Disorders; Drug Approval; Histamine; Histamine Agonists; Histamine H3 Antagonists; Humans; Imidazoles; Male; Metabolic Clearance Rate; Motor Activity; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3; Schizophrenia; Sulfur Radioisotopes

Despite lacking evidence for its safety and efficacy, antipsychotic cotreatment is common in schizophrenia.. To evaluate therapeutic and adverse effects of antipsychotic cotreatment vs monotherapy in schizophrenia.. Cochrane Schizophrenia Group register and hand searches of relevant journals/conference proceedings.. Randomized controlled trials comparing antipsychotic monotherapy to cotreatment with a second antipsychotic.. Two authors independently extracted data. For homogenous dichotomous data, we calculated random effects, relative risk (RR), 95% confidence intervals (CIs), and numbers needed to treat (NNT). For continuous data, weighted mean differences were calculated.. In 19 studies (1229 patients) with 28 monotherapy and 19 cotreatment arms, antipsychotic cotreatment was superior to monotherapy regarding 2 a priori defined coprimary outcomes: less study-specific defined inefficacy (N = 22, n = 1202, RR = 0.76, CI = 0.63-0.90, P = .002, NNT = 7, CI = 4-17, P = .0008, I(2) = 78.9%) and all-cause discontinuation (N = 20, n = 1052, RR = 0.65, CI = 0.54-0.78, P < .00001). Results were consistent using Clinical Global Impressions thresholds of less than much (P = .006) and less than minimally (P = .01) improved. Specific psychopathology and adverse event data were insufficient to yield meaningful results. In sensitivity analyses, 5 efficacy moderators emerged: concurrent polypharmacy initiation, clozapine combinations, trial duration >10 weeks, Chinese trials, and second-generation + first-generation antipsychotics. In a meta-regression, similar dose combinations, second-generation + first-generation antipsychotics and concurrent polypharmacy initiation remained significant.. In certain clinical situations, antipsychotic cotreatment may be superior to monotherapy. However, the database is subject to possible publication bias and too heterogeneous to derive firm clinical recommendations, underscoring the need for future research.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Databases as Topic; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Polypharmacy; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In patients with schizophrenia who do not have an optimal response to clozapine, it remains unclear if there is an evidence base to support a second antipsychotic in combination with clozapine. The present systematic review was therefore carried out to determine the efficacy of various clozapine combination strategies with antipsychotics. Relevant studies were located by searching the Cochrane Schizophrenia Group Trials Register, Medline, and Embase (up to November 2007). Only studies randomly allocating patients to clozapine plus another antipsychotic vs clozapine monotherapy were included. The search yielded 21 studies suitable for reanalysis. In 3 trials, clozapine was combined with a phenothiazine, in 8 trials with a benzamide, and in the remaining trials with risperidone. While the majority of randomized trials were not double blind, 6 studies were double-blind placebo-controlled trials. A total of 14 randomized open studies significantly favored clozapine combination strategy in terms of mean difference (random effect standardized mean difference [SMD] = -0.80, 95% confidence interval [CI] = -1.14 to -0.46); however, data extracted from 6 randomized double-blind studies did not show a statistically significant positive effect of this combination strategy in terms of mean difference (SMD = -0.12, 95% CI = -0.57 to 0.32). In terms of percentage of patients failing to show an improvement, a total of 10 randomized open studies significantly favored clozapine combination strategy (random effect relative risk [RR] = 0.64, 95% CI = 0.42 to 0.97), but data extracted from 6 randomized double-blind studies did not show a statistically significant positive effect of this combination strategy (RR = 0.91, 95% CI = 0.75 to 1.11). We conclude that the evidence base supporting a second antipsychotic in addition to clozapine in partially responsive patients with schizophrenia is weak. This weak evidence indicates modest to absent benefit.

Topics: Antipsychotic Agents; Clozapine; Databases as Topic; Double-Blind Method; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Early-onset psychotic illnesses in children and adolescents are not as rare as is commonly believed. These disorders, which include schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, and major depression with psychotic features, often have a chronic and severe course and poor long-term outcome. Many patients with early-onset schizophrenia have greater functional impairments than most patients with adult-onset schizophrenia. Magnetic resonance imaging studies show that patients with early-onset schizophrenia experience substantial gray matter loss during adolescence, which is not observed in studies of patients with adult-onset schizophrenia. The chronic course, severe functional impairments, and poor prognosis of early-onset psychosis create a great need to identify effective and safe treatments for youth with psychosis. Although atypical anti-psychotics have been considered superior to traditional antipsychotics, there has been little controlled information to inform clinical decisions until recently. Over the past 5 years, several studies have been initiated to address these questions. The results of the studies completed to date are reviewed.

Topics: Adolescent; Adult; Age of Onset; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brain Diseases; Child; Chronic Disease; Clozapine; Comorbidity; Disease Progression; Humans; Magnetic Resonance Imaging; Olanzapine; Piperazines; Prognosis; Psychotic Disorders; Quinolones; Schizophrenia; Thiazoles; Treatment Failure

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Pulmonary Embolism; Schizophrenia

Second generation antipsychotic medications have become synonymous with "atypicality." To support the clinical lore of equivalent efficacy with reduced risk of extrapyramidal symptoms, clinical trials have overwhelmingly chosen a high-potency first-generation antipsychotic (e.g., haloperidol) as a comparator. Very few clinical trials have compared a second-generation antipsychotic with a low- or mid-potency first-generation antipsychotic medication.. We identified eight completed, published, double-blind, randomized clinical trials that compared a second-generation antipsychotic with a low- or mid-potency first-generation antipsychotic and reviewed outcome measures for efficacy and extrapyramidal symptoms; 1,241 patients were represented in these eight trials.. Although data are very limited, mid- and low-potency first-generation antipsychotics show efficacy and extrapyramidal side effects that are comparable to those of second-generation antipsychotics.. Aside from clozapine, first-generation and second-generation antipsychotics represent a diverse group of medications that have heterogenous receptor profiles and side effects but comparable clinical efficacy and potential to cause extrapyramidal symptoms. Clinicians may provide better treatment for patients by considering the unique pharmacological and side-effect profile of each particular antipsychotic independent of its classification as a first- or second-generation agent.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cognition Disorders; Haloperidol; Humans; Quality of Life; Schizophrenia

Substance use disorder is common in patients with schizophrenia and dramatically worsens their outcome. The typical antipsychotic medications, introduced more than 50 years ago, are effective for the treatment of psychosis but may have only limited efficacy in patients with these co-occurring disorders because patients continue to use substances while taking them. In preliminary studies, however, several of the atypical antipsychotic medications have shown promise for reducing alcohol and drug use in patients with schizophrenia. A neurobiological formulation is discussed, suggesting that the use of substances in patients with schizophrenia may be based on a dysfunction within the dopamine-mediated brain reward circuitry and that clozapine, in particular, may potentially ameliorate this dysfunction and lessen the desire for substance use. Medications for the treatment of alcohol use disorders, such as disulfiram, naltrexone, and acamprosate, as well as other adjunctive medications, may also be useful. Further studies are required to establish a solid evidence base of best practices for the use of medications in these patients.

Topics: Acamprosate; Alcohol Deterrents; Antipsychotic Agents; Clozapine; Disulfiram; Drug Interactions; Humans; Naltrexone; Narcotics; Schizophrenia; Substance-Related Disorders; Taurine

N-methyl-D-aspartate receptor (NMDAR) hypo-function theory of schizophrenia proposes that impairment in NMDAR function be associated with the pathophysiology of schizophrenia and suggests that enhancement of the receptor function may produce efficacy for schizophrenia. Consistent with this theory, for the last decade, clinical trials have demonstrated that the enhancement of NMDAR function by potentiating the glycine site of the receptor is efficacious in the treatment of schizophrenia. Full agonists of the glycine site, glycine and D-serine and a glycine transporter-1 inhibitor, sarcosine, added to antipsychotic drugs, have been shown to be effective in the treatment of negative symptoms and possibly cognitive symptoms without significantly affecting the positive symptoms of schizophrenia. A partial agonist of the glycine site, D-cycloserine, added to antipsychotic drugs, can be effective for the negative symptoms at the therapeutic doses. However, these drugs have not shown clinical efficacy when added to clozapine, suggesting that the interactions of clozapine and the glycine site potentiators may be different from those of other antipsychotic drugs and the potentiators. This article suggests that the glycine site potentiators may produce efficacy for negative and cognitive symptoms by blocking apoptosis-like neuropathological processes in patients with chronic schizophrenia and thereby can deter progressive deterioration of the disorder. This article proposes a polypharmacy of glycine site potentiators augmented with antipsychotic drugs to control positive and negative symptoms in a synergistic manner and block deterioration in schizophrenia. Since the NMDAR complex consists of multiple sites modulating receptor functions, the efficacy of glycine site potentiators for schizophrenia suggests the possibility that manipulation of other modulating sites of the NMDAR can also be efficacious in the treatment of schizophrenia.

Topics: Acetamides; Alanine; Antipsychotic Agents; Clozapine; Cognition; Cycloserine; Dopamine Agents; Drug Synergism; Drug Therapy, Combination; Glycine; Glycine Agents; Glycine Plasma Membrane Transport Proteins; Humans; Monoamine Oxidase Inhibitors; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Sarcosine; Schizophrenia; Schizophrenic Psychology; Serine

Topics: Adult; Antipsychotic Agents; Bromocriptine; Clozapine; Dopamine Agonists; Dopamine Antagonists; Drug Antagonism; Female; Haloperidol; Humans; Hyperprolactinemia; Pituitary Neoplasms; Prolactin; Prolactinoma; Schizophrenia

Although the role of clozapine is well established for treatment-resistant schizophrenia, it is rarely used in pediatric populations, mainly due to its potentially serious adverse effects.. To summarize practical aspects of use of clozapine in treating children with schizophrenia and management of associated adverse effects.. Available studies in the literature using clozapine in the pediatric population are summarized and the NIMH experience in treating refractory childhood-onset schizophrenia cases with clozapine is discussed.. Despite a higher incidence of adverse effects in children, clozapine appears to be a uniquely beneficial second-line agent for treating children with refractory schizophrenia.

Topics: Adolescent; Age of Onset; Akathisia, Drug-Induced; Antipsychotic Agents; Child; Child, Preschool; Clozapine; Drug Resistance; Humans; Neutropenia; Schizophrenia; Seizures; Weight Gain

Clozapine is an atypical antipsychotic with superior efficacy in the treatment of refractory schizophrenia. But it can cause agranulocytosis, which occurs in one to two percent of patients. This paper was prepared to discuss the condoned and controversial issues of therapy with this drug, but only within a haematological context. The feasibility of attempting therapeutically controversial blood monitoring regimes, as opposed to following standardised Western guidelines, given the differences in terms of accessibility, convenience and financial considerations between the public and private sector medical care will also be discussed. The proposal of adopting a structured pro forma, with a risk-benefit assessment, in the event of unavoidable veering from the guidelines may allay medicolegal implications, especially in countries where blood monitoring is not mandatory. It is hoped that this article will stimulate further research in our region, bearing in mind the increasing awareness and focus on genetic polymorphism, and the possibility of drawing up our own monitoring guidelines in the near future.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Developing Countries; Drug Monitoring; Humans; Liability, Legal; Patient Education as Topic; Practice Guidelines as Topic; Schizophrenia

Clozapine is one of the original atypical antipsychotics. It was withdrawn from the market in 1974 because of haematological safety concerns, but since 1989 has enjoyed a renaissance for the management of treatment-resistant schizophrenia under systems where case registration allows regular haematological monitoring. Clozapine continues to show enduring superiority across many aspects of the clinical pharmacology of the treatment of schizophrenia, e.g. it has specific anti-suicidal properties and recent broader trials have shown continuing superiority in wide groups of patients. This article considers some of the arguments for unshackling clozapine from its current license for schizophrenia (its superiority overall in treatment-resistant schizophrenia, its potential for use in first-episode patients, and its anti-suicidal potential), and tries to synthesise these into some of the national guidelines available for the treatment of schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

To conduct a meta-analysis of randomized placebo-controlled trials (RCTs) of clozapine augmentation with another antipsychotic drug in patient with schizophrenia who partially respond to clozapine and compare the results with the findings of relevant open studies.. A systematic literature search was conducted to identify eligible RCTs. All baseline, posttreatment, and change scores in these trials were included in the meta-analysis. For change in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale total scores, the effect size was calculated, and for the proportion of patients with a reduction in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale scores of 20% or more, the relative risk was calculated.. There was a total of 166 participants in the 4 eligible RCTs. Pooling effect sizes across these studies revealed clinically important heterogeneity (I = 63.5%). Analyzing by duration accounted for the heterogeneity (I = 0%), whereas analyzing by drug did not (I = 57.5%). The 2 RCTs lasting 10 weeks or more gave an odds ratio of response to treatment of 4.41 (95% confidence interval, 1.38 to 14.07). In 8 open studies identified, the same pattern of response was seen. The main treatment-emergent side effects reported were extrapyramidal side effects and raised serum prolactin.. Augmentation of clozapine with another antipsychotic drug in patients with schizophrenic illness that has partially responded to clozapine is worthy of an individual clinical trial. This trial may need to be longer than the 4 to 6 weeks usually recommended for acute antipsychotic monotherapy.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; GABA Antagonists; Humans; Prolactin; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin Antagonists

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Histamine; Receptors, Muscarinic; Receptors, Opioid; Receptors, Serotonin; Schizophrenia

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyslipidemias; Glucose Metabolism Disorders; Humans; Insulin Resistance; Mental Disorders; Obesity; Olanzapine; Phenothiazines; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Thiazoles

This article opens with a brief history of pharmacologic treatment of schizophrenia. It then discusses the definition and treatment of treatment-resistant schizophrenia, with particular attention to clinical, biological and neuroimaging correlates, as well as the best treatment options, including the use of clozapine in patients who meet the definition of treatment-resistant schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Polypharmacy; Radiography; Schizophrenia

In recent years, there has been a growing interest in developing adequate treatments for patients with a diagnosis of schizophrenia and a comorbid substance use disorder (SUD). In the present paper we aim to critically review published reports on the use of conventional and second-generation antipsychotics in the treatment of patients with schizophrenia and comorbid SUD, to provide clinicians with a clearer view of the pharmacological treatment of this highly prevalent dual diagnosis based upon the evidence arising from the scientific literature.. A search of the relevant literature from Medline, PsycLIT and EMBASE databases, included in the Science Citation Index, and available up to November 2006 was conducted using the terms: 'schizophrenia', 'substance use disorder' and 'antipsychotics'.. While research on the use of conventional antipsychotics has remained limited, the majority of studies suggest the effectiveness of second-generation antipsychotics, particularly clozapine, for patients with schizophrenia and a comorbid substance use disorder.. In the absence of randomized controlled trials that could provide more reliable information, clinical decisions may need to rely on indirect data provided by the increasing number of case reports, open trials and retrospective studies showing a decrease in cigarette smoking, alcohol, cocaine or cannabis use and an improvement of overall psychiatric symptoms.

Topics: Alcoholism; Antipsychotic Agents; Clozapine; Cocaine-Related Disorders; Combined Modality Therapy; Comorbidity; Cross-Sectional Studies; Diagnosis, Dual (Psychiatry); Humans; Marijuana Abuse; Schizophrenia; Smoking Cessation; Substance-Related Disorders

Most of the data evaluating the potential relationship between diabetes, schizophrenia, and anti-psychotics currently derive from retrospective analysis. Relevant confounders of such data include screening and selection bias. Prospective data collected from randomized controlled trials may reduce such biases. As no single trial has glucose comparisons as a primary endpoint, we undertook a systematic review of available data.. Embase, HealthStar, MEDLINE, Pre-MEDLINE, and PsycINFO databases were searched online for relevant articles. Abstracts from major congresses held between January 2000 and April 2006 were included. Search terms included all currently available antipsychotics: olanzapine, risperidone, clozapine, quetiapine, ziprasidone, aripiprazole, haloperidol, chlorpromazine, and zotepine.. Prospective clinical trials involving schizophrenia patients with no stated previous glucose abnormalities randomly assigned to cohorts receiving active or placebo comparator antipsychotic medications were included with no restrictions on study length. 16 studies were from peer-reviewed publications, 4 were from posters at major congresses, and 2 were available only on Internet-based sites.. Glucose parameters reported included fasting and random glucose and glycosylated hemoglobin. Data reported included mean changes and categorical reports of abnormal levels.. Data were available in 6329 patients from 22 trials. The most common comparator agents were aripiprazole and olanzapine in 4 studies including 1432 patients. 14 studies reported fasting and 9 studies reported nonfasting data. 15 studies were a minimum of 5 months, with 8 studies of at least 1 year's duration. No consistent significant glucose differences were found between any comparator antipsychotics or placebo in any trial.. In contrast to some of the retrospective data, an analysis of prospective data from randomized clinical trials showed no consistent significant differences in the incidence of treatment-emergent glucose abnormalities in patients treated with antipsychotics. The reduction in both screening and selection biases may be relevant. Although one third of the studies had at least 1 year's duration, the data are not sufficient to reach conclusions regarding patients receiving longer-term treatment with atypical antipsychotics.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Humans; Olanzapine; Piperazines; Quinolones; Schizophrenia

The aim of the present paper is to review the various aspects of refractory schizophrenia regarding issues such as definitions, clinical aspects, psychobiological correlates, pharmacological and non-pharmacological treatment options and predictors of treatment response.. Medline search as well as articles of the authors.. Refractory schizophrenia affects at least one third of patients with schizophrenia and the best evidence shows that is monotherapy with clozapine remains the mainstay for the treatment of such condition. Antipsychotic polipharmacy is not supported by current evidence and recent clinical trials have shown that clozapine augmentation with antipsychotics has no benefit over placebo.

Topics: Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Clozapine; Cognitive Behavioral Therapy; Drug Resistance; Drug Therapy, Combination; Humans; Polypharmacy; Schizophrenia; Treatment Outcome

This meta-analytic review examines the efficacy of antipsychotic medications in ameliorating schizophrenia-related long-term memory (LTM) impairments. Twenty-three studies were reviewed that compared schizophrenia spectrum patients treated (a) with atypical versus typical antipsychotic medications, or (b) with various atypical treatments. In 17 atypical versus typical trials aggregating 939 participants, superior overall (verbal and nonverbal) LTM was detected in patients assigned to atypical trials. However, this difference was small (effect size estimate (ES) 0.17; 95% Confidence Interval (CI) 0.04 to 0.31) and specific to certain atypical treatments. Relative to typical antipsychotic trials, LTM superiority was marginally significant for risperidone trials (ES 0.20; 95% CI -0.03 to 0.44) and significant for olanzapine trials (ES 0.29; 95% CI 0.08 to 0.49). In contrast, clozapine trials did not produce a LTM advantage over typical trials (ES -0.06; 95% CI -0.35 to 0.23). Due to the lack of available studies, the effect of quetiapine was indeterminate. Direct comparison between atypical trials revealed a similar effect pattern. A marginally significant superiority in overall LTM was detected for risperidone and olanzapine compared to clozapine (ES 0.28; 95% CI -0.04 to 0.59), which reached significance for verbal LTM (ES 0.36; 95% CI 0.04 to 0.67). Finally, the beneficial impact of antipsychotic medications emerged as a function of differences in the anticholinergic properties of the treatment arms being compared.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Memory Disorders; Olanzapine; Retention, Psychology; Risperidone; Schizophrenia

Treatment-refractory early-onset schizophrenia is a rare but severe form of the disorder associated with poor premorbid function and long-term disability. The currently available evidence suggests that clozapine remains the most efficacious treatment for the amelioration of both positive and negative symptoms of the disorder and problematic aggressive behaviors. Clozapine use in children and adolescents, however, is limited by its association with hematologic adverse events and an increased frequency of seizure activity. Further studies are needed to examine the usefulness of antipsychotic combinations and of augmentation therapies to antipsychotic medications in order to treat persistent residual psychotic symptoms in children and adolescents who have schizophrenia and who have not responded to several sequential trials of antipsychotic monotherapy.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Child; Clozapine; Drug Resistance; Humans; Olanzapine; Schizophrenia

Schizophrenia is a serious lifelong mental illness for which current treatments may only be partially effective. All antipsychotic medications available at present are thought to exert their main antipsychotic effect through antagonism of dopamine D2 receptors. Clozapine is the most effective antipsychotic drug currently available, but it can cause serious side effects, including agranulocytosis and diabetes. Pharmacologic factors that distinguish clozapine from other antipsychotic drugs have been studied to try to develop safer drugs with similar efficacy to clozapine. These have met with limited success. Neurochemical imaging techniques, such as positron emission tomography, single photon emission tomography and magnetic resonance spectroscopy, have been used to study antipsychotic drug action in living human subjects. These techniques shed a great deal of light on the mechanisms of antipsychotic action and have revealed a number of novel targets for future drug development in schizophrenia. Next-generation antipsychotic medications will aim to improve on the efficacy and tolerability of currently available medications. The authors believe that they are likely to achieve this through drug action at non-D2 sites. Future research and drug development, including the development of medications to prevent progression from the prepsychotic stage to schizophrenia, will rely heavily on neurochemical imaging methods at all stages in the drug-discovery pipeline.

Topics: Animals; Antipsychotic Agents; Brain Chemistry; Clozapine; Diagnostic Imaging; Drug Design; Expert Testimony; Humans; Receptors, Dopamine; Schizophrenia

Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Eating; Energy Metabolism; Humans; Neurobiology; Olanzapine; Reward; Schizophrenia

Current treatments for schizophrenia target the dopamine system. Developments of new treatments that target the glutamate system, however, are under progress, in particular, for the N-methyl-D-aspartate-type glutamate receptor. Compared with dopaminergic treatments, these treatments may show improved efficacy in the treatment of persistent negative symptoms.. During the past year, clinical trials have been published with several agonists at the glycine site of the N-methyl-D-aspartate receptor, including glycine, D-serine, D-alanine and with the glycine transport inhibitor, sarcosine. Studies published during the past year indicate highly significant beneficial effects on negative symptoms when these compounds are added to both conventional and newer atypical antipsychotics in efficacy models although an effectiveness trial of current formulations of glycine and D-cycloserine failed to show an overall benefit. Relevant issues across studies may include the compound chosen, its formulation and tolerability, populations studied, and the nature and dose of the base antipsychotic treatment.. The present findings continue to support the use of N-methyl-D-aspartate/glycine site agonists as potential new treatments for persistent negative symptoms of schizophrenia. Ongoing work with novel compounds and new formulations may assist in the translation of these advances into clinic-ready pharmacotherapies.

Topics: Antimetabolites; Antipsychotic Agents; Clozapine; Cycloserine; Drug Therapy, Combination; Glutamic Acid; Glycine; Humans; Receptors, N-Methyl-D-Aspartate; Sarcosine; Schizophrenia

Atypical antipsychotics are frequently used as augmentation agents in clozapine-resistant schizophrenic patients. Risperidone (RIS) is the one most studied as a clozapine (CLZ) adjunct. The aim of this study is to critically review all published studies regarding the efficacy and safety of RIS as an adjunctive agent in CLZ-resistant schizophrenic or schizoaffective patients.. A MEDLINE search from January 1988 to June 2005 was conducted. Identified papers were examined against several clinical, pharmacological and methodological parameters.. A total of 15 studies were found (2 randomized controlled trials, 3 open-label trials (OTs) and 8 case-studies (CSs)) comprising 86 schizophrenic or schizoaffective patients (mean age 38.4 years). Mean CLZ dosage during the combined treatment was 474.2 mg/day. Plasma CLZ levels were assessed in 62 patients (72.1%). RIS was added at a mean dosage of 4.6 mg/day for a mean of 7.9 weeks. Significant improvement in psychopathology was reported for 37 patients (43%). A lower RIS dosage and a longer duration of the trial seemed to be associated with a better outcome. Main side effects reported were: extrapyramidal symptoms or akathisia (9.3%), sedation (7%) and hypersalivation (5.8%).. Existing evidence encourages the use of RIS as an adjunctive agent in CLZ-resistant schizophrenic or schizoaffective patients.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Sialorrhea; Treatment Outcome

Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes agranulocytosis in 0.8% of patients. The risk factors for clozapine-induced agranulocytosis (CIA) and the underlying mechanisms are unclear.. To ascertain the genetic and immunological risk factors for CIA, and on the basis of these findings to construct an explanatory model for CIA.. We reviewed the literature via Medline (from 1966 to May 2004) and EMBASE (from 1980 to May 2004) using the search terms 'clozapine' and 'agranulocytosis'.. We found 8 case-control studies that fulfilled our selection criteria. In schizophrenia patients, CIA appeared to be significantly associated with certain haplotypes of HLA (human leukocyte antigens) genes, with the 4b,3d microsatellite alleles of TNF (tumor necrosis factor), with variant genes of HSP 70 (heat-shock protein), and with NQO2 (dihydronicotinamide riboside quinone oxidoreductase) gene polymorphism. Most of these genetic findings are interrelated. Gene abnormalities of this kind probably play an important aetiological role in CIA and may provide a basis for the construction of an immuno-toxic explanatory model for CIA.. It seems likely that CIA can be explained on the basis of genetic and immunotoxic factors. The model should help us to understand how agranulocytosis can be caused by various antipsychotics and how it can be treated. However, it is not yet possible to identify patients who are particularly at risk for CIA.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genetic Predisposition to Disease; HLA Antigens; Humans; Major Histocompatibility Complex; Risk Factors; Schizophrenia

Co-occurring substance use disorder is common among patients with schizophrenia, and its presence greatly worsens the course of schizophrenia. A number of theories have been introduced to explain the increased rate of substance use disorder in these patients. These theories include the notion that substance use could trigger psychotic symptoms in vulnerable individuals and the idea that the substances are used to self-medicate symptoms of schizophrenia. Our group and others have advanced a neurobiological hypothesis to explain this comorbidity-that a mesocorticolimbic brain reward circuit underlies the substance use disorder in patients with schizophrenia. Treatment of substance use disorder in these patients is best done with integrated treatment programs that combine psychosocial interventions with pharmacotherapy. Recent data suggest that the atypical antipsychotic clozapine and perhaps other atypical agents may lessen substance use in patients with schizophrenia. My colleagues and I have proposed that clozapine's effect in these patients may be related to its ability to decrease the brain reward circuit dysfunction. Research is continuing on the use of atypical antipsychotics in patients with schizophrenia and comorbid substance abuse. The adjunctive use of naltrexone or other agents also may be helpful. Further research on the optimal pharmacologic approach to patients with dual diagnosis is needed.

Topics: Alcohol Deterrents; Alcoholism; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Disulfiram; Drug Therapy, Combination; Humans; Naltrexone; Narcotic Antagonists; Schizophrenia; Substance-Related Disorders; Treatment Outcome

Second-generation antipsychotics make up one of the fastest growing segments of the rapidly growing pharmaceutical sector. Given limited health care resources, assessment of the value for the cost of second-generation antipsychotics relative to first-generation antipsychotics is critical for resource-allocation decisions.. With a MEDLINE search, the authors identified eight studies (based on six randomized clinical trials) that analyzed the cost-effectiveness of second-generation antipsychotics relative to first-generation antipsychotics in individuals with schizophrenia disorders. The authors reviewed appropriate methods of measurement, analysis, and design of cost-effectiveness studies in randomized clinical trials and evaluated the validity of economic results derived from the studies in light of appropriate methods.. The eight randomized clinical trial-based cost-effectiveness studies of antipsychotic medications faced a variety of threats to validity related to 1) measurement of costs, 2) measurement of effectiveness, 3) analysis of costs, 4) measurement of sampling uncertainty, 5) analysis of incomplete cost data, 6) minimizing loss to follow-up, and 7) threats to external validity.. Economic claims made by the authors of a number of trial-based economic evaluations have generally been favorable to second-generation antipsychotics. However, the methodological issues the authors of the current study identified suggest that there is no clear evidence that atypical antipsychotics generate cost savings or are cost-effective in general use among all schizophrenia patients. Psychiatrists, researchers, and administrators should consider the methodological issues highlighted in interpreting study results. These issues should be addressed in future trial designs.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cost-Benefit Analysis; Costs and Cost Analysis; Drug Costs; Health Care Costs; Humans; Olanzapine; Patient Dropouts; Randomized Controlled Trials as Topic; Reproducibility of Results; Research Design; Resource Allocation; Risperidone; Schizophrenia; Treatment Outcome

Thirty years ago, psychiatrists had only a few choices of old neuroleptics available to them, currently defined as conventional or typical antipsychotics, as a result schizophrenics had to suffer the severe extra pyramidal side effects. Nowadays, new treatments are more ambitious, aiming not only to improve psychotic symptoms, but also quality of life and social reinsertion. Our objective is to briefly but critically review the advances in the treatment of schizophrenia with antipsychotics in the past 30 years. We conclude that conventional antipsychotics still have a place when just the cost of treatment, a key factor in poor regions, is considered. The atypical antipsychotic drugs are a class of agents that have become the most widely used to treat a variety of psychoses because of their superiority with regard to extra pyramidal symptoms. We can envisage different therapeutic strategies in the future, each uniquely targeting a different dimension of schizophrenia, be it positive, negative, cognitive or affective symptoms.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Receptors, Dopamine; Receptors, Serotonin; Risperidone; Schizophrenia; Thiazoles

Schizophrenia is noted for the remarkably high prevalence of substance use disorders (SUDs) including nicotine (>85%), alcohol and stimulants. Mounting evidence supports the hypothesis that the endophenotype of schizophrenia involves hypofunction of a subpopulation of cortico-limbic NMDA receptors. Low doses of NMDA receptor antagonists such as ketamine replicate in normal volunteers positive, negative and cognitive symptoms of schizophrenia as well as associated physiologic abnormalities such as eye tracking and abnormal event related potentials. Genetic studies have identified putative risk genes that directly or indirectly affect NMDA receptors including D-amino acid oxidase, its modulator G72, proline oxidase, mGluR3 and neuregulin. Clinical trials have shown that agents that directly or indirectly enhance the function of the NMDA receptor at its glycine modulatory site (GMS) reduce negative symptoms and in the case of D-serine and sarcosine improve cognition and reduce positive symptoms in schizophrenic subjects receiving concurrent anti-psychotic medications. Notably, the GMS partial agonist D-cycloserine exacerbates negative symptoms in clozapine responders whereas full agonists, glycine and D-serine have no effects, suggesting clozapine may act indirectly as a full agonist at the GMS of the NMDA receptor. Clozapine treatment is uniquely associated with decreased substance use in patients with schizophrenia, even without psychologic intervention. Given the role of NMDA receptors in the reward circuitry and in substance dependence, it is reasonable to speculate that NMDA receptor dysfunction is a shared pathologic process in schizophrenia and co-morbid SUDs.

Topics: Acamprosate; Alcohol Deterrents; Animals; Antipsychotic Agents; Clozapine; Diagnostic Imaging; Glutamates; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Substance-Related Disorders; Taurine

The advent of second-generation antipsychotics (SGA) in the wake of clozapine, the prototype for atypical antipsychotics, represents a breakthrough in the pharmacologic treatment of schizophrenia. There is growing evidence that most of the SGA can offer advantages over first-generation antipsychotics within the effective dose range, such as improvement in negative symptoms and cognitive impairment, fewer extrapyramidal side effects, and less hyperprolactinemia. However, the essential pharmacological properties that confer the different therapeutic effects of the SGA have remained elusive, and the search for novel antipsychotics without dopamine D2 receptor antagonism has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current predominant theories of mechanisms of action of SGA, including the serotonin-dopamine hypothesis, the "fast-off-D2 theory," and regional specificity. In addition, it focuses on the roles of N-methyl-D-aspartate receptors, dopamine DI receptors, and alpha-adrenergic receptors in the pharmacology of SGA.

Topics: Animals; Antidepressive Agents, Second-Generation; Clozapine; Dopamine D2 Receptor Antagonists; Humans; Receptors, Adrenergic, alpha; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Cognition Disorders; Drug Tolerance; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Piperazines; Quinolones; Risperidone; Schizophrenia; Sulpiride; Time Factors

Hypersalivation is frequently observed in patients treated with clozapine. Current strategies to counteract sialorrhea include the introduction of antimuscarinergic (anticholinergic) and alpha(2)-agonistic treatment. However, the use of these substances is limited in part by lack of efficacy and by adverse side effects. In cases of intractable sialorrhea, the application of botulinum toxin may be a new and safe therapeutic option. We here present an overview on current treatment strategies for sialorrhea and describe a patient who received botulinum toxin B for clozapine-induced hypersalivation.

Topics: Adult; Botulinum Toxins; Botulinum Toxins, Type A; Clozapine; Humans; Male; Muscarinic Antagonists; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Sialorrhea

To evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-D-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia.. All relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Group's Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively.. Eighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, D-serine, D-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and D-serine are effective in reducing negative symptoms (N = 132, fixed effect model SMD = -0.66, 95% CI -1.02 to -0.29, p = 0.0004) of schizophrenia, the magnitude of the effect is moderate. D-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N = 119, fixed effect model SMD = -0.11, 95% CI -0.48 to 0.25, p = 0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or D-serine (N = 80, random effect model WMD = -2.79, 95% CI -6.17 to 0.60, p = 0.11).. In the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia.

Topics: Clozapine; Cycloserine; Dioxoles; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Agents; Glycine; Humans; Hydro-Lyases; Molindone; Piperidines; Schizophrenia

Suicide remains a major cause of premature mortality among patients with schizophrenia. Evidence of reduced suicidal risk with available psychiatric treatments is limited, but emerging data suggest such an effect of clozapine in chronically psychotic patients, leading us to compile the reported evidence.. We searched for published studies with contrasting rates of suicides or attempts by psychotic patients treated with clozapine vs. other agents.. Among six such studies, random-effects meta-analysis indicated a substantially lower overall risk of suicidal behaviors with clozapine vs. other treatments (risk-ratio 3.3; 95% confidence interval [CI] 1.7-6.3; p<0.0001). For completed suicides, the risk ratio (RR) was 2.9 ([CI 1.5-5.7]; p=0.002).. Long-term treatment with clozapine was associated with three-fold overall reduction of risk of suicidal behaviors. However, available findings are quantitatively inconsistent, well-designed studies remain rare, and the only randomized trial did not find reduced risk of completed suicide. Additional randomized comparisons among modern treatments for psychotic disorders are required to clarify their impact on mortality.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia; Suicide, Attempted

The first atypical antipsychotic, clozapine (Clozaril), dramatically improved the outcome of treatment of patients with schizophrenia in two ways. First, it reduced psychotic symptoms without eliciting significant neurological side effects. Second, it was effective in approximately 30% of individuals who were previously refractory to treatment. Efforts to develop similar drugs have been partially successful in that newer antipsychotics are also less likely to produce neurological side effects. However, it has not yet been established that the newest antipsychotics are more effective than conventional agents in individuals who are refractory to treatment. In the first part of this review, the results of studies that evaluated the new antipsychotics and provided an outcome measure of response rate (regardless of how this index was defined) are summarized. Even with this broad criterion, the evidence suggests that the newer antipsychotics do not share the clinical advantages of clozapine. To explore the possible mechanisms for the clinical advantage of clozapine, evidence of antipsychotic-induced dopamine release in the brain is discussed in the second half of this article. This analysis indicates that acute clozapine administration induces the release of more dopamine in the cortex than in the striatum or limbic system. With conventional antipsychotics, this relationship is reversed. The newest antipsychotics do not show a preference among these sites. Moreover, after long-term treatment, tolerance develops to haloperidol, but not to clozapine, with regard to the amount of dopamine released in the brain. No data are available on the newest antipsychotics. Although more studies need to be done-especially studies of the effects of long-term administration of various conventional and atypical antipsychotics-this distinction might be relevant to the unique clinical advantage of clozapine.

Topics: Antipsychotic Agents; Brain; Clinical Trials as Topic; Clozapine; Dopamine; Drug Tolerance; Humans; Schizophrenia

Typical antipsychotic medications have considerably improved clinical outcome of patients suffering from schizophrenic psychoses, but up to 40% of the cases show treatment resistant symptoms. Even therapy with atypical antipsychotic drugs such as risperidone, quetiapine, olanzapine, sulpiride, amisulpride, and ziprasidone often fails to reach complete remission due to resistant, positive or negative symptoms or dose-limiting side effects. As this also holds true in the case of monotherapy with clozapine, a substance known to be effective against treatment-resistant schizophrenia, increasing numbers of patients receive atypical antipsychotic drugs in addition to clozapine. This review systematically evaluates case reports and clinical investigations on the use of clozapine combined with risperidone, olanzapine, quetiapine, sulpiride, amisulpride, or ziprasidone. Details on indication, methodology, and effects of the investigations are summarized. Only one double blind, placebo-controlled trial on the combination with sulpiride exists within a number of altogether 31 publications about 1182 treatments. Favorable effects on positive and/or negative symptoms or improvements of clozapine-induced side effects were described for every combination approach. In some cases pharmacokinetic interactions or serious unfavorable effects occurred. In conclusion it might be accepted that most of the combination therapies follow a neurobiological rational. There a major differences in the level of evidence that they are safe, tolerable and effective. We discuss criteria for the indication for augmenting clozapine therapy and the differential indication for existing alternatives. Additional randomized prospective trials are needed in order to evaluate these strategies systematically.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Combinations; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Treatment Outcome

Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17-0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; MEDLINE; Neuropsychological Tests; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Utilization; Evidence-Based Medicine; Humans; Practice Patterns, Physicians'; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; United States

Schizophrenia and obsessive-compulsive disorder (OCD) have historical, clinical, and epidemiological links. The clinical use of atypical neuroleptics (ie, dual serotonin-dopamine antagonists) to treat both conditions sheds a new light on them. We report the first two cases of obsessive-compulsive symptoms (OCS) induced by quetiapine in schizophrenia patients. A case of successful augmentation by quetiapine in refractory OCD is also presented. A review of the literature on OCS induced by atypical neuroleptics follows. This paradoxically induced OCD symptomology in schizophrenia patients administered atypical neuroleptics is discussed from new pathophysiological and clinical perspectives. The discussion emphasizes the prognostic implications of OCS in schizophrenia and available therapies for this comorbidity.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Male; Obsessive-Compulsive Disorder; Olanzapine; Quetiapine Fumarate; Schizophrenia

Approximately 40-70% of treatment-resistant schizophrenic patients fail to benefit from clozapine monotherapy or are partial responders. During the last years several clozapine adjunctive agents have come into clinical practice. This study aims to critically review all published randomized, double-blind, placebo-controlled clinical trials (RCTs) regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. A MEDLINE search for RCTs on clozapine adjunctive agents published from January 1980 to February 2004 was conducted. All identified papers were critically reviewed and examined against several methodological features as well as clinical and pharmacological parameters. Eleven trials including 270 patients, partial or non-responders to clozapine, assessed the efficacy of sulpiride, lithium, lamotrigine, fluoxetine, glycine, d-serine, d-cycloserine and ethyl-eicosapentanoate (E-EPA) as clozapine adjuncts. There were eight parallel-group and three crossover trials. The inclusion criteria varied widely. The duration as well as the dosage of clozapine monotherapy were reported adequate in only one trial. Plasma clozapine levels were assessed in only three trials. Main side-effects reported were hypersalivation, sedation, diarrhea, nausea, hyperprolactinaemia. The outcome favored clozapine augmentation with sulpiride, lamotrigine and E-EPA. Lithium was shown to benefit only schizoaffective patients. However, the methodological shortcomings of trials analyzed limit the impact of evidence provided.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

The introduction of antipsychotics in the 1950s revolutionised the treatment of schizophrenia, but it soon became apparent that a substantial number of patients demonstrated a suboptimal response to these antipsychotics. Clozapine proved to be beneficial in patients whose symptoms were treatment resistant, but it too had limitations, with as many as 40-70% of those treated with clozapine demonstrating inadequate response to this drug as well. The availability of other 'atypical' antipsychotics offers options, but clozapine appears to remain the most effective option in treatment-resistant schizophrenia. This, of course, raises the question of what to do when clozapine is only partially effective. To address the issue of treatment in patients who have demonstrated a suboptimal response to clozapine, efforts have focused on a variety of augmentation strategies, including numerous medications and electroconvulsive therapy. The current body of evidence consists largely of data from smaller open trials and case series/reports, although data from a limited number of controlled studies are now available. Not surprisingly, the evidence drawn from the former is more supportive of augmentation strategies, although the controlled trials are not without positive findings. The available information is certainly not so overwhelming as to endorse any single augmentation approach. Indeed, it argues for more controlled data and cautions us regarding the cost-benefit ratio in adopting this strategy. Over and above the added adverse effects of another treatment, there is evidence to indicate that actual clinical worsening can occur. Without compelling evidence, clinicians must resort to guiding principles. The potential benefits of augmentation cannot be ruled out, but it should be approached with caution and in a systematic fashion. Factors compromising clozapine response should first be ruled out, and any augmentation trials should be guided by existing evidence and a treatment plan that incorporates a clear understanding of target symptoms. A means of evaluating outcome effectively needs to be in place, and the trial should be circumscribed to prevent needless polypharmacy. A priori, an endpoint needs to be established and the trial discontinued unless results firmly support added benefits.

Topics: Animals; Antipsychotic Agents; Clozapine; Cross-Over Studies; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Electroconvulsive Therapy; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

A case of necrotizing enterocolitis in a 19-year old man treated for schizophrenic disorder, induced by a drug association involving clozapine and requiring surgical treatment, is presented. To our knowledge only few reports have described the occurrence of this complication with atypical antipsychotics. Evidence for linking this complication to clozapine was reinforced by the absence of any viral or bacterial infection. The authors present a review of similar cases, stress the potential hazards induced by such drug combinations and discuss supposed mechanisms of this enterocolitis.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Clozapine; Creatine Kinase; Enterocolitis, Necrotizing; Humans; Male; Schizophrenia

Topics: Antipsychotic Agents; Brain; Carrier Proteins; Chlorpromazine; Clozapine; Dopamine; Dopamine Antagonists; Dysbindin; Dystrophin-Associated Proteins; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Models, Neurological; Nerve Tissue Proteins; Neuregulin-1; Schizophrenia; Social Alienation; Synapses

Tardive dyskinesia (TD), the principal adverse effect of long-term conventional antipsychotic treatment, can be debilitating and, in many cases, persistent. We sought to explore the incidence and management of TD in the era of atypical antipsychotics because it remains an important iatrogenic adverse effect.. We conducted a review of TD incidence and management literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, management, therapy, neuroleptics, antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Additional articles were obtained by searching the bibliographies of relevant references. We considered articles that contributed to the current understanding of both the incidence of TD with atypical antipsychotics and management strategies for TD.. The incidence of TD is significantly lower with atypical, compared with typical, antipsychotics, but cases of de novo TD have been identified. Evidence suggests that atypical antipsychotic therapy ameliorates long-standing TD. This paper outlines management strategies for TD in patients with schizophrenia.. The literature supports the recommendation that atypical antipsychotics should be the first antipsychotics used in patients who have experienced TD as a result of treatment with conventional antipsychotic agents. The other management strategies discussed may prove useful in certain patients.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Dyskinesia, Drug-Induced; Humans; Incidence; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Thiazoles

It is known that 9-13% of individuals with a diagnosis of schizophrenia commits suicide. In addition, patients with schizophrenia have approximately a 50% lifetime risk for attempting suicide. The authors review the identified risk factors for suicide in schizophrenia. The most significant risk factors include the age of the patient, male gender, depression, presence of positive symptoms and substance abuse. There is evidence that implicates the serotonin system in the suicide of individuals with schizophrenia. Overactivity of the hypothalamo-pituitary-adrenal axis has also been reported in individuals who went on to attempt suicide. The authors review the molecular biology of suicide in schizophrenia. With regard to prevention of suicide, pharmacological intervention with typical antipsychotics and antidepressants may be helpful. It is suggested that atypical anti-psychotics, in particular clozapine may provide additional benefit in reducing the rate of suicide attempts. The authors emphasise the importance of early treatment of individuals with a diagnosis of schizophrenia, the role of maintenance therapy and the importance of a collaborative approach between in- and outpatient services.

Topics: Age Factors; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Female; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Risk Factors; Schizophrenia; Schizophrenic Psychology; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Substance-Related Disorders; Suicide; Suicide Prevention

Topics: Amisulpride; Antipsychotic Agents; Chlorpromazine; Clozapine; Cognitive Behavioral Therapy; Dibenzothiepins; Family Therapy; Haloperidol; Humans; Patient Compliance; Risperidone; Schizophrenia; Secondary Prevention; Sulpiride; Thioridazine

Post-mortem investigations have confirmed that glutamatergic NMDA, AMPA, and kainate receptors are involved in the pathophysiology of schizophrenia. It is still unclear, however, whether the altered number of receptors is caused by the disease itself or the medication. Therefore, animal models were investigated for effects of antipsychotic medication after treatment periods of up to 6 months, the results of which are summarized here. Generally, NMDA receptor binding was found to be increased in striatum and nucleus accumbens after therapy with haloperidol, whereas clozapine only increased the number of receptors in nucleus accumbens. While haloperidol led to an increase in AMPA receptors in the posterior cingulate gyrus, striatum, insular cortex, and n. accumbens, clozapine was found to elevate ligand binding in the anterior cingulate gyrus and infralimbic cortex. Although kainate receptor binding was increased in hippocampus by both antipsychotics, clozapine was significantly more effective. In conclusion, data reveal different effects from the typical neuroleptic haloperidol and the atypical antipsychotic clozapine. The results suggest that post-mortem findings in patients with schizophrenia may at least partially be explained by drug effects and plasticity changes induced by long-term medication with antipsychotics.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Disease Models, Animal; Haloperidol; Humans; Long-Term Care; Neuronal Plasticity; Neurons; Rats; Receptors, Glutamate; Schizophrenia; Synaptic Transmission

During the last few years, several case reports and studies have been published on the potential diabetes mellitus (DM)-inducing effect of some atypical antipsychotics, especially clozapine and olanzapine. The purpose of our study was to evaluate diabetogenic effects of atypical antipsychotics in the literature. In order to give a full-scale overview, both peer-reviewed publications and oral and poster presentations on this subject were screened. We found 27 case reports of new-onset DM for clozapine, 39 for olanzapine, 4 for risperidone, and 3 for quetiapine. Related to the year of introduction of these drugs on the market and the number of treatment days of each drug during the last 6 years in 13 western countries, Brazil, and Japan, the cases show an over-representation of cases related to olanzapine and clozapine. In the majority of cases, risk factors (DM family history, obesity, Negroid ethnicity) were present. Eighty-four percent of the cases arose in patients < 50 years, in contrast to the general population (most cases, > 50 years). Comparative epidemiological studies point in the same direction, with two studies showing no differences between the atypical drugs. Antipsychotic agents are used often for treatment of schizophrenia, a condition that appears to be associated with DM also in untreated subjects. Some antipsychotics appear to induce new-onset diabetes mellitus. In view of the health risks of DM and the predisposition in patients with schizophrenia, it is advised to be cautious with prescription of antipsychotics that are associated with new-onset DM. Especially in predisposed patients (family history of DM, obese, Negroid ethnicity), reticence in this respect is required. Moreover, careful monitoring of weight, BMI, and glucose levels is advised both before these antipsychotics are prescribed and during treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risk; Risperidone; Schizophrenia

The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved by atypical antipsychotics like clozapine and amisulpride. In patients whose symptomatology cannot be ameliorated by monotherapy, it might be necessary to combine two atypical antipsychotics. While clozapine interacts with a variety of neurotransmitter receptors, amisulpride predominantly binds with high affinity to D3/D2-dopamine receptors. Combination can be considered if a supplementary dopamine-receptor blockade is desired.. We report on the therapy of 15 patients using a combination regimen of amisulpride and clozapine. Data were collected from patient records. The case reports document previous treatment attempts, describe the reason for the combination therapy, and determine its effect.. Major (six cases) or at least marked (eight cases) improvement of previously treatment-resistant positive and negative symptoms could be achieved by using a mean clozapine dose of 375 mg/day (serum level 0.38 mg/l) and an amisulpride dose of 527 mg/day. Additionally, by reducing the clozapine dose compared to monotherapy by 24 %, a significant reduction of side effects was observed.. The combination of amisulpride with clozapine considerably enriches the therapeutic arsenal in cases of severe schizophrenic psychoses. Additional prospective studies are needed in order to systematically evaluate this new treatment strategy.

Topics: Adult; Amisulpride; Antipsychotic Agents; Body Weight; Clozapine; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Sulpiride

The development of new "atypical" antipsychotic agents, which are safer than classical neuroleptics and also active against the negative symptoms and neurocognitive deficits caused by the illness, has produced a significant advancement in the treatment of schizophrenia. The atypical (or "second generation") antipsychotics have several therapeutical properties in common, however they can significantly differ with regard to clinical potency and side effects. The main features regarding pharmacodynamics, pharmacokinetics and pharmacological interactions of the most important atypical antipsychotics, namely clozapine, olanzapine, quetiapine and risperidone, are treated herein. Several analytical methods available for the therapeutic drug monitoring of these drugs are also presented, as well as the novel formulations, which can notably improve the therapy of schizophrenia. Other very recent atypical agents, such as ziprasidone, aripiprazole, iloperidone, sertindole and zotepine will also be briefly described.

Topics: Antipsychotic Agents; Benzodiazepines; Chemistry, Pharmaceutical; Clinical Trials as Topic; Clozapine; Cytochrome P-450 Enzyme System; Dibenzothiazepines; Drug Interactions; Drug Monitoring; Humans; Molecular Structure; Olanzapine; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles

Atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine and ziprasidone offer many advantages over conventional neuroleptics. These agents reduce negative symptoms of schizophrenia, are effective in treatment refractory cases, and have a markedly lower incidence of extrapyramidal symptoms and tardive dyskinesia. However, there is considerable patient-to-patient variability in therapeutic dose requirements of atypical antipsychotics and the propensity for side effects. Hence, the initial excitement since the introduction of atypical antipsychotics in late 1980s is now shifting towards a focus on individualization of pharmacotherapy and elucidation of the mechanistic basis of interindividual variability in drug response with use of pharmacokinetic and pharmacodynamic biomarkers. Pharmacogenomics, introduced in late 1990s, is the study of variability in drug response using information from the entire genome of a given individual patient. Both pharmacogenomics and conventional therapeutic drug monitoring (TDM) share the similar goal of improving pharmacotherapy through better explanation of individual variability in drug response. Hence, pharmacogenomic biomarkers offer a unique opportunity to complement and expand the scope of traditional TDM in clinical psychopharmacology. Importantly, pharmacogenomics enables the investigation of factors distal to drug exposure in the plasma compartment (e.g. drug targets at the biophase), thereby providing a more complete portrayal of sources of variability in psychotropic drug response. We discuss (1). the definitions for biomarkers and surrogate endpoints in the context of pharmacogenomics, (2). genetic variations in isozyme-specific atypical antipsychotic metabolism in vivo, (3). selected examples of pharmacogenomic variability in pertinent drug targets and, (4). the anticipated roadmap from implementation of pharmacogenomics to changes in healthcare and therapeutic policy. In addition, a conceptual framework that outlines the theoretical advantages of pharmacogenomics-guided TDM is presented using recent clinical applications as precedence.

Topics: Antipsychotic Agents; Biomarkers; Clinical Trials as Topic; Clozapine; Cytochrome P-450 Enzyme System; Drug Delivery Systems; Drug Interactions; Drug Monitoring; Humans; Pharmacogenetics; Schizophrenia

The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.

Topics: Acetates; Amines; Anticonvulsants; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cyclohexanecarboxylic Acids; Drug Utilization; Gabapentin; gamma-Aminobutyric Acid; Humans; Polypharmacy; Risperidone; Schizophrenia; Valproic Acid

Undoubtedly, the pharmacological treatment of schizophrenia has changed dramatically over the last 10 years. Large, double-blind, placebo-controlled trials have ushered the availability of each new antipsychotic. However, there has been an information lag because of the relative paucity of long term, comparative studies among second-generation antipsychotics. While we await such evidence, naturalistic studies have helped to provide useful information on the pattern of use, patient response, and tolerability of these new agents in clinical practice. This review provides an account of representative studies for each second generation antipsychotic, which illustrate the contributions of naturalistic studies to our understanding of the evolving pharmacotherapy of schizophrenia.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Patient Compliance; Piperazines; Polypharmacy; Quetiapine Fumarate; Quinolones; Research Design; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome

Second generation antipsychotics have become the standard of modern pharmacotherapy of schizophrenia. Amisulprid, clozapine, olanzapine, quetiapine, risperidone, sertindol, ziprasidone are the second generation antipsychotics registered in Hungary. They are more efficacious and their side effects are less stigmatizing than those of the first generation of antipsychotic drugs. Their use is limited by the availability of different formulations, by the lack of experience of some physicians, however the main limitation is the economic barrier.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Serotonin Antagonists; Sulpiride; Thiazoles

Atypical antipsychotics offer superior safety and similar efficacy compared with conventional agents in adults with psychotic disorders. Consequently, atypical antipsychotics have been increasingly used in children and adolescents. Because most information now available on pediatric use comes from case reports and small open-label studies rather than large controlled trials, treatment in pediatric patients is often guided by experience with adults or based on limited evidence in youths. Although the literature contains reports on the use of each agent in this class in children, risperidone has been the focus of the greatest number of reports. However, the atypical antipsychotics are not interchangeable; each has a unique pharmacologic profile and may differ considerably in terms of adverse effects. Evidence on the use of atypical antipsychotics in children and adolescents is summarized in this review.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Attention Deficit and Disruptive Behavior Disorders; Benzodiazepines; Bipolar Disorder; Child; Child Development Disorders, Pervasive; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles; Tic Disorders

The Texas Medication Algorithm Project (TMAP) has been a public-academic collaboration in which guidelines for medication treatment of schizophrenia, bipolar disorder, and major depressive disorder were used in selected public outpatient clinics in Texas. Subsequently, these algorithms were implemented throughout Texas and are being used in other states. Guidelines require updating when significant new evidence emerges; the antipsychotic algorithm for schizophrenia was last updated in 1999. This article reports the recommendations developed in 2002 and 2003 by a group of experts, clinicians, and administrators.. A conference in January 2002 began the update process. Before the conference, experts in the pharmacologic treatment of schizophrenia, clinicians, and administrators reviewed literature topics and prepared presentations. Topics included ziprasidone's inclusion in the algorithm, the number of antipsychotics tried before clozapine, and the role of first generation antipsychotics. Data were rated according to Agency for Healthcare Research and Quality criteria. After discussing the presentations, conference attendees arrived at consensus recommendations. Consideration of aripiprazole's inclusion was subsequently handled by electronic communications.. The antipsychotic algorithm for schizophrenia was updated to include ziprasidone and aripiprazole among the first-line agents. Relative to the prior algorithm, the number of stages before clozapine was reduced. First generation antipsychotics were included but not as first-line choices. For patients refusing or not responding to clozapine and clozapine augmentation, preference was given to trying monotherapy with another antipsychotic before resorting to antipsychotic combinations.. Consensus on algorithm revisions was achieved, but only further well-controlled research will answer many key questions about sequence and type of medication treatments of schizophrenia.

Topics: Algorithms; Ambulatory Care; Ambulatory Care Facilities; Antipsychotic Agents; Aripiprazole; Clozapine; Decision Trees; Drug Administration Schedule; Drug Therapy, Combination; Humans; Piperazines; Practice Guidelines as Topic; Quinolones; Schizophrenia; Schizophrenic Psychology; Texas; Thiazoles; Treatment Outcome

The use of atypical antipsychotic agents is associated with the induction of both an indolent progression to insulin-resistant diabetes and an idiosyncratic beta-cell toxicity presenting as diabetic ketoacidosis, both of which are usually reversible or improved subsequent to cessation of treatment. The underlying mechanisms are unclear at present. Nonetheless, in light of the now numerous reports on the adverse metabolic effects of these drugs, the Consensus Development Conference which met in November 2003 recommends that metabolic risks be considered when starting atypical antipsychotic drugs. Their operative checklist includes baseline screening of candidates for antipsychotic treatment, which includes personal/family history of diabetes, weight, waist circumference, blood pressure, fasting plasma glucose and fasting lipid profile, and then follow-up of these parameters. Furthermore, the health professionals, patients, family and caregivers should be aware of the signs and symptoms of diabetes, especially when acute decompensation occurs which is commensurate with diabetic ketoacidosis. We wish, through this short report, to raise the awareness of physicians treating psychiatric patients to the possibility of new-onset diabetes during therapy with atypical antipsychotic drugs and to emphasize the necessity for increased vigilance and close metabolic follow-up of these patients. Moreover, the choice of the best antipsychotic treatment for each patient should take into consideration the diabetogenic effect of the different treatment options as well the other side effects.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Diabetic Ketoacidosis; Female; Glucose; Humans; Male; Olanzapine; Risperidone; Schizophrenia

One of the conundrums of neuropharmacology is to understand the therapeutic mechanisms of action of antipsychotic drugs. Every drug with antipsychotic activity is a dopamine (DA) D(2)-like receptor antagonist and therefore this function is critical to reducing psychotic symptoms. However, the actions of the archetypal atypical antipsychotic drug clozapine go beyond antipsychotic effects because the drug is efficacious in treating psychotic symptoms that do not respond to drugs mainly directed at antagonizing the DA D(2) receptor, has benefits in cognition and has recently been shown to reduce levels of suicide. A growing understanding of the mechanisms of clozapine and other atypical antipsychotic drugs suggests that both partial and inverse agonism, as well as receptor antagonism, at specific neurotransmitter receptors is required to give full therapeutic benefits. It is, therefore, timely to review the evolving nature of the mechanisms of action of different antipsychotic drugs.

Topics: Animals; Antipsychotic Agents; Brain; Brain Chemistry; Clozapine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Humans; Muscarinic Agonists; Neuropharmacology; Psychotic Disorders; Rats; Receptors, Dopamine D2; Schizophrenia; Serotonin Receptor Agonists

Tardive dyskinesia is a chronic drug-induced movement disorder that tends to be persistent in older adults who are treated with antipsychotics. Tardive dyskinesia can affect older patients both physically and psychologically, leading to frequent falls, difficulty eating, and depression. While atypical antipsychotics may cause tardive dyskinesia, the percentage is usually significantly lower than with conventional antipsychotics. Using atypical antipsychotics, particularly at lower doses, may aid in preventing symptoms of tardive dyskinesia in older adults.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Incidence; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

Numerous clinical studies demonstrate that subanaesthetic doses of dissociative anaesthetics, which are non-competitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms and brain functional abnormalities of schizophrenia. Post-mortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia, who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that the glycine modulatory site on the NMDA receptor is a valid therapeutic target for improving cognition and associated negative symptoms in schizophrenia.

Topics: Animals; Clozapine; Cognition Disorders; Double-Blind Method; GABA Antagonists; Glycine; Humans; Randomized Controlled Trials as Topic; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology

Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.. This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha(7) nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha(7) nicotinic receptor agonists may ameliorate some of these deficits.. Impaired auditory sensory gating has been linked to the alpha(7) nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha(7) nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha(7) nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures.. Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.

Topics: Acoustic Stimulation; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Benzylidene Compounds; Chromosomes, Human, Pair 15; Clozapine; Evoked Potentials, Auditory; Humans; Neural Inhibition; Nicotinic Agonists; Polymorphism, Single Nucleotide; Pyridines; Receptors, Nicotinic; Schizophrenia; Sensation Disorders

Clozapine-induced hepatotoxicity is not infrequent and usually transient. It mostly causes asymptomatic elevation of liver transaminases. "Elevation in liver enzymes to what extent should preclude further treatment?" or "Is only a dose-reduction sufficient?" are questions yet to be answered. The present article uses a case report to discuss the treatment alternatives when liver enzymes reach three times the upper normal limits during the clozapine therapy.. In the following case report, the authors describe a 27-year-old male patient diagnosed with schizophrenia, resistant to different atypical and typical antipsychotics. Based on the pathological findings of our patient and a review of the literature, the author summarizes the reasons for the liver enzymes increase and treatment alternatives during clozapine treatment.. Substantial improvement was achieved with clozapine therapy. Increase in liver enzymes at the beginning of the clozapine treatment was successfully managed with a multidisciplinary approach: the treatment was initially withdrawn, afterwards restarted, and carefully continued.. The authors demonstrate that clozapine may be cautiously continued in selected patients who showed marked psychiatric improvement with clozapine in the face of liver enzyme elevation.

Topics: Adult; Alanine Transaminase; Antipsychotic Agents; Clozapine; Drug Monitoring; gamma-Glutamyltransferase; Humans; Liver; Male; Schizophrenia

Treatment-emergent obsessive-compulsive symptoms (OCSs) have raised concern since the widespread introduction of serotonin-dopamine antagonists (SDAs) for the treatment of schizophrenia. Further investigations of SDA-emergent OCSs and their response to anti-obsessional agents will be beneficial for clinicians in helping patients who suffer from this problem. We present three cases of schizophrenia in which distressing OCSs occurred during clozapine or risperidone treatment. OCSs were assessed consecutively using the Yale-Brown Obsessive-Compulsive Scale. The OCSs of these three patients were responsive to anti-obsessional agents, including fluvoxamine, clomipramine, and paroxetine. We also review the current literature and discuss the possible pathophysiology and psychopathology of SDA-emergent OCSs.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Obsessive-Compulsive Disorder; Risperidone; Schizophrenia; Treatment Outcome

Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings.. A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached.. Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations.. The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Cataract; Clozapine; Diabetes Mellitus, Type 2; Health Status; Humans; Hyperlipidemias; Hyperprolactinemia; Long QT Syndrome; Monitoring, Physiologic; Myocarditis; Obesity; Practice Guidelines as Topic; Schizophrenia; Sexual Dysfunctions, Psychological; Weight Gain

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Humans; Middle Aged; Olanzapine; Risk Factors; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

Clozapine is the most effective antipsychotic available for the treatment of schizophrenia that has proved resistant to other medications and the only antipsychotic licensed for this indication. Although the drug is increasingly being used more widely in patients with schizophrenia and with other psychiatric and neurological disorders, it is still underused. The main reasons for this are that it can cause adverse effects such as weight gain and sedation, and the need for regular blood test monitoring because of the risk of agranulocytosis. While these hurdles are unavoidable, another problem in the UK has been the historical practice of admitting patients to hospital to initiate treatment with clozapine. However, protocols have now been developed for both home and day-hospital initiation. The experience of one assertive community treatment team of starting clozapine in patients' own homes has been positive, with no major adverse events reported. This approach is, however, extremely demanding of staff resources and for many services the use of day-hospitals to initiate treatment with clozapine is more appropriate. Research into staff and patients' views about community initiation of clozapine, and its economic costs, would be welcome.

Topics: Antipsychotic Agents; Clinical Protocols; Clozapine; History, 20th Century; History, 21st Century; Humans; Residence Characteristics; Risk; Schizophrenia; United Kingdom

The effect of funding source on the outcome of randomized controlled trials has been investigated in several medical disciplines; however, psychiatry has been largely excluded from such analyses. In this article, randomized controlled trials of second generation antipsychotics in schizophrenia are reviewed and analyzed with respect to funding source (industry vs. non-industry funding).. A literature search was conducted for randomized, double-blind trials in which at least one of the tested treatments was a second generation antipsychotic. In each study, design quality and study outcome were assessed quantitatively according to rating scales. Mean quality and outcome scores were compared in the industry-funded studies and non-industry-funded studies. An analysis of the primary author's affiliation with industry was similarly performed.. Results of industry-funded studies significantly favored second generation over first generation antipsychotics when compared to non-industry-funded studies. Non-industry-funded studies showed a trend toward higher quality than industry-funded studies; however, the difference between the two was not significant. Also, within the industry-funded studies, outcomes of trials involving first authors employed by industry sponsors demonstrated a trend toward second generation over first generation antipsychotics to a greater degree than did trials involving first authors employed outside the industry (p=0.05).. While the retrospective design of the study limits the strength of the findings, the data suggest that industry bias may occur in randomized controlled trials in schizophrenia. There appears to be several sources by which bias may enter clinical research, including trial design, control of data analysis and multiplicity/redundancy of trials.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Double-Blind Method; Drug Industry; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Research Support as Topic; Retrospective Studies; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome

Dyslipidemia is an increasing problem in most industrialized societies and is a risk factor for coronary heart disease (CHD). Imbalances in individual lipid components, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides, have each been shown to contribute to this increased risk. Certain psychiatric patient populations, such as those afflicted with schizophrenia, are of particular concern. Psychiatric patients with schizophrenia are naturally at increased risk for dyslipidemia and obesity, in part due to poor diet and sedentary lifestyle, but these conditions can be exacerbated by some antipsychotic medications. Clozapine and olanzapine, for example, appear to be associated with hyperlipidemia, which may be associated with changes in body weight. Other, newer antipsychotic agents may exhibit less liability for weight gain and the development of dyslipidemia. This review is intended to briefly highlight the association between dyslipidemia and cardiovascular disease, the changes in serum lipids associated with some antipsychotic agents, and how these changes in serum lipids affect the monitoring of schizophrenia patients.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol; Cholesterol, VLDL; Clozapine; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Obesity; Olanzapine; Risk Factors; Schizophrenia; Triglycerides; Weight Gain

Suicide accounts for approximately 10% of patient deaths in schizophrenia. The atypical antipsychotic clozapine (Clozaril), successful in treatment-resistant patients with schizophrenia, may have an additional antisuicidal effect. Numerous published reports, including the collaborative International Suicide Prevention Trial, have compared mortality rates between clozapine recipients and patients receiving other forms of antipsychotic treatment and observed a significant reduction in patient risk for suicide with clozapine therapy. Preliminary reports indicate improvements in suicidality in schizophrenia patients treated with other modern atypical antipsychotics, for example olanzapine [Zyprexa], risperidone [Risperdal] and sertindole [Serdolect], but further investigation is required to clarify their role as antisuicidal drugs. It has been estimated that 53 suicides in treatment-resistant patients could have been prevented by clozapine, but the number of lives saved may be significantly higher if clozapine therapy was extended to treatment responders at a high risk for suicide.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Humans; Risk Factors; Schizophrenia; Suicide

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; Haloperidol; Humans; Olanzapine; Patient Compliance; Perazine; Pimozide; Risperidone; Schizophrenia; Sulpiride

As a consequence of its prevalence, early onset and chronicity, schizophrenia imposes clinical and economic impediments to healthcare practitioners and society alike. Among the many antipsychotics available to treat the symptoms of this devastating illness, clozapine has emerged and differentiated itself from the others as the agent most efficacious for the treatment of refractory patients. Since the patent for Clozaril (Novartis) expired in 1998, three manufacturers of generic clozapine have submitted abbreviated new drug applications to the US FDA for review and approval to market a generic clozapine product. In each case, the US FDA deemed the generic formulations to be bioequivalent to the brand name Clozaril. Apart from case reports, industry-sponsored studies have been conducted comparing Clozaril with two generic formulations. In one case, a generic formulation of clozapine manufactured by Creighton Products Corporation (formerly a subsidiary [generic house] of Sandoz Pharmaceuticals) was found to be bioequivalent to Clozaril. On the other hand, studies (sponsored by Novartis) have challenged the bioequivalence, therapeutic equivalence and interchangeability between Clozaril and a generic formulation manufactured by Zenith Goldline Pharmaceuticals (now IVAX Corporation). The IVAX Corporation-sponsored studies refuted these claims citing data from two patient registry database studies and one small clinical trial. Apart from a single in-house bioequivalence study, no further investigations have been conducted with a third generic formulation manufactured by Mylan Pharmaceutical. Although the clinical significance of the above discrepancy is obvious, what is less than obvious is the pharmacoeconomic implications that arises from this debate. Clearly, if the brand name and generic formulations are 'truly' bioequivalent, then the cost savings realised would be the difference in acquisition cost. On the other hand, if the various formulations are not bioequivalent, then the economic benefits of a lower-priced generic formulation may be compromised. In the worst-case scenario, if a patient decompensates as a result of switching from Clozaril to a generic formulation, the added direct costs (i.e. hospitalisation) and indirect cost (i.e. lost productivity) will most certainly offset any cost savings resulting from the use of a generic formulation. Until further studies have been conducted, we suggest that patients who are treatment refractory and stabilise

Topics: Antipsychotic Agents; Clozapine; Economics, Pharmaceutical; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Schizophrenia; Therapeutic Equivalency

The atypical antipsychotic agent clozapine is associated with a lower propensity for extrapyramidal symptoms than classical antipsychotic agents. The pharmacokinetics of clozapine are affected by wide interpatient variability and a potential for drug interactions. Some studies have shown a relationship between plasma concentrations, duration of treatment and antipsychotic clinical response. Clozapine (mean 274.2 mg/day; n = 490) had a greater preventive effect on suicidality among patients with schizophrenia or schizoaffective disorder at high risk for suicide than olanzapine (mean 16.6 mg/day; n = 490) in a randomised, rater-blinded, multicentre study (p < 0.05; a 22-24% improvement). Other prospective noncomparative trials of the effects of clozapine on suicidal ideation or attempts endorsed these results, while results from retrospective trials are equivocal. Clozapine is commonly associated with sedation, hypersalivation, tachycardia, dizziness, constipation and orthostatic hypotension. Agranulocytosis, diabetes mellitus and weight gain may also occur.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Tolerance; Humans; Psychotic Disorders; Schizophrenia; Suicide Prevention

Although life prevalence of substance use disorders among patients with schizophrenia is close to 50%, few studies have been carried out to date to identify an integrated pharmacological treatment for this comorbidity. So far, the most promising results, that we report here, have been obtained with clozapine. To a lesser extent, quetiapine and olanzapine, both clozapine analogues, have also shown promising results. Further to these observations, the present paper critically reviews the advantages associated with clozapine, quetiapine and olanzapine, and their relevance to the treatment of addiction among schizophrenic patients. Six characteristics seem to distinguish clozapine, quetiapine and olanzapine from the first-generation antipsychotics: (1) acting preferentially on the reward system, these second-generation antipsychotics (mainly clozapine and quetiapine) induce almost no extrapyramidal symptoms; (2) quickly dissociating from D(2), theses drugs (mainly clozapine and quetiapine) seem not to induce dysphoria, unlike conventional antipsychotics like haloperidol;(3) these drugs (mainly clozapine) seem more effective in the treatment of negative symptoms than conventional antipsychotics; (4) because of a diversified activity on several serotoninergic and noradrenergic receptors, these drugs positively alter mood, which does not seem to be the case with conventional antipsychotics, except for flupenthixol; (5) these drugs have a positive impact on cognition, which is not the case with the first-generation antipsychotics; (6) unlike conventional antipsychotics, these drugs seem to have a moderate affinity for 5-HT(3), the receptor on which ondansetron, an anti-craving medication, acts.

Topics: Affect; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Cognition; Comorbidity; Dibenzothiazepines; Drug Therapy, Combination; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Schizophrenia; Substance-Related Disorders; Treatment Outcome

Pharmacological treatment remains the mainstay of the management of schizophrenia. Older, "typical" antipsychotics carry a significant burden of side effects, notably extrapyramidal and neurocognitive side effects. Newer, "atypical" agents carry a lower risk of extrapyramidal side effects. They appear to have added benefit for treating negative and cognitive symptoms of schizophrenia, and hence can enhance the quality of life of some patients. The choice of particular agents for individual patients requires a balancing of efficacy and side effects. Medication is only one element of what should be an individualised comprehensive treatment plan for people with schizophrenia.

Topics: Amisulpride; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia; Sulpiride

Pharmacogenetics uses genetic information to tailor drug treatment to the individual, maximizing clinical response and minimizing side effects. Failure to respond to medication and adverse side effects are common problems in psychiatry. Intolerable side effects can lead to discontinuation of medication. Individual genetic differences can determine both clinical responses to medications and the adverse side effects experienced. To fully predict clinical response to psychotropic drug treatment we must consider social, demographic and clinical factors such as compliance, social support and history of birth trauma, in addition to genetic influence on susceptibility and etiology.

Topics: Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme System; Drug Resistance; Dyskinesia, Drug-Induced; Haloperidol; Humans; Pharmacogenetics; Polymorphism, Genetic; Schizophrenia; Weight Gain

Clozapine (Clozaril) is a novel and unique prototype atypical, tricyclic, dibenzodiazepine-derivative, antipsychotic agent. It has been proven effective and significantly superior to placebo, as well as to conventional neuroleptics, in several placebo-controlled, double-blind studies in treatment-resistant schizophrenia. It has also been found to produce an incidence of extrapyramidal symptoms (EPS) as low as that found with placebo. Approximately 30-60% of all schizophrenic patients who fail to respond to typical antipsychotics may respond to clozapine. It was the first major advance that marked a turning point in the treatment of schizophrenia and other psychotic disorders since the introduction of the typical antipsychotic agents, i.e., chlorpromazine and haloperidol in the 1950s and 1960s, respectively. After its introduction in clinical studies in the United States in the early 1970s, it was withdrawn in 1974, and was not approved for clinical use in the United States until February 1990, because of the risk of agranulocytosis. Its novel pharmacological profile, lack of propensity to cause EPS in both short- and long-term uses, lack of effects on serum prolactin, and ameliorative effects on tardive dyskinesia have resulted in the expansion of its use from refractory schizophrenia to schizoaffective disorders, affective disorders, some neurological disorders, aggression, as well as psychosis in patients with dementia and parkinsonism. This review covers the history, pharmacology, management of side effects, and fetal and neonatal effects of clozapine.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Lactation; Pregnancy; Pregnancy Complications; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is the gold standard and 'last resort' in treatment of refractory schizophrenia. It is important to know whether a trial with clozapine is adequate or not. Six studies show a significantly higher response rate at clozapine plasma trough levels above a therapeutic threshold of 350-400 micro g/L. The absolute risk reduction is about 40%. An additional study found best results with plasma levels between 300 and 700 micro g/L, and one (probably too small) study could not detect a significantly different response rate for 350-450 micro g/L in comparison to 200-300 micro g/L. In addition, two extension studies showed conversion from nonresponders to responders if plasma levels increased above the threshold. Investigations on time to response in treatment with clozapine are often hampered by not controlling for time until plateau of dose titration or clozapine concentration. One of the better studies found 34 responders within 8 weeks after the last dose escalation. The remaining 16 non-responding patients did not change their status during a mean follow-up of 75 weeks. A second 1 year trial found a superior differential response rate for clozapine in comparison to haloperidol only during the first 6 weeks. A third study combined regular clozapine plasma level assays with assessment of response status. At the time of response 17 out of 19 responders showed clozapine concentrations above 350 micro g/L. The nine non-responders remained below this threshold throughout the rest of the year. These results favour an approach of raising the clozapine plasma level in treatment-refractory schizophrenic patients who do not respond to an initial low-to-medium dose treatment with clozapine. Some patients, especially young male smokers, will need dosages higher than 900 mg/day. Addition of low-dose fluvoxamine while closely monitoring clozapine levels can help decrease the high number of necessary pills. An adequate trial with clozapine should last at least 8 weeks on a plasma trough level above 350-400 micro g/L.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance; Humans; Schizophrenia; Time Factors

Topics: Adult; Age of Onset; Aged; Antipsychotic Agents; Chlorpromazine; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Electroconvulsive Therapy; Haloperidol; Humans; Middle Aged; Reference Standards; Risk Factors; Risperidone; Schizophrenia; Schizophrenic Psychology

Although there is a consensus that clozapine is more effective than conventional antipsychotic drugs for treatment-resistant schizophrenia, there is great heterogeneity among results of relevant trials.. To re-evaluate the evidence comparing clozapine with conventional antipsychotics and to investigate sources of heterogeneity.. Individual studies were inspected with assessment of clinical relevance of results. Meta-regression analysis was performed to investigate sources of heterogeneity.. Ten trials were examined. Recent large-scale studies have not found a substantial advantage for clozapine, especially in terms of a clinically relevant effect. Meta-regression showed that shorter study duration, financial support from a drug company and higher baseline symptom score consistently predicted greater advantage of clozapine.. It may be inappropriate to combine studies in meta-analysis, given the degree of heterogeneity between their findings. The benefits of clozapine compared with conventional treatment may not be substantial.

Topics: Antipsychotic Agents; Clozapine; Drug Industry; Financial Support; Humans; Patient Readmission; Randomized Controlled Trials as Topic; Schizophrenia; Time Factors; Treatment Failure; Treatment Outcome

The introduction of a number of new antipsychotics in the last decade has generated considerable excitement regarding the treatment of schizophrenia and related psychotic conditions. Clinically, it has produced changing expectations regarding treatment outcome, while academically it has encouraged a re-evaluation and expansion of theories of the pathophysiology of schizophrenia and antipsychotic activity. In this review, the development of antipsychotics is traced, beginning with chlorpromazine's introduction in the early 1950s, and followed to the present. Despite 50 years of use and a plethora of antipsychotics available worldwide, our conceptualization of their major mode of action remains essentially unchanged. It was shortly after their development that attention turned to the importance of dopamine, and in particular the dopamine D2 receptor. Current thinking has elaborated on this model, with serotonin and glutamate receiving the greatest attention most recently, but D2 antagonism remains the sine qua non of antipsychotic activity. Although the notion of "atypical" remains somewhat of a moving target, we do have at our disposal a new generation of antipsychotics that reflect a different clinical profile from their conventional counterparts. The precise degree of these differences and the underlying mechanisms remain unclear, however. The direction new antipsychotic development takes will undoubtedly hinge on answers to these questions.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Humans; Receptors, Dopamine D2; Schizophrenia; Treatment Outcome

The frequency and severity of extrapyramidal syndrome (EPS) were evaluated in patients with DSM-III or DSM-IV schizophrenia in the acute phase (- 8 weeks) of randomized, double-blind, controlled trials from the integrated olanzapine clinical trial database.. This retrospective analysis included 23 clinical trials and 4611 patients from November 11, 1991, through July 31, 2001. Incidences of dystonic, parkinsonian, and akathisia events were compared using treatment-emergent adverse-event data. Categorical analyses of Simpson-Angus Scale and Barnes Akathisia Scale (BAS) scores, use of anticholinergic medications, and baseline-to-endpoint changes in Simpson-Angus Scale and BAS scores were compared.. A significantly smaller percentage of olanzapine-treated patients experienced dystonic events than did haloperidol- (p <.001) or risperidone-treated patients (p =.047). A significantly greater percentage of haloperidol-treated patients experienced parkinsonian (p <.001) and akathisia (p <.001) events than did olanzapine-treated patients. Categorical analysis of Simpson-Angus Scale scores showed significantly more haloperidol- (p <.001) or risperidone-treated patients (p =.004) developed parkinsonism than did olanzapine-treated patients. Olanzapine-treated patients experienced significantly greater reductions in Simpson-Angus Scale scores than did haloperidol- (p <.001), risperidone- (p <.001), or clozapine-treated (p =.032) patients. Categorical analysis of BAS scores showed significantly more haloperidol-treated patients experienced treatment-emergent akathisia versus olanzapine-treated patients (p <.001). Significantly greater reductions in BAS scores were experienced during olanzapine treatment versus placebo (p =.007), haloperidol (p <.001), and risperidone (p =.004) treatments. A significantly smaller percentage of olanzapine-treated patients received anticholinergic medications compared with that of haloperidol- (p <.001) or risperidone-treated patients (p =.018). Compared with that in olanzapine-treated patients, the duration of anticholinergic cotreatment was significantly longer among haloperidol- (p <.001) or risperidone-treated patients (p =.040) and significantly shorter among clozapine-treated patients (p =.021).. This analysis of available data from olanzapine clinical trials lends additional support to olanzapine's favorable EPS profile.

Topics: Acute Disease; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Cholinergic Antagonists; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Placebos; Randomized Controlled Trials as Topic; Retrospective Studies; Risperidone; Schizophrenia

Research on the optimal pharmacotherapy for people with schizophrenia and co-occurring substance use disorders remains in its infancy. This report reviews existing data and provides an update on recent research. The confluence of findings is consistent with a model of a reward dysfunction inherent in the neuropathology of schizophrenia, leading to a heightened vulnerability of people with schizophrenia to substance use disorders. Studies indicate that patients with dual disorders have difficulty tolerating conventional antipsychotics, have higher rates of medication nonadherence, and have greater impulsivity and sensation seeking. Limited evidence suggests that clozapine treatment may be associated with reduced substance abuse, with weaker evidence suggesting that other novel antipsychotics may have similar, but potentially less potent, effects. Controlled trials to test the effects of these medications are underway. A number of recent studies indicate that bupropion can facilitate reduced tobacco smoking among patients with schizophrenia. The preferential use of novel antipsychotics, a lower threshold for prescription of clozapine, the use of bupropion for smoking cessation, careful monitoring of compliance, and possible use of other medications for substance use disorders when indicated are recommended in pharmacologic management for people with co-occurring substance use disorders and schizophrenia.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Bupropion; Clozapine; Humans; Schizophrenia; Smoking Cessation; Substance-Related Disorders; Treatment Outcome

Topics: Adolescent; Adult; Antipsychotic Agents; Brain; Child; Clozapine; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Pyramidal Cells; Schizophrenia

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clinical Trials as Topic; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Glucose; Haloperidol; Humans; Intellectual Disability; Male; Mental Disorders; Metabolic Syndrome; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Time Factors; Weight Gain

The pharmacotherapy of schizophrenia remains an ongoing challenge for researchers and clinicians alike. Current medications remain suboptimal to effectively treat this illness despite the recent surge of what are considered to be better antipsychotics: the atypicals. The atypicals cause fewer extrapyramidal symptoms and tardive dyskinesia, but there is growing concern regarding the significant long-term metabolic and cardiac adverse effects of these novel antipsychotics. There are differences among the atypicals in their propensity to produce these adverse effects, and clinicians should weigh the risk-benefit ratio for each drug with each individual patient. Diabetes, heart disease, obesity, and unhealthy lifestyle choices are on the rise in the general population, and individuals with chronic schizophrenia are even more at risk. The dilemma clinicians face in trying to avoid the neurological morbidity of the typicals (extrapyramidal side effects and tardive dyskinesia) is the risk of consequently exposing patients to both the morbidity and potential mortality of the atypicals (cardiovascular, endocrine, and metabolic adverse effects). The importance of baseline investigations and monitoring at regular intervals as well as identification of patients at risk for obesity, diabetes, and cardiovascular morbidity has become crucial. Informed decision making is essential for successful antipsychotic pharmacotherapy. For a condition, which often necessitates long-term pharmacotherapy, the importance of prevention and (or) minimization of morbidity and mortality related to adverse effects of such pharmacotherapy cannot be understated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Diabetes Mellitus; Humans; Hyperlipidemias; Long QT Syndrome; Myocarditis; Schizophrenia; Torsades de Pointes

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; Cognitive Behavioral Therapy; Dibenzothiepins; Haloperidol; Humans; Olanzapine; Patient Compliance; Perazine; Pimozide; Risperidone; Schizophrenia; Sulpiride

For young people experiencing a first-episode of schizophrenia, the first and most important matter to be attended to, once the diagnosis of schizophrenia has been made and patients have entered the care system, is to establish a treatment alliance. The next step is to conceive an individually tailored treatment programme (non-pharmacological as well as pharmacological). The use of antipsychotic drugs needs to be carefully discussed with both patients and families, as medication tends to have a poor public perception. Maintaining treatment is vitally important in terms of relapse prevention, but people who suffer a first-episode tend to terminate treatment early. Patients often discontinue their medication because of side-effects, although a number of other factors can also exert a negative influence on the continuous intake of medication. Among others, these include insufficient information provided to patients and significant others as well as lack of insight and problems in the doctor-patient-relationship. The published data indicate that the outcome of treatment is better for younger patients in a first-episode of schizophrenia than it is for patients who are more chronically ill. However, young patients are much more sensitive to compliance problems than older patients. The main challenge in this phase of the illness is therefore to convince patients that maintenance treatment is necessary in order to assure the best possible outcome.

Topics: Age Factors; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Medication Adherence; Olanzapine; Patient Education as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Randomized clinical trials have limitations because they focus on small samples of highly selected patients. Observational studies, which follow large cohorts of typical patients receiving pharmacological treatments, should overcome some of these trial limitations and provide information that cannot be generated with clinical trials. The present study aimed to compare experimental and observational studies of clozapine-treated subjects with treatment-resistant schizophrenia. A systematic review of experimental and observational studies evaluating clozapine-treated subjects in treatment-resistant schizophrenia was carried out. We identified 50 studies that met the inclusion criteria. Less than one-third of clinical trials enrolled more than 50 patients compared to 44% of prospective and nearly 90% of retrospective studies. In addition, 78% of prospective and 89% of retrospective observational studies lasted more than 12 weeks, while the majority of trials lasted less than 8 weeks. Most clinical trials defined treatment-resistant schizophrenia according to Kane's criteria, while the majority of observational studies adopted implicit criteria. In comparison with clinical trials, observational studies provided a higher weighted mean rate of clozapine-responders and a lower weighted mean rate of clozapine-dropouts. This literature survey suggests that the role of observational studies in the evaluation of medicines should be reconsidered. A new generation of observational studies should be developed to provide evidence on patient outcome in typical settings and under real-world circumstances, and on variables which may affect outcome.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Schizophrenia; Treatment Failure

Topics: Antipsychotic Agents; Behavior Therapy; Clozapine; Combined Modality Therapy; Family Therapy; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. The rapidly evolving disciplines of pharmacogenetics and pharmacogenomics seek to uncover this genetic variation in order to predict treatment outcomes. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up-individualized therapy. Pharmacogenomic studies utilize genomic technologies to identify chromosomal areas of interest and novel putative drug targets, while pharmacogenetic strategies rely on studying sequence variations in candidate genes suspected of affecting drug response or toxicity. The candidate gene variants that affect function of the gene or its protein product have the highest priority for investigation. This review will provide demonstrative examples of functional candidate gene variants studied in a variety of antipsychotic response phenotypes in the treatment of schizophrenia. Serotonin and dopamine receptor gene variants in clozapine response will be examined, and in the process the need for sub-phenotypes will be pointed out. Our recent pharmacogenetic studies of the subphenotype of neurocognitive functioning following clozapine treatment and the dopamine D(1) receptor gene (DRD1) will be presented, highlighting our novel neuroimaging data via [(18)F]fluoro-2-deoxy-D-glucose (FDG) metabolism position emission tomography (PET) that demonstrates hypofunctioning of several brain regions in patients with specific dopamine D(1) genotype. Preliminary candidate gene studies investigating the side-effect of clozapine-induced weight gain are also presented. The antipsychotic adverse reaction of tardive dyskinesia and its association with the dopamine D(3) receptor will be critically examined, as well as the added influence of antipsychotic metabolism via the cytochrome P450 1A2 gene (CYP1A2 ). Results that delineate the putative gene-gene interaction between DRD3 and CYP1A2 are also presented. We have also utilized FDG-PET subphenotyping to demonstrate increased brain region activity in patients who have the dopamine D(3) genotype that confers increased risk for antipsychotic induced tardive dyskinesia. The merits and weaknesses of neuroimaging technologies as applied to pharmacogenetic analyses are discussed. To the extent that the above data become more widely verified and repli

Topics: Antipsychotic Agents; Clozapine; Dyskinesias; Humans; Pharmacogenetics; Schizophrenia; Weight Gain

To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials.. A computerized Medline search supplemented by an examination of cross-references and reviews was performed.. Empirical evidence for the efficacy of combining antipsychotics is too limited to draw firm conclusions. The practice of augmenting clozapine with more 'tightly bound' D2 receptor antagonists as exemplified by risperidone augmentation of clozapine has some empirical and theoretical support. The risks of augmentation strategies have not been studied systematically. No study has examined the economic impact of combination treatment.. Further trials of antipsychotic combination therapies are needed before this currently unsupported practice can be recommended. Rationales for combination treatment include a broadening of the range of receptor activity or an increase in D2 receptor occupancy with certain atypical agents. Trial methodology needs to take into account subject characteristics, duration of treatment, optimization of monotherapy comparators, and appropriate outcome measures.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Delirium; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Risk; Risperidone; Schizophrenia; Schizophrenic Psychology; Sialorrhea; Treatment Outcome

Topics: Antipsychotic Agents; Brain; Brain Chemistry; Clozapine; Humans; Receptors, Dopamine; Schizophrenia

Topics: Antipsychotic Agents; Behavior Therapy; Clozapine; Combined Modality Therapy; Family Therapy; Humans; Schizophrenia; Schizophrenic Psychology

The treatment of aggressive symptoms in schizophrenic patients is a relevant clinical problem. We systematically review the efficacy of the different atypical neuroleptics on acute or persistent aggressive symptoms also regarding methodological problems. Currently typical neuroleptics are still first choice in treating acute aggressive symptoms, while risperidone and olanzapine could be alternatives. In persistent aggression clozapin shows the best specific results. Typical depot neuroleptics should be considered in cases when medication compliance is a problem.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Hostility; Humans; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology

Innovation in atypical antipsychotic agents continues with new preparations of available drugs as well as novel agents. In this article, we provide an update on these novel products by reviewing information from a computerised literature search, recent abstracts and discussions with industry representatives. A generic formulation of clozapine is now available. It may be less well absorbed and/or less effective than Clozaril, although evidence is conflicting. A fatty acid amide derivative of clozapine is in early development. A liquid formulation of risperidone is currently available, which may be a useful treatment for psychotic agitation as well as a preferable alternative to tablets for some patients. A depot formulation is in development for the long-term management of psychosis. An orally disintegrating tablet formulation of olanzepine is a useful alternative to standard tablets. A short-acting injectable formulation of the drug is in development for psychotic agitation. Sachets and slow-release formulations of quetiapine are in development. Ziprasidone, a recently launched agent, is available in tablet form for schizophrenia/schizoaffective disorder, psychotic depression and mania. A short-acting injectable formulation is in development for psychotic agitation. Aripiprazole (tablets) and iloperidone (tablets and depot injection) are two antipsychotics in development for schizophrenia/schizoaffective disorder (available information regarding iloperidone is very limited). These new formulations and agents should broaden options for the treatment of psychosis.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dosage Forms; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Pirenzepine; Quinolones; Risperidone; Schizophrenia; Thiazoles

Clozapine is one of the most clinically potent drugs currently available for treating the symptoms of schizophrenia. Compared with conventional antipsychotics it surpasses its predecessors in its ability to treat a wider range of symptoms in otherwise refractory patients, while possessing a low propensity to produce extrapyramidal symptoms. Despite its significant advantages, not all patients benefit from treatment. Some patients react adversely to therapy while others fail to respond adequately. If those most likely to benefit from clozapine could be identified prior to treatment, this would significantly improve the clinical management of these patients. Genetic alterations in drug-metabolising enzymes have previously been demonstrated to influence the efficacy of clinically relevant drugs. It is possible that similar alterations in these and other systems may influence the response variability of patients to clozapine. Pharmacogenetic studies are at present investigating genes encoding drug receptors, drug-metabolising enzymes and neurotransmitter transporters to identify genetic variants that may be important. To date polymorphisms within serotonergic and dopaminergic pathways have been implicated, though the involvement of similar variants in other candidate systems is also likely. This information will ultimately enable the genetic prediction of patients most likely to benefit from the drug, and in the process would alleviate the unnecessary exposure of predisposed individuals to potentially serious adverse effects.

Topics: Antipsychotic Agents; Clozapine; Genetic Variation; Genotype; Humans; Patient Selection; Polymorphism, Genetic; Prognosis; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Treatment Outcome

The aim of this study was to evaluate the effectiveness of newer atypical antipsychotic drugs in comparison to clozapine for schizophrenia. Publications in all languages were searched from all relevant databases and all randomized controlled trials comparing clozapine with newer atypical drugs were included. The review and meta-analysis includes eight studies, most of them short in duration. Newer atypical drugs were broadly similar to clozapine when improvement was measured using a psychosis symptom rating scale or a global index. There was a trend for clozapine to be more effective than the others for positive symptoms, and less effective for the negative symptoms. The adverse effect profile of clozapine and newer atypical drugs was dissimilar: while clozapine produced more fatigue, hypersalivation, and orthostatic dizziness, new atypical drugs, with the exception of olanzapine, produced more extrapyramidal symptoms. As these results were obtained from few studies and a relatively small amount of patients, the equal effectiveness and tolerability of new atypical drugs in comparison with clozapine is not yet demonstrated. More trials of sufficient power, with longer duration, and measuring clinically important outcomes are urgently needed.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Animals; Antipsychotic Agents; Cholinergic Agonists; Disease Models, Animal; Dopamine Antagonists; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Mice; Mice, Transgenic; Nitric Oxide Synthase; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotensin; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists

"Atypical" antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a "pharmacological shotgun" strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Dopamine Antagonists; Drug Monitoring; Haloperidol; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Dopamine D4; Risperidone; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Sulpiride; Thiazoles; Treatment Outcome

Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics.. Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT(2) and dopamine D(4) receptors in atypicality.. Neuroimaging data show that optimal dopamine D(2) occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D(2) occupancy, not from high 5-HT(2) occupancy. If D(2) occupancy is excessive, atypicality is lost even in the presence of high 5-HT(2) occupancy. Animal data show that a rapid dissociation from the D(2) receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that the single most powerful predictor of atypicality for the current generation of atypical antipsychotics is fast dissociation from the D(2) receptor, not its high affinity at 5-HT(2), D(4), or another receptor.. The authors propose that fast dissociation from the D(2) receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. In contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.

Topics: Antipsychotic Agents; Benzodiazepines; Brain; Clozapine; Dopamine D2 Receptor Antagonists; Haloperidol; Humans; Olanzapine; Pirenzepine; Psychotic Disorders; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Serotonin; Risperidone; Schizophrenia; Terminology as Topic; Tomography, Emission-Computed

The authors conducted a review and meta-analysis of studies that compared the efficacy and tolerability of typical and second-generation antipsychotics for patients with treatment-resistant schizophrenia.. A systematic search revealed 12 controlled studies (involving 1,916 independent patients), which were included in the review. For the seven studies that compared clozapine to a typical antipsychotic, a meta-analysis was performed to examine clozapine's effects on overall psychopathology, response rate, extrapyramidal symptoms, and tardive dyskinesia.. The meta-analysis confirmed that treatment-resistant schizophrenic patients have more favorable outcomes when treated with clozapine rather than a typical antipsychotic, as reflected by Brief Psychiatric Rating Scale total score, categorical response rate, Scale for the Assessment of Negative Symptoms score, Simpson-Angus Rating Scale score, and compliance rate. Clozapine also conferred benefits on the sickest treatment-resistant schizophrenic patients. Patients treated with olanzapine also had more favorable outcomes with regard to categorical response and compliance rates.. In the aggregate, the results of a meta-analysis indicated that clozapine exhibits superiority over typical antipsychotics in terms of both efficacy (as measured by improvement in overall psychopathology) and safety (in terms of reduced extrapyramidal side effects). However, the magnitude of the clozapine treatment effect was not consistently robust. Efficacy data for other second-generation antipsychotics in the treatment of patients with refractory schizophrenia were inconclusive. There is, therefore, a growing need to consider new and different treatment strategies, whether they be adjunctive or monotherapeutic, for schizophrenia that continues to be resistant or only partially responsive to treatment.

Topics: Adolescent; Adult; Age of Onset; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Female; Humans; Male; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In general, antipsychotic agents have diverse actions on a wide range of neurotransmitter systems. Data strongly suggest that a number of these systems may play a role in the regulation of body weight. In addition to having very distinct pharmacologic profiles, individual agents possess discrete weight gain liabilities. This article briefly reviews the evidence for the involvement of specific neurotransmitter systems in the control of body weight and describes the relevant pharmacologic characteristics of individual antipsychotic agents. By comparing the pharmacologic profiles of specific antipsychotic agents with their respective weight gain liabilities, this article attempts to gain an insight into the specific receptors underlying a drug's propensity to induce weight gain. However, there is still much to be learned concerning weight control mechanisms, and the role of many of the receptors at which antipsychotic agents are active remains unclear. In spite of this, an overview of current knowledge in the field may facilitate prediction of a potential novel antipsychotic agent's weight gain liability.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Eating; Humans; Olanzapine; Piperazines; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Rats; Receptors, Neurotransmitter; Schizophrenia; Thiazoles; Weight Gain

Cytokines are pivotal mediators of the interaction between immunocompetent cells. Moreover, they mediate the interaction between the immune system and other physiological systems, including the CNS. It has been shown recently that the antipsychotic drug clozapine stimulates in vivo the release of cytokines and soluble cytokine receptors. This holds true for the tumor necrosis factor(TNF)-system, the interleukin(IL)-2-system, IL-6, and granulocyte colony-stimulating factor (G-CSF). The present paper discusses the clinical relevance of these findings for the pathophysiology of clozapine-induced side-effects. It is very probable that TNF-alpha plays an important role in clozapin-induced fever and in the hematopoetic side effects, including agranulocytosis. Moreover, it is likely that TNF-alpha and other cytokines are involved in metabolic (weight gain, diabetes), cardiac (myocarditis), CNS (sedation) and other rare side effects. The mechanisms underlying clozapine-induced immunomodulation are unknown. Hence, further studies are very important to enhance our understanding of clozapins's side effects and to develop strategies for prevention and treatment.

Topics: Antipsychotic Agents; Clozapine; Cytokines; Humans; Nervous System; Receptors, Cytokine; Schizophrenia; Schizophrenic Psychology

Clozapine remains the most effective agent for treatment-resistant patients with schizophrenia. Recently, treatment with clozapine has been linked to a number of metabolic disturbances, including weight gain, diabetes mellitus, and serum lipid abnormalities. Despite the potential risks of medical morbidities, clozapine continues to have a major role in the care of treatment-resistant patients with schizophrenia. This article discusses the diagnosis and significance of the above metabolic abnormalities and potential mechanisms for these abnormalities as well as recommendations for monitoring and treatment.

Topics: Cholesterol; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Glucose Tolerance Test; Humans; Hyperlipidemias; Hypertriglyceridemia; Schizophrenia; Weight Gain

The available literature suggests that patients with schizophrenia are at risk for diabetes mellitus and taking antipsychotic medication further increases the chance of developing non-insulin-dependent hyperglycemia. Case reports, chart reviews, and some results from clinical drug trials implicate a relationship between glucose levels and treatment with clozapine or olanzapine in patients with schizophrenia, although a few cases of hyperglycemia have also been reported in patients taking risperidone and quetiapine. These studies indicate that hyperglycemia is not dose dependent, is reversible on cessation of treatment with clozapine or olanzapine, and reappears on reintroduction of these therapies. The postulated underlying mechanisms involved in this process in patients with schizophrenia include (1) a decreased sensitivity to insulin that is independent of atypical medication, (2) an increased insulin resistance related to atypical medications, (3) the effects of atypical medications on serotonin receptors, and (4) overuse of insulin due to weight gain. These mechanisms are discussed in detail, and recommendations for the administration of atypical antipsychotics are offered. Overweight, ethnicity, family or personal history of diabetes mellitus or hypertension, and weight gain during the course of treatment have all been identified as risk factors in the development of hyperglycemia in patients with schizophrenia. However, it is difficult to statistically assess the true incidence of diabetes within each type of antipsychotic medication group with the exclusive dependence on available case studies and without proper epidemiologic research.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Comorbidity; Diabetes Mellitus; Female; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Prevalence; Risk Factors; Schizophrenia; United States

Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha-adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF-alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Energy Metabolism; Female; Genetic Predisposition to Disease; Homeostasis; Humans; Hypothalamus; Male; Obesity; Pharmacogenetics; Receptors, Adrenergic; Receptors, Histamine; Schizophrenia; Serotonin; Tumor Necrosis Factor-alpha; Weight Gain

Prescribing an antipsychotic for a patient with schizophrenia requires a risk-benefit analysis. Weight gain has become an issue recently as a result of reports that 2 of the atypical antipsychotic agents, clozapine and olanzapine, are associated with a higher risk than other drugs of causing excessive weight gain. Some degree of weight gain may occur with any atypical antipsychotic agent, particularly early in treatment. A more important consideration is the long-term effects of the atypical antipsychotic on body weight, since many of the patients in this population require chronic therapy. This is important because weight gain is an adverse effect that is associated with noncompliance and medical problems. In this article, I review recent reports about the weight effects of different atypical antipsychotic drugs. To provide accurate understanding of the effects of atypical antipsychotic agents, data analyses should include both short-term and long-term findings, the relationship of changes in body weight to pretreatment body mass index (BMI), relationship to dose, both intent-to-treat and complete analyses, and presentation of both mean and median changes in weight. It is also important to know whether the studies have been done in an inpatient or outpatient setting, since patients who are institutionalized may be less likely to exhibit increases in body weight. Such complete information and multidimensional analysis would minimize obfuscation about the true nature of a drug's impact on body weight.

Topics: Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Hospitalization; Humans; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Research Design; Schizophrenia; Thiazoles; Weight Gain

The high costs and efficacy of clozapine warrant a systematic pharmacoeconomic evaluation to assess its relative cost-utility compared with that of older antipsychotic therapies. An economic analysis of clozapine consisted of a meta-analysis and a cost-utility analysis. Clozapine was compared with haloperidol and chlorpromazine. An incidence-based deterministic decision analysis was used to model the management of chronic schizophrenia over one year. Probabilities of clinical outcomes were obtained from a random effects, single arm meta-analysis. Utility weights were evaluated in a cohort of patients by using a standard gamble methodology. A government payer perspective was adopted for this analysis. Clozapine was the dominant therapy in this analysis because it was associated with the lowest overall expected cost and highest expected number of quality-adjusted life years (QALYs). Compared with chlorpromazine, clozapine might save $38,879/year while producing 0.04 more QALYs. This analysis was limited in that studies were of short duration, the sample size for health utility analysis was small and the analysis was based on a model. Clozapine appears to be a very cost effective therapy in patients with treatment-resistant schizophrenia compared with haloperidol and chlorpromazine.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Cost-Benefit Analysis; Decision Support Techniques; Economics, Pharmaceutical; Haloperidol; Humans; Quality of Life; Schizophrenia

"Atypical" antipsychotics are associated with a much lower propensity for extrapyramidal side effects and, with some exceptions, a lack of sustained prolactin elevation. The authors propose that a low-affinity and fast dissociation (in molecular terms) from the dopamine D(2) receptor, along with administration of the drug in doses that lead to appropriate levels of dopamine D(2) receptor blockade, are the most important requirements for atypicality. Actions at other receptors (5-HT(2), D(4), etc.) may not be necessary to achieve atypicality, and while action at these receptors may have benefits on symptoms such as mood and cognition, this is as yet to be conclusively proven. Why clozapine is effective in refractory patients is still elusive and efforts to make antipsychotics that are devoid of effects on the dopamine D(2) receptors so far have been unsuccessful. In light of this, the authors provide a heuristic model linking pathophysiology and therapeutics and suggest that the ideal treatment for schizophrenia is unlikely to be single-drug with multireceptor blockade (a sort of one-size-fits-all polypharmacy) but will require several specific and targeted treatment strategies that are titrated to match the variable expression of different dimensions of schizophrenia in each patient.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Models, Neurological; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine D2; Risperidone; Schizophrenia; Sulpiride

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Cytoskeletal Proteins; Dibenzothiazepines; Dopamine; Dopamine Antagonists; Humans; Nerve Tissue Proteins; Olanzapine; Pirenzepine; Proto-Oncogene Proteins c-fos; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Serotonin Antagonists

Recent data and clinical experience confirm that, in spite of superior efficacy for treatment-refractory schizophrenia, a substantial proportion of patients receiving clozapine will continue to experience disabling symptoms. Optimizing clozapine monotherapy is the first step in the management of "clozapine nonresponders." Described here is a synthesis of the available literature on the range and efficacy of clozapine augmentation strategies that may be used when monotherapy fails. Treatment options include adjunctive antipsychotic medications, mood stabilizers, selective serotonin reuptake inhibitors, glycinergic agents, and electroconvulsive therapy. The evidence favoring one augmentation strategy over another is lacking; overall, adjunctive therapy is associated with only modest clinical improvement. Moreover, case series and open-labeled clinical trials dominate the extant literature, and there is a dearth of double-blind trials comparing these augmentation agents. Current systematic efforts to enhance the treatment of these patients with adjunctive therapies are worthy of being studied in carefully conducted clinical trials.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States

Clozapine is a dibenzodiazepine derivative and a truly atypical anti-psychotic. Its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. Although it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its general use is limited because of the risk of agranulocytosis.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Interactions; Humans; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Humans; Pharmacogenetics; Schizophrenia

On the heels of clozapine, we now have a number of newer agents (risperidone, olanzapine, quetiapine, sertindole, and ziprasidone). Are they all the same? What are the differences? How do we best understand them? In this article we review current clinical evidence to compare these issues on four measures of atypicality: EPS, prolactin elevation, superior efficacy in refractory/positive symptoms and efficacy against negative symptoms. All the newer agents are superior on EPS and, with the exception of risperidone, avoid prolactin elevation. Clozapine shows the most convincing efficacy in refractory schizophrenia, although comparative data concerning risperidone's benefit in this respect are also emerging. It is unclear, however, whether any of the agents produce a greater effect than conventional antipsychotics against positive symptoms in responsive patients. Both clozapine and olanzapine have demonstrated superior efficacy against negative symptoms, although it remains controversial whether this is an effect on primary or secondary symptoms. The precise pharmacologic mechanisms underlying "atypicality" remain unclear, but several conceptual frameworks are highlighted that characterize, and perhaps differentiate, these newer agents.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Humans; Prolactin; Schizophrenia; Terminology as Topic

The reintroduction of clozapine, the prototype of atypical antipsychotics, in the late 1980s has led to significant advances in the pharmacological management of schizophrenia. Since then, there has been a rapid development of novel "atypical" antipsychotic agents that have been pharmacologically modeled, to a certain extent, after their predecessor clozapine. As with all antipsychotics, there is variability among individuals in their response to these "atypical" drugs. Pharmacogenetics can provide a foundation for understanding this interindividual variability in antipsychotic response. This review first provides a rationale for the pharmacogenetic investigation of this variable trait. Studies of pharmacokinetic and pharmacodynamic factors of antipsychotic therapy are considered in the development of this rationale. Next, the molecular genetic techniques used to study this interindividual variation in response are described. This is followed by a review and discussion of the published studies examining genetic factors involved in clozapine response. From this, several recommendations for future pharmacogenetic investigations of antipsychotic response are proposed. Although still in its early stages, psychiatric pharmacogenetics should provide a basis for individualized pharmacotherapy of schizophrenia, and may also lead to the development of newer, more efficacious antipsychotic agents.

Topics: Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Genetic Predisposition to Disease; Humans; Individuality; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Schizophrenia; Treatment Outcome

Four new antipsychotic medications--clozapine, risperidone, olanzapine, and quetiapine--have been introduced in the United States during the past decade. These new medications now account for the majority of antipsychotic prescriptions. The author reviews specific issues related to the use of traditional antipsychotic medications and then highlights the emerging clinical research data regarding the new medications, which have all been shown to be efficacious in the treatment of schizophrenia. Clinical research data indicate that they are also more useful for a broader array of symptoms associated with schizophrenia than traditional compounds. Furthermore, movement disorder side effects are substantially decreased--a property that leads to higher acceptability. Surprisingly, there has been little relationship between the pivotal trials designed for FDA approval and current dosing strategies in broader clinical settings. These dosing issues are described. New uses, including treatment of mood disorders and conduct disorder, are also discussed. These medicines offer substantial hope for improved treatment of schizophrenia.

Topics: Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Prolactin; Quetiapine Fumarate; Risperidone; Schizophrenia

Depressive symptoms and syndromal depression commonly occur in patients with schizophrenia. Schizophrenia is also associated with aggression directed at self and others. For this article, the available literature regarding the efficacy of clozapine, risperidone, olanzapine, quetiapine, and ziprasidone in the treatment of depression, hostility, and suicidality in patients with schizophrenia was reviewed. These studies suggest that atypical antipsychotics may exert therapeutic effects on depression and hostility as well as psychosis and that clozapine and olanzapine may reduce suicidality in patients with schizophrenia. These therapeutic actions appear to represent additional advantages of atypical antipsychotics compared with standard agents.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Depression; Depressive Disorder; Dibenzothiazepines; Hostility; Humans; Multicenter Studies as Topic; Olanzapine; Piperazines; Pirenzepine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Suicide; Thiazoles; Treatment Outcome

Given the problematic nature of tardive dyskinesia in persons taking conventional antipsychotics, evaluation of newer atypical antipsychotic agents should include a systematic assessment of tardive dyskinesia liability. Results of a prospective double-blind, randomized study of schizophrenic patients who participated in 3 preclinical olanzapine studies and were treated with 5 to 20 mg/day of olanzapine (N = 1192) or haloperidol (N = 522) recently indicated a significantly lower risk of development of tardive dyskinesia with olanzapine treatment than haloperidol treatment. This article discusses the known effects of atypical antipsychotic medications on tardive dyskinesia movements (both withdrawal and persistent) and the incidence rate of tardive dyskinesia among schizophrenic patients undergoing long-term treatment with olanzapine or haloperidol.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Haloperidol; Humans; Incidence; Molindone; Olanzapine; Pirenzepine; Prospective Studies; Risk Factors; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Survival Analysis

The enthusiasm produced by the introduction of antipsychotic medication in the 1950s gave way to a certain frustration in the 1970s and 1980s. Despite the development of a large number of new drugs, little progress was made in treatment because these new agents were, in essence, therapeutically equivalent. This lack of progress was perhaps also related to an emphasis on tardive dyskinesia in the 1970s, i.e., the preoccupation with a negative effect of treatment. The reverse is taking place today. Clozapine and the other atypical antipsychotics are associated in people's minds with fewer or absent extrapyramidal symptoms and less tardive dyskinesia than the older typical agents. As a result, a certain amount of complacency exists. Tardive dyskinesia not only may be painful and disfiguring, but it also predicts poor outcome in patients with schizophrenia. Although many treatments have been tried, none have proven completely efficacious. The best treatment for tardive dyskinesia and dystonia is prevention, which is a function of medication choice. Pharmacologic interventions for tardive dyskinesia include clozapine and the other atypical antipsychotics. If typical antipsychotics must be used, they should be started at the lowest possible levels. Studies of risperidone suggest that it, too, should be used at very low doses to minimize the risk of tardive dyskinesia. It is also possible that schizophrenic patients taking atypical antipsychotics may experience fewer spontaneous dyskinesias, although further study is warranted.

Topics: Adult; Akathisia, Drug-Induced; Algorithms; Antipsychotic Agents; Benzodiazepines; Clozapine; Decision Trees; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Male; Olanzapine; Pirenzepine; Probability; Reserpine; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Tetrabenazine; Treatment Outcome; Vitamin E

Atypical neuroleptic drugs have enriched our treatment programs, especially in childhood and adolescent schizophrenia. Reviewed here is the use of atypical neuroleptics in children and adolescents with a schizophrenic disorder. The receptor binding profile and pharmacological properties, indications, side effects, clinical application, and trials of atypical neuroleptic drugs are compared to the classical neuroleptic drug haloperidol in the treatment of adolescent schizophrenia. Special attention is paid to the most common atypical neuroleptics clozapine, olanzapine and risperidone since most studies are carried out with these compounds, most often with clozapine. More clinically controlled trials have to be conducted since only one has been performed to date. The place of atypical neuroleptic drugs is discussed and further studies are necessary in order to differentiate, and eventually broaden the spectrum of the indications tested thus far.

Topics: Adolescent Psychiatry; Antipsychotic Agents; Benzodiazepines; Child; Child Psychiatry; Clozapine; Germany; Humans; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

Long-term drug treatment of schizophrenia with conventional antipsychotics has limitations: 25-33% of patients have illnesses that are treatment-resistant. Clozapine is an atypical antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment.. To evaluate the effects of clozapine for schizophrenia in comparison to typical antipsychotic drugs.. Publications in all languages were searched from the following databases: Biological Abstracts (1982-1999), The Cochrane Library CENTRAL (Issue 2, 1999), Cochrane Schizophrenia Group's Specialised Register (1999), EMbase (1980-1999), ISI Citation Index, LILACS (1982-1999), MEDLINE (1966-1999), and PsycLIT (1974-1999). Reference list screening of included papers was performed. Authors of recent trials and the manufacturer of clozapine contacted.. All randomised controlled trials comparing clozapine with typical antipsychotic drugs were included by independent assessment by at least two reviewers.. Data were extracted independently by at least two reviewers. Authors of trials published since 1980 were contacted for additional and missing data. Odds ratios (OR) and 95% confidence intervals (CI) of homogeneous dichotomous data were calculated with the Peto method. A random effects model was used for heterogeneous dichotomous data. Where possible the numbers needed to treat (NNT) or needed to harm (NNH) were also calculated. Weighted or standardised means were calculated for continuous data.. Currently the review includes 31 studies, 26 of which are less than 13 weeks in duration. These studies include 2589 participants, most of whom were men (74%). The average age was 38 years. There was no difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at end of the study. Clinical improvement was seen more frequently in those taking clozapine (random effects OR 0.4 CI 0.2-0.6, NNT 6) both in the short and the long term. Also, in the short term, participants on clozapine had fewer relapses than those on typical antipsychotic drugs (OR 0.6 CI 0.4-0.8, NNT 20 CI 17-38), and this may be true for long-term treatment as well. Symptom assessment scales showed a greater reduction of symptoms in clozapine-treated patients. Clozapine treatment was more acceptable than low-potency antipsychotics such as chlorpromazine (OR 0.6 CI 0.4-0.9) but did not differ from acceptability of high-potency neuroleptics such as haloperidol (random effects OR 0.8 CI 0.4-1.5). Clozapine was more acceptable in long-term treatment than conventional antipsychotic drugs (random effects OR 0.4 CI 0.2-0.7, NNT 6 CI 3-111). Patients were more satisfied with clozapine treatment (OR 0.5 CI 0.3-0.8, NNT 12 CI 7-37), but they experienced more hypersalivation, temperature increase, and drowsiness than those given conventional neuroleptics. However, clozapine patients experience fewer motor side effects and less dry mouth. The clinical efficacy of clozapine was more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (random effects OR 0.2 CI 0.1-0.5, NNT 5 CI 4-7) and symptom reduction. Thirty-two percent of treatment resistant people had a clinical improvement with clozapine treatment.. This systematic review confirms that clozapine is convincingly more effective than typical antipsychotic drugs in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse. Patients were more satisfied with clozapine treatment than with typical neuroleptic treatment. (ABSTRACT TRUNCATED

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Clozapine is an atypical antipsychotic drug, which is claimed to have superior efficacy and to cause fewer movement disorders. However, clozapine carries a significant risk of serious blood disorders. Newer atypical antipsychotics are safer alternatives that might share the benefits of clozapine. It is thus of interest to compare the effectiveness of newer atypical antipsychotics with the effectiveness of clozapine.. To evaluate the clinical effects of newer atypical antipsychotic drugs in comparison to clozapine for schizophrenia.. Publications in all languages were searched from the following databases: Biological Abstracts/BIOSIS (1980-1999), The Cochrane Schizophrenia Group's Register of Trials (1998), The Cochrane Library CENTRAL Register (Issue 4, 1999), EMBASE (1980-1998), MEDLINE (1966-1999), LILACS/CD-ROM (1998), and PsycLIT/PsycINFO (1974-1999). Trials were also sought from recent conference proceedings and reference lists of included papers. Authors of recent trials and the manufacturers of clozapine, iloperidone, olanzapine, quetiapine, remoxipride, risperidone, sertindole, ziprasidone and zotepine were contacted.. All randomised controlled trials comparing clozapine with newer atypical antipsychotic drugs were included by independent assessment by two reviewers.. Data were extracted independently by two reviewers. Relative risks (RR) and 95% confidence intervals (CI) of homogenous dichotomous data were calculated. A random effects model was used for heterogeneous dichotomous data. Where possible the number needed to treat (NNT) statistic with 95%CI were also calculated. Weighted or standardised means were calculated for continuous data. Due to the small number of included studies, sensitivity analyses or funnel plot statistics were not undertaken for this version of the review.. The current review includes eight studies (22 papers), of which three studies are 4-6 weeks in duration and only one study is of more than 12 weeks' duration. Newer atypical drugs seemed to be broadly similar to clozapine using a clinical global index or trialists' definitions of improvement, but this result was obtained from a relatively small number of studies. Due to the small number of studies and patients, wide confidence intervals were seen when their effectiveness as measured by symptom rating scales was compared. Social functioning was better in patients on newer atypical medication (risperidone) than in those on clozapine, but this finding is based on a single underpowered trial and has to be interpreted with caution. Clozapine and newer atypical drugs showed their adverse effect profile to be dissimilar: while clozapine produced more fatigue, hypersalivation, nausea, and orthostatic dizziness, new atypical drugs, with the exception of olanzapine, produced more extrapyramidal symptoms. The impact of these drugs and their effects on patients' day-to-day quality of life, service use, hospital admission, and pharmacoeconomics was not measured.. The equal effectiveness and tolerability of new atypical drugs in comparison with clozapine is not yet demonstrated. Lack of statistical power to determine the comparative efficacy and effectiveness of newer atypical drugs makes it difficult to judge whether newer drugs are more effective, less effective or equivalent. Trials of sufficient power, with longer duration, measuring clinically important outcomes, are needed to assess the true comparative clinical effectiveness, tolerability and cost effectiveness of newer drugs in relation to clozapine.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

The results of controlled studies of the efficacy of the new atypical neuroleptics in treating negative symptoms show that these antipsychotics have a more pronounced effect on negative symptoms in acute schizophrenic patients than the classical neuroleptics. Supplementary complex statistical analyses substantiate that the increased efficacy of the atypical neuroleptics in treating negative symptoms can only partially be explained by indirect effects of better extrapyramidal tolerability, better effects on productive psychotic symptoms, etc. Instead, it is due largely to the stronger direct effect of these atypical neuroleptics. Clinical studies to evaluate their efficacy in chronic schizophrenic patients with stable, predominantly negative symptoms are still mostly lacking. First results support the presumption that atypical neuroleptics have a direct effect. Parallel to the evaluation of the new atypical neuroleptics, important progress has been made in the methodology of clinical studies in this area.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Double-Blind Method; Dyskinesia, Drug-Induced; Humans; Imidazoles; Indoles; Neurotransmitter Agents; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Sulpiride; Thiazoles

While clozapine has been demonstrated to be efficacious in refractory schizophrenia and possibly schizoaffective as well as bipolar disorders, a substantial number of patients still remain unresponsive. One strategy in treating these refractory patients is to augment clozapine with other somatic treatments. This article reviews the efficacy and safety of the combination of clozapine with other somatic treatments. A total of 70 articles were obtained from a manual, as well as computerized (Medline), search of the English language literature from 1978 to March 1998. Few controlled studies exist; most were case reports/series. From these data, the greatest risk of adverse effects seems to be associated with clozapine combined with benzodiazepines, valproate, or lithium, but no currently evaluated combination is absolutely unsafe. In terms of efficacy, the data suggest a number of potential augmentation strategies, although controlled data are few. Combination therapies with clozapine are common in clinical practice, despite a lack of empirical data, and the benefits and risks of these combinations need to be systematically reviewed.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Humans; Schizophrenia

Risperidone is one of a number of 'atypical antipsychotics' which are currently being marketed for the treatment of those with schizophrenia, largely on the basis of claims of improved tolerability and effectiveness compared to much cheaper conventional antipsychotics. The efficacy of risperidone has already been compared to conventional drugs, but it remains unclear how risperidone compares with other atypical antipsychotic drugs such as clozapine.. To determine the effects of risperidone compared with other atypical antipsychotic drugs for schizophrenia.. Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 2000), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted.. All randomised controlled clinical trials that compared risperidone to other atypical antipsychotic treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment.. Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, standardised and weighted mean differences were calculated (SMD, WMD). All data were inspected for heterogeneity.. Nine studies were obtained, comparing risperidone with clozapine (five studies - largely amongst treatment resistant patients); olanzapine (three studies); and amisulpiride (one study). The research was beset by problems of high attrition rates and short term follow up. Clozapine does seem equally acceptable to risperidone in the short term (leaving the study early, n=466, RR 1. 00 CI 0.73-1.37). For most other outcomes wide confidence intervals were obtained, which meant that it was impossible to judge whether the two compounds were equally effective, or whether one was in fact superior to the other. Olanzapine and risperidone seem broadly similar according to numbers of patients responding to treatment (40% reduction in PANSS scores: n=339, RR 1.14, CI 0.99-1.32). Olanzapine caused fewer people to leave the study early (n=404, RR 1. 31 CI 1.06-1.60; NNT 8 CI 4-32) and fewer extrapyramidal side effects (n=339, RR 1.67 CI 1.14-2.46; NNH 8 CI 5-33), although comparative doses of risperidone were higher than those recommended in practice. In one single study (n=228) amisulpiride seemed broadly similar to risperidone in most respects. There were no useful data presented relating to service use and costs. Very few data relating to quality of life were presented.. The equivalence of clozapine and risperidone for treatment resistant schizophrenia cannot yet be assumed and there seems to be little to chose between risperidone and both olanzapine and amisulpiride. The research is limited in many respects, and longer term studies measuring clinically important outcomes, including service use and quality of life are needed to judge the comparative value of the various atypical drugs.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Olanzapine; Pirenzepine; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia

In recent years several new antipsychotics have come to market in the Netherlands (i.e. risperidone, olanzapine and quetiapine). These compounds are called atypical for their lack of the extrapyramidal side effects typical of older antipsychotics. Clozapine, which was developed earlier, is also an atypical antipsychotic drug. The new antipsychotics have proven to be more effective than the old ones in reducing the negative symptoms and in improving the cognitive deficits of schizophrenia. Moreover, they indeed induce less extrapyramidal side effects than the older antipsychotics. Head-to-head comparisons of the atypical antipsychotics are sparse. Studies comparing low-dose regimens of the typical antipsychotics with the atypical drugs as well as relapse prevention studies are needed before it can be decided whether the atypical drugs can replace the older compounds.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Netherlands; Olanzapine; Pirenzepine; Psychopharmacology; Quetiapine Fumarate; Risperidone; Schizophrenia; Serotonin Agents

Topics: Antipsychotic Agents; Clozapine; Dopamine Uptake Inhibitors; History, 20th Century; Humans; Psychiatry; Schizophrenia; Selective Serotonin Reuptake Inhibitors; United States

Although antagonism of mesolimbic dopamine D(2) receptors by neuroleptics such as haloperidol attenuates positive symptoms of schizophrenia, a significant population of "resistant" patients fails to respond while negative and cognitive symptoms are little modified. Furthermore, concomitant blockade of striatal D(2) receptors is associated with extrapyramidal motor side effects. The superior "atypical" antipsychotic profile of clozapine appears to reside in its broad pattern of interaction with D(2) receptors and a diversity of other monoaminergic sites. In this regard, serotonergic mechanisms are of particular relevance both in view of their modulation of dopaminergic transmission and their key role in the control of mood, cognition, and motor behavior. While most attention has focused on potential advantages of preferential 5-HT(2A) versus D(2) receptor blockade, 5-HT(1A) receptors likewise represent a valid target for improved antipsychotic agents. In this regard, rather than selective agents, ligands interacting with both 5-HT(1A) and D(2) receptors appear of interest. A modest level of efficacy appears optimal, that is, sufficient to engage highly sensitive 5-HT(1A) autoreceptors while blocking their low-sensitivity postsynaptic counterparts. Such a profile may counter negative and cognitive symptoms, improve mood, diminish extrapyramidal 5-HT(1A) motor side effects, and, perhaps, enhance efficacy in refractory patients. Notably, "partial agonist" properties of clozapine at 5-HT(1A) receptors may contribute to its distinctive functional profile. However, notwithstanding this compelling body of experimental data, clinical studies of antipsychotics interacting with 5-HT(1A) receptors are required to establish their genuine pertinence to the-hopefully improved-treatment of schizophrenia.

Topics: Affect; Antipsychotic Agents; Clozapine; Cognition; Humans; Receptors, Dopamine; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Schizophrenia

To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia.. Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines.. 12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics.. Overall symptom scores. Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects.. For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs. Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity. When the dose was

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Costs; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Quetiapine Fumarate; Regression Analysis; Risperidone; Schizophrenia; Sulpiride

Atypical neuroleptics have enriched our treatment programmes, especially in childhood and adolescent schizophrenia. This article reviews the use of atypical neuroleptics in children and adolescents with schizophrenic disorder. It considers the receptor binding profile and pharmacological properties, indications, side effects, clinical applications and trials of atypical neuroleptics in comparison to the classical neuroleptic haloperidol in adolescent schizophrenia. Special emphasis is placed on the most common atypical neuroleptics clozapine, olanzapine and risperidone since most studies are carried out with these compounds, especially with clozapine. More clinically controlled trials have to be conducted since only one was performed so far. The place of the atypical neuroleptics is discussed and further studies are necessary in order to differentiate the indications tested so far and to find out if the spectrum of indications can be broadened.

Topics: Adolescent; Adolescent Psychiatry; Antipsychotic Agents; Benzodiazepines; Binding Sites; Brain; Clozapine; Female; Humans; Male; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Tomography, Emission-Computed

Schizophrenia is a seriously disturbing disorder, both for the victim and for their families. Although treatments are available which can effectively control symptoms, their side effects are severe enough to cause many sufferers to discontinue taking them and their actions are not properly understood.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Delusions; Dopamine Antagonists; Female; GABA Antagonists; Hallucinations; Humans; Magnetic Resonance Angiography; Male; Neurotransmitter Agents; Receptors, Dopamine D2; Schizophrenia; Synapses; Tomography, Emission-Computed

The introduction of conventional antipsychotics revolutionized the management of psychotic disorders in the 1950s. The use of these agents has been marked by several shortcomings, including their association with severe motor disturbances and their limited efficacy in treating the negative and cognitive symptoms of schizophrenia. Patients noncompliance has largely been the result of subjectively distressing extrapyramidal motor side-effects (EPMS). It was therefore necessary to develop antipsychotic drugs with selective pharmacological profiles, e.g. limbic selectivity. A defining characteristic of atypical neuroleptics is a higher ratio of serotonin receptor blockade to D2 receptor blockade. Their primary advantage is their superior side-effect profile. The implications of EPMS reduction touch several domains of pathology in schizophrenia such as short- and long-term movement disorders, noncompliance, relapse rate, negative symptoms and cognitive dysfunction. Novel antipsychotics may represent the second pharmacological revolution in the treatment of psychotic disorders. There is, however, still a need for a critical evaluation of the risk-benefit-ratio of differing atypical agents.

Topics: Aged; Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Controlled Clinical Trials as Topic; Dibenzothiazepines; Dibenzothiepins; Haloperidol; Humans; Imidazoles; Indoles; Multicenter Studies as Topic; Olanzapine; Piperazines; Pirenzepine; Placebos; Quetiapine Fumarate; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Sulpiride; Thiazoles

Topics: Agranulocytosis; Clozapine; Female; Humans; Incidence; Israel; Male; Risk Assessment; Sampling Studies; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Cognition; Drug Monitoring; Humans; Patient Selection; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

Elderly patients with schizophrenia and dementia patients with agitation are frequently candidates for antipsychotic treatment. Conventional neuroleptics have relatively little effect on negative symptoms and may cause considerable side effects, especially in elderly patients. The authors have found a 29% cumulative annual incidence of tardive dyskinesia (TD) in middle-aged and elderly outpatients treated with relatively low doses of conventional neuroleptics Newer antipsychotics are less likely to cause extrapyramidal symptoms and may be associated with a lower risk of TD. They are generally effective for both positive and negative symptoms and may also improve some aspects of cognition, but these drugs have their own side effects. Dosing requirements for elderly patients tend to be much lower than those for younger adults.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Dementia; Dibenzothiazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

Cost-effectiveness analyses determine whether a new therapy will find a place in clinical practice, based on the cost of its use and the health outcomes it produces, compared with other available therapies. Clozapine, indicated for treatment-resistant schizophrenia, has been evaluated in uncontrolled, mirror-image studies; clinical decision analysis models; and prospective, randomized clinical trials. Results from randomized trials demonstrate that clozapine controls symptoms of psychopathology and improves quality of life slightly more effectively than traditional neuroleptic medications. It has a lower incidence of extrapyramidal side effects than traditional medications, resulting in a lower drop-out rate. Beginning in the second year of treatment, clozapine may produce cost savings for the health care system, when its higher acquisition cost begins to be offset by reduced hospitalization. Mirror-image studies and clinical decision analysis models provide further support for these findings.

Topics: Clozapine; Cost-Benefit Analysis; Double-Blind Method; Drug Costs; Economics, Pharmaceutical; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

The past 5 years have witnessed an intense period of change in the pharmacotherapy of schizophrenia. Several new antipsychotic agents have become available for clinical use, and more are likely to appear over the next few years. The new agents require that clinicians treating patients with schizophrenia adopt new ways of thinking regarding the pharmacotherapy of this illness. Longer drug trials than have traditionally been used may be required to determine response to the newer agents, and response should be measured across negative symptoms, cognitive symptoms, and broader rehabilitative dimensions. Clozapine has an established role in treatment-resistant schizophrenia. Other new antipsychotics are being used with broader clinical indications. The relative efficacy of these agents, particularly in treatment-refractory patients, remains to be determined. The availability of the newer agents may represent an opportunity to reduce the incidence of tardive dyskinesia and to gain better management of comorbid substance abuse and aggression among schizophrenic patients. Significant cost savings could accrue from more effective disease management.

Topics: Aggression; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Comorbidity; Cost-Benefit Analysis; Drug Costs; Dyskinesia, Drug-Induced; Health Care Costs; Humans; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders; Treatment Outcome

Although some patients with schizophrenia may have a single episode and recover, the vast majority remain ill and unable to work for life. In the United States, patients with schizophrenia use 2.5% of the annual total health care allocations. The atypical antipsychotics, particularly when combined with psychosocial treatment, hold the promise of improving outcome and reducing the economic burden on society. Both clinical outcome and cost effectiveness are best evaluated in the context of a comprehensive assessment of a range of meaningful outcome measures studied in clinical situations. Evidence exists that the atypical antipsychotics not only reduce positive and negative symptoms and cause fewer side effects than conventional neuroleptics, but also lessen cognitive impairment, lead to a better quality of life, and have antidepressant effects, all of which should result in improved outcome in patients with schizophrenia. Increasing the availability of the atypical agents should be cost effective for society by restoring productivity in some patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Drug Costs; Female; Follow-Up Studies; Health Care Costs; Humans; Male; Neuropsychological Tests; Outcome Assessment, Health Care; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cognition Disorders; Humans; Reaction Time; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

The syndrome of schizophrenia often includes negative symptoms and severe cognitive deficits that are resistant to change with conventional pharmacotherapy. The efficacy of clozapine in the reduction of the negative syndrome has prompted a series of studies implicating circumscribed cognitive improvements. Restrictions on the use of clozapine have encouraged the development and introduction of novel compounds with a clinical efficacy profile similar to clozapine that are hoped also to have beneficial cognitive effects. The present review summarizes studies of the cognitive efficacy of novel antipsychotic medications, particularly in regard to issues in experiment design and study implementation that might facilitate additional research. Although preliminary support exists for relatively circumscribed improvement of cognitive status with the use of clozapine and risperidone--and more general improvement with the use of olanzapine--specific inferences relating cognitive change to particular treatments will remain speculative until more sophisticated investigations are completed. The present review emphasises the most relevant design limitations in past studies to provide practical suggestions for the implementation of subsequent investigations Previous results have established the possibility of a medication-based change in cognitive status in schizophrenia Future research will determine the validity of these changes, the cerebral mechanism involved, and their significance to improved prognosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dibenzothiazepines; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia; Severity of Illness Index

Typical antipsychotic agents produce central nervous system effects, especially extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Nearly every patient who receives neuroleptic therapy has one or more identifiable risk factors for TD, among the most significant of which are older age, female gender, presence of EPS, diabetes mellitus, affective disorders, and certain parameters of neuroleptic exposure (i.e. dose and duration of therapy). The typical course of TD is a gradual onset after several years of drug therapy, followed by slow improvement or remission, but a large number of patients have persistent TD with irreversible symptoms. In the management of TD, the patient's mental status is of primary concern. Currently, no uniformly safe and effective therapies for TD exist, though a variety of therapeutic agents, including some of the atypical neuroleptics, have been reported to treat TD successfully in some patients. Because TD liability is so much lower with novel antipsychotic therapy, all patients who have TD or are at risk for TD, as well as EPS, should be considered candidates for switching to these new drugs.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Sex Factors

Strategies for preventing relapse during the maintenance or stable phase of schizophrenia are discussed for both conventional and newer antipsychotics. For conventional agents, strategies focus on finding dosages that minimize antipsychotic drug side effects and provide adequate protection against psychotic relapse. Although few studies are available to compare older and newer antipsychotics for preventing relapse, there are reasons for proposing that newer drugs will be shown to be superior. Because of their milder side effects, clinicians can choose drug dosages that provide maximum protection against relapse. Further, since patients on the newer drugs are likely to experience fewer discomforting side effects, they may be more likely to take their medications as directed. Other potential advantages of the newer drugs over the older drugs include the likelihood that they are more effective against negative and cognitive symptoms of schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Secondary Prevention

The pharmacoeconomic evaluation of atypical antipsychotics for patients with schizophrenia requires focus on both clinical and quality of life effects and impact on the cost of medical resources. The results of pharmacoeconomic studies help clinicians and health care decision makers identify treatments that provide the most benefit to patients at the most acceptable cost. The cost-effectiveness of antipsychotic drugs has been evaluated using noncontrolled, mirrorimage (i.e. retrospective/prospective) cohort study designs; clinical decision analysis models; and randomized clinical trials. The current pharmacoeconomic evidence suggests that clozapine is a cost-effective therapy for neuroleptic-refractory schizophrenia and that although olanzapine and risperidone therapy may be cost neutral, they improve outcome in patients treated for schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cost-Benefit Analysis; Humans; Olanzapine; Pirenzepine; Research Design; Risperidone; Schizophrenia

Cognitive impairment is a central feature of schizophrenia and has been correlated with negative symptoms and impaired social functioning. There is a growing body of data suggesting that the so-called atypical antipsychotic drugs (e.g. clozapine, risperidone, and olanzapine) are better at enhancing cognitive function than traditional neuroleptics. Preclinical studies of information processing using a pre-pulse inhibition model show that the mechanism of action of both olanzapine and clozapine for cognitive enhancement may involve glutamatergic/N-methyl-D-aspartate (NMDA) antagonism. Using positron emission tomography, we have described the metabolic and neurochemical correlates of cognitive impairment induced by glutamatergic/NMDA antagonism. A better understanding of the underlying causes of cognitive impairment may contribute to elucidating the pathophysiology of schizophrenia and the development of more efficacious treatments for this disorder.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Glutamic Acid; Haloperidol; Humans; N-Methylaspartate; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology

Olanzapine is a novel antipsychotic agent displaying a unique and pleotrophic pharmacology, which distinguishes it from other existing treatments. Clinical investigations employing olanzapine have demonstrated a number of potential therapeutic advantages in reference not only to placebo but also to contemporary drug standards in the management of psychosis. This paper reviews data on the pharmacokinetics, efficacy and safety of olanzapine, its benefits for quality of life, and economic aspects to assist clinicians in determining where they can usefully employ it.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Depressive Disorder; Drug Resistance; Humans; Olanzapine; Pirenzepine; Prolactin; Psychotic Disorders; Quality of Life; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia

Olanzapine possesses a broad pharmacological profile, interacting with a range of different neurotransmitter receptors. Although its affinity for muscarinic receptors is relatively greater than for dopamine receptors, on schedule-controlled behaviour olanzapine displays a profile resembling a dopamine antagonist. Likewise, in a test of cognitive function, olanzapine does not produce anticholinergic-like deficits. In drug discrimination assays, olanzapine substitutes for clozapine in clozapine-trained animals and clozapine generalises to olanzapine in olanzapine-trained animals. Olanzapine also reverses the behavioural deficits produced by inhibiting N-methyl-D-aspartate receptor glutamatergic transmission. This profile suggests that olanzapine will be effective against both positive and negative symptoms of schizophrenia while producing minimal extrapyramidal side-effects.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Cholinergic Antagonists; Clozapine; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Humans; Maze Learning; Motor Activity; Muscarinic Antagonists; Olanzapine; Pharmaceutical Vehicles; Phencyclidine; Pirenzepine; Schizophrenia; Scopolamine; Social Isolation

The recent introduction of the atypical antipsychotics into the treatment arena for psychoses and related disorders comes with justifiable excitement. These newer antipsychotics offer several clinical benefits over the conventional antipsychotics, which have been the mainstays of care thus far. The primary advantage of these atypical agents is their superior side effect profiles, particularly with regard to extrapyramidal side effects (EPS). The implications from a reduction in EPS touch on virtually every aspect of pathology in schizophrenic illness, including short- and long-term movement disorders, negative symptoms, noncompliance, cognitive dysfunction, and dysphoria. It should be emphasized that while atypical antipsychotics share many clinical attributes, there are also substantial differences among them. This review will examine the pharmacology, clinical efficacy, and side effect profiles of the atypical antipsychotics and attempt to relate the attributes observed in clinical practice and clinical trials to their basic pharmacologic profiles. There is a fair, but not perfect, correspondence between the pharmacologic profiles of the different atypical antipsychotics and their respective clinical attributes. After a comparative overview of their receptor-binding profiles, a brief pharmacokinetic summary will be provided. Finally, the clinical profiles of these agents will be summarized with regard to both their efficacy and adverse effects.

Topics: Animals; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dose-Response Relationship, Drug; Humans; Limbic System; Models, Biological; Olanzapine; Pirenzepine; Psychotic Disorders; Receptors, Neurotransmitter; Risperidone; Schizophrenia

Recent advances in our understanding of schizophrenia along with neuroscience insights into antipsychotic medication mechanisms of action have led to a renaissance in new drug development, including an expanded therapeutic spectrum encompassing more of the symptoms encountered in schizophrenia. Atypical antipsychotics, or new generation therapies, also demonstrate greater selectivity for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern armamentarium of drugs spans a wide range of pharmacologies, and it is more accurate to envision shades of gray rather than a black-and-white description for typical versus atypical properties of medications. As our paradigms for antipsychotic efficacy have shifted, a reexploration of the "older" neuroleptics is warranted to determine if they possess pharmacologic attributes that might have been overlooked during the era of high-dose neuroleptic therapy. Loxapine appears to be in the center of this spectrum, somewhere between haloperidol and risperidone. Dosing implications for drugs with a more even serotonin-2A (5-HT2A) receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine might have a window of partial atypicality at doses < or = 50 mg/day. These lower doses might have potential as both monotherapy in responsive patients with persistent psychotic disorders and as an adjunctive treatment in partially responding patients on concurrent atypical antipsychotic treatments. The pharmacologic properties of loxapine within its usable dosage range are quite complex and are the net sum of the parent's plus metabolites' contributions (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic effects include alpha-adrenergic blockade, inhibition of the noradrenergic transporter protein (reuptake inhibition), and antimuscarinic effects. Drug interactions and cigarette smoking might alter the parent-to-metabolite concentration ratios, affecting the relative atypicality of this antipsychotic therapy. Moreover, with the intramuscular formulation, which does not undergo first-pass metabolism, the parent compound of loxapine, i.e., not its metabolites, is predominantly detected in the plasma of patients, reducing the likelihood for EPS during emergency interventions in patients with positive symptoms. Further study is warranted to determine loxapine's place in our treatment of schizophrenia.

Topics: Antipsychotic Agents; Carrier Proteins; Clozapine; Cytochrome P-450 Enzyme System; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Humans; Loxapine; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Schizophrenia; Serotonin Plasma Membrane Transport Proteins

Three atypical antipsychotics are currently considered to be first-line therapies for schizophrenia, namely risperidone, olanzapine, and quetiapine. Deciding which one of these agents to choose for any given patient can be a daunting task because head-to-head comparisons of these 3 agents are just beginning, and most published trials are comparisons with typical antipsychotics, not with another atypical antipsychotic. Furthermore, results from clinical trials often do not match findings from clinical practice. Thus, guidelines for selection and use of the atypical antipsychotics are evolving from controlled studies as well as from clinical judgment based on the practical use of these agents once they have entered clinical practice. The atypical properties of first-line atypical antipsychotics as well as clozapine are reviewed here, with clinical pearls and dosing tips for each based upon a consensus of information from both clinical trials and clinical practice. The conventional antipsychotic loxapine is also reviewed and proposed as a potentially valuable agent to augment atypical antipsychotics when patients do not experience an acceptable treatment response from monotherapy with an atypical antipsychotic. By integrating information from clinical trials and clinical practice, the prescriber can be in a better position to choose which atypical antipsychotic to select for any given patient.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Humans; Olanzapine; Pirenzepine; Practice Guidelines as Topic; Quetiapine Fumarate; Risperidone; Schizophrenia; Terminology as Topic

The management of agitation and aggression in psychiatric inpatients is a significant clinical dilemma. Establishing a clear diagnosis and distinguishing whether aggression is an acute manifestation or a long-standing or repetitive problem are fundamental antecedents of medication treatment. For acute aggression, either benzodiazepines or antipsychotic medications (typical and atypical) are recommended choices. Currently, on the basis of efficacy, ease of use, and availability in multiple (tablet, liquid, intramuscular) preparations, typical antipsychotics such as loxapine should be considered as first choice for acute aggression (in psychosis). On the other hand, atypical antipsychotics, particularly clozapine, should be considered when aggression in psychosis persists and/or is repetitive. Typical antipsychotics are indicated for persistent aggression in psychosis when medication noncompliance is the obstacle to effective treatment.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Loxapine; Mental Disorders; Olanzapine; Pirenzepine; Psychomotor Agitation; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

Clozapine has recently been found to be associated with neuroleptic malignant syndrome (NMS). Our objective is to determine if clozapine causes NMS, if the presentation of clozapine-induced NMS differs from that of traditional agents, and which set of diagnostic criteria will most readily allow diagnosis of NMS associated with clozapine.. Two new cases of clozapine-associated NMS are presented, along with previously reported cases from the literature, identified by using a MEDLINE search (1966-August 1998). From all cases, concomitant medications and washout periods were examined (if available) to assess clozapine as the likely cause of NMS. Characteristics of clozapine and traditional antipsychotic-induced NMS were compared. Different diagnostic criteria for NMS were applied to the cases to determine which were more likely to diagnose the syndrome.. Clozapine was deemed a highly probable cause of NMS in 14 cases, a medium probability cause in five cases, and a low probability cause in eight cases. The most commonly reported clinical features were tachycardia, mental status changes, and diaphoresis. Fever, rigidity, and elevated creatine kinase were less prominent than in NMS associated with classical neuroleptics.. Clozapine appears to cause NMS, although the presentation may be different than that of traditional antipsychotics. Levenson's original and Addonizio's modified criteria were more likely to diagnose NMS than were other criteria. Clozapine-associated NMS may present with fewer clinical features. Limitations are the lack of detailed information provided by many of the case reports and the use of "modified" diagnostic criteria for retrospective diagnosis.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Schizophrenia

Considerable progress has been made during the past 10 years in the treatment of schizophrenia; however, the disease still represents a great challenge for the clinician. Frequently encountered problems include the patient who is only partially responsive to treatment or is treatment resistant and long-term relapse prevention. Patient compliance, long-term efficacy, drug dose, safety, and the duration of treatment are all important factors determining the degree of success of maintenance treatment in the prevention of relapse. This review discusses those aspects that should affect the clinicians' choice of treatment, including the recent introduction of atypical antipsychotics such as clozapine.

Topics: Ambulatory Care; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Administration Schedule; Health Care Costs; Hospital Costs; Humans; Patient Compliance; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Despite the introduction of antipsychotic treatment for schizophrenia, the outcome for many patients has remained poor. This is largely due to the treatment-resistant nature of schizophrenia in some patients and inadequate long-term maintenance treatment. The definition of treatment resistance remains controversial in spite of its importance. This review discusses the importance of treatment resistance and the factors affecting its definition in the light of recent advances in knowledge and treatment. A decade ago, positive symptoms were thought to be the prime outcome measure for schizophrenia and were the standard by which treatment resistance was largely assessed. More recently, however, a wider range of outcome measures has been recognized, including both negative symptoms and cognitive function. All of these outcome measures affect quality of life such that the patient may consider any outcome other than a return to premorbid levels of functioning as inadequate. Furthermore, patient responsiveness should be recognized as a continuum rather than as a dichotomy of response or nonresponse; partial response to treatment may not be accepted as satisfactory. Definitions of treatment resistance should reflect these factors. Patients may benefit from pharmacotherapy with atypical antipsychotics even if they do not meet criteria for narrowly defined treatment resistance. Although clozapine use has often been restricted to treatment-resistant patients, the benefit it bestows outweighs the potential risk of side effects in patients with less stringently defined treatment resistance.

Topics: Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Drug Resistance; Humans; Prospective Studies; Psychiatric Status Rating Scales; Psychometrics; Quality of Life; Schizophrenia; Schizophrenic Psychology; Terminology as Topic; Treatment Outcome

Compliance with conventional antipsychotic medication is often poor, with many patients discontinuing treatment only a few months after commencing therapy. The side effects of treatment, which are not necessarily restricted solely to motor symptoms, are often considered to be responsible for this noncompliance. In contrast to conventional antipsychotics, clozapine is associated with only minimal extrapyramidal symptoms, and in most patients, its use results in significant improvements in compliance. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. Clozapine therapy is associated with a beneficial risk/benefit ratio in the majority of treatment-resistant schizophrenic patients. With careful hematologic control, the risk of agranulocytosis can be minimized. The marked increase in the well-being of patients receiving clozapine should stimulate psychiatrists to broaden its use and not limit it to severely treatment-resistant individuals.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Electroencephalography; Fatigue; Humans; Patient Compliance; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Seizures; Sialorrhea; Tachycardia; Treatment Outcome

Clozapine represents the "gold standard" therapy for treatment-resistant schizophrenia including use for symptom reduction and use in patients intolerant of extrapyramidal side effects associated with other antipsychotics. Despite its clear benefit in these areas, its use has been associated with a serious, and sometimes life-threatening, risk for agranulocytosis. Effective white blood cell monitoring systems have been developed by Novartis affiliates across the world to ensure its safe use and to meet local health standards. The goals of the monitoring programs include: (1) weekly white blood cell monitoring during the initial months of therapy for early detection of severe leukopenia; (2) immediate discontinuation of clozapine if severe leukopenia is observed; (3) exclusion from reexposure to clozapine if a patient experiences clozapine-induced agranulocytosis; and (4) early cessation of treatment if hematologic guidelines are not followed ("no blood, no drug" policy). Together, these systems have demonstrated a worldwide reduction in the observed rate of agranulocytosis and in fatalities related to the emergence of agranulocytosis when rigorous monitoring systems are in place.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Resistance; Humans; Leukocyte Count; Leukopenia; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Cognitive function may be markedly impaired in patients with schizophrenia; however, it has only recently been recognized as an important factor in determining patient outcome. Research has shown that improvements in cognitive functioning occur independently of improvements in positive or negative clinical symptoms, and whereas typical antipsychotics may improve clinical symptoms, they have little or no efficacy in improving cognitive dysfunction. However, there is evidence that the atypical antipsychotic clozapine may improve this core deficit of schizophrenia. This review summarizes 12 published studies that assessed the effect of clozapine on cognitive functioning. As a group, these studies suggest that psychomotor speed, verbal fluency, and verbal learning and memory may be improved by treatment with clozapine. Such cognitive improvements with clozapine treatment may offer an advantage to patients with schizophrenia by enhancing the possibility of better vocational functioning and quality of life.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition; Cognition Disorders; Humans; Memory; Neuropsychological Tests; Schizophrenia; Schizophrenic Psychology; Verbal Learning; Visual Perception

It is widely accepted that schizophrenia originates from abnormalities occurring during the early stages of neural development. Although large studies have revealed behavioral precursors of schizophrenia in childhood, the disorder is usually not evident until patients are in their 20s or 30s. Some patients will be resistant to typical antipsychotic treatment at this first-onset of schizophrenia; however, treatment resistance develops in the majority of patients during the course of successive episodes. This ongoing deterioration suggests that a degenerative process operates during the active psychotic phase of the illness. This review presents evidence of neurodevelopmental and neurodegenerative mechanisms for the development of schizophrenia. These data indicate the importance of effective treatment at the first onset of schizophrenia to improve patient outcome. In addition, animal studies suggest that treatment with clozapine may prevent the neurodegenerative component responsible for the development of treatment resistance.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Disease Models, Animal; Drug Resistance; Female; Humans; Magnetic Resonance Imaging; Male; Mice; Neurodegenerative Diseases; Pregnancy; Rats; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Aggressive behavior in schizophrenic patients, although infrequent, is a serious problem. It is, however, a relatively common reason for psychiatric admission and poses an increasing threat as more patients are cared for in the community. There is a strong association between substance abuse and violent behavior, and comorbid substance abuse in schizophrenia is also a major problem. The recent introduction of the atypical antipsychotics has brought hope for the pharmacologic management of this group of patients. These newer agents are thought to have antiaggressive effects and perhaps decrease cravings for illicit substances and alcohol. Data from a number of studies have demonstrated that clozapine has antiaggressive effects. A retrospective analysis of 331 schizophrenic patients assessed the effects of clozapine on hostility and aggression. At baseline, 31.4% of patients showed overt physical aggression, and after an average of 47 weeks of treatment with clozapine, this rate had fallen to 1.1%. The antiaggressive effects of clozapine were relatively specific and could not be explained by sedation or general antipsychotic effects. These effects were more pronounced than the effects on other symptoms and were also present in those patients who showed the highest pretreatment levels of hostility and aggression. Clozapine may also be of benefit in the treatment of schizophrenic patients with comorbid substance abuse. After 6 months of treatment with clozapine, substance abusers and nonabusers with schizophrenia or schizoaffective disorder showed similar improvements on measures of psychopathology and psychosocial functioning.

Topics: Adult; Aggression; Antipsychotic Agents; Clozapine; Comorbidity; Humans; Psychotic Disorders; Quality of Life; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Substance-Related Disorders; Treatment Outcome; Violence

Clinical studies with clozapine have clearly demonstrated its superior efficacy over that of conventional antipsychotics in treatment-resistant schizophrenic patients. In comparative trials with these drugs, considerably more patients respond to treatment with clozapine than to conventional antipsychotic medication. Recently, new antipsychotics, such as olanzapine, quetiapine, risperidone, sertindole, and zotepine, have been introduced, but extensive data on their effects in treatment-resistant patients are not yet available. Published studies have drawn criticism in terms of inappropriate titration schedules, nonequivalent dosing between treatment groups, short treatment duration, and inadequate sample sizes. Further research will be needed to determine whether novel antipsychotics may substitute for clozapine in the future or whether clozapine will retain its unique role in the management of patients suffering from difficult-to-treat schizophrenic disorders.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Double-Blind Method; Drug Resistance; Humans; Olanzapine; Pirenzepine; Placebos; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The purpose of this study was to evaluate all available trial-based evidence on the effectiveness of clozapine in schizophrenia as compared with conventional neuroleptics.. All randomized, controlled trials comparing clozapine with a conventional neuroleptic in which there was satisfactory concealment of patients' treatment allocation were located through electronic searches in all languages of several databases and through contacting authors of recent trials as well as the manufacturer of clozapine. At least two independent reviewers assessed trials for inclusion in the study and extracted data for meta-analysis.. The review included 2,530 randomly assigned participants in 30 trials, most of them short-term. Clozapine-treated patients showed more clinical improvement and experienced significantly fewer relapses during treatment, although the risk of blood dyscrasias in long-term treatment may be as high as 7%. Scores on symptom rating scales showed greater improvement among clozapine-treated patients, who were also more satisfied with their treatment. However, there was no evidence that the superior clinical effect of clozapine is reflected in levels of functioning; on the other hand, global functional and pragmatic outcomes were frequently not reported. Clinical improvement was most pronounced in patients with treatment-resistant illness.. This meta-analysis confirms that clozapine is more effective than conventional neuroleptics in reducing symptoms of patients with both treatment-resistant and nonresistant schizophrenia. Future trials should be long-term pragmatic community trials or should address the effectiveness of clozapine in special patient populations. An international standard set of outcomes, including pragmatic assessments of functioning, would greatly enhance the comparison and summation of trials and future assessments of effectiveness.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Child; Clozapine; Humans; Middle Aged; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cytochrome P-450 Enzyme System; Dibenzothiazepines; Drug Interactions; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia

It is nearly a decade since the first atypical antipsychotic, clozapine, was launched in the UK. There are now several other similar drugs on the market. They are all more expensive than traditional antipsychotics and the question of whether they are a cost-effective use of scare NHS resources is an important one. This article reviews the evidence in the area of treatment-resistant schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Humans; Risperidone; Schizophrenia; Treatment Failure

The treatment of schizophrenic patients who fail adequate trials of typical neuroleptics is a major challenge. For these patients, the availability of atypical antipsychotics is a useful therapeutic advance. Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenia, particularly its negative symptoms, with a substantially more favorable safety profile than conventional antipsychotic agents (e.g., haloperidol). However, little information on the clinical effects of olanzapine is available in Japan. This article provides information on the efficacy of olanzapine for various symptoms of schizophrenic patients and drug safety. Olanzapine is significantly superior to haloperidol in positive, negative, and depressive symptoms of patients, and for tardive dyskinesia and extrapyramidal symptoms. Significantly greater improvement in avolition-apathy is achieved with olanzapine as compared to risperidone. These advantages are related to high affinity at the 5-HT2 binding site, no association with an alteration in dopamine A9 firing rates, and lower D2 striatal receptor blockade of olanzapine. Treatment with 10 mg/day olanzapine is more appropriate for positive symptoms, and 12.5-17.5 mg/day olanzapine is more effective for negative symptoms. Patients will need help adapting to a new level of functioning after a successful switch to olanzapine, and overcoming the disappointment that eventually occurs when the limitations of olanzapine become apparent.

Topics: Antipsychotic Agents; Benzodiazepines; Binding Sites; Clinical Trials as Topic; Clozapine; Dopamine D2 Receptor Antagonists; Haloperidol; Humans; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Serotonin

Research on the impact of nicotine on schizophrenia and antipsychotic medications was reviewed to determine ways to improve treatment planning for patients with schizophrenia who smoke and to evaluate smoking cessation programs for this population.. All major research databases were searched. The review focuses on reports published since 1990.. Smoking improves processing of auditory stimuli (sensory gating) by patients with schizophrenia and may lessen negative symptoms by increasing dopamine in the nucleus accumbens and the prefrontal and frontal cortex. Use of traditional antipsychotics may result in patients' smoking more, whereas patients taking atypical antipsychotics may smoke less. Patients who smoke metabolize antipsychotics faster than nonsmoking patients. Smoking cessation programs for outpatients with schizophrenia report a success rate of about 12 percent after six months. No studies of cessation programs for chronically ill inpatients with schizophrenia have been published. Several hospitals have implemented smoking bans with equivocal results.. Nicotine affects both schizophrenia and antipsychotic medications. Neurobiological and psychosocial factors reinforce the high use of nicotine by patients with schizophrenia

Topics: Antipsychotic Agents; Auditory Perception; Chlorpromazine; Chronic Disease; Clozapine; Databases as Topic; Dopamine; Dose-Response Relationship, Drug; Frontal Lobe; Humans; Nicotine; Nucleus Accumbens; Prefrontal Cortex; Schizophrenia; Severity of Illness Index; Smoking Cessation

The pharmacologic treatment of schizophrenia remains a critical component in the short- and long-term management of this disease. Considerable progress has been made in delineating different domains of this illness, ranging from positive and negative symptoms to cognitive dysfunction and psychosocial vulnerabilities. Increasingly, treatments are being studied in relation to a variety of different outcome measures with functional ability and quality of life achieving appropriate emphasis. The introduction of a new generation of antipsychotic drugs has helped to raise optimism and expectations. Overall, second-generation drugs do provide clear advantages in terms of reducing adverse effects (particularly drug-induced Parkinsonism, anesthesia, and, hopefully, tardive dyskinesia). Advantages in alleviating refractory symptoms, negative symptoms, depression, and suicidal behavior are found in some reports; however, much remains to be done methodologically in establishing the relative merits of specific drugs in the multiple domains of interest.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Recurrence; Risperidone; Schizophrenia

In addition to their neurochemical effects, antipsychotic (neuroleptic) drugs produce structural brain changes. This property is relevant not only for understanding the drugs' mode of action, but because it complicates morphological studies of schizophrenia. Here the histological neuropathological effects of antipsychotics are reviewed, together with brief mention of those produced by other treatments sometimes used in schizophrenia (electroconvulsive shock, lithium and antidepressants). Most data come from drug-treated rats, though there are also some human post-mortem studies with broadly congruent findings. The main alteration associated with antipsychotic medication concerns the ultrastructure and proportion of synaptic subpopulations in the caudate nucleus. In rats, synapses and dendrites in lamina VI of the prefrontal cortex are also affected. The changes are indicative of a drug-induced synaptic plasticity, although the underlying mechanisms are poorly understood. Similarly, it is unclear whether the neuropathological features relate primarily to the therapeutic action of antipsychotics or, more likely, to their predisposition to cause tardive dyskinesia and other motor side-effects. Clozapine seems to cause lesser and somewhat different alterations than do typical antipsychotics, albeit based on few data. There is no good evidence that antipsychotics cause neuronal loss or gliosis, nor that they promote neurofibrillary tangle formation or other features of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Caudate Nucleus; Clozapine; Dyskinesia, Drug-Induced; Humans; Neuronal Plasticity; Rats; Schizophrenia

Between 20% and 40% of schizophrenic patients are thought to be resistant to conventional antipsychotic therapy, although this may be an underestimate of the scale of the problem. The causes of nonresponsiveness are likely to be multifactorial, and there have been reported associations between refractoriness and neuropsychological impairment, negative symptoms, and abnormal brain morphology. For some patients, treatment resistance may in fact represent an intrinsic part of the schizophrenic illness. Treating the refractory patient should begin with a full, preferably multidisciplinary, review of diagnosis, symptoms, and side effects. Although an increased dose of a conventional antipsychotic agent can be effective for some patients, consideration should be given to reducing the dose and combining treatment with psychosocial management, or switching to one of the newer atypical antipsychotics.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Combined Modality Therapy; Dibenzothiazepines; Drug Administration Schedule; Drug Therapy, Combination; Humans; Male; Middle Aged; Polypharmacy; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In conclusion, the newer agents all have behavioural profiles which can be clearly differentiated from those of the older, classical agents. Behavioural data indicate that to a greater or lesser extent, all the newer antipsychotics will produce fewer acute EPS than the older agents. However, the new 'atypical' agents all have distinct profiles. Olanzapine has a profile similar to that of clozapine, albeit somewhat more potent. Olanzapine, like clozapine, displays a wide margin between the doses predictive of efficacy and those which induce EPS. The compound also substitutes for clozapine in drug discrimination assays and increases punished responding in a conflict paradigm. Quetiapine also has a clozapine-like profile, although it lacks the cholinergic receptor affinity and is relatively weak in most behavioural assays. Quetiapine, like olanzapine, also reverses PCP-induced deficits, and substitutes for clozapine in drug discrimination assays. However, no data are currently available regarding quetiapine's action in anxiolytic tests. Risperidone, sertindole and ziprasidone have profiles of activity different from those of older agents, predominantly due to their 5-HT2a affinity. All these agents possess some properties similar to those of clozapine, but there are some differences: for example, risperidone and sertindole fail to substitute for clozapine in drug discrimination assays and are inactive in classical conflict models of anxiety. It is more difficult to make an accurate assessment of the behavioural profile of ziprasidone, due to a lack of published data. Given the behavioural differences exhibited by animals receiving the new antipsychotic agents, one would predict that these drugs will have distinct clinical profiles. All the agents display activity indicative of agents with a reduced propensity to induce EPS. However, significant differences may be observed in their efficacy against negative and cognitive symptoms. It will be important to assess the clinical profiles of these agents carefully if the predictive value of the pre-clinical 'models' is to be improved.

Topics: Animals; Antipsychotic Agents; Basal Ganglia Diseases; Behavior; Clozapine; Dopamine Antagonists; Humans; Rats; Schizophrenia; Serotonin Antagonists

As antipsychotic treatment evolves toward a broader range of efficacy and more benign side effect profiles, our criteria for treatment-refractory schizophrenia may become more subtle. Unidimensional concepts of treatment resistance may be replaced by multiaxial descriptions of the target symptoms, side effects, and compliance issues that limit the ultimate goals of enhanced psychosocial function and quality of life. Augmentation strategies, increasing insight into dose response relationships, and atypical agents may benefit patients who failed to respond to or tolerate previous therapies. The advantages of newer agents in treatment-resistant schizophrenia may arise in part from their preferential targeting of newer agents in treatment-resistant schizophrenia may arise in part from their preferential targeting of mesolimbic compared with motor and tuberoinfundibular dopaminergic pathways.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Diagnosis, Differential; Humans; Imidazoles; Indoles; Olanzapine; Patient Compliance; Pirenzepine; Psychiatric Status Rating Scales; Receptors, Dopamine D2; Risperidone; Schizophrenia; Schizophrenic Psychology; Terminology as Topic; Treatment Failure

Classically, the D2 receptors formed the core of the dopamine hypothesis for schizophrenia. Recently, the dopamine D4 receptors have received particular attention in this context. This is due to the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, and displays a ten-fold higher affinity for D4 compared to D2 or D3 receptors. Following various reports presenting the interest of D4 receptors in treating schizophrenia, multiple chemical developments were made. During the last five years, various structures were described with a high selectivity for D4 receptor subtype. Currently, although the first clinical report was very disappointing, the observation which support the idea that D4 might serve as a target for clozapine have significantly modified and extended the understanding of mechanism underlying atypical antipsychotic treatment of schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Dopamine Antagonists; Drug Design; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4; Schizophrenia

The Clozaril National Registry (CNR) was created to help protect patients from developing potentially fatal agranulocytosis secondary to treatment with the antipsychotic medicine clozapine. The CNR, designed and maintained by the manufacturer of the branded Clozaril (clozapine), has the principal goals of (1) prophylaxis-preventing inappropriate retreatment, and (2) quality assurance-overseeing adherence to a "no blood, no drug" policy. This article reviews the estimated impact of the CNR on clozapine-related morbidity and mortality over the first 5 years of commercial experience in the United States.. Complete data on leukopenia and agranulocytosis, gathered from the CNR database for the period of 1990-1994, were reviewed and compared with data from the pre-CNR period.. Use of clozapine in 99,502 patients according to package labeling requirements (distribution of the medicine linked to mandated white blood cell count testing) was associated with a total of 382 cases of agranulocytosis (0.38%) versus an expected cumulative total of 995 cases (based on the pre-CNR rate of 1% to 2%). Based on the expected agranulocytosis rate, up to 149 deaths might have been anticipated. Instead, there were only 12 deaths attributed to complications of agranulocytosis.. The CNR provides for universal rechallenge protection as well as controlled dispensing of clozapine. It also serves as an early warning system to promote the safe and effective use of clozapine. The CNR includes quality assurance mechanisms designed to enhance compliance. Despite the added logistic requirements this system places upon physician, pharmacist, and manufacturer, the CNR has helped to reduce substantially potential fatal outcomes. The CNR reinforces both patient and treatment system compliance. Based on this favorable experience concerning agranulocytosis and associated fatalities, the Neuropsychopharmacology Advisory Committee to the U.S. Food and Drug Administration has unanimously recommended a reduction in frequency of the white blood cell count testing requirement after 6 months to every 14 days, instead of weekly. Finally, the CNR database containing white blood cell count and demographic data on every patient in the United States who has received the medicine has served as a unique epidemiologic database.

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Clozapine; Databases, Factual; Drug Approval; Drug Information Services; Humans; Leukocyte Count; Leukopenia; Registries; Schizophrenia; United States

Suicide is the major cause of premature death in patients with schizophrenia. Among these patients, 40% report suicidal thoughts, 20% to 40% make unsuccessful suicide attempts, and 9% to 13% end their lives by suicide. Traditional antipsychotic drugs undertreat many schizophrenic patients and can produce serious side effects, such as tardive dyskinesia. Clozapine is the only antipsychotic drug that has been shown in controlled clinical trials to be effective in reducing both positive and negative symptoms in schizophrenic patients who fail to respond to typical neuroleptic drugs. The potential decrease in suicide among schizophrenic patients treated with clozapine is estimated to be as high as 85%. Treatment with clozapine is cost-effective, and the significant decrease in the risk of suicide far outweighs the very low risk of mortality from agranulocytosis. Clozapine should be considered for treatment of both neuroleptic-resistant and neuroleptic-responsive schizophrenic patients who have persistent suicidal thoughts or behavior.

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cost-Benefit Analysis; Dyskinesia, Drug-Induced; Female; Humans; Infant, Newborn; Male; Middle Aged; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention

Noncompliance with medication is common among patients who have schizophrenia and is a leading cause of rehospitalization in this population. Both standard and subjective risk-factor assessments have been used to identify patients who are likely to refuse or discontinue treatment. Noncompliant patients who have schizophrenia commonly have been treated with potent D2 dopamine-receptor antagonists and therefore may have experienced extrapyramidal side effects. The newer antipsychotics (i.e., serotonin-dopamine antagonists) are efficacious in reducing the symptoms of schizophrenia without associated dysphoria and motor side effects. Clozapine and other newer antipsychotics may improve certain aspects of cognition. The improved psychiatric state and cognitive function may facilitate "involved compliance" as a result of increased insight, awareness, and judgment. These cognitive faculties allow patients to appreciate their improved state and take steps to maintain it. The periodic visits for blood monitoring mandated for clozapine therapy also facilitate the formation of a therapeutic alliance that allows the clinician to monitor compliance. Facilitating involved compliance this way among patients who have schizophrenia may reduce the cost of this disorder to society.

Topics: Antipsychotic Agents; Clozapine; Cognition; Drug Monitoring; Haloperidol; Health Care Costs; Humans; Patient Compliance; Quality of Life; Risk Factors; Risperidone; Schizophrenia; Treatment Refusal

Approximately half of the patients who suffer from schizophrenia are also substance abusers at some time during their illness. The motivational drive toward abusive consumption is compounded in individuals with schizophrenia who turn toward substances with reinforcing properties to alleviate aspects of psychosis. This review examines the prevalence, etiology, and clinical effects of substance abuse (e.g., alcohol, nicotine, cocaine) among individuals with schizophrenia. Clearly, substance abuse persists despite and in spite of treatment with typical antipsychotics. The efficacy of newer generation antipsychotics in the reduction of substance abuse among the schizophrenic population has yet to be established, but clozapine has been shown to reduce alcohol, smoking, and cocaine use. Hence, clozapine is a therapeutic option for dually diagnosed patients because of its superior efficacy relative to conventional neuroleptics and its capacity to control substance abuse.

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Cost-Benefit Analysis; Diagnosis, Dual (Psychiatry); Drug Monitoring; Humans; Precipitating Factors; Prevalence; Schizophrenia; Substance-Related Disorders

Neuroleptics were the first modern class of pharmacotherapeutic agents available for the treatment of schizophrenia. Although they were effective in reducing florid psychotic symptoms, up to 90% of treated individuals subsequently developed extrapyramidal symptoms (EPS) (akathisia, dystonia, or parkinsonism), and about 20% developed tardive dyskinesia (TD). When clozapine became commercially available for treatment-resistant and treatment-intolerant (i.e., prone to EPS and TD) schizophrenic individuals, it became apparent that an antipsychotic need not induce motor side effects to be efficacious in reducing the symptomatology of schizophrenia. Sociodemographic, behavioral, and clinical predictors of TD are useful in identifying a subset of schizophrenic individuals who would benefit from treatment with clozapine, the prototype atypical antipsychotic whose efficacy and motor side effect profile are superior to those of chlorpromazine. This favorable motor side effect profile of clozapine contributes to improved patient outcomes by reducing noncompliance, substance abuse, and suicide, resulting in improved quality of life and savings on health care costs.

Topics: Age Factors; Aged; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Prevalence; Risk Factors; Schizophrenia; Substance-Related Disorders; Suicide; Suicide Prevention; Treatment Outcome; Treatment Refusal

Since its introduction to the United States in 1990, the benefits of clozapine use have been repeatedly validated. Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia. Because clozapine has been part of the psychiatric pharmacopeia for considerably less time than neuroleptics, which have dominated the field for over 4 decades, its underutilization may be partly attributed to a lack of experience in managing associated side effects. Most side effects associated with clozapine are typical of antipsychotics in general, and with clozapine, these side effects are typically benign, tolerable, and manageable. It is conceivable that there remains a concern over the risk of agranulocytosis. However, the mandatory blood monitoring carried out through the Clozaril National Registry has considerably reduced the incidence of fully developed cases of agranulocytosis from premarketing values of approximately 1% to 2% to current values of 0.38% and virtually prevented mortalities. These values are likely to decrease further with the application of cytokine augmentation therapy among patients developing blood dyscrasias. Many side effects of clozapine are observed early after treatment onset and are greatly reduced by dose adjustments. Appropriate management of side effects will facilitate a maximization of the benefits of clozapine treatment. Clearly, the benefits of clozapine therapy far outweigh its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Drug Administration Schedule; Drug Monitoring; Humans; Incidence; Risk Factors; Schizophrenia; Sleep Wake Disorders; Tachycardia; Urinary Incontinence; Weight Gain

Clozapine is the only antipsychotic agent that is effective in treatment-resistant schizophrenia. Despite its superior efficacy to chlorpromazine and the fact that it has fewer extrapyramidal side effects than conventional antipsychotics do, clozapine is relatively underused. This may be due in part to a lack of appreciation of clozapine's favorable risk-benefit ratio in many patients. In addition, clozapine is only indicated for use in patients who fail to respond adequately to standard antipsychotic treatment. Treatment with clozapine considerably improves psychiatric well-being and reduces readmission to the hospital and reduces family burden in many severely ill patients. However, clozapine is associated with severe side effects, including weight gain, tachycardia, sedation, seizures, and agranulocytosis. These risks must be weighed against the risks associated with schizophrenia (e.g., suicide). The death rate attributed to clozapine-induced agranulocytosis has been low, a fact that is largely attributable to safety measures such as the Clozaril National Registry. Determining the optimal dosage for each patient will maximize the benefits of treatment while reducing side effects. In some patients, monitoring plasma levels of drug may aid in optimizing treatment. The optimal plasma level of clozapine is 200 to 350 ng/mL. This usually corresponds to a daily dose of 200 to 400 mg, although dosage must be individualized. If patients improve significantly during treatment with clozapine, they should continue to be treated with clozapine and should be withdrawn from this treatment only when medically warranted. Psychotic relapse rates may be as high as 80% among patients switched from clozapine to other novel antipsychotic agents.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Information Services; Drug Monitoring; Humans; Registries; Schizophrenia; Treatment Outcome

Antipsychotic medications are the mainstay of treatment for schizophrenia. The recent advent of atypical antipsychotics has provided new clinical options and set higher expectations for the treatment of schizophrenia. It is not yet clear how each different drug will fit within the therapeutic armamentarium and this lack is most evident with considering patients with treatment refractory schizophrenia. On the other hand, the expectation of superior efficacy, more benign side effect profile and potential to impact the longitudinal course of schizophrenia provide a rationale for the use of novel antipsychotics as a first-line treatment of schizophrenia.

Topics: Antipsychotic Agents; Behavioral Symptoms; Benzodiazepines; Clozapine; Dibenzothiazepines; Dopamine Antagonists; Drug Resistance; Dyskinesia, Drug-Induced; Humans; Neurobehavioral Manifestations; Olanzapine; Pirenzepine; Psychopharmacology; Quetiapine Fumarate; Schizophrenia; Serotonin Antagonists

Inevitably, the greater availability of more costly antipsychotic medications has resulted in attempts to regulate the use of these agents. Early objections over the cost of treatment with clozapine or risperidone have in part been mollified by preliminary statistics on the cost effectiveness of these agents. However, this issue is complex and requires careful consideration of pharmacoeconomic principles in the development and clinical distribution of novel antipsychotics. Future cost-effectiveness studies need to consider a balance of public and private perspectives. These studies should be conducted in several settings, preferably also within the context of broader, multimodal treatment intervention strategies.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Cost-Benefit Analysis; Humans; Olanzapine; Pirenzepine; Risperidone; Schizophrenia

The evolution of resistance of positive symptoms to antipsychotic therapy may represent a valuable means of subtyping schizophrenia. In contrast, resistance of negative symptoms and cognitive function to antipsychotic agents seems to be present from the first episode of psychotic symptoms and does not evolve over time to the same extent. If these findings are validated, this clearly points toward differences in the etiology of these components of schizophrenia. Data from a cohort of 223 patients with unsatisfactory responses to classical antipsychotic therapy are evaluated, at least 60% of whom responded to subsequent treatment with clozapine. Comparisons were made between the subgroups of patients with primary and delayed onset treatment resistance. Both subgroups responded to clozapine therapy, although better response was evident for patients with delayed resistance. The withdrawal of clozapine from patients who had previously been responsive to classical antipsychotic therapy was capable of inducing treatment resistance.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Schizophrenia

With a decade of neuroreceptor imaging of antipsychotics behind us, this article attempts to synthesise what has been learnt about the mechanism of action of antipsychotics using these techniques. The data show that: (i) the 'typical' antipsychotics bind mainly to the dopamine D2 receptor, and that 60-80% D2 occupancy may provide optimal antipsychotic response with little extrapyramidal side effects; (ii) all the clinically available 'atypical' antipsychotics show a higher occupancy of the 5-HT2 than D2 receptors; (iii) however, these 'atypical' antipsychotics differ in their D2 occupancy. The D2 occupancy of risperidone is within the typical range (i.e. > 60%) while that of clozapine is clearly lower (< 60%); (iv) antipsychotics with combined 5-HT2/D2 antagonism lose some of their 'atypical' properties if used in doses where their D2 occupancy is too high (> 80%). Based on these data a framework is suggested wherein antipsychotics may be classified on the basis of their D2 and 5-HT2 occupancy in patients at steady state while taking clinically relevant doses. Within this framework typical antipsychotics are classified as 'high-D2', resperidone as 'high-D2 high-5HT2' and clozapine as a 'low-D2 high-5HT2' antipsychotic. The justification, limitations and the value of this framework in understanding and investigating newer antipsychotics is discussed.

Topics: Antipsychotic Agents; Binding, Competitive; Clozapine; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Models, Psychological; Protein Binding; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

The atypical antipsychotic drug clozapine was introduced to clinical practice in 1972. It is a dibenzodiazepine derivative with, among other known receptor site activities, a relatively high D1/D2 receptor affinity ratio. The serious side effects of bone marrow suppression and agranulocytosis delayed the acceptance of clozapine into common clinical practice but scrupulous application of a monitoring protocol led to adequate protection from these side effects. There is now a broad consensus about the benefits of clozapine which supports the use of clozapine as a first-line treatment of schizophrenia. There is good evidence that relapse and rehospitalization drop to 22% of the incidence in preclozapine treatment patients. The majority of responders are identified within 4 months of treatment. Clozapine has been demonstrated to be an effective treatment for neuroleptic refractory patients. Forty percent of clozapine-treated patients show significant improvement, with 11% of treated patients showing no residual psychosis. This review also describes the results of clozapine on aggressive and violent assault in a patient population characterized by severe functional deficits, typically chronic schizophrenia with severe impairment, chronic brain syndromes, and developmental handicap. Prior to the introduction of clozapine therapy, in a chronically disrupted milieu that precluded adequate psychosocial programming, seriously assaultive behaviour resulting in peer and staff injury was a common occurrence. Evidence suggests that clozapine is an effective medical treatment for the target symptoms of hostile agitation, threatening, and assaultive violence.

Topics: Administration, Oral; Aggression; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Forensic Psychiatry; Humans; Lithium Carbonate; Ontario; Restraint, Physical; Schizophrenia; Schizophrenic Psychology; Social Isolation

The authors' goal was to analyze reported cases of neuroleptic malignant syndrome in patients given clozapine and risperidone.. They assessed 19 cases of clozapine-induced neuroleptic malignant syndrome and 13 cases of risperidone-induced neuroleptic malignant syndrome against three criteria sets and against extent of exclusionary workup and then designated them as high or low probability of being neuroleptic malignant syndrome.. Nine of the 19 cases of clozapine-related neuroleptic malignant syndrome and eight of the 13 cases of risperidone-related neuroleptic malignant syndrome were designated as having high probability of being neuroleptic malignant syndrome. The remainder were designated as having low probability because presentations were not linked to treatment or failed to meet criteria for the syndrome.. Neuroleptic malignant syndrome can occur in patients given atypical antipsychotics and resembles "classical" neuroleptic malignant syndrome. However, side effect profiles overlap considerably with neuroleptic malignant syndrome criteria, and atypical antipsychotics may cause neurotoxicities unrelated to (but misattributed as) neuroleptic malignant syndrome. Insufficient evidence exists for "atypical" neuroleptic malignant syndrome with novel antipsychotics.

Topics: Adolescent; Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Confidence Intervals; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Probability; Psychotic Disorders; Risperidone; Schizophrenia

Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Central Nervous System Diseases; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Gastrointestinal Diseases; Humans; Schizophrenia

To review the existing literature on the efficacy and tolerability of antipsychotics for adolescent psychosis. The review focuses in particular on literature regarding adverse effects that are thought to have an increased incidence in young patients and on the possible neurobiological bases for such differential sensitivity.. Pertinent studies were sought using Medline searches, supplemented by selected bibliographies, and reviewed.. There is a relative paucity of research in this area; in particular, well-controlled trails are lacking. The existing literature suggests fairly good efficacy of both typical and atypical antipsychotics in the treatment of psychotic disorders in children and adolescents. However, the incidence of certain side effects, particularly extrapyramidal symptoms (EPS). is found to be higher in younger patients compared with adults. Positron emission tomography (PET) receptor studies in adults have demonstrated that the incidence of EPS is related to dose-dependent dopamine type-2 (D2) receptor occupancy and that there is a significant relationship between the number of these receptors and age.. Improved tolerability is leading to the increasing us of atypical antipsychotics for adolescent patients, though these new drugs to have specific adverse effects of their own. There is a need for more controlled studies of atypical antipsychotics in children and adolescents. In particular, dose-finding studies are needed to determine the optimal dose range to produce the greatest improvement with the least side effects for each of these drugs.

Topics: Adolescent; Adolescent Psychiatry; Age Factors; Antipsychotic Agents; Benzodiazepines; Cholinergic Fibers; Clozapine; Controlled Clinical Trials as Topic; Corpus Striatum; Disease Susceptibility; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

The advent of the atypical antipsychotics marked a new era in the history of the treatment of psychotic disorders. To evaluate the published literature about the available atypical antipsychotics--clozapine, risperidone, olanzapine, and quetiapine--and select the most appropriate treatment for specific patients, physicians need to understand the outcome measures used in clinical studies, the pharmacologic differences that explain varying side effect profiles, and pharmacoeconomic assessments that are used in the decision-making process. While the atypical antipsychotics have established efficacy in the overall treatment of schizophrenia, they may differ in their effects on factors such as cognitive function, overall quality of life, adverse events, and hospitalization status. Each of these factors should be considered when weighing treatment options for an individual patient.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Cost-Benefit Analysis; Dibenzothiazepines; Drug Approval; Health Care Costs; Health Status; Hospitalization; Humans; Meta-Analysis as Topic; Olanzapine; Outcome Assessment, Health Care; Pirenzepine; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States; United States Food and Drug Administration

The incidence of acute extrapyramidal symptoms (EPS)--akathisia, dystonia, and parkinsonism--associated with traditional antipsychotics varies, but most researchers agree that neuroleptic-induced EPS occur in 50% to 75% of patients who take conventional antipsychotics. Atypical antipsychotics were developed to widen the therapeutic index and to reduce EPS. Although the mechanisms are unclear, the risk of EPS is less with the novel antipsychotics than with conventional drugs, and agents that produce low levels of acute EPS are likely to produce less tardive dyskinesia. Nevertheless, clinicians should exercise caution when comparing data from investigations of the novel antipsychotics and, until long-term data become available, should administer the new drugs at doses below the EPS-producing level.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Substance Withdrawal Syndrome

Attempts to clarify the domains of schizophrenia gained importance when the atypical antipsychotics joined the armamentarium of schizophrenia treatments because of evidence that these agents are superior to conventional antipsychotics for the treatment of negative symptoms. Negative symptoms can be divided into 3 components: (1) deficit or primary enduring negative symptoms that may or may not respond to treatment, (2) primary nonenduring negative symptoms, and (3) secondary negative symptoms that are associated with positive symptoms, extrapyramidal symptoms, depression, and environmental deprivation. The atypical antipsychotics have generally been found to be more effective than conventional antipsychotics against the totality of negative symptoms, but their effects on specific components are still under study. Sophisticated statistical tools such as path analysis have been used in investigations of the direct and indirect effects of atypical antipsychotics on negative symptoms, but these tools have limitations. Future study is needed to identify specific components of negative symptoms that may respond preferentially to one or another of the atypical antipsychotics.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Delusions; Depressive Disorder; Hallucinations; Humans; Models, Statistical; Multivariate Analysis; Psychiatric Status Rating Scales; Regression Analysis; Risperidone; Schizophrenia; Schizophrenic Psychology

Cognitive deficits are an integral feature of schizophrenia and have a deleterious effect on the ability of schizophrenic patients to work and function in a social environment. Drugs that bring about substantial cognitive improvement represent a major contribution in improving the quality of life in schizophrenia. Recent studies have suggested that the atypical antipsychotics may be more useful than conventional agents for improving cognition. There is evidence that scores on neuropsychological assessments have improved after treatment with clozapine, risperidone, and quetiapine. Future research is needed to characterize and quantify the cognitive effects of the atypical antipsychotics.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition Disorders; Dibenzothiazepines; Humans; Neuropsychological Tests; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Depression in schizophrenia may be partially responsible for the increased suicide rate in schizophrenic patients, which is more than 20 times higher than that found in the general population. Affective disorders in patients with schizophrenia are associated with a poor outcome, an increased risk of relapse, and a high rate of suicide. There is evidence that atypical antipsychotics may contribute to a reduction in suicidality, and although the new drugs are marketed for the treatment of schizophrenia, their novel psychopharmacologic effects suggest the possibility of other therapeutic applications. Recent studies of the efficacy of the novel antipsychotics found that these agents may produce an antidepressant effect in schizophrenia and may be used as either an adjunctive medication or an alternative to mood stabilizers in patients with affective disorders.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Comorbidity; Depressive Disorder; Humans; Mood Disorders; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention

Atypical antipsychotics have become the treatment of choice for patients experiencing a first episode of schizophrenia. In addition, they are often prescribed for conditions such as bipolar disorder and dementia. While clinical trials have not yet established the efficacy of the atypical antipsychotics for these uses, a number of reports offer preliminary evidence that the atypical antipsychotics may be beneficial for affective disorders, substance abuse disorder, senile dementia, and pathologic aggression. Atypical agents may be particularly effective and tolerable in elderly patients who are especially susceptible to the adverse effects of conventional antipsychotic medication. Lower dosages are more necessary for the elderly than for younger adults. Current evidence suggests that clozapine is the most effective atypical antipsychotic for neuroleptic-resistant patients. Risperidone, olanzapine, and quetiapine may also be effective in a subset of these patients.

Topics: Adult; Age Factors; Aged; Algorithms; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Decision Trees; Dementia; Dibenzothiazepines; Female; Humans; Male; Mood Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia

Severe psychotic decompensation during clozapine withdrawal has been reported previously. Less attention has been paid to movement disorders following abrupt clozapine withdrawal. This report describes 4 subjects who experienced severe dystonias and dyskinesias upon abrupt clozapine withdrawal.. Current and past medical records of 4 subjects with DSM-IV schizophrenia or schizo-affective disorder were reviewed.. All subjects had a history of neuroleptic-induced extrapyramidal symptoms, 1 had a history of severe dystonias, and 1 had neuroleptic malignant syndrome. All had mild orolingual tardive dyskinesia prior to clozapine treatment. All subjects had received clozapine for several months, and 3 of the 4 subjects stopped clozapine abruptly. Two subjects experienced cholinergic rebound symptoms within hours, which resolved quickly. These subjects had severe limb-axial and neck dystonias and dyskinesias 5 to 14 days after clozapine withdrawal. Two subjects were unable to ambulate, and 1 had a lurching gait. Two gagged while eating or drinking. Two subjects were returned to clozapine, 1 was started on low-dose risperidone treatment, and 1 was started on olanzapine treatment. All experienced significant improvements in their mental state and movement disorders.. Severe movement disorders, which may be worse than the movements prior to clozapine treatment, and cholinergic rebound symptoms may occur upon abrupt clozapine withdrawal and must be recognized in addition to the severe psychotic decompensation noted in some patients. Patients, families, and caregivers must be alerted to this possibility. Where possible, a slow clozapine taper, the use of anticholinergic agents, and symptomatic treatment may help minimize these withdrawal symptoms, and reintroduction of clozapine or treatment with the newer atypical agents can help in the clinical management of these symptoms.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

A substantial portion of schizophrenic patients demonstrate suboptimal response to conventional antipsychotics. These agents are primarily effective in the treatment of psychotic symptoms; their efficacy in other domains of psychopathology such as negative symptoms, chronic aggressive behavior, and cognitive deficits, is limited or non-existent. In this group of refractory patients, the novel atypical antipsychotic clozapine has demonstrated robust efficacy, with response rates approaching 60% after twelve weeks of treatment. Efficacy of clozapine extends to symptom domains other than psychosis, including negative symptoms, mood stabilization, aggressive behavior and compulsive water drinking. Several novel agents, each of which shares some, but not all, of the preclinical and clinical characteristics that make clozapine so unique, have been introduced in the last 4 years. These agents demonstrate a broader spectrum of efficacy and an improved side effect profile in non-refractory patients. Initial data on their efficacy in refractory patients suggests that olanzapine does not achieve overall superior efficacy in this patient population compared to conventional agents although there is some evidence of relatively greater efficacy in negative symptoms and aggressivity. Several studies suggest that the efficacy of risperidone is superior to that of conventional agents in refractory patients. Preliminary conclusions are not possible for quetiapine because of a paucity of data in the literature. The literature supports a risperidone trial prior to a clozapine trial in a treatment algorithm for refractory patients because of its more favorable risk/benefit profile.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Humans; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Cognition Disorders; Humans; Olanzapine; Pirenzepine; Schizophrenia; Schizophrenic Psychology

Topics: Clozapine; Decision Making; Drug Costs; Health Care Costs; Health Policy; Humans; Practice Guidelines as Topic; Program Evaluation; Risperidone; Schizophrenia

This article reviews the published clinical experience with atypical neuroleptics in children and adolescents.. A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug.. We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder.. The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.

Topics: Adolescent; Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Child; Child Development Disorders, Pervasive; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Remoxipride; Risperidone; Schizophrenia; Treatment Outcome

This article will briefly familiarize the reader with the positive and negative signs and with the symptoms of Schizophrenia. After describing these signs and symptoms, the atypical anti-psychotic medications of Risperidone, Olanzapine and Clozapine will be reviewed as to their pharmacodynamics, dosages, and side effects in treating of these sign and symptoms. Within the scope of practice for advance practice nurses, the care being rendered and the implementation of those atypical drugs will be described. Thanks to their educational and clinical background, the advanced practice nurses find themselves in a unique set of circumstances to positively contribute in the treatment and maintenance of Schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Nurse Clinicians; Olanzapine; Pirenzepine; Psychiatric Nursing; Risperidone; Schizophrenia

New, so-called atypical antipsychotic medications will no doubt supplant the traditional, or "typical," antipsychotic medications, just as the new generation of antidepressant agents has replaced the older tricyclic drugs. At issue with most of the new drugs is not acute efficacy, but long-term tolerability. Side effects must be minimized to enhance compliance and prevent relapse. It appears that many of the new antipsychotic drugs have fewer or less troublesome side effects than the older agents. In addition, the "atypical" antipsychotic agents hold promise for treating refractory schizophrenia. At present, only clozapine, with its risks for agranulocytosis and seizures, is clearly established as a treatment for refractory illness. Risperidone may be an alternative for treatment-resistant schizophrenia, but this has not yet been clearly proved. Olanzapine has recently been introduced. Sertindole should be available soon, and quetiapine and ziprasidone should quickly follow. Safety, efficacy, and cost will guide their use. None of these newer agents have been compared head-to-head with clozapine. More research is needed to place these new drugs into clinical perspective.

Topics: Antipsychotic Agents; Clozapine; Drug Costs; Humans; Psychotic Disorders; Risperidone; Schizophrenia; United States

To present aspects of preclinical and clinical pharmacology of new antipsychotic drugs and to emphasize those preclinical drug characteristics which might predict desirable clinical actions.. Review of the relevant literature and publicly presented data.. Traditional neuroleptics have considerable effectiveness in treating positive symptoms of psychosis but can cause serious motor side effects. Clozapine produces no motor side effects and delivers a unique antipsychotic action. Risperidone also produces low motor side effects, but only at relatively low doses. Olanzapine and sertindole are newly introduced. Both have potent antipsychotic actions, with greatly reduced motor side effects. Both drugs also have possible advantages in negative symptoms.. These data support the conclusion that several new antipsychotics are becoming available for general use which are safe and effective in the treatment of psychosis and have several advantages over traditional neuroleptics.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The aim of this paper is to assess the risk/benefit ratio of clozapine in the elderly.. MedLine and Internet searches, followed by cross-checking for further articles, identified the references. Reports on efficacy as well as side effects were examined. Five psychogeriatric patients treated by the authors are presented.. The review of the literature highlighted the lack of studies on the use of clozapine in the elderly. Retrospective studies and case reports dominate. There is only one double-blind placebo-controlled study of six patients extant. Although efficacy seemed to parallel that in the younger age groups, the incidence of leukopenia, agranulocytosis, postural hypotension and confusion was greater in the elderly. Two of the five patients reported by the authors developed agranulocytosis, bringing the Australian experience of agranulocytosis in patients over 65 years of age to 4/55.. The risk/benefit ratio in the elderly is distinctly higher than found in the younger population. With specific reference to agranulocytosis alone, the frequently quoted risk of 1% for patients is likely to be 5-10 times higher in the over 65 population. Caution is advised when prescribing clozapine in the psychogeriatric population.

Topics: Aged; Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Schizophrenia

Withdrawal symptoms for typical antipsychotics are generally mild, self-limited and do not include development of psychotic symptoms. In contrast, withdrawal symptoms for clozapine can be severe with rapid onset of agitation, abnormal movements, and psychotic symptoms. Different pathophysiologic etiologies have been suggested for these severe symptoms, including dopaminergic supersensitivity and rebound.. Three case reports of clozapine withdrawal symptoms are presented. A review of previous case reports and discussion of the etiology of withdrawal symptoms of typical antipsychotics and clozapine are provided.. These three patients developed delirium with psychotic symptoms that resolved rapidly and completely upon resumption of low doses of clozapine.. The severe agitation and psychotic symptoms after clozapine withdrawal in these three patients were due to delirium, perhaps the result of central cholinergic rebound. The withdrawal symptoms and delirium resolved rapidly with resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine and/or simultaneously substituting another psychotropic with high anticholinergic activity, such as thioridazine.

Topics: Adult; Clozapine; Delirium; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Middle Aged; Psychoses, Substance-Induced; Psychotic Disorders; Receptors, Dopamine; Recurrence; Schizophrenia; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Thioridazine

Clozapine is increasingly being used for clinical indications in addition to treatment-resistant schizophrenia; this article reviews the relevant literature. The first section reassesses the risks associated with clozapine treatment, particularly agranulocytosis. The next section discusses its use for schizophrenia in patients who are treatment resistant, not treatment resistant, and intolerant of traditional drug treatments. Subsequent sections address its use in mood disorders, neurologic conditions, comorbid substance abuse, aggressive behavior, and childhood schizophrenia. Each includes the initial rationale for the use of clozapine in the disorder, a critical evaluation of the relevant literature, and theories as to why clozapine's unique pharmacodynamic profile may be efficacious for the specific condition. This body of literature suggests clozapine may be an effective treatment for a wide range of disorders.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Mood Disorders; Nervous System Diseases; Schizophrenia

This is an exciting time for research into the drug treatment of schizophrenia. Modern techniques in imaging and molecular biology have contributed to our understanding of the receptor mechanisms of antipsychotic drug action. Several new antipsychotics are, or will shortly be, available and each of these new drugs promise improvements over classical antipsychotics. This review will discuss the concept of atypicality in antipsychotic drugs, and will describe some of the models for identification of improved antipsychotic action. The various receptor mechanisms proposed to underlie atypical antipsychotic action, several of which have featured in recent debates in this journal, will be considered in the light of the pharmacology of some of the newly-emerging antipsychotic drugs.

Topics: Antipsychotic Agents; Clozapine; Dopamine D2 Receptor Antagonists; Humans; Schizophrenia

Early intervention with antipsychotic treatment has been shown to reduce the risk of relapse and to improve long-term morbidity in patients with schizophrenia. However, treatment with conventional neuroleptics carries with it a significant risk of developing extrapyramidal side effects. Conventional neuroleptics exert their antipsychotic effects at doses similar to those that cause extrapyramidal side effects. Although anticholinergic medication (e.g. benztropine) may reduce the severity of these side effects, anticholinergics are themselves associated with significant side effects, such as dry mouth, constipation, blurred vision, urinary retention and sexual dysfunction. Anticholinergic drugs are also associated with impaired cognition and worsening of the patient's psychosis. Newer antipsychotic drugs, such as risperidone, which have a dual mechanism of action (serotonin-dopamine antagonism) are reported to have a lower risk of extrapyramidal side effects than conventional agents. In particular, risperidone produces significant antipsychotic effects at doses lower than those that cause extrapyramidal side effects. Patients presenting with a first episode of psychosis and who are antipsychotic drug-naïve may exhibit abnormal movements before treatment is initiated. Unless these patients are carefully assessed at baseline these movements could be mistaken for drug-induced extrapyramidal side effects. It is important to develop treatment strategies for these patients that improve positive and negative psychotic symptoms as quickly as possible, with a minimal risk of extrapyramidal side effects developing. Prompt and appropriate antipsychotic treatment can substantially reduce the risk of relapse. Whereas approximately 60% of unmedicated patients will relapse in the first year following resolution of the acute psychotic episode, prophylactic antipsychotic medication can reduce this rate to less than 20%. Recent clinical experience in Canada has shown that risperidone is effective in the treatment of patients with first-episode psychosis. Moreover, lower doses of risperidone were required than those previously used to treat chronically ill patients with a history of multiple psychotic episodes and prolonged exposure to conventional neuroleptics. As further data are accumulated, the mean daily dose of risperidone required by first-episode patients has been shown to be close to 4 mg. The low incidence of extrapyramidal side effects in these patients (< 10% req

Topics: Adolescent; Adult; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dopamine Antagonists; Drug Administration Schedule; Guidelines as Topic; Humans; Male; Patient Compliance; Risperidone; Schizophrenia; Serotonin Antagonists

The atypical antipsychotic clozapine has been reported to be effective in otherwise refractory psychoses. This, and its low potential for inducing extrapyramidal side effects and tardive dyskinesia, predestines this drug for the treatment of psychotic disorders in late life. However, not much is known about the efficacy, safety and pharmacokinetics of clozapine in the treatment of aged patients. There are some studies and reports available about clozapine in the treatment of psychosis in patients suffering from dementia, schizophrenia and Parkinson's disease, which are reported here. They give some evidence that even low doses of clozapine are effective in controlling psychotic symptoms in the elderly. To avoid side effects, patient-specific factors and changes of pharmacokinetics in the elderly have to be considered. However, side effects including sedation, delirium, posturnal hypotension and the risk of agranulocytosis in particular limits the use of clozapine in elderly patients.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Dementia; Female; Humans; Male; Neurocognitive Disorders; Schizophrenia; Treatment Outcome

The unprecedented level of activity in the development of new antipsychotic medications can be traced to the 1989 approval of clozapine by the US Food and Drug Administration for treatment of refractory schizophrenia. This has encouraged the development of other new agents that share some of clozapine's receptor binding characteristics. A wide range of clinical trial designs are being used during the development of new antipsychotic medications. This article describes both basic designs and more innovative ones: flexible-dose designs that include placebo and conventional neuroleptic agents as controls; fixed-dose designs with multiple doses of experimental medication; and fixed-dose designs with multiple doses of the experimental and comparator medication. The strengths and weaknesses of each are identified. The need for long-term maintenance studies of newer agents is emphasized because psychotic disorders in general, and schizophrenia in particular, are chronic relapsing illnesses. The current status of four newer antipsychotic medications is considered: clozapine, risperidone, olanzapine, and sertindole. The importance of direct comparison among the newer antipsychotic medications in both short- and long-term trials is highlighted.

Topics: Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clinical Trials as Topic; Clozapine; Drug Administration Schedule; Drug Approval; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Placebos; Psychotic Disorders; Recurrence; Research Design; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States; United States Food and Drug Administration

The authors review the various methods of evaluating quality of life in schizophrenics and note the limitations of that type of method in terms of both form and content. In practical terms, the patients' cognitive disorders may constitute a bias when the questionnaire is addressed. Using a 'subjective quality of life profile' by Gerin et al., the authors interviewed 22 patients presenting with 'recalcitrant schizophrenia' and treated with clozapine for more than 3 years. The patients were asked to assess the change in their quality of life by comparison with previous neuroleptic chemotherapies. For all the items investigated, the responses were in favor of clozapine.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Patient Satisfaction; Psychiatric Status Rating Scales; Quality of Life; Recurrence; Schizophrenia; Schizophrenic Psychology

The discovery of clozapine in the mid-sixties and the demonstration of its clinical efficacy vis-à-vis recalcitrant schizophrenia contributed to the development of specific psychopharmacological research addressing the concept of atypical antipsychotics. The research has a dual aim. First, identifying the action sites, in the brain, specific to clozapine and to conventional neuroleptics, in order to classify those drugs on the basis of the observed differences in pharmacoclinical profile (low incidence of neurological side effects, activity on schizophrenic deficiency symptoms, activity vis-à-vis certain forms of recalcitrant schizophrenia). Recent studies have used tools derived from molecular biology to determine the action sites. The results of those studies suggest that there are at least four classes of antipsychotics (reverse neuroleptics, conventional neuroleptics, atypical neuroleptics and atypical antipsychotics). The second aim of the research is to determine the behavioral effects of each of the recognized classes of medication in order to determine the neurobiological substrates specific to the elementary cognitive operations impaired in schizophrenia. There is preclinical evidence to suggest that, in each area investigated (low incidence of neurological side effects, negative symptoms, cognitive symptoms), clozapine, a "dirty" drug, acts on different neurotransmission systems. The research thus aims to determine the pharmacological profile of the drugs of the future, designed to treat the cognitive deficiencies specific to the various types of schizophrenia.

Topics: Antipsychotic Agents; Brain; Clozapine; Humans; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The efficacy of conventional neuroleptics in the treatment of the negative symptoms of schizophrenia is highly controversial. Clozapine, the leading atypical neuroleptic, has been shown to be effective, in the majority of the controlled studies, on both the positive and negative symptoms of the disease. It appears to be active vis-à-vis both the primary and secondary negative symptoms. However, several weeks (at least 12) are required for the effect on primary negative symptoms to clearly emerge. The position of clozapine in the treatment of patients presenting with a state of deficiency remains more debatable.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Depression; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The research criteria of treatment-resistance in schizophrenia are reviewed and discussed, and the following definition for the use in the clinic is proposed: At least two periods of treatment with conventional antipsychotics from two different chemical classes at adequate doses for a period of at least four weeks, each without significant symptomatic relief. In addition, patients have to meet the criteria of clinical significant psychopathology, reduced psychosocial function or reduced quality of life. The article also reviews efficacy studies and the recommendations for the psychopharmacological treatment of therapy-resistant schizophrenia. Placebo-controlled and open trials have shown clozapine to be clearly effective in 30-60% of patients resistant to conventional antipsychotic treatment. Up to one half of the patients may respond between three months and a year of treatment. Clozapine has been found to reduce positive and negative symptoms as well as enhancing both cognitive and psychosocial function in schizophrenics. The first drug of choice today, after treatment-resistance has been established is a trial of clozapine for at least six months. The optimal dose range of clozapine appears to be 300-600 mg/day for most patients. Some schizophrenics cannot be treated with clozapine because of contraindications or do not respond sufficiently. In these patients conventional antipsychotics have to be prescribed and augmentated with benzodiazepines, antidepressants, mood-stabilizers, or electroconvulsive treatment.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Schizophrenia

With the arrival of atypical antipsychotic drugs, questions have arisen as to their efficacy, compared with classical antipsychotics, and their impact on the clinical and psychosocial behavior of schizophrenic patients. This paper reviews the development of antipsychotic drugs from the prototype chlorpromazine in the 1950s to the atypical antipsychotics--clozapine, risperidone, olanzapinein--in the 1990s. Particular attention is given to the medications' effect on positive and negative symptoms and on patients' quality of life. Experience to date with the atypical antipsychotic drugs is that they are as effective as traditional treatments, with a possibly greater action in treating negative symptoms and with a lower extrapyramidal side effects profile. For comprehensive treatment of schizophrenia, the author advocates a polydimensional approach encompassing psychopharmacology, psychotherapy, psychosocial interventions (particularly with family members), and vocational training.

Topics: Antipsychotic Agents; Behavioral Symptoms; Benzodiazepines; Clozapine; Family Health; Humans; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Social Adjustment

Tardive dyskinesia (TD) is the most feared and troublesome extrapyramidal side-effect of prolonged neuroleptic (NL) treatment. We present a review of TD. Its pathophysiology remains elusive, although extrapyramidal symptoms (EPS) increase the liability for TD. Nowadays, therefore, avoidance of all EPS remains the best preventive strategy, as it is not possible to predict which liable patients will develop TD, or of what type or severity. TD frequently includes dystonic features, and is more disabling when these dystonias are present. Clozapine (CLZ) has been reported to be effective in suppressing nearly 60% of TD syndromes, specially those with dystonic features. Based on the few reports in the literature on CLZ and TD by the early 1980s, we started to videotape the first severe TD patient treated with CLZ in 1984. We present the first three case reports of severe TD, with prominent disabling dystonic features, treated with CLZ and videotaped since pretreatment and then periodically for 12, 8 and 5 years of follow-up, respectively. The patients' current diagnosis, gender and age are: Case 1, DSM-IV Schizophrenia Residual Type, male, 39 years; Case 2, DSM-IV Polysubstance Related Disorder, Borderline Personality Disorder, female, 28 years; Case 3, DSM-IV Schizoaffective Disorder, male, 40 years. Two of them presented with a recurrence of TD because of CLZ interruption within the first 2 months of treatment, with no further breakthrough to date. The first two cases have complete remission of TD; the third case is still improving after 5 years of CLZ treatment, with only minor dystonic features persisting that constitute no impairment for work or daily routines at present. All patients, independent of their psychiatric primary diagnosis, have shown significant and progressive improvement in both motor and psychosocial aspects. None of them has been rehospitalized. Long-term treatment and follow-up is required to avoid TD recurrence and to assure full assessment of treatment effectiveness. Ideally, periodic video recording with standardized examination is advisable for long-term follow-up and outcome assessment. At present, CLZ could be regarded as the drug of choice for patients with TD, specially for those with disabling and or dystonic features and who require ongoing NL therapy. The use of novel antipsychotic agents for TD treatment and prevention, with their low EPS liability, is promising, but has yet to be tested.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Schizophrenia; Substance-Related Disorders; Videotape Recording

The effectiveness of clozapine in the treatment of the negative symptoms of schizophrenia remains controversial, as improvements in negative symptoms are invariably accompanied by improvements in positive symptoms and neurological side effects. We examined the effectiveness of treatment with clozapine on negative symptoms in a cohort of patients with minimal positive symptoms. Improvements in positive and negative symptoms were measured by BPRS ratings in a subgroup of schizophrenic patients (n=17, from a state hospital cohort of 75) with minimal positive symptoms, who had received clozapine for 6 months. In this subgroup, significant improvements were noted by a composite score on the three negative symptom items of emotional withdrawal, blunted affect, and motor retardation. Positive and depressive symptoms remained unchanged. The remaining cohort (n=58) showed improvements in overall psychopathology including positive, negative, and depressive symptoms. Interestingly, nearly 50% of each group were discharged from the hospital. These findings suggest that clozapine may be beneficial in the treatment of core negative symptoms, even in the absence of other improvements in psychopathology. This effect of clozapine may be a function of its unique pharmacological profile.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Delusions; Depression; Female; Hospitals, Psychiatric; Hospitals, State; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Treatment-resistant schizophrenia is the object of intense interest because of recent developments in its treatment and aetiology. The actual definition of treatment-resistant schizophrenia is, however, still controversial. It should reflect the legitimate and varied needs and perspectives of people with schizophrenia, their family members, mental health care givers, mental health administrators, public health officials, and those who fund the direct and indirect costs of treating schizophrenia. The most common definition of treatment-resistant schizophrenia denotes patients with schizophrenia who, despite at least two adequate trials of classical neuroleptic drugs, have persistent moderate to severe positive, or disorganisation, or negative symptoms together with poor social and work function over a prolonged period of time. This definition reflects the viewpoint of people with this illness, their family members, and mental health care givers. Approximately 30% (range 10-45%) of schizophrenic patients meet these criteria. While this definition is adequate for many purposes, it should be realised that the remaining 70% of schizophrenic patients, whose positive symptoms respond adequately to neuroleptic treatment, may also have clinically significant negative symptoms, poor social and work function, clinically significant cognitive dysfunction, poor quality of life relative to the normal population, and constitute a significant burden to family and society. The lifetime suicide rate in both treatment-resistant and responsive schizophrenic patients is 9-13%, indicating that conventional definitions of neuroleptic response do not convey lower risk of suicide. However, before defining a patient as treatment resistant, it is important to consider whether the patient has received an inadequate duration of treatment, and/or too low, or possibly too high, doses of neuroleptic drugs. Using these stringent criteria, treatment resistance may be present at the time of initial diagnosis and treatment, but if not present initially, it will usually develop subsequently-sometimes not until after multiple acute exacerbations over a period of years. During the first months and years after the diagnosis of schizophrenia has been made, clinicians should be especially alert in identifying a patient as treatment resistant in order to diminish the severe social disability and suicidality which may ensue if it is not recognised and correctly treated. Once present, treatment resi

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Clinical Trials as Topic; Clozapine; Cognition; Cost-Benefit Analysis; Drug Resistance, Multiple; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Patient Compliance; Quality of Life; Schizophrenia; Treatment Outcome

Evidence from diverse sources, including postmortem investigations, in vivo imaging studies and animal models, suggests that schizophrenia has its origins in early cortical maldevelopment, which in turn may lead to dysfunctional connectivity during brain maturation and clinical symptomatology in early adulthood. Antipsychotic drugs, including the atypical agent clozapine, appear to act at key sites involved in higher cortical-limbic connectivity, possibly mediated by a variety of neurotransmitters. Studies of gene expression may provide a better understanding of how antipsychotic drug effects are integrated at the postsynaptic level. The data from schizophrenia research are discussed within a neurodevelopmental framework.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Humans; Schizophrenia

The therapeutic success of clozapine and risperidone has focused attention on the interaction between serotonin and dopamine systems as an avenue for superior therapeutics in schizophrenia. The authors review the neurobiological basis for this interaction and its clinical relevance.. The authors synthesized information from more than 100 published articles obtained through electronic and bibliography-directed searches.. The serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain. Serotonergic antagonists release the dopamine system from this inhibition. This disinhibition of the dopamine system in the striatum may alleviate neuroleptic-induced extrapyramidal symptoms, and a similar disinhibition in the prefrontal cortex may ameliorate negative symptoms. However, the benefits of combined serotonergic-dopaminergic blockade may be observed in only a narrow dose range and may be lost with doses that produce suprathreshold dopaminergic blockade.. Serotonergic modulation of dopaminergic function provides a viable mechanism for enhancing therapeutics in schizophrenia, but much remains unclear. Future research will have to establish the existence of this interaction in humans in vivo, specify the conditions under which it leads to optimal therapeutic benefits, and explore the possibility of using specific serotonergic treatments as flexible adjuncts to typical neuroleptics, rather than the present trend toward using single drugs with combined actions.

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Disease Models, Animal; Dopamine; Dopamine Agents; Drug Interactions; Humans; Mesencephalon; Neural Pathways; Prefrontal Cortex; Prosencephalon; Risperidone; Schizophrenia; Serotonin; Serotonin Agents

Since the average lifespan is becoming longer, the number of older patients with psychoses is expected to increase. Late-life schizophrenia is prototypical of these chronic psychotic disorders. Antipsychotic drugs are the most effective symptomatic treatment. Pharmacotherapy in older patients, however, is complicated by alterations in pharmacokinetics and pharmacodynamics. The risk of many adverse effects is considerably higher in the elderly. For example, we found the cumulative annual incidence of tardive dyskinesia among patients over age 45 to be 26%, which was five to six times greater than that reported in younger patients. Studies suggest that most patients with schizophrenia relapse without neuroleptic maintenance therapy, exemplifying the need for improved pharmacologic regimens. Data concerning the use of the newer serotonin-dopamine antagonists in patients with late-life psychoses are limited. Initial studies suggested that clozapine is efficacious, but its use is limited by side effects. Risperidone is also clinically beneficial and is generally well tolerated, but needs to be prescribed in lower doses than those recommended for younger adults. Antipsychotic use in the elderly should be accompanied by careful conservative dosing and close patient monitoring.

Topics: Adult; Age Factors; Age of Onset; Aged; Clozapine; Drug Administration Schedule; Humans; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for diagnosing schizophrenia require the presence of characteristic symptoms and disabilities, as well as the specific exclusion of other disorders with similar symptomatology. Once schizophrenia is diagnosed, the classification of schizophrenic symptoms as psychotic, disorganized, or negative can help clinicians predict treatment outcomes and individualize both pharmacologic and psychosocial treatment. Three treatment phases (acute, resolving, and maintenance) have been described; each has different medication strategies and goals. The introduction of novel antipsychotic agents, such as clozapine and risperidone, has enhanced the clinicians' ability to manage schizophrenic patients. Nonetheless, psychosocial treatment remains an important component of overall patient management.

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Diagnosis, Differential; Humans; Psychiatric Status Rating Scales; Psychotherapy; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

We examined a Ser-9-Gly polymorphism in the dopamine D3 receptor gene for allelic association with schizophrenia in 133 patients currently treated with clozapine and 109 controls. Allele 1 (Ser-9) was significantly more frequent in the patients (69%) than in the controls (56%) (P = 0.004). The 1-1 genotype was more common (43% vs 30%) and the 2-2 genotype less common (5% vs 18%) in patients than in controls. When the patient group was subdivided on the basis of clinical response to clozapine, using a 20-point improvement in the global assessment scale as cut-off, genotype 1-1 was found to be more frequent among the non-responders (53% vs 36%, P = 0.04). To place our results in the context of previous studies of this polymorphism and schizophrenia, we performed a meta-analysis of all published data including the present sample. The combined analysis shows evidence for a modest association between genotype 1-1 and schizophrenia (odds ratio 1.25, 95% confidence interval 1.05-1.49, P = 0.01). These results suggest that the Ser-9 allele, or a nearby polymorphism in linkage disequilibrium, results in a small increase in susceptibility to schizophrenia.

Topics: Alleles; Antipsychotic Agents; Base Sequence; Clozapine; Disease Susceptibility; Gene Dosage; Gene Frequency; Genotype; Humans; Molecular Sequence Data; Polymorphism, Genetic; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia

The causes and the pathogenesis of tardive dyskinesia are not well understood. There is no therapy currently available that has been shown to alter the overall course. However, it is possible to influence the development or the progression of this disorder. A decision tree of feasible therapeutic choices is presented here, to prevent or treat tardive dyskinesia in patients who need long term neuroleptic therapy.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Long-Term Care; Neurologic Examination; Schizophrenia; Substance Withdrawal Syndrome

The current literature describing the pharmacokinetics of the atypical antipsychotics clozapine and risperidone is reviewed, and discussion on the clinical significance of these data is presented. These drugs are well absorbed when taken orally but are poorly bioavailable because of presystemic elimination. They are highly cleared by hepatic metabolism involving specific P450 isozymes. Risperidone elimination produces a potent active metabolite. Neither of the drugs has received extensive study related to drug-drug interactions, but several are potentially important because a purported therapeutic plasma concentration range is proposed for clozapine and a possible curvilinear dose response relationship has been reported for risperidone. The current clinical pharmacokinetic database for these atypical antipsychotics suggests that much can be learned with additional study that would be of value in individualizing their dosage regimens.

Topics: Antipsychotic Agents; Biological Availability; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Humans; Metabolic Clearance Rate; Risperidone; Schizophrenia; Schizophrenic Psychology

Clozapine is an atypical antipsychotic with a low extrapyramidal side effect profile, and is often useful in the treatment of schizophrenics who do not respond to classical neuroleptics. While the dopamine D2-receptor is believed to be the primary target of classical neuroleptics, clozapine has greater affinity to the dopamine D4-receptor (DRD4). Great variability has been reported for the DRD4 gene and in the receptor itself. It is now possible to investigate if this variation influences individual differences in response to clozapine treatment or in the genetic susceptibility to schizophrenia. Till now the examined variations in the DRD4 gene do not seem to influence response to clozapine treatment or genetic susceptibility to schizophrenia. However, some of clozapine's side effects might be mediated through DRD4 binding.

Topics: Antipsychotic Agents; Clozapine; Humans; Receptors, Dopamine; Schizophrenia

To report and review the use of cytokines for the treatment of clozapine-induced neutropenia.. Case report and review of literature.. Cytokines, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), appear to shorten the duration of clozapine-induced neutropenia.. G-CSF or GM-CSF therapy should be considered in patients with profound neutropenia of prolonged duration (high-risk neutropenia).

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocytes; Humans; Injections, Subcutaneous; Leukocyte Count; Male; Neutropenia; Schizophrenia; Schizophrenic Psychology

The concept of negative symptoms is derived from Kraeplin's description of the dissolution of the personality in patients with schizophrenia. Negative symptoms may be either primary, or secondary to positive symptoms, antipsychotic side effects, dysphoric affect and environmental deprivation. Primary negative symptoms represent core features of the illness, and have been termed deficit symptoms. The differentiation of primary from secondary negative symptoms has important treatment implications, as treatment approaches vary greatly for the different types of negative symptoms. Specific pharamacological and psychosocial treatments are available for secondary negative symptoms. However, to date, there are no known effective treatments for primary negative symptoms. The importance of developing effective treatments for primary negative symptoms is underscored by the relationship of these symptoms to poor social, occupational, and global outcome.

Topics: Antipsychotic Agents; Clozapine; Humans; Personality Assessment; Prognosis; Schizophrenia

Determining the optimal dose of antipsychotic for an acute schizophrenic episode has been an elusive goal. Empirical dose adjustment with conventional neuroleptics has generally led to excessive drug exposure, in part due to the lag time between initiation of therapy and response and in part due to the indefinite nature of the response. Data from dose- and plasma concentration-response studies and from imaging studies have provided some guidance. In particular, newer antipsychotic drugs such as risperidone and sertindole have been evaluated in multiple fixed-dose designs to determine the optimal dose or dose range. To devise an overall treatment strategy for an acute psychotic episode, we reviewed and incorporated data from a number of controlled studies.

Topics: Acute Disease; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Delivery Systems; Haloperidol; Humans; Risperidone; Schizophrenia

The introduction of clozapine into clinical practice represented a major breakthrough in antipsychotic pharmacotherapy. However, in spite of 5 years of use and a extensive research, there has previously been no clinically useful means to predict response to clozapine. Six recent studies have examined the utility of clozapine plasma concentrations in predicting response in treatment-refractory patients with schizophrenia. Five of these studies found that clozapine plasma concentrations above 350 to 420 ng/ml significantly increase the likelihood of clinical response in this patient population. Thus, there is now compelling evidence that clozapine plasma concentrations may play an important role in maximizing the probability of clinical response to clozapine in treatment-refractory schizophrenia. This article provides an overview of studies investigating the relationship between clozapine plasma concentrations and clinical response. The discussion includes guidelines regarding the clinical use of clozapine plasma concentrations in the pharmacological management of persons with treatment-refractory schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Developments over the past 20 years in maintenance treatment have substantially reduced problems with relapses, rehospitalization, and serious psychopathology and dysfunction for most patients with schizophrenia. Therapeutic gains can be accomplished with minimal dosing strategies, targeted drug therapy for medication-refusing patients, psychosocial interventions, and new drugs. Although minimal dose maintenance requires close clinical monitoring and effective collaboration, this strategy reduces side effects and negative symptoms and may thereby translate into greater medication compliance. Psychosocial therapeutics that include family intervention in conjunction with antipsychotic drug treatment reduce relapse rates, but further study is needed. Lithium, carbamazepine, benzodiazepines, beta-blockers, and antidepressant drugs along with electroconvulsive therapy and social skills training provide other relevant approaches in maintenance treatment. Before a maintenance role for new drugs such as clozapine and risperidone is clarified, controlled studies are needed. However, the advantages with motor side effects and secondary negative symptoms should enhance clinical course and medication compliance, and superior antipsychotic prophylaxis is hypothesized. Special issues in maintenance treatment include difficulty in predicting relapse, increased risk of adverse drug effects in elderly patients, and complication of the nonpsychotic aspects of schizophrenia by continued use of antipsychotic drugs. Optimal maintenance treatment incorporates early detection and outpatient management of symptom exacerbation, minimal dosing to increase compliance and reduce adverse effects, psychosocial intervention to reduce relapse rates and enhance functioning, and the integration of several therapeutic modalities and the provision of case managers and assertive community treatment teams.

Topics: Ambulatory Care; Antipsychotic Agents; Case Management; Clozapine; Combined Modality Therapy; Community Mental Health Services; Drug Administration Schedule; Drug Therapy, Combination; Humans; Recurrence; Risperidone; Schizophrenia; Schizophrenic Psychology

Despite the proven efficacy of antipsychotic medication in the treatment of schizophrenia, a substantial proportion of patients derive little if any benefit from traditional medications. Though alternative strategies (e.g., increasing dosage, switching antipsychotic, or adding adjunctive medication) are frequently employed, success rates are often disappointing. Clozapine has shown to be effective in some poor or partially responsive patients in three prospective, random assignment, double-blind trials. Risperidone has not yet been extensively studied in treatment-resistant patients, but may also be a useful alternative.

Topics: Antipsychotic Agents; Clozapine; Double-Blind Method; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Treatment Outcome

In this review, we have examined the effects of neuroleptic medications on neurocognitive functions in articles published since 1990. Based on recent work and reviews of older studies, neuroleptics do not appear to have marked positive or negative effects on working memory or secondary memory. In contrast, neuroleptic medications appear to have a salutary effect on sustained vigilance or response readiness. The relationship or lack thereof between changes in cognition and changes in clinical state (produced by neuroleptics) is also discussed.

Topics: Antipsychotic Agents; Attention; Clozapine; Cognition; Humans; Intelligence; Memory; Motor Skills; Neuropsychological Tests; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Wechsler Scales

Treatment cost can have a dramatic effect on treatment availability, and clinicians may find themselves unable to provide expensive treatments they believe their patients should receive. The introduction of new, premium-priced antipsychotic medications has provided visible examples of this problem. Cost considerations must be part of treatment decisions, since resources are often insufficient to provide all potentially helpful treatments. However, the key question regarding expensive drugs is whether other savings can be expected to offset the higher drug price, or if not, whether improved effectiveness justifies the added cost. Pharmacoeconomic research attempts to integrate relevant information on both effectiveness and cost so that clinicians, patients, and other decision-makers can make meaningful treatment choices. This article presents a conceptual framework for cost-effectiveness analysis, illustrates pharmacoeconomic methods with studies of the cost-effectiveness of clozapine treatment, and describes the steps in designing cost-effectiveness research on novel antipsychotic agents.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cost-Benefit Analysis; Drug Costs; Economics, Pharmaceutical; Humans; Patient Selection; Psychotic Disorders; Research Design; Retrospective Studies; Risperidone; Schizophrenia

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

Topics: Antipsychotic Agents; Clozapine; Humans; Quality of Life; Schizophrenia; Schizophrenic Psychology; Social Support

To describe the concept of memory impairment in schizophrenia and the clinical implications of this concept in terms of patient assessment and neuroleptic drug use.. Narrative literature review.. Individuals suffering from schizophrenia normally exhibit some degree of memory impairment. Recent work in psychopathology indicates that the impairment is comprehensive, involving the sensory, short-term, and long-term memory stores. Memory impairment appears to be a primary symptom of the disease, and its underlying causes are likely organic. A number of medications, however (for example, traditional neuroleptics and drugs that have pronounced anticholinergic activity), may cause or exacerbate impairment. In particular, anticholinergic agents used to treat extrapyramidal symptoms, a common complication of neuroleptic drugs, appear to have a deleterious effect on memory.. Memory impairment is an important consideration in the clinical assessment and management of patients with schizophrenia. The use of atypical antipsychotics like risperidone appears to have no impact on memory function; because risperidone is associated with a low incidence of extrapyramidal side effects, it can obviate the need for anticholinergic medications-thus offering greater hope of nondebilitative intervention. The advent of medications that are safer (on cognition) could also lead to generally better outcomes by facilitating compliance with drug regimens and rehabilitation programs.

Topics: Amnesia; Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Dibenzothiazepines; Humans; Mental Recall; Neuropsychological Tests; Quetiapine Fumarate; Retention, Psychology; Risperidone; Schizophrenia; Schizophrenic Psychology

Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence, of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.

Topics: Animals; Antipsychotic Agents; Basal Ganglia Diseases; Behavior, Animal; Biogenic Amines; Brain; Clozapine; Dopamine; Dose-Response Relationship, Drug; Haloperidol; Humans; Receptors, Dopamine; Schizophrenia

Plasma level monitoring of clozapine and metabolites may prove beneficial in treating patients who show unusual drug metabolic activity. A threshold plasma level for patients who will respond to this medication is suggested. The interaction of gender, age, smoking, other medication and side effects with plasma clozapine and metabolites are discussed. Plasma level monitoring of clozapine and/or metabolites is recommended in patients who do not respond at usual therapeutic dose, who show untoward side effects at low dose or who are treated with other medications. Finally monitoring of patients who require more than 600 mg/day should be implemented because there is evidence that the incidence of seizures increases significantly above this dosage level. There is some evidence that high plasma clozapine levels are associated with seizures.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Humans; Risk Factors; Schizophrenia

This review will focus on three categories of poor response of patients with schizophrenia to an antipsychotic medication. The first category includes patients who continue to demonstrate positive psychotic symptoms when they receive adequate trials of an antipsychotic. These individuals may improve when their drug doses are altered or when they receive other drugs such as lithium or benzodiazepines in addition to their antipsychotic. Clozapine has been shown to result in substantial improvement in a majority of these patients. Additional evidence suggests that risperidone will also be effective in these individuals. The second category of poor responders consists of patients who are unable to tolerate the side effects of antipsychotics. These individuals may respond when they are changed to a newer antipsychotic. The third category includes patients who have persistent negative symptoms while they are treated with an antipsychotic. There is substantial evidence that these patients will demonstrate improvement in negative symptoms when they receive clozapine and risperidone as well as newer antipsychotics including olanzapine, sertindole, and quetiapine.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Lithium; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

Cognitive impairment is a relatively frequent aspect of schizophrenia. Deficits are most prominent in tasks involving attention, memory, and executive function. Although some research suggests that deterioration is progressive, these deficits appear to be relatively stable over time. Imaging and biochemical studies show that schizophrenia is characterized by a number of morphological, hemodynamic, and neurochemical abnormalities within systems integrating the cortex, temporal lobes, and various limbic structures. Neurochemical assays suggest that the neurotransmitters serotonin, dopamine, and glutamate play a significant role in the disease-associated decrement. Cognitive impairment in schizophrenia impedes psychosocial performance and eventual reintegration into society and is therefore an especially relevant target in the development of new therapeutic modalities. Atypical agents, such as clozapine and olanzapine, hold special promise in this area.

Topics: Antipsychotic Agents; Benzodiazepines; Cerebral Cortex; Clozapine; Cognition Disorders; Dopamine; Glutamic Acid; Humans; Limbic System; Olanzapine; Pirenzepine; Schizophrenia; Schizophrenic Psychology; Serotonin

Long-term outcomes for patients with schizophrenia have been disappointing. The article discusses how the typical antipsychotics (clozapine and risperidone) as well as several agents that should be available in the near future (olanzapine, sertindole, quetiapine, and ziprasidone) might improve outcome and then focuses on antipsychotic relapse rates and the newly released antipsychotic olanzapine. Considerable evidence shows that relapse rates for compliant patients maintained on atypical antipsychotics are substantially lower than rates for those maintained on conventional antipsychotics. Also, the decreased extrapyramidal symptom liability of the newer medications will make it easier to prescribe more effective doses of antipsychotic that can maximize relapse prevention without simultaneously interfering with the patient's quality of life or motor functioning. The authors describe clinical observations of olanzapine based on their 3 years of clinical experience using this agent in a phase 3 clinical trial. They suggest that as atypical antipsychotics like olanzapine are more widely used, some problems associated with the long-term use of conventional antipsychotics will diminish, but other issues and concerns will be more common. In particular: (1) Despite their better side effect profiles, atypical antipsychotics will not solve the noncompliance problem. A significant proportion of patients with schizophrenia will still need depot therapy. (2) There will be problems arising from "awakenings" phenomena where patients will become more in touch with their losses and painful inner feelings. It seems likely that the need for rehabilitation services will be increased as more patients improve to the point where they will be amenable to psychiatric rehabilitation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Quality of Life; Recurrence; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Although neuroleptic drugs have become the mainstay of treating acute and chronic psychosis, they are substantially limited by troublesome side effects. The traditional neuroleptic drugs have a wide array of central nervous system and peripheral system side effects that often lead to problems in management or patient noncompliance. Of particular difficulty are the extrapyramidal symptoms and tardive dyskinesia. However, other side effects of seizures, sedation, neuroleptic malignant syndrome and cardiovascular, hematologic, endocrinological, and weight gain problems remain as clinical management challenges posed by existing antipsychotic drug therapy. Considerable progress has been made in improving the motor side effect profile with the advent of clozapine and risperidone. However, each of these drugs has its own dose-limiting side effect profile. Two new drugs, olanzapine and sertindole, are now added to the pharmacopeia for treating psychosis. They further improve the benefit/ risk ratio because they have even fewer EPS and other side effects. Overall, these new antipsychotic agents greatly improve the treatment of psychosis by reducing drug-induced morbidity and improving the quality of life for patients.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Imidazoles; Indoles; Neuroleptic Malignant Syndrome; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Schizophrenia; Seizures; Sleep; Weight Gain

Clozapine represented the first significant advance in the pharmacotherapy of schizophrenia since the introduction of conventional antipsychotic drugs in the 1950's. Despite its superior efficacy and potential to reduce substantially the morbidity of schizophrenia and improve the outcomes, of patients, clozapine has not been used on a widespread basis or as a first-line treatment due to its potential for agranulocytosis. With the introduction of risperidone and the imminent prospect of other atypical antipsychotic drugs (olanzapine, sertindole, quetiapine, ziprasidone), clinicians may be able to improve dramatically the methods and manner in which they treat schizophrenia and related psychotic disorders. If we accept the premise that atypical antipsychotic drug provide superior efficacy, reduced side effects, and the prospect of better compliance, their greatest impact may be when used in patients at the beginning of their illness. The following article provides a rationale and hypothesis for the use of atypical antipsychotic drugs as a first-line treatment of schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Clozapine; Humans; Middle Aged; Patient Compliance; Recurrence; Risperidone; Schizophrenia; Treatment Outcome

Topics: Brain; Clozapine; Humans; Ondansetron; Psychiatric Status Rating Scales; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Resistance; Family Therapy; Humans; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Dangerous Behavior; Humans; Patient Admission; Patient Compliance; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Violence

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Patient Compliance; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology

Standard neuroleptic medications have been augmented by the introduction of risperidone and clozapine into clinical practice. A great deal of attention has also been focused on efficacy and the lower propensity to extrapyramidal side-effects associated with the new agents. However, antipsychotic medication, both old and new, can cause a range of other adverse effects, some of which are serious, and many of which have the potential greatly to diminish the quality of life of patients who need to take medication in the long term. Of particular significance are postural hypotension, cardiotoxicity, peripheral and central anticholinergic effects, sedation, weight gain, and endocrine and haematological effects. Various antipsychotic compounds differ substantially with regard to propensity to adverse effects. Side-effects can be minimized by optimization of clinical strategies, including choice of appropriate drug, slow titration and dosage reduction. It is also vital to explain carefully to both patients and carers the nature of the side-effects which can be anticipated. The choice of antipsychotic is often determined by evaluation of the potential impact of the various adverse effects on a particular patient. New drugs, such as risperidone, are well tolerated, with fewer side-effects, and should now be considered as a first-line option.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Neurologic Examination; Patient Education as Topic; Risperidone; Schizophrenia

Clozapine does not constitute a first-line treatment due to the occurrence of agranulocytosis. However, the benefit/risk ratio fully justifies its use in two situations: résistance to neuroleptics; intolerance to neuroleptics. There are no internationally recognized objective criteria to devine resistance. The ones defined in the well-restricted methodological environment of a clinical trial are generally not applicable to daily practice. In particular, the accepted criteria do not always take into account the personal factors, the social and environmental context and rehabilitation programs. May et al. for example defined in 1988 the degree of response to therapy based on clinical improvement as well as social integration. It As was widely recognized that if the severity of residual symptoms (grade 5 response) requires the hospitalization, treatment with clozapine is warranted. For partial responders to classical treatment (grade 4 response) who could benefit from clozapine, the risk ratio of clozapine needs to be further evaluated. The identification of predictive factors of response to therapy would allow a nosel approach of this indication. According to certain authors, paranoid type responds best to therapy. However, the evidence collected to date needs to be confirmed. In particular, the effects of clozapine on predominantly negative symptoms require further investigations. In contrast to several european studies, intolerance to neuroleptics is rarely a reason for initiation of clozapine therapy. This would indicate that the appreciation of intolerance to neuroleptics notably varies from one country to the next. Intolerance criteria to be further specified as well as the benefit/risk ratio.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Schizophrenia

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Drug Therapy, Combination; Humans; Lithium; Psychotropic Drugs; Risperidone; Schizophrenia

The clinical use of clozapine and risperidone is reviewed. Traditional antipsychotic drugs are effective for treating the positive symptoms of schizophrenia but have little or no effect on the negative symptoms of this disease. Newer antipsychotic agents, such as clozapine and risperidone, are effective for treating both positive and negative symptoms in acutely ill and treatment-resistant patients. Clozapine and risperidone also have a lower incidence of extrapyramidal symptoms (EPS) than traditional antipsychotic drugs. Three hypotheses have been proposed to account for the newer agents' ability to relieve negative symptoms: (1) Improvement in negative symptoms may be linked to improvement in positive symptoms. (2) Negative symptoms may improve in the absence of the EPS often caused by traditional agents. (3) The newer antipsychotic agents may directly affect the neural circuits that trigger negative symptoms.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Female; Formularies as Topic; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia

A rapidly growing body of data suggests that dysfunction in serotonergic (5-HT) function may be involved in the pathophysiology of schizophrenia, and that pharmacologic agents for this illness have their therapeutic effects mediated through serotonergic mechanisms. The purpose of this paper is to critically review data relevant to 5-HT's role in the pathophysiology and drug treatment of schizophrenia. Pathophysiologic evidence includes the psychotomimetic effects of lysergic acid (LSD), postmortem studies, single-dose 'challenge' studies and investigations of CSF and peripheral levels of 5-HT and its metabolites. The current nomenclature, potential therapeutic effects and importance of 5-HT receptor subtype antagonism will be examined. In addition, relatively novel strategies of 5-HT uptake blockade and direct acting 5-HT agonists will be assessed. A hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for positive symptoms and a decrease in prefrontal 5-HT function responsible for negative symptoms is proposed. Future implications of these data are discussed.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Isoxazoles; Piperazines; Piperidines; Risperidone; Schizophrenia; Serotonin; Tryptophan

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Isoxazoles; Piperidines; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia

Negative symptoms in schizophrenia comprise a psychopathologic and pathophysiologic syndrome which is absent from normal mental function. Renewed interest in negative symptoms has led to the development of better measuring instruments, among which is the Positive And Negative Syndrome Scale (PANSS), which provides a way of measuring and reporting positive and negative symptoms in a balanced and convenient form. A number of strategies are being investigated for treating negative symptoms. Dopamine agonists such as levodopa, amphetamines and bromocriptine have been shown to produce improvements in negative symptoms, although good, well-controlled clinical trials are lacking. Partial dopamine agonists, such as MAR 327, are also currently under investigation and results are expected soon. Tricyclic, selective serotonin reuptake inhibitors and monoamine oxidase antidepressants appear to be able to modify negative symptoms in schizophrenia, although, once again, carefully designed trials are needed. Modification of GABAergic transmission has shown little promise, but the use of glycine to augment transmission at N-methyl-D-aspartate (NMDA) synapses suggests that the strategy may be beneficial. These results also imply that altered glutamate receptor function may be partly responsible for negative symptoms. One strategy that has been shown to have a beneficial effect against negative symptoms is combined serotonin/dopamine antagonism. Clozapine was found to have this profile after its introduction, and the recently introduced antipsychotic, risperidone was developed intentionally to be a combined 5-HT2/D2 antagonist. Both risperidone and clozapine have been shown to be effective against negative symptoms. One problem associated with the assessment of drug effects on negative symptoms, however, is that drugs can act on both primary and secondary negative symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Affective Symptoms; Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Risperidone; Schizophrenia; Schizophrenic Psychology; Syndrome

Mood disorders in schizophrenia are common and are associated with a poor outcome, an increased risk of relapse and a high rate of suicide. Consequently, treatment strategies need to take mood disorders into account. In depressed and actively psychotic schizophrenic and schizoaffective patients, treatment with neuroleptic plus antidepressant may be less effective than neuroleptic alone. However, patients with post-psychotic depression on maintenance neuroleptics respond well to tricyclic antidepressants. Mood disorders can be caused by neuroleptics and if so will often improve if the dose is reduced or if the drug is changed. Anticholinergics may also help. In schizoaffective disorder, lithium is usually beneficial, especially for patients with classical affective disorder. Carbamazepine may be more effective in patients with schizoaffective and schizophreniform disorders. At doses comparable with those effective in schizophrenia, clozapine may be as good or better than conventional neuroleptics in schizophrenic patients with psychotic mood disorder or schizoaffective disorder. In patients with high BPRS anxiety/depression scores, risperidone (8 mg/day) was more effective than haloperidol (10 mg/day). Risperidone at a mean dose of 8.6 mg/day was also more effective than haloperidol (mean dose 9.2 mg/day) or levomepromazine (methotrimeprazine -- mean dose 125 mg/day) on the Psychotic Anxiety Scale. Mood-related symptoms are therefore amenable to treatment. Risperidone and clozapine appear to be good candidates for the long-term treatment of mood disorders in schizophrenia, although long-term, double-blind, controlled studies are needed to confirm this.

Topics: Affective Symptoms; Antidepressive Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Isoxazoles; Lithium; Long-Term Care; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

Antipsychotic medication remains the mainstay of both acute and long-term treatment for schizophrenia. Recent research has underscored the need for optimum dosing strategies. Relatively few patients benefit from high doses (e.g. greater than 15-20 mg per day of haloperidol or 500-800 mg/day of chlorpromazine). In poor or partial responders clozapine continues to be the treatment of choice. Risperidone is an effective antipsychotic with a good safety profile. Its potential advantages in terms of efficacy need to be further studied. An expanded data base from maintenance trials supports the use of continuing maintenance medication and provides guidelines for dosage requirements.

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Behavior Therapy; Clozapine; Cognitive Behavioral Therapy; Family Therapy; Humans; Isoxazoles; Piperidines; Psychotherapy; Rehabilitation, Vocational; Risperidone; Schizophrenia

Clozapine is the first of a new generation of antipsychotic drugs which constitutes a major advance in the treatment of schizophrenia. Numerous theories have been proposed to explain the advantages of clozapine over typical neuroleptics. Most of these focus on its effects on dopaminergic and serotonergic neurotransmission. This article reviews the effects of clozapine and related antipsychotic drugs on dopamine (DA) D1, D2, and D4, and serotonin (5-HT) 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, as well as its ability to modulate DA and 5-HT release. Clozapine and other atypical antipsychotic drugs share the ability to cause fewer extrapyramidal symptoms at clinically effective doses. This may be related to their potent 5-HT2A and weak D2 receptor blocking properties, a profile shared by risperidone, melperone, olanzapine, amperozide, HP-873, seroquel, sertindole, and ziprasidone. The basis for the superior ability of clozapine to treat negative symptoms and enhance cognitive function compared to typical neuroleptic drugs in schizophrenic patients has not yet been ascertained, but there is evidence that its effect on 5-HT2A, D2, or D4 receptors may be important. Other aspects of the pharmacology of clozapine which may contribute to its actions include potent alpha 1-adrenergic, M1, M2, M3, and M5 receptor blocking properties, as well as M4 agonist effects.

Topics: Antipsychotic Agents; Clozapine; Dopamine; Humans; Parkinson Disease; Receptors, Dopamine D1; Schizophrenia; Serotonin

To present a critical overview of the selected literature published in the past 7 years on the efficacy and safety of psychoactive agents in conduct disorder, schizophrenia, separation anxiety disorder, selective mutism, obsessive-compulsive disorder, panic disorder, major depressive disorder, bipolar disorder, and sleep and eating disorders.. Reports of double-blind and placebo-controlled trials and open studies were reviewed and selected studies presented.. Employment of larger samples of diagnostically homogeneous patients and a more sophisticated design and methodology led to progress in the treatment of most of these conditions. Data have been accumulated on dose range and safety of lithium in this age group, and there is supportive evidence that lithium is useful in reducing aggression.. For a rational treatment approach, further studies are needed, particularly in depression and conduct disorder; psychosocial-environment contributions and possible biological markers should be investigated in order to identify children who require psychopharmacological treatments and those who will respond to psychosocial interventions or the combination of both. Symptoms targeted to require pharmacotherapy and symptoms targeted to respond to psychosocial interventions have to be identified.

Topics: Adolescent; Alprazolam; Anticonvulsants; Antipsychotic Agents; Anxiety, Separation; Bipolar Disorder; Carbamazepine; Child; Child Behavior Disorders; Child, Preschool; Clonidine; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Feeding and Eating Disorders; Fluoxetine; Humans; Imipramine; Lithium; Mutism; Obsessive-Compulsive Disorder; Phenobarbital; Phenytoin; Phobic Disorders; Schizophrenia; Sleep Wake Disorders; Tranquilizing Agents

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Cyclic AMP; Dopamine; Haloperidol; Neurotensin; Pyrazoles; Quinolines; Receptors, Dopamine; Receptors, Neurotensin; Schizophrenia; Signal Transduction

Historically, first case-report of resistant schizophrenia were described under insulin therapy. Later on, the development of classical neuroleptics has permitted a better outcome but the persistence of a lack of improvement in certain patients has induced the individuation of treatment-refractory schizophrenia criteria. The difficulties in defining the refractory schizophrenic patients are described: variability of the schizophrenia diagnostic criteria, variability of outcome, lack of consensus about the good practices in neuroleptic treatment, difficulties in defining response criteria and the confusion between resistance, chronicity and severity. Three kinds of treatment refractory schizophrenia criteria are available: by Kane et al., May et Dencker, Brenner Dencker et al. There are few studies including resistant schizophrenic patients: their results are not homogeneous, perhaps because the prevalence of treatment-refractory schizophrenia is poorly known, with ranges from 5 to 25%. The following factors are hypothesized as being readily associated to a poor outcome and perhaps resistance: male sex, early illness beginning, severity of negative or formal thought disorder, absence of an affective syndrome, morphological CT scans abnormalities, pharmacological factors, late treatment initiation, variability of biodisposibility... Then the therapeutic point of view is considered under three main axes: neuroleptic drugs (NLP) are the basis of chemotherapy, but other therapeutic approaches complete the biological treatment: coherent institutional work and implication of family environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Social Environment

The neurological effects of neuroleptic drugs are well known from the very beginning of their history and are even part of the initial definition of this therapeutic class. However, these effects are not necessary for an antipsychotic efficacy as demonstrated by the fully effective "atypical" neuroleptics, which induce minimal neurological side-effects. The neurobiological mechanisms underlying this "atypicity" are not well elucidated but could involve a preferential action on mesocorticolimbic dopaminergic system. This preferential action on mesocorticolimbic dopaminergic system. This specificity of action seem especially interesting in the case of patients suffering of severe tardive dyskinesia. Hence, the absence of rebond of preexistent dyskinesia when stopping a long term treatment with clozapine suggest that the pursuit of neuroleptic with this substance in dyskinetic patients would not worsen the long term prognosis of their dyskinesia. Available data on other atypical neuroleptics are insufficient to conclude if this benefit action on tardive dyskinesia is specific of clozapine or shared with other new neuroleptics.

Topics: Antipsychotic Agents; Brain; Clozapine; Dyskinesia, Drug-Induced; Humans; Nervous System Diseases; Neurologic Examination; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

In common with other chronic illness, schizophrenia places a major economic burden on society, in terms of direct costs (in and outpatient care, residential care, drug therapy, etc.) and indirect costs (lost activity and earnings due to illness) and intangible costs (e.g. suffering experienced by the patient and family). Of the psychiatric illness, schizophrenia is by far the most costly: it develops early in life, results in high morbidity, is associated with a high suicide rate, and lacks a standard effective treatment. Analysis of worldwide epidemiological studies published during the last 30 years indicates that the prevalence of schizophrenia ranges from 0.6 to 9 cases per 1,000 population. The prevalence of treatment-resistant schizophrenia ranges from 5 to 30% patients. In other hand, clinical options for the management of treatment-resistant schizophrenia appears to be limited. Clozapine, an antipsychotic agent with relatively weak central antidopaminergic activity, displays atypical pharmacological and clinical properties towards the standard antipsychotics. Furthermore, clozapine is effective in a substantial proportion of patients who are refractory therapy. Although the acquisition cost of clozapine is high in comparison with that of standard antipsychotics, preliminary cost-effectiveness estimates in patients with treatment-resistant schizophrenia suggest that the clinical benefits of the drug (viz improved psychopathology; social functioning and quality of life) may confer medium to long term economic benefits, primarily by reducing the need for psychiatric hospital service.

Topics: Adult; Clozapine; Cost of Illness; Cost-Benefit Analysis; Cross-Cultural Comparison; Cross-Sectional Studies; Female; Humans; Incidence; Male; Middle Aged; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology

Ever since clozapine was discovered, researchers have been attempted to answer the question of what makes it different and how to relate its many pharmacological actions to its clinical features. Its clinical profile conflicts with the hypothesis that antipsychotic effect is due entirely to D2 dopamine receptor blockade. Clozapine is known to interact with many neurotransmitters systems. To date, four main hypothesis have been proposed in an attempt to explain some or all for clozapine's atypical properties: selective blockade of mesolimbic dopamine function; D1, D2, D3 and D4 receptor blockade; 5-HT2 and D2 receptor blockade; Potent alpha 1 adrenergic blockade. These hypothesis are reviewed in relation to the clozapine clinical profile. No hypothesis fully accounts for clozapine's spectrum of neurotransmitter interactions. Such a multiplicity of action would preclude a unified mechanism.

Topics: Brain; Clozapine; Humans; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission

Clozapine, an atypical antipsychotic medication, is the most significant pharmacological advancement in the treatment of chronic schizophrenia in years. Effective in treating the nearly 30 percent of people with schizophrenia who do not respond to conventional pharmacological and psychosocial therapies, clozapine offers new hope to many. However, high cost, a potentially lethal side effect, and a weekly mandatory monitoring system have hampered access to clozapine treatment. This article reviews a brief history of clozapine use in the United States and also the unique features of the medication. Economic, ethical, and personnel resource issues of clozapine use are summarized. The author describes her clinical experiences with the psychosocial issues faced by those who respond to clozapine treatment, case highlights, and social work interventions. Social work advocacy for increased access to clozapine, the potential contributions of social workers in the selection of patients for treatment, and the logistical management issues confronting social workers in inpatient and outpatient mental health settings are addressed.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Health Care Rationing; Humans; Patient Advocacy; Schizophrenia; United States

A growing literature suggests that the atypical antipsychotic agent clozapine may be effective in schizoaffective and psychotic mood disorders.. To evaluate the efficacy and tolerability of clozapine in severe mood disorders, we reviewed published studies on clozapine in schizophrenia, bipolar disorder, schizoaffective disorder, major depression, and organic disorders with psychotic or major affective syndromes, identified through the MEDLINE data base.. Patients in manic or psychotic phases of schizoaffective or bipolar disorder were significantly more likely to respond to clozapine than patients with schizophrenia (p = .006) or severe depressive syndromes (unipolar, bipolar, and schizoaffective depression combined; p = .001). There was no significant difference in the side effect profile secondary to clozapine in patients with severe mood disorders compared to patients with schizophrenia.. Clozapine appears to be effective and well-tolerated in the short-term and maintenance treatment of severe or psychotic mood disorders, particularly in the manic-excited phases of schizoaffective and bipolar disorders, even in patients who have not responded well to conventional pharmacotherapies.

Topics: Bipolar Disorder; Clozapine; Controlled Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; MEDLINE; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Treatment Outcome

Topics: Clozapine; Frontal Lobe; HLA Antigens; Humans; Parkinson Disease; Schizophrenia

Issues in clozapine treatment were considered in terms of implications for resource management.. A critical review of the literature on time course and pattern of response to clozapine was used to address treatment of negative symptoms, late responders, and extent of clinical benefit in ordinary settings.. Superior efficacy of clozapine for partial and poor neuroleptic responders is observed in about one-half of the cases. Response is rapid once a therapeutic dose is reached, and the data do not support the proposition that some patients first respond only after 3-12 months of therapy. The cumulative benefit over several months of treatment and the broad range of symptoms involved in response are similar to those for typical neuroleptic drugs, suggesting that clozapine's superiority is based on greater effectiveness rather than a unique profile of treatment effects. Clozapine appears to be effective for secondary, but not primary, negative symptoms. Modal response is moderate, and extensive rehabilitation and clinical services are required to substantially enhance functional outcome.. Many more patients merit trials with clozapine. Economic costs and adverse drug effects can be minimized by selecting patients most likely to benefit and discontinuing clozapine treatment when benefit is not observed within 2-4 months. Appropriate patients include 1) those with good responses to typical neuroleptics who experience substantial adverse effects and 2) those whose disorders respond poorly to standard neuroleptics and are defined by psychotic symptoms, thought disorder, and hostility. Treatment of primary negative symptoms is not supported by the current experimental data.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cost-Benefit Analysis; Double-Blind Method; Humans; Patient Selection; Prescription Fees; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triage

The dibenzoepine derivative clozapine is seen as a prototype of an atypical neuroleptic, because clozapine has good antipsychotic efficacy but only minimal dopamine antagonistic properties in common animal paradigms. The latter is reflected by the observation that extrapyramidal symptoms during clozapine are a rare phenomenon. Furthermore, recent studies in the USA demonstrated a superior efficacy of clozapine in schizophrenic patients who are nonresponsive to classic neuroleptics. Therefore, the introduction of clozapine in the USA was performed in 1990 despite the well-known risk of agranulocytosis (1-2% during the first year of treatment); however, under restricted conditions regarding the mandatory weekly control of the white blood cell count. For the use of clozapine in Europe, it should be underlined that in 1992 the indication was restricted to "acute and chronic forms of schizophrenia" whereas formerly it was permitted to treat several other neuroleptic resistant syndromes with clozapine, e.g. severe psychotic excitement, aggressive behavior or manic or atypical psychosis. The usage of clozapine in these indications is now only permitted under the restricted legal conditions of a "therapeutic trial" in selected patients. However, several indications for which clozapine has been used successfully in Europe are currently re-investigated in the USA, hopefully leading to a redefinition and extension of the indication spectrum. On the other hand, the American multicenter trials lead to the conclusion that the treatment with clozapine is not furthermore the treatment of last choice but a serious therapeutic alternative which should be available for all schizophrenic patient in case of neuroleptic resistance or of severe side effects of standard neuroleptics. Clozapine treatment leads to an improvement of the quality of life in one third of these schizophrenics and, moreover, results in a marked reduction of costs mainly by reducing the rehospitalisation rates. On the other hand, the list of well-known side effects of clozapine (e.g. agranulocytosis, increased risk of seizures, initial sedation) has to be extended (e.g. transient leucocytosis or eosinophilia, rare but severe complications like cardiorespiratory arrest and "sudden death" during combination with benzodiazepines, case reports of pericarditis, pancreatitis or polyserositis). On the background of possible cardiorespiratory complications we recommend to start the first treatment with clozapine

Topics: Clozapine; Drug Approval; Europe; Humans; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States

This paper is intended to help American clinicians and investigators further their understanding of the clinical use of clozapine by reviewing experience with the drug in Russia, where it was introduced 17 years before it became available in the United States.. Key articles on clozapine from the Russian clinical research literature were reviewed by the first two authors, former Russian clinical investigators. The third author comments briefly about the implications of this work from a contemporary American perspective.. The review found that although clozapine was not widely distributed in Russia, it was investigated at several large psychiatric research institutions and hospitals. It was not reserved for neuroleptic-resistant disorders but instead was used with some success as a first-line treatment in acute disorders. Although no controlled clinical trials were conducted, results of long-term outcome studies of treatment-resistant schizophrenia were largely in agreement with those of controlled trials and clinical follow-up studies in the U.S. The studies found short-term gains for previously refractory patients as well as improvements in social functioning that continued for extended periods in some cases. Russian investigators described clozapine as an effective antipsychotic agent that lacked the extrapyramidal side effects of other neuroleptics.

Topics: Clinical Trials as Topic; Clozapine; Cross-Cultural Comparison; Drug Approval; Humans; Neurologic Examination; Russia; Schizophrenia; Schizophrenic Psychology

Many studies have detected in the brain of schizophrenic patients various morphological and structural abnormalities in various regions and in particular in the cortical and limbic areas. These abnormalities might in part result from neurodevelopmental disturbances suggesting that schizophrenia might have organic causes. These abnormalities may be the primary event in schizophrenia and be responsible for altered dopaminergic, but not only dopaminergic, neurotransmission in these regions. If schizophrenia is in some way strictly related to brain morphological abnormalities it becomes hard to believe that a curative treatment will ever be possible. Considering this scenario, treatment of schizophrenia will be restricted to symptomatic and preventive therapy and therefore, more effective and better tolerated antipsychotics are necessary. The widely used classical antipsychotic drugs present some disadvantages. They do not improve all symptoms of schizophrenia, are not effective in all patients, produce a number of unpleasant and serious, and partly irreversible, motor side effects. The atypical antipsychotic clozapine constitutes a major advance in particular for patients not responding to conventional neuroleptics. To explain the unique therapeutic effect of clozapine many hypothesis have been proposed. Most of the explanations given so far assume that the D2 blockade is the basis for the antipsychotic activity of clozapine and that the difference in respect to other antipsychotics is due to the contribution of other receptor interactions. Considering the dopaminergic receptor, in particular the recently discovered D4 receptor subtype, it has been observed that even if several classical neuroleptics exhibit high affinity to the D4 receptor, clozapine is more selective for this subtype compared to D2 receptors. Moreover clozapine, differently from all other conventional neuroleptics, is a mixed but weak D1/D2 antagonist. This observation has prompted speculation that the synergism between D1 and D2 receptors might allow antipsychotic effects to be achieved below the threshold for unwanted motor side effects. Probably the D1 antagonistic activity exerted by clozapine at low doses enhances preferentially the extracellular concentration of dopamine in specific areas of the brain, such as the prefrontal cortex, where a dopaminergic hypoactivity has been suggested to be in part responsible for negative symptoms of schizophrenia. The clozapine enhancement of dopam

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Dopamine; Humans; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia

Clozapine (Clozaril) represents the first major advance in the pharmacological treatment of schizophrenia since the introduction of antipsychotics into clinical practice in the 1950s. Studies consistently support its efficacy for reducing positive symptoms in acutely psychotic patients and in treatment-resistant patients, for preventing positive symptom exacerbations as a maintenance treatment, and for reducing symptoms of hostility and violence. There is evidence to suggest that clozapine may improve social and occupational functioning and quality of life and may reduce affective symptoms, hospitalizations, secondary negative symptoms, and tardive dyskinesia. Its most significant side effects include agranulocytosis, seizures, weight gain, hypotension and tachycardia, sedation, and perhaps rebound psychosis (with abrupt discontinuation of medication).

Topics: Antipsychotic Agents; Clozapine; Humans; Psychiatric Status Rating Scales; Rehabilitation, Vocational; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Treatment Outcome

Clozapine's effectiveness in reducing symptoms and facilitating discharge among patients with chronic schizophrenia who were resistant to neuroleptics was studied.. All 169 such patients in a public psychiatric hospital were given clozapine. BPRS ratings (0-5 scale) were completed before treatment and 21 months later. Patients were followed for about 2.5 years.. Clozapine was discontinued in 37.8% of cases due to non-compliance, non-response, or side-effects. At follow-up 41% of clozapine recipients and 25.9% of the drop-outs were discharged and remained so, and 33% of recipients and 24.1% of drop-outs were being prepared for discharge. Longer treatment was associated with more improvement. Decline in average BPRS total scores of recipients was significantly more than drop-outs (32.7, s.d. 16.8 v. 12.1, s.d. 14.1, d.f. = 155, t = 7.5, P = 0.000).. Clozapine appears to be effective for treating some chronic neuroleptic nonresponding schizophrenic patients.

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Chronic Disease; Clozapine; Drug Resistance; Hospitalization; Humans; Middle Aged; Schizophrenia; Treatment Outcome

The published case reports of clozapine-induced neuroleptic malignant syndrome (NMS) are reviewed, to which the authors add three, and possibly four, new cases seen in Australia, occurring in and estimated 1,250 patients exposed to the drug. The review suggests that typical NMS does occur with clozapine and that its incidence may be as common as with the classic neuroleptics. The features of clozapine-induced NMS may be somewhat different, with fewer extrapyramidal side effects and a lower rise in creatine kinase levels. The occurrence of NMS with clozapine raises important issues with regard to our understanding of the pathophysiology of the syndrome.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Australia; Child; Clozapine; Creatine Kinase; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Neurologic Examination; Schizophrenia

Topics: Antipsychotic Agents; Brain; Clozapine; Dyskinesia, Drug-Induced; Extrapyramidal Tracts; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine; Receptors, Serotonin; Remoxipride; Risperidone; Schizophrenia; Schizophrenic Psychology

Clozapine has proved effective in alleviating a wide range of psychiatric symptoms in schizophrenia. Its effects on cognitive function in schizophrenia are more variable. Clozapine appears to have a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions. This profile may be related to the affinity of clozapine for dopaminergic type I and muscarinic receptors and relative lack of affinity for dopaminergic type II receptors.

Topics: Clozapine; Cognition; Cognition Disorders; Dopamine; Humans; Isoxazoles; Neuropsychological Tests; Piperidines; Receptors, Dopamine; Receptors, Muscarinic; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Traditional antipsychotic medications have targeted the dopamine system. Yet, the isolation and cloning of multiple dopamine receptor subtypes and the recognition of non-dopaminergic pathways (for example, serotonin) in schizophrenia have led to the development of new pharmacological strategies in pharmacotherapy. The author summarizes recent biochemical and pharmacological data and the clinical experience with novel antischizophrenic compounds.

Topics: Antipsychotic Agents; Brain; Clozapine; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology

The major advance in the psychopharmacology of schizophrenia has been the rediscovery of clozapine and the development of other novel antipsychotic drugs, all of which are superior to typical neuroleptic drugs with regard to extrapyramidal symptoms. Clozapine, the best studied of these agents, is also superior in efficacy with regard to psychopathology and cognitive function and has been shown not to cause tardive dyskinesia. A variety of other novel agents, e.g., risperidone, olanazpine, amperozide, seroquel, sertindole, zaprisidone and melperone, must be further studied to establish their efficacy relative to clozapine or the typical neuroleptics, or both. It is likely that these novel agents will displace the typical neuroleptic drugs as the primary treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Dopamine; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Clozapine, risperidone and remoxipride are three neuroleptics that represent an interesting alternative in the psychopharmacological treatment of schizophrenia. Pharmacodynamic and pharmacokinetic properties, efficacy, dosages as well as the indication of these three substances are studied. In certain particular situations, a complementary treatment is of important therapeutic use, the addition of benzodiazepines, lithium, carbamazepine or beta-blockers are discussed.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Isoxazoles; Piperidines; Psychotropic Drugs; Remoxipride; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Anticonvulsants; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Generalized; Humans; Prognosis; Schizophrenia; Schizophrenic Psychology

Clozapine-treatment of schizophrenic psychoses under observation of the producer's directions regarding indication, warnings, information of the patient and control-examinations is no measure which entails (according to section 1904 of German Civil Code-"Betreuungsrecht") the existing risk that the person concerned will die or suffer a serious or lasting health-injury. Therefore, in case of patient's inability to consent, the curator's approval after proper information is regarded to be sufficient in most cases of an intended treatment with clozapine. An approval by the Guardianship Court according to section 1904 should be applied for when--because of medical reasons after evaluating risks and benefits--clozapine-treatment is taken into consideration despite risks and contraindications according to the producer's informations.

Topics: Antipsychotic Agents; Clozapine; Germany; Humans; Informed Consent; Patient Education as Topic; Risk Factors; Schizophrenia; Schizophrenic Psychology

Although antipsychotic drugs are the mainstay of treatment in older patients with schizophrenia, much of the theoretical work underpinning their use is based on evidence gained from younger patients. With respect to dosages, there has been little work comparing plasma concentrations of antipsychotics in older patients with those of younger patients. However, there are well documented changes in the pharmacokinetics of these drugs in the elderly, particularly in their hepatic metabolism and renal excretion. There is also evidence that older patients experience more adverse effects from antipsychotics than younger patients. Such effects include extrapyramidal symptoms, postural hypotension and falls. For these reasons it is recommended that starting doses of antipsychotic drugs in older patients should be in the region of 25 to 50% of that recommended for younger patients, and should be slowly increased. Selection of a particular antipsychotic agent is best made on the basis of individual patient characteristics and the adverse effect profiles of particular drugs.

Topics: Aged; Aging; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Drug Prescriptions; Dyskinesia, Drug-Induced; Dystonia; Humans; Parkinson Disease, Secondary; Schizophrenia

The development of antipsychotic drugs has followed two complementary approaches, either towards highly specific actions (e.g. on the dopamine receptor) or targeting a broad range of receptors. The properties of 'atypical' agents challenge the original dopamine hypothesis and suggest roles for a variety of dopamine receptors and for other pathways, such as serotonin. Older drugs, despite their proven efficacy in relieving many schizophrenic symptoms, have several drawbacks, being ineffective in some patients, relatively ineffective against negative symptoms, and causing adverse neurological effects which may, in turn, be associated with poor compliance. Among newer agents, currently available ones, such as clozapine and risperidone, offer the possibility of more effective control of negative symptoms and an improved side-effect profile, while others are in earlier stages of development. However, much still remains to be understood about their mechanisms of action.

Topics: Agranulocytosis; Anemia, Aplastic; Antipsychotic Agents; Brain; Clozapine; Humans; Neurologic Examination; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Dopamine Antagonists; Humans; Receptors, Dopamine; Schizophrenia

Because of its superior clinical efficacy, clozapine is considered the new "reference" antipsychotic agent. Currently, there is an intensive investigational effort attempting to delineate which of clozapine's many biochemical effects are important for its impressive clinical profile. In this paper, the effects of clozapine on noradrenergic function are examined. Preclinical and clinical studies indicate that clozapine selectively increases noradrenergic activity and norepinephrine outflow. Moreover, data are presented demonstrating that clozapine causes fivefold increases in plasma norepinephrine in schizophrenic patients and that these increases are related to its superior clinical efficacy. A novel hypothesis for its superior efficacy is proposed that involves complex actions on noradrenergic systems that result in robust norepinephrine outflow. Implications of heightened norepinephrine outflow are discussed.

Topics: Animals; Brain; Clozapine; Haloperidol; Humans; Norepinephrine; Rats; Receptors, Adrenergic; Schizophrenia; Treatment Outcome

Seizures are an important adverse effect of clozapine therapy; a cumulative 10% risk of tonic-clonic seizures is estimated after 3.8 years of treatment. Although the risk of seizures may be increased by rapid upward titration and higher doses, recent data do not clearly confirm the dose-dependent effect. The vast majority of clozapine-related seizures are tonic-clonic, although myoclonic seizures also occur. The role of the EEG in predicting the occurrence of clozapine-induced seizures remains uncertain. In patients with clozapine-related seizures, either reducing the dose or adding an antiepileptic medication usually allows continuation of therapy.

Topics: Anticonvulsants; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Tonic-Clonic; Humans; Incidence; Risk Factors; Schizophrenia

A pharmacoeconomic analysis of clozapine is of particular importance because clozapine has a unique profile of benefits, risks, and costs relative to typical neuroleptic drugs and because it is currently approved for use in only two populations, i.e., neuroleptic-resistant and neuroleptic-intolerant schizophrenic patients, although it has also been found to be useful in a variety of other indications, e.g., refractory bipolar patients.. The three studies of the primary data relevant to a pharmacoeconomic analysis of clozapine in the treatment of schizophrenia were reviewed.. The results suggest that clozapine as a treatment of neuroleptic-resistant schizophrenia leads to better outcome and lower costs in treatment-resistant patients compared with typical neuroleptic drugs because of decreased hospitalization, even when the costs associated with dropouts from clozapine are included. No pharmacoeconomic data are available for other indications of clozapine.. Clozapine has been found to produce superior outcome compared with prior treatment with typical neuroleptic drugs in neuroleptic-resistant patients in dimensions that can be readily transformed into cost-utility measures such as decreased psychopathology, improved cognition, decreased rehospitalization, decreased suicide attempts, and better work function. If the frequency of hospitalization of patients has been appreciable, and dropouts from clozapine are in the range of 30% to 50% and occur within 1 to 4 months of starting treatment, it is likely that clozapine will be a cost-effective treatment. Cost-effectiveness studies comparing clozapine with standard treatments are needed for each application of clozapine, including use in neuroleptic-intolerant patients.

Topics: Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Drug Costs; Hospitalization; Humans; Schizophrenia; Treatment Outcome

Several lines of evidence, including the effect of antipsychotic drugs on neurotensin-containing neurons, have implicated the neurotensin system in the mechanism of action of antipsychotic drugs. Thus far, all clinically efficacious antipsychotics have been found to increase neurotensin concentrations in the nucleus accumbens; "typical" antipsychotic drugs increase neurotensin concentrations in both the nucleus accumbens and the caudate nucleus, whereas "atypical" antipsychotics increase neurotensin concentrations only in the nucleus accumbens. The effects of antipsychotic drugs on neurotensin-containing neurons in the nucleus accumbens may be predictive of clinical antipsychotic efficacy whereas the effects on neurotensin in the caudate nucleus may be predictive of extrapyramidal side effects. In addition to this evidence that antipsychotic drugs may act at least in part on neurotensin-containing neurons to produce their clinical effects is a considerable data base indicating that there are alterations in neurotensin-containing neurons in schizophrenia.

Topics: Animals; Antipsychotic Agents; Caudate Nucleus; Clozapine; Haloperidol; Humans; Neurotensin; Nucleus Accumbens; Rats; Receptors, Neurotensin; Schizophrenia

The focus of this article will be on toxic symptoms associated with blockade of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. We have been studying two parallel phenomena: NMDA-antagonist neurotoxicity (NAN) in rats and NMDA-antagonist psychotogenicity (NAP) in humans. These phenomena have a common denominator--NMDA receptor hypofunction, which is putatively a mechanism operative in schizophrenia. We have found that the NAN reaction in rats can be prevented by specific drugs that prevent NAP in humans and by certain antipsychotic agents, including clozapine, that ameliorate symptoms in schizophrenia. By studying mechanisms by which clozapine prevents the NAN reaction in rats, we hope to gain insight into mechanisms by which clozapine or other atypical antipsychotics ameliorate symptoms in schizophrenia.

Topics: Adolescent; Adult; Animals; Clozapine; Excitatory Amino Acid Agonists; Humans; Psychoses, Substance-Induced; Rats; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Clozapine has multiple clinical advantages that differentiate it from typical neuroleptics but that it may share with other novel antipsychotic drugs such as risperidone and olanzapine. There may be more than one pharmacologic feature that contributes to its advantages in improving psychopathology, cognition, affect, tardive dyskinesia, etc. Clozapine has < 10 nM affinity for the serotonin (5-HT)2A, 5-HT2C, 5-HT6, 5-HT7, D4, m1, and alpha 1-adrenergic receptor but weak affinity for the D2 receptor. Current evidence suggests the 5-HT2A and D4 receptor antagonist properties of clozapine, together with its weak D2 blocking properties, contribute the most to its advantages and should be sought in drug development programs. However, the other effects of clozapine may also be contributory. Clozapine is effective in a variety of conditions and at a range of plasma levels. The effects that are important in various indications may differ.

Topics: Animals; Clozapine; Humans; Rats; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia

Studies of brain morphology in schizophrenia may be informative about basic pathophysiologic processes, provide clinically useful indicators of treatment response, and lead to the identification of markers for selective treatment effects. This paper reviews findings from magnetic resonance imaging studies of patients with schizophrenia conducted at Hillside Hospital, with special attention to (1) findings that have helped distinguish patients who respond well to typical neuroleptics from those who have gone on to trials of clozapine, (2) the capacity of morphological measures to predict clozapine treatment response, and (3) the possibility that selective hypertrophy of striatal structure may be caused by chronic treatment with typical neuroleptics, but not by clozapine.

Topics: Atrophy; Basal Ganglia; Brain; Clozapine; Corpus Striatum; Humans; Magnetic Resonance Imaging; Schizophrenia

Cognitive dysfunction may underlie some of the psychopathology of schizophrenia as well as contribute to impaired social and vocational function in this disorder. Chronic treatment with typical neuroleptics has been reported to produce only minimal improvement in and may impair cognitive function in schizophrenia. We have studied the effect of clozapine, an atypical antipsychotic drug, on cognitive function in 36 patients with treatment-resistant schizophrenia. In addition, patients with non-treatment-resistant schizophrenia were randomly assigned to clozapine (N = 24) or typical neuroleptics (N = 23). Cognitive function in the treatment-resistant schizophrenia group was studied after 6 weeks and 6 months of treatment, while the non-treatment-resistant patients were also studied at 12 months of treatment. Clozapine treatment improved several domains of cognitive function, especially attention and verbal fluency in both treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. On the other hand, typical neuroleptic treatment produced minimal improvement in cognitive function. The effect of clozapine on some tests of attention and verbal fluency was significantly greater than that of typical neuroleptic treatment in non-treatment-resistant schizophrenia. These data suggest that clozapine treatment was superior to typical neuroleptics in improving cognitive function in schizophrenia. The possibility that this is related to normalization of dopaminergic function by clozapine is discussed.

Topics: Antipsychotic Agents; Clozapine; Cognition Disorders; Dopamine; Humans; Neuropsychological Tests; Psychiatric Status Rating Scales; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Word Association Tests

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine Antagonists; Gene Expression Regulation; Humans; Polymorphism, Genetic; Rats; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; RNA, Messenger; Schizophrenia

The introduction of neuroleptics over 40 years ago was a landmark in medical history. Although effective, antipsychotics have many side-effects, some severe. Because of the great needs in this therapeutic area, there has been a risk of viewing the introduction of new agents such as clozapine as panaceas. The true advantages of the new atypical neuroleptics need to be assessed realistically, by critically evaluating their effects on positive and negative symptomatology, potential adverse effects and cost benefit. Due in part to the toxic effects of neuroleptics, obtaining consent to treatment is fraught with complexities of a legal and ethical nature. However, despite the many burdensome aspects of this disease, including the high risk of suicide among patients, clinicians should foster patients insight and a collaborative approach to coping with schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Ethics, Medical; Humans; Informed Consent; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

A number of new agents to treat schizophrenia have been, or will soon be, introduced that address the limitations of traditional neuroleptics. The new class of atypical neuroleptics promises better efficacy and/or side-effects profiles, leading to improved overall clinical outcomes. However, in order to assess the potential clinical value of these new therapies, it is important not only to study the results of various clinical trials, but also to analyze the methodology and design of the trials themselves. An understanding of the relevant patient-related issues, outcome measures, pharmacological and non-pharmacological factors is necessary to apply the findings of clinical trials to daily clinical practice.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Isoxazoles; Neurologic Examination; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Despite the enormous benefits provided by antipsychotic medication in the management of schizophrenia, available compounds have serious limitations. Firstly, they are not always effective. Secondly, positive psychopathological symptoms may benefit more than negative or deficit symptoms. Thirdly, antipsychotics are generally associated with a variety of neurological adverse effects. Three drugs have recently been or are close to being introduced into widespread clinical use: clozapine, risperidone and remoxipride. Each of these compounds appears to have some advantages over traditional antipsychotic agents, particularly in terms of reduced propensity to induce adverse neurological effects. All three drugs have been shown to be clinically effective in large scale trials. Future clinical trials are required to establish their relative merits in comparison with one another.

Topics: Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Piperidines; Remoxipride; Risperidone; Schizophrenia; Treatment Outcome

Topics: Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Benzodiazepines; Carbamazepine; Clozapine; Drug Therapy, Combination; Humans; Lithium; Propranolol; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Dopamine; Female; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Serotonin; Serotonin Receptor Agonists

Clozapine is a great advance in the treatment of schizophrenia. It should be tried in any neuroleptic-resistant schizophrenic as well as some who are neuroleptic intolerant. If progress is made in controlling its agranulocytosis, clozapine could be the drug of choice for all types of schizophrenia and perhaps other conditions as well for which neuroleptic drugs are employed, e.g., mania resistant to mood stabilizers. Its advantage with regard to lower risk of tardive dyskinesia indicates that potent antipsychotic activity and liability to cause tardive dyskinesia can be dissociated. This must be the object of future antipsychotic drug development. Risperidone could be the next clozapine but at the time of this writing, there is too little data to pass judgment on this. Its low EPS profile and apparent effects on negative symptoms at lower doses are promising. Remoxipride may be useful because of its low EPS profile. How much better tolerated it is than currently available drugs, especially thioridazine, is not clear. Many other novel agents are being tested. Clinicians will be challenged to follow this emerging field closely and identify the most promising new agents that may be indicated for specific stages of, or subtypes of, schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Humans; Schizophrenia

Although antipsychotic drugs originally helped to discover dopamine receptors, the five dopamine receptors presently identified and cloned are facilitating the search for and discovery of more selective antipsychotic and antiparkinson drugs. The D1-like dopamine receptors, D1 and D5, are sensitive to the same drugs as the D1 receptor in native tissues, but D5 is about 10 times more sensitive to dopamine than D1. The D2-like receptors, D2, D3, and D4, have approximately similar sensitivities to dopamine, but bromocriptine and raclopride are both about two orders of magnitude weaker at D4, whereas clozapine is one order more potent at D4, as compared with D2 and D3. The human dopamine D4 receptor has many variants. The sensitivities to clozapine of human variants D4.2, D4.4, and D4.7 are approximately similar, with dissociation constants between 5 and 24 nM, matching the spinal fluid concentration of clozapine under therapeutic conditions. Thus antipsychotic action may be effected through blockade of either dopamine D2 or D4 receptors.

Topics: Animals; Antiparkinson Agents; Antipsychotic Agents; Brain; Clozapine; Humans; Parkinson Disease; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia

The pharmacologic treatment of the schizophrenic patient has remained substantively unchanged during the last 35 years. It is evident that as our knowledge of neuropharmacology has grown--the notion of schizophrenia being merely caused by a hyperdopaminergic state may be too simplistic. Multiple neurotransmitter systems may be involved in the manifestations of this illness. Conventional neuroleptics--the mainstay of antipsychotic treatment--have proved to be only partially effective and their untoward side effects have led to notorious patient noncompliance and iatrogenic morbidity. The demonstration that clozapine possesses both increased efficacy and reduced neurotoxicity, however, has forever altered the conventional wisdom that held all antipsychotics to be equally efficacious and uniformly neurotoxic. The pharmacologic legacy of clozapine promises to provide clinicians with biologic therapies that are at once safe, effective, and easy to administer.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Long-Term Care; Neurologic Examination; Schizophrenia; Schizophrenic Psychology

Topics: Brain; Brain Diseases; Clozapine; Corpus Striatum; Functional Laterality; Humans; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia

The side-effect profile of Clozapine (Leponex) plays a major role both from a negative and a positive perspective. Prevention and management of the most important and most frequent side-effects, of interest in daily patient practice, are primordial concerns. Additionally, attention is also paid to the question treatment and to potential problems with medication discontinuation.

Topics: Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Topics: Basal Ganglia Diseases; Clozapine; Humans; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists

Schizophrenia is the most prevalent of the major psychoses, but the underlying neurobiology of this debilitating disorder remains mysterious. Recent developments in molecular biology, neuroanatomic pathology, neurochemistry, and functional imaging suggest that a number of factors converge to produce schizophrenia. Specifically, an early neurodevelopmental "lesion," possibly within the mesial temporal lobe, may contribute to later temporolimbic-prefrontal dysfunction as the nervous system matures. Genetic factors appear to facilitate liability to schizophrenia, and dopaminergic and possibly other neurotransmitter systems may mediate clinical expression of the illness through newly recognized receptor subtypes.

Topics: Brain; Brain Diseases; Clozapine; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Neurobiology; Radiography; Receptors, Dopamine D2; Schizophrenia; Temporal Lobe

The introduction of clozapine has given clinicians a unique agent for treating patients with schizophrenia that is refractory to other neuroleptics. Despite its efficacy, the drug continues to be prescribed with trepidation due to the incidence of agranulocytosis. This article reviews the pharmacokinetic and pharmacological properties of clozapine and the clinical implications for monitoring plasma concentrations. Various assays have been developed for clozapine that include gas-liquid chromatography, radioimmunoassay and high performance liquid chromatography. Only a few studies have examined the pharmacokinetics of clozapine in patients with schizophrenia. These studies have revealed a wide interpatient variability in pharmacokinetic parameters that include: time to reach peak plasma concentrations 1.1 to 3.6h; elimination half-life 9.1 to 17.4h; clearance 8.7 to 53.3 L/h; and a volume of distribution of 1.6 to 7.3 L/kg. Clozapine is metabolised via the hepatic microsomal enzyme system into 2 principle metabolites: demethyl-clozapine and clozapine N-oxide. Urine samples have reported the ratio of clozapine:demethyl:N-oxide to be 1:1:2. The clozapine N-oxide binding affinity with 3H-haloperidol was 4 times lower than clozapine and its conversion back to clozapine is hypothesised. Although the exact pharmacological mechanism of action of clozapine is not fully understood, the drug does possess significant binding affinity for different dopamine receptors, with recent evidence supporting binding to the D4 receptor subtype. Clozapine transiently increases serum prolactin levels with minimal changes in homovanillic acid plasma levels. Limited studies investigating the relationship between clinical response and plasma clozapine concentrations have investigated the range between 100 and 800 micrograms/L. In the treatment of patients with refractory schizophrenia, a minimum concentration of 350 micrograms/L was suggested as needed. The occurrence of agranulocytosis could have a genetic basis and patients should be rigorously monitored during treatment. The incidence of tardive dyskinesia and extrapyramidal side effects is minimal. Clozapine can lower the seizure threshold in a dose- and time-dependent manner. Careful patient selection and monitoring are required when clozapine therapy is used in patients with schizophrenia.

Topics: Clozapine; Humans; Schizophrenia

The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

Topics: Adult; Brain; Catecholamines; Clozapine; Dose-Response Relationship, Drug; Female; Homovanillic Acid; Humans; Longitudinal Studies; Male; Methoxyhydroxyphenylglycol; Psychiatric Status Rating Scales; Schizophrenia

Essential fatty acids (EFAs) and their eicosanoid derivatives are important constituents of the brain and regulators of neuronal function. There is direct and indirect evidence of impaired metabolism of prostaglandin (PG)E1 in schizophrenia. There is also direct evidence of abnormal EFA biochemistry with plasma phospholipids from five populations and brain phospholipids from another all showing reduced levels of linoleic acid and elevated levels of 22-carbon EFAs of both n-6 and n-3 series. Clinical trials of PGE1 and of the PGE1 precursors, gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA) have shown modest therapeutic effects. In view of lack of therapeutic process involving drugs based on the dopamine concept of schizophrenia, it is time for new approaches based on the EFA/PG concept to be evaluated thoroughly.

Topics: Alprostadil; Brain Chemistry; Clozapine; Diabetes Complications; Dietary Fats; Dopamine; Double-Blind Method; Dyskinesia, Drug-Induced; Eicosanoids; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linolenic Acids; Niacin; Phospholipids; Schizophrenia

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Schizophrenia

The ability to use pharmacological treatment for schizophrenia is progressing in a most efficacious fashion, while the risk of adverse effects is declining. An important reevaluation of minimal effective antipsychotic drug dosages for both acute and extended treatment has taken place. Clozapine has provided clinical practitioners with a useful new alternative for treatment-refractory patients, and new research has helped clarify the role of different maintenance and prophylactic medication strategies. The author summarizes recent progress in these areas.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Humans; Schizophrenia; Schizophrenic Psychology

The practice of pharmacotherapy of schizophrenia in Germany is based both on clinical experience and research findings. Experience and studies emphasize that neuroleptic medication is severely limited by side effects including acute extrapyramidal syndromes and tardive dyskinesia. Comparing neuroleptic doses in both acute and maintenance therapy have clinicians encouraged to evaluate methods for treating patients with the lowest effective dose. Other studies have shown that the plasma level may be helpful when deciding which is the best treatment for the illness. More precise results for determining the optimum dose of antipsychotic compounds in the future may be available from positron emission tomography (PET), and from fluorine-magnetic-resonance spectroscopy (FMRS). The management of patients whose illness are refractory to conventional neuroleptics is also discussed. Benzamides and clozapine, both atypical neuroleptics, may be more effective than other available compounds for the severely ill, or for patients who are unable to tolerate the neurological side effects of typical neuroleptics.

Topics: Antipsychotic Agents; Clinical Protocols; Clozapine; Depression; Drug Therapy, Combination; Germany; Humans; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

The treatment and management of neuroleptic-resistant schizophrenic patients, who comprise 5 to 25 percent of all patients with that diagnosis, are major problems for psychiatry. In addition, another large group of schizophrenic patients, perhaps 5 to 20 percent, are intolerant of therapeutic dosages of neuroleptic drugs because of extrapyramidal symptoms, including akathisia, parkinsonism, and tardive dyskinesia. Because about 60 percent of neuroleptic-resistant schizophrenic patients respond to clozapine and a large percentage of neuroleptic-intolerant patients are able to tolerate clozapine, it should be considered the treatment of choice for such patients until other therapies are proven to be superior. A trial of clozapine alone should usually be continued for up to 6 months before it is terminated or supplemental agents are tried. Plasma levels of clozapine may be useful to guide dosage. The major side effects of clozapine are granulocytopenia or agranulocytosis (1%-2%) and a dose-related increase in the incidence of generalized seizures. Psychosocial treatments such as education of the patient and the family about the nature of the illness, rehabilitation programs, social skills training, and assistance in housing are generally needed to obtain optimal benefit from clozapine, as with other somatic therapies. If clozapine is unavailable, unacceptable, or not tolerated, a variety of approaches may be employed to supplement typical antipsychotic drugs for patients who do not respond adequately to these agents alone. These include lithium; electroconvulsive therapy; carbamazepine or valproic acid; benzodiazepines; antidepressant drugs; reserpine; L-dopa and amphetamine; opioid drugs; calcium channel blockers; and miscellaneous other pharmacologic approaches. The evidence for the efficacy of these ancillary somatic therapies in treatment-resistant patients is relatively weak. Polypharmacy should be tried only for discrete periods and with clear goals. If these are not achieved, supplemental medications should be discontinued. Psychosurgery is not a recommended alternative at this time.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Studies published since 1988 describing the treatment of schizophrenia are reviewed. Antipsychotic agents play a dominant role in treatment, but, except for clozapine, no one drug has been proved more effective than any other. Ineffective medication and medication noncompliance may contribute to apparent treatment resistance. Used in conjunction with drug treatment, supportive psychotherapy that incorporates social skills training appears to be useful. Environmental interventions such as supervised housing and work with families appear to help patients function better in the community and avoid relapse. Trials of new antipsychotic agents and improved understanding of the neurochemistry of schizophrenia offer hope that improved therapies will become available.

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Humans; Psychotherapy; Schizophrenia; Schizophrenic Psychology; Social Environment

This paper reviews the epidemiology and pathogenesis of clozapine-associated agranulocytosis. According to present clinical experience, granulocytopenia can be expected in approximately 3% of patients during clozapine treatment. The risk of serious sequelae of granulocytopenia can be minimised by regular white blood cell count monitoring. Although research suggests that some patient groups may be at higher risk of developing this serious adverse reaction, we cannot yet predict the susceptible patients, so all patients exposed to clozapine should receive regular blood monitoring throughout treatment. Because of the risk of agranulocytosis, clozapine should only be used in schizophrenic patients who are resistant to, or intolerant of, conventional antipsychotic medications. Unless compliance with blood monitoring is assured, clozapine treatment should not be recommended.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Female; Humans; Leukocyte Count; Male; Schizophrenia

The treatment of patients with schizophrenia who fail to respond to antipsychotic medications remains a challenge. Despite numerous attempts to establish effective somatic treatment approaches for this population, clozapine appears to be the only well established alternative. Depending upon trial duration and response criteria, between 30% and 60% of previously unresponsive patients appear to derive clinically significant benefit from clozapine. Clozapine also has important advantages in terms of its reduced propensity to produce extrapyramidal side-effects. Agranulocytosis remains an important risk, so strategies to improve the benefit-to-risk ratio should be explored. Issues such as trial duration, dosage, blood levels and predictors of response require additional study.

Topics: Agranulocytosis; Basal Ganglia Diseases; Clozapine; Female; Humans; Male; Schizophrenia; Schizophrenic Psychology

Various outcome measures following clozapine administration to neuroleptic-resistant schizophrenic patients are considered. The importance of a multidimensional perspective is emphasised. There was significant improvement in positive symptoms, some negative symptoms, quality of life, some types of cognitive function (e.g. semantic memory), extrapyramidal function, and tardive dyskinesia. Readmission to hospital, and family burden were markedly reduced, which achieved significant savings in the cost of treatment. Compliance with clozapine and weekly blood testing can be achieved in the majority of treatment-resistant cases. These benefits may occur independently of each other.

Topics: Adult; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Patient Compliance; Patient Readmission; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

For over a decade it has been generally assumed that all the pharmacological and biochemical actions of dopamine within the central nervous system and periphery were mediated by two distinct dopamine receptors. These receptors, termed D1 and D2, were defined as those coupled to the stimulation or inhibition of adenylate cyclase, respectively, and by their selectivity and avidity for various drugs and compounds. The concept that two dopamine receptors were sufficient to account for all the effects mediated by dopamine was an oversimplification. Recent molecular biological studies have identified five distinct genes which encode at least eight functional dopamine receptors. The members of the expanded dopamine receptor family, however, can still be codifed by way of the original D1 and D2 receptor dichotomy. These include two genes encoding dopamine D1-like receptors (D1 [D1A]/D5 [D1B]) and three genes encoding D2-like receptors (D2/D3/D4). We review here our recent work on the cloning and characterization of some of the members of the dopamine receptor gene family (D1, D2, D4, D5), their relationship to neuropsychiatric disorders and their potential role in antipsychotic drug action.

Topics: Amino Acid Sequence; Animals; Brain; Cloning, Molecular; Clozapine; Dopamine; Humans; Molecular Sequence Data; Receptors, Dopamine; RNA, Messenger; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Double-Blind Method; Humans; Schizophrenia

Clozapine is a neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has been classified as an atypical neuroleptic drug due to its unique neuropharmacologic profile. Clozapine has a weak binding affinity for dopamine D-1 and D-2 receptors by its slightly greater preference for D-1 receptors, as noted with a D-1:D-2 receptor binding ratio of 1.3. Other neuroreceptors are involved, as the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2. Clozapine also has antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. Electrophysiologic studies show that it differs from other typical neuroleptics in that its actions appear to be specific for the cortical-limbic dopamine A-10 tract. In animal paradigms, in contrast to typical neuroleptics, clozapine did not produce catalepsy and had only transient effects in antagonizing other dopamine agonists. The drug is rapidly absorbed orally with a bioavailability of 0.27. After a single oral dose the elimination half-life was approximately 8-10 hours, but with several doses it increased to 14.1 hours. The agent is extensively metabolized by hepatic microsomal enzymes that forms the N-desmethyl and N-oxide metabolites. It is an effective neuroleptic that has been studied in short-term and long-term clinical trials, and multicenter trials. Clozapine was superior to chlorpromazine in the treatment of refractory schizophrenia that failed to respond to previous neuroleptic therapy. Reports of extrapyramidal side effects are minimal, and no case reports of tardive dyskinesia have been published. Indeed, clozapine has been used to treat tardive dyskinesia and other movement disorders. Agranulocytosis is the major adverse effect and its prevalence appears to differ among various ethnic groups. Other adverse effects that have been reported include hypersalivation, orthostatic hypotension, and constipation. Clozapine can lower the seizure threshold in a dose-dependent manner. The drug represents a significant advancement in the treatment of mental illness.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Evaluation; Dyskinesia, Drug-Induced; Humans; Receptors, Dopamine; Schizophrenia

Many patients with schizophrenia continue to have significant disabling symptoms despite adequate trials of different types and doses of traditional neuroleptics. Clinicians treating these neuroleptic-resistant patients must look to other treatments in the hope of providing some relief. The literature on many of the alternative treatments is too scanty for firm conclusions. We offer criteria for deciding which treatments may warrant consideration. We review the evidence for the eight treatments we found to meet these criteria and discuss clinical points salient to their use in this population. Although not always conclusive, the data do offer clues for treatment guidelines and an approach to choosing among the available treatments is suggested.

Topics: Anti-Anxiety Agents; Antipsychotic Agents; Benzodiazepines; Carbamazepine; Clozapine; Double-Blind Method; Electroconvulsive Therapy; Humans; Levodopa; Lithium; Propranolol; Reserpine; Schizophrenia

Last year's introduction of clozapine, an atypical antipsychotic, in the United States was the most significant advance in schizoprenia treatment since the advent of chlopromazine in the 1950s. However, clozapine has a disturbingly high incidence of agranulocytosis. The drug manufacturer designed a complex and expensive mandatory blood monitoring system that was dismantled after public pressure earlier this year. There is hope that clozapine will become more widely available to schizoprenic patients.

Topics: Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Topics: Clozapine; Humans; Loxapine; Schizophrenia

Topics: Clozapine; Humans; Schizophrenia

Clozapine (CLOZ) is an atypical antipsychotic drug being used with increasing frequency throughout the world and has recently been commercially marketed in the United States. Its unique properties make it a promising but challenging drug to use in the treatment of schizophrenia. In order to use CLOZ most effectively and efficiently, clinicians must be aware of its potential benefits and risks. This report is a review and critical evaluation of current knowledge regarding the clinical efficacy and side effects of CLOZ. Although CLOZ has proven to be effective in some treatment-refractory schizophrenic patients and to produce relatively few extrapyramidal side effects compared to classical neuroleptic drugs, several issues require further investigation including what defines neuroleptic intolerance, the optimal dose range, and the appropriate duration of a CLOZ treatment trial. Similarly, studies are needed to determine what role CLOZ should have in the treatment of patients with predominantly negative symptoms and those patients who are only partially responsive to standard neuroleptics. In addition, important questions remain as to what other conditions might be indications for CLOZ, for example, schizoaffective disorder, affective psychoses, and idiopathic Parkinson's disease.

Topics: Agranulocytosis; Basal Ganglia Diseases; Clozapine; Humans; Nervous System; Schizophrenia

Topics: Clozapine; Dizziness; Dopamine Antagonists; Fatigue; Humans; Schizophrenia; Serotonin Antagonists

Clozapine offers several very distinct clinical advantages, namely a therapeutic profile that appears to be superior to typical neuroleptic agents. This is particularly true in otherwise treatment refractory schizophrenics. Unfortunately, not all schizophrenic patients respond to clozapine therapy. The second major advantage of clozapine is its paucity of acute neurological effects and its apparent unlikelihood to produce tardive dyskinesia. The clinical benefits of clozapine must be weighed against the risk of cardiovascular side-effects that can occur with too rapid a titration, and the possibility of AGC. Given the fact that careful titration of dosage and white blood cell count monitoring can easily be used to avoid the serious side-effects of clozapine, it would appear that the clinical advantages of this medication clearly outweigh its risks.

Topics: Clozapine; Humans; Schizophrenia

Clozapine holds great clinical promise for some chronic schizophrenic patients. However, limitations on access to the drug by the largest subgroup who need it, the indigent, are causing frustration for patients, their families, physicians, and public-sector mental health systems. The drug is available only through the manufacturer's proprietary monitoring system; many public-sector professionals and agencies feel that the system is overpriced, is unfairly exclusive, and has thus far kept the drug out of reach of most patients who need it. Arguments that patient improvement will lead to dollar savings in the long run seem overly optimistic. The ethical issue of access to treatment remains. The author discusses these and related issues and reports early experience from several public mental health systems.

Topics: Agranulocytosis; Chronic Disease; Clozapine; Cost-Benefit Analysis; Dibenzazepines; Health Services Accessibility; Humans; Medicaid; Medical Indigency; Risk Factors; Schizophrenia; Schizophrenic Psychology; United States

Topics: Clozapine; Community Pharmacy Services; Humans; Medication Systems; Monitoring, Physiologic; Schizophrenia; United States

Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug's wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics.

Topics: Clozapine; Humans; Schizophrenia; Schizophrenic Psychology

Clozapine can produce greater clinical improvement in both positive and negative symptoms than typical antipsychotic drugs in neuroleptic-resistant schizophrenic patients. The clinical response may occur rapidly in some patients but is delayed in others. Clozapine has also been reported to produce fewer parkinsonian symptoms, to involve a lower risk of producing tardive dyskinesia, and to produce no serum prolactin elevations in man. It seems likely that these effects are the result of a common biological mechanism or related mechanisms, rather than unrelated effects. Other atypical antipsychotic drugs, such as melperone and fluperlapine, share at least some of these properties. A relatively low affinity for the D-2 dopamine (DA) receptor and high affinity for the 5-HT2 receptor, producing a high 5-HT2/D-2 ratio, best distinguishes atypical antipsychotics like clozapine from typical antipsychotic drugs. Through its weak antagonist action on D-2DA receptors and a potent inhibitory effect on 5-HT2 receptors, as well as its ability to increase DA and 5-HT2 release, clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions. The numerous advantages of clozapine over typical neuroleptics are consistent with the primary importance of DA to the pathophysiology of schizophrenia. The secondary but still significant role of 5-HT in the action of clozapine may either be direct or via the effect of 5-HT on dopaminergic mechanisms. Some aspects of schizophrenia could be due to a dysregulation of the interaction between serotonergic and dopaminergic neurotransmission.

Topics: Antipsychotic Agents; Clozapine; Dibenzazepines; Humans; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists

Neuroleptic drugs remain a critical component of the treatment of schizophrenia. Although their use in other conditions such as bipolar disorders and organic mental disorders is also widespread, further research is necessary to validate specific indications and to assess benefit-to-risk ratios. In recent years substantial attention has been focused on establishing minimum effective dosage requirements for both acute and long-term treatment of schizophrenia. Considerable progress has been made in this area. In addition, alternative maintenance-treatment strategies such as targeted or intermittent neuroleptic therapy have been studied. The management of patients who fail to respond to an adequate trial (or trials) of neuroleptic drugs continues to be an enormous clinical challenge. Few data are available on which to base subsequent treatment decisions. Recent research with clozapine suggests that this compound may be helpful in some such individuals, but further efforts to establish other potentially effective treatment strategies for treatment-refractory patients should receive a high priority.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Schizophrenia

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed. Clozapine is a dibenzazepine compound chemically similar to loxapine but with a distinct pharmacologic profile. Unlike currently available medications, clozapine has a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity. It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors. Clozapine given orally is nearly completely absorbed and readily metabolized. Urinary excretion is the major route of metabolite elimination. Clozapine has been used to treat schizophrenia, nonschizophrenic psychotic states, depression, neuroses, and behavioral disorders. Double-blind comparative studies have shown clozapine to be superior to haloperidol, chlorpromazine, and placebo in treating the symptoms of schizophrenia, as measured with validated psychiatric rating scales. Adverse effects include orthostatic hypotension, tachycardia, benign hyperthermia, hypertension, seizures, and sedation. Many of these effects are transient. Because of the risk of agranulocytosis, a comprehensive case-management system has been developed. In treating acute psychosis, the optimum dosage of clozapine is 300-450 mg/day given orally in divided doses. The high cost of clozapine may be offset by improved patient response and reduced hospital costs. Clozapine may be superior to other agents in the treatment of refractory schizophrenia and is associated with a negligible incidence of extrapyramidal symptoms.

Topics: Antipsychotic Agents; Clozapine; Dibenzazepines; Humans; Schizophrenia

The concept of negative symptoms tries to operationalize a deficit syndrome observed in schizophrenia, but also in other disorders. The instruments for the measurement developed so far are unclear in their dimensional structure and validity. Further methodological development is needed. A new scale for measuring negative symptoms was derived from the AMDP-system and applied to results of drug trials with clozapine, fluperlapine, and haloperidol. The three drugs were equally effective on negative symptoms of acute and chronic schizophrenics.

Topics: Antipsychotic Agents; Clozapine; Humans; Prognosis; Schizophrenia; Schizophrenic Psychology

The so-far successful development of the atypical neuroleptic clozapine had been interrupted by the Finnish epidemic of agranulocytosis in 1975. However, though the strong regulatory control of prescribing clozapine, since then its clinical use has increased steadily, particularly recently. This may be due mainly to the considerable number of patients whose psychotic states or at least whose negative symptoms do not respond to other neuroleptics, or who have problems with extrapyramidal side effects. Due to its significant antipsychotic, and to its probable even if mild antidepressive efficacy as well as to its possible efficacy against some negative symptoms of schizophrenia, clozapine is currently a real and indispensable alternative to other existing neuroleptics. Further research should be directed both to the clinical validation of the latter mentioned therapeutically desired effects and to the causes and predictability of agranulocytosis, as yet the main risk of clozapine therapy. Theoretically profitable would be the clarification of the causes of hyperthermia and particularly of those of the mutual independency of extrapyramidal motor disturbances and antipsychotic efficacy.

Topics: Antipsychotic Agents; Clozapine; Dibenzazepines; Germany, West; Humans; Schizophrenia

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Schizophrenia; Time Factors

Clozapine is an antipsychotic without the extra-pyramidal adverse effects associated with currently marketed antipsychotics. In animals, this drug has not been shown to induce catalepsy and only weakly antagonizes the stereotypic movements induced by apomorphine and the amphetamines. Clozapine is rapidly absorbed after both single and repeated oral doses, with steady-state concentrations attained within eight to ten days after beginning therapy. It is metabolized to N-oxideclozapine and N-desmethylclozapine, which have less pharmacological activity than the parent compound and are excreted in the urine and, to a lesser extent, in the feces. Clozapine has overall therapeutic efficacy and/or superiority to currently marketed antipsychotics in the treatment of refractory schizophrenia. Usual doses (25-900 mg/d) of clozapine cause fewer extrapyramidal adverse reactions than available antipsychotics. Hypotension, dizziness, salivation, and sedation are the most frequently reported adverse effects and tend to subside over time. Agranulocytosis is the most serious adverse reaction, and those receiving clozapine should undergo weekly white blood cell count determinations. Clozapine is useful for those treatment-resistant patients who have not responded to adequate trials of other antipsychotics.

Topics: Clozapine; Dibenzazepines; Humans; Schizophrenia

The advent of antipsychotic drugs represented a milestone in psychotherapeutics. Despite their proven efficacy, antipsychotic drugs are limited by side effects and treatment resistance in some patients. Since the introduction of chlorpromazine and the subsequent development of numerous neuroleptic compounds, there have been no significant qualitative advances in the clinical efficacy of antipsychotic drugs. Clozapine is an experimental neuroleptic with atypical properties. In clinical testing, this agent has shown superior antipsychotic efficacy in treatment-refractory schizophrenics and a more favorable extrapyramidal side effect profile in comparison with standard neuroleptics. Because clozapine represents a potential contribution to our therapeutic armamentarium, this article provides an overview of its pharmacology, efficacy, and methods of clinical utilization.

Topics: Clinical Trials as Topic; Clozapine; Dibenzazepines; Humans; Informed Consent; Psychotic Disorders; Schizophrenia

Clozapine administration to schizophrenic patients was found to produce dopamine2 (D-2) and serotonin2 (5-HT2) receptor blockade, as evidenced by the ability to block the increases in growth hormone and cortisol secretion produced by apomorphine and MK-212, respectively, direct acting dopamine (DA) and 5-HT2 agonists. Clozapine did not increase plasma prolactin (PRL) levels nor did it block the apomorphine-induced decrease in plasma PRL concentration, as would be expected from a D-2 receptor antagonist. These PRL results are consistent with the observation that clozapine may increase DA release. Clozapine also decreased plasma tryptophan, plasma homovanillac acid (HVA) and basal plasma cortisol levels. Rodent studies suggest clozapine also increases 5-HT release. We hypothesize that antagonism of D-2 and 5-HT2 receptors and enhancement of DA and 5-HT release are critical elements in the action of clozapine to minimize both positive and negative symptoms without producing significant extrapyramidal symptoms or plasma PRL increases. It is proposed that schizophrenia may also involve a dysregulation of 5-HT2- and D-2-mediated neurotransmission, and that a more normal balance in serotonergic and dopaminergic neurotransmission is at least partially restored by clozapine.

Topics: Clozapine; Dibenzazepines; Dopamine; Humans; Schizophrenia; Serotonin

In Denmark, the use of clozapine has increased markedly (15-25% per year) since 1983, when the drug was relaunched--after its withdrawal in 1975. Several factors have contributed to this development: 1) the interesting pharmacology of clozapine, especially the atypical influence on dopamine transmission, including a relatively high D-1/D-2 receptor affinity ratio, 2) the potent anti-anxiety and anti-psychotic effect in severe and otherwise therapy-resistant psychotic patients, and 3) the lack of extrapyramidal side effects. A special monitoring form (for registration of total and differential leucocyte counts, ECG, body weight, drugs, doses and reason for possible withdrawal of the clozapine) is used in most Danish psychiatric institutions. This form secures the regular control of vital parameters and serves as an instrument for surveys of the use of clozapine in Denmark. Also, more selective studies are being carried out, e.g., on the effect of clozapine monotherapy versus combined therapy, and on the influence of clozapine on cardiovascular functions, including left ventricular output (echocardiography).

Topics: Clozapine; Denmark; Dibenzazepines; Humans; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dibenzazepines; Humans; Schizophrenia; United States

Topics: Antipsychotic Agents; Benzamides; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Metoclopramide; Prospective Studies; Schizophrenia; Sulpiride; Tiapamil Hydrochloride

Topics: Acetylcholine; Adrenergic beta-Antagonists; Aminobutyrates; Clozapine; Corpus Striatum; Dopamine; Globus Pallidus; Humans; Neurons; Nucleus Accumbens; Receptors, Neurotransmitter; Schizophrenia; Time Factors

Clozapine and olanzapine are some of the most effective antipsychotics, but both are associated with weight gain and relevant metabolic disturbances, including pre-diabetes and diabetes. Non-pharmacological/behavioural interventions have had limited effects counteracting these adverse effects. Semaglutide, a glucagon-like peptide 1 receptor agonist, is approved for the treatment of type 2 diabetes and obesity. We will investigate the long-term effects of add-on treatment with semaglutide once a week versus placebo once a week on the metabolic status in pre-diabetic (glycated haemoglobin A1c (HbA1c) 35-47 mmol/mol (5.4%-6.4%) and diabetic (HbA1c 48-57 mmol/mol (6.5%-7.4%)) patients diagnosed with a schizophrenia spectrum disorder who initiated clozapine or olanzapine treatment within the last 60 months.. This is a 26-week, double-blinded, randomised, placebo-controlled trial. Altogether, 104 patients diagnosed with a schizophrenia spectrum disorder, aged 18-65 years, with pre-diabetes or diabetes will be randomised to injections of 1.0 mg semaglutide once a week or placebo for 26 weeks. The primary endpoint is change from baseline in HbA1c. Secondary endpoints include changes in body weight, hip and waist circumference and plasma levels of insulin, glucagon, glucose, and C-peptide, insulin sensitivity, beta cell function, hepatic function, fibrosis-4 score, lipid profile, incretin hormones, bone markers, body composition, bone density, proteomic analyses and oxidative stress markers. Together with alcohol, tobacco and drug use, potential effects on the reward value of a sweet-fat stimulus, psychopathology, level of activity and quality of life will also be assessed.. This study is approved by the Danish Medicines Agency and the regional scientific ethics committee of the Capital Region of Denmark (committee C, #H-20019008) and will be carried out in accordance with International Council for Harmonisation Good Clinical Practice guidelines and the Helsinki Declaration. The results will be disseminated through peer-review publications and conference presentations.. NCT04892199.

Topics: Clozapine; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Olanzapine; Prediabetic State; Proteomics; Quality of Life; Randomized Controlled Trials as Topic; Schizophrenia

Quick symptomatic remission after the onset of psychotic symptoms is critical in schizophrenia treatment, determining the subsequent disease course and recovery. In this context, only every second patient with acute schizophrenia achieves symptomatic remission within three months of initiating antipsychotic treatment. The potential indication extension of clozapine-the most effective antipsychotic-to be introduced at an earlier stage (before treatment-resistance) is supported by several lines of evidence, but respective clinical trials are lacking.. Two hundred-twenty patients with acute non-treatment-resistant schizophrenia will be randomized in this double-blind, 8-week parallel-group multicentric trial to either clozapine or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end of week 8 according to international consensus criteria ('Andreasen criteria'). Secondary endpoints and other assessments comprise a comprehensive safety assessment (i. e., myocarditis screening), changes in psychopathology, global functioning, cognition, affective symptoms and quality of life, and patients' and relatives' views on treatment.. This multicentre trial aims to examine whether clozapine is more effective than a highly effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia patients who do not meet the criteria for treatment-naïve or treatment-resistant schizophrenia. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia can improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and long-term disease chronicity.

Topics: Antipsychotic Agents; Clozapine; Humans; Multicenter Studies as Topic; Olanzapine; Quality of Life; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

In treatment-resistant schizophrenia (TRS), Clozapine is only approved treatment with undesirable side-effects, warranting better alternatives. Our hypothesis is acute followed by maintenance Electroconvulsive Therapy (M-ECT) will be comparable in efficacy and safety to Clozapine in TRS.. In this open-label trial, 60 TRS patients were randomized equally to M-ECT (following an acute-course) or Clozapine. Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Schizophrenia Scale (CGI-SCH), Montreal Cognitive Assessment (MoCA), and Global assessment of functioning (GAF) were measured and compared within and between the groups at baseline, 6 weeks, 12 weeks, and 24 weeks. SPECT-CT brain was done at baseline and 24 weeks to compare the changes in regional cerebral perfusion between the groups and correlate with the changes in the outcome-measures.. The PANSS-T scores changes from baseline over the observation-points were significant in both M-ECT and clozapine groups (P < .001), with comparatively better reduction with M-ECT (P < .001). Similar trends were observed in PANSS subscales, CGI-SCH and GAF in both groups, with significantly better improvement with M-ECT over the study-period. After 24 weeks, there was significantly better perfusion with M-ECT in bilateral prefrontal and temporal cortices (P < .05). With M-ECT, a positive correlation was found between changes in PANSS-P scores and left-lateral Temporal cortical perfusion (r = .465, P = .017).. Acute followed by M-ECT was more effective than clozapine over 6 months in reducing the positive and negative symptoms, general psychopathology, illness-severity, and improving the global functionality in TRS [clinicaltrials.gov: NCT03807882].

Topics: Antipsychotic Agents; Cerebrovascular Circulation; Clozapine; Electroconvulsive Therapy; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant; Treatment Outcome

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC).. A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks.. NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26).. NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with "Australian and New Zealand Clinical Trials" on the 30 May, 2016 (Registration Number: ACTRN12615001273572).

Topics: Acetylcysteine; Antipsychotic Agents; Australia; Clozapine; Double-Blind Method; Humans; Quality of Life; Schizophrenia; Treatment Outcome

Although clozapine is an effective option for treatment-resistant schizophrenia (TRS), there are still 1/3 to 1/2 of TRS patients who do not respond to clozapine. The main purpose of this randomized, double-blind, placebo-controlled trial was to explore the amisulpride augmentation efficacy on the psychopathological symptoms and cognitive function of clozapine-resistant treatment-refractory schizophrenia (CTRS) patients.. A total of 80 patients were recruited and randomly assigned to receive initial clozapine plus amisulpride (amisulpride group) or clozapine plus placebo (placebo group). Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Clinical Global Impression (CGI) scale scores, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Treatment Emergent Symptom Scale (TESS), laboratory measurements, and electrocardiograms (ECG) were performed at baseline, at week 6, and week 12.. Compared with the placebo group, amisulpride group had a lower PANSS total score, positive subscore, and general psychopathology subscore at week 6 and week 12 (P. This study indicates that amisulpride augmentation therapy has important clinical significance for treating CTRS to improve clinical symptoms and cognitive function with tolerability and safety. Trial registration Clinicaltrials.gov identifier- NCT03652974. Registered August 31, 2018, https://clinicaltrials.gov/ct2/show/NCT03652974.

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Cognition; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant; Sulpiride

Treatment with antipsychotics is associated with an increased risk of type 2 diabetes mellitus (T2D), and increased levels of inflammatory biomarkers are present in patients with T2D. We previously demonstrated that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. This study aims to assess the involvement of cytokines in the therapeutic effects of liraglutide.. Serum concentrations of 10 cytokines (interferon-γ [IFN-γ], tumor necrosis factor-α, interleukin 1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13) from fasting prediabetic and normal glucose-tolerant (NGT) patients with schizophrenia-spectrum disorders were measured using multiplexed immunoassays. Prediabetic patients were randomized to 16 weeks of treatment with liraglutide or placebo, and cytokines were measured again at the end of the treatment.. IFN-γ (1.98 vs 1.17 pg/ml, P = .001), IL-4 (0.02 vs 0.01 pg/ml, P < .001), and IL-6 (0.73 vs 0.46 pg/ml, P < .001) were significantly higher in prediabetic (n = 77) vs NGT patients (n = 31). No significant changes in cytokine levels following treatment with liraglutide (n = 37) vs placebo (n = 40) were found.. Prediabetic vs NGT patients with schizophrenia treated with clozapine or olanzapine had increased serum levels of several proinflammatory cytokines, further substantiating the link between inflammation and T2D. Treatment with liraglutide did not affect the investigated cytokines. Further testing of these findings in larger numbers of individuals is needed.

Topics: Biomarkers; Clozapine; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Interleukin-4; Interleukin-6; Liraglutide; Olanzapine; Prediabetic State; Schizophrenia

Accumulated studies have investigated pharmacological interventions for first-episode schizophrenia (FES) patients. However, studies on subsequent treatment steps, which are essential to guide clinicians, are largely missing. This Sequential Multiple-Assignment Randomized Trials comparing Antipsychotic Treatments (SMART-CAT) program intends to evaluate the effectiveness of commonly used antipsychotic drugs in FES patients. The major goals of this study are to examine: 1) what would be the optimal subsequent sequential treatment if the first antipsychotic drug failed; 2) whether clozapine could be used in those first-trial failed and have superior efficacy compared to other atypical antipsychotics. In this article we will report the detail protocol of SMART-CAT. The SMART-CAT is a randomized controlled clinical multicenter trial in which 9 institutions in China will participate. A total of 720 FES patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase; participants who do well on an assigned treatment will remain on that treatment for the duration of the 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment. Phase 1 is a randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Subjects who fail to respond after 8 weeks will enter the phase 2 randomization. Phase 2 is an equipoise-stratified randomization trial, and patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for 8 weeks. Subjects who fail to respond after phase 2 will enter an open label trial (phase 3); patients who receive clozapine in phase 2 and fail to respond will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B). The primary outcome for the treatment phase is the treatment efficacy rate, which is defined as at least 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score. We hypothesize that clozapine is more therapeutically effective than any other SGAs to patients who failed to meet efficacy criteria in Phase 1, and earlier treatm

Topics: Antipsychotic Agents; Benzodiazepines; China; Clozapine; Humans; Randomized Controlled Trials as Topic; Schizophrenia

Schizophrenia is associated with a lowered bone mineral density. The antidiabetic and body weight lowering glucagon-like peptide-1 receptor agonist liraglutide has shown to mitigate overweight and impaired glucose tolerance associated with olanzapine and clozapine. As liraglutide has been proposed to affect bone metabolism, we evaluated the effect of liraglutide on bone turnover markers (BTM) in patients with prediabetes and schizophrenia treated with olanzapine or clozapine. Patients diagnosed with a schizophrenia spectrum disorder treated with the antipsychotic compounds clozapine and/or olanzapine, having prediabetes and a BMI above 27 kg/m

Topics: Adult; Antipsychotic Agents; Biomarkers; Body Weight; Bone and Bones; Bone Density; Bone Remodeling; Clozapine; Collagen Type I; Fasting; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Olanzapine; Overweight; Prediabetic State; Schizophrenia

Treatment of violence in schizophrenia remains a challenging problem, especially in patients with conduct disorder. Previous clinical studies did not select patients on the basis of violence and did not focus on conduct disorder. This study is a head-to-head comparison of clozapine, olanzapine, and haloperidol in the treatment of violent schizophrenia patients with and without conduct disorder.. Physically assaultive schizophrenia patients (N=99) were randomly assigned to receive clozapine, olanzapine, or haloperidol in a 12-week double-blind trial. They were characterized on the basis of the presence or absence of conduct disorder before age 15. Assaults were recorded; their frequency and severity were scored on the Modified Overt Aggression Scale. Psychiatric symptoms were evaluated through the Positive and Negative Syndrome Scale.. Patients with a history of conduct disorder had more frequent and severe assaults than those without conduct disorder during the 12-week trial. Clozapine was superior to haloperidol and olanzapine in reducing assaults; olanzapine was superior to haloperidol. Clozapine's greater antiaggressive efficacy over haloperidol was substantially more pronounced in patients with conduct disorder than in patients without conduct disorder. In patients with conduct disorder, clozapine was four times more likely than haloperidol to result in lower violence; in patients without conduct disorder, it was three times more likely to do so. Olanzapine's superiority over haloperidol was also more pronounced in patients with conduct disorder.. This study is the first to examine the effect of clozapine in violent schizophrenia patients with conduct disorder. When conduct disorder is present, clozapine is the optimal treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Conduct Disorder; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Violence

Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders.. We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue.. Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients' BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α.. Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.

Topics: Adult; Animals; Antipsychotic Agents; Blood Glucose; Clozapine; Cytokines; Humans; Inflammation Mediators; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Middle Aged; Schizophrenia; Tumor Necrosis Factor-alpha

Although clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia, it leads to a poor or partial response in 40 to 70% of patients. Augmentation of clozapine with electroconvulsive therapy (ECT) is a highly effective and relatively safe treatment for these clozapine-resistant patients. However, parameters are not yet well specified, such as the optimal number of sessions, their frequency, and the relevance of maintenance ECT. Our objective is to compare the efficacy and tolerance between two protocols of combined ECT and clozapine treatment in patients with ultra-resistant schizophrenia (URS): a 6-month protocol (short protocol with 20 ECT sessions) and a 12-month protocol (long protocol with 40 ECT sessions).. Sixty-four patients with schizophrenia with persistent psychotic symptoms despite clozapine treatment will be enrolled in a prospective multicentric assessor-blinded randomized controlled trial. Patients will be randomly assigned to the short or the long protocol. The main outcome is the response rate assessed by the Positive and Negative Symptoms Scale (PANSS) 3 months after the end of the treatment in patients following the long protocol compared to those following the short protocol. The response was defined as a 30% reduction on the PANSS baseline. Clinical assessments (PANSS, BPRS, HAMD-21, YMRS, CGI, GAF, Modified Overt Aggression Scale (MOAS), and Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS)) and plasma clozapine concentration will be performed at baseline and at 2, 4, 6, 9, 12, and 15 months. Neuropsychological measures (MMSE, RL/RI-16, Doors test, D2 Test of Attention, Copy of the Rey-Osterrieth complex figure) will be performed at baseline and at 6 and 15 months.. The aims of this research are to optimize protocols of combined ECT with clozapine in patients with URS and to offer specific recommendations for these patients' care.. ClinicalTrials.gov NCT03542903 . Registered on May 31, 2018. Id RCB: 2017-A02657-46.

Topics: Antipsychotic Agents; Clozapine; Electroconvulsive Therapy; Humans; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Schizophrenia; Treatment Outcome

To test whether: (1) psychiatrists will prescribe clozapine more often if they can delegate the monitoring tasks to an advanced nurse practitioner (ANP), (2) clozapine monitoring by an ANP is at least as safe as monitoring by a psychiatrist. Patients from 23 Dutch outpatient teams were assessed for an indication for clozapine. ANPs affiliated to these teams were randomized to Condition A: clozapine monitoring by an ANP, or Condition B: monitoring by the psychiatrist. The safety of monitoring was evaluated by determining whether the weekly neutrophil measurements were performed. Staff and patients were blinded regarding the first hypothesis. Of the 173 patients with an indication for clozapine at baseline, only seven in Condition A and four in Condition B were prescribed clozapine (Odds Ratio = 2.24, 95% CI 0.61-8.21; p = 0.225). These low figures affected the power of this study. When we considered all patients who started with clozapine over the 15-month period (N = 49), the Odds Ratio was 1.90 (95% CI 0.93-3.87; p = 0.078). With regard to the safety of the monitoring of the latter group of patients, 71.2% of the required neutrophil measurements were performed in condition A and 67.3% in condition B (OR = 0.98; CI = 0.16-3.04; p = 0.98). Identifying patients with an indication for clozapine does not automatically lead to improved prescription rates, even when an ANP is available for the monitoring. Clozapine-monitoring performed by an ANP seemed as safe as that by a psychiatrist.

Topics: Adult; Antipsychotic Agents; Clozapine; Cluster Analysis; Drug Monitoring; Female; Humans; Male; Middle Aged; Nurse Practitioners; Patient Safety; Prescriptions; Professional Role; Schizophrenia

Social inequality in medical rehabilitation is receiving increasing attention. The present study examined the impact of the social status on the long-term effectiveness of the pain competence and depression prevention training "Debora" among patients with chronic low back pain (CLBP) in an inpatient multidisciplinary rehabilitation.. In general, patients of the lower class showed significantly worse values in depressive symptoms, functional capacity, and subjective work ability compared to the upper class. In addition, positive long-term effects could not be found among patients of the lower class. In contrast, patients of the middle and upper class improved, especially in the IG. Furthermore, only the IG showed long-term improvements in subjective work capacity.. This study confirms the influence of the social status on the psychophysical health. Moreover, social inequality in long-term success of rehabilitation of CLBP was suggested, which could be mediated by health literacy. Therefore, these aspects should be taken into account already in the conception and especially in the application of psychological group trainings in inpatient rehabilitation.. Die soziale Ungleichheit in der medizinischen Rehabilitation findet zunehmend Beachtung. Die vorliegende Studie untersuchte die langfristige Wirksamkeit des Schmerzkompetenz- und Depressionspräventionstrainings Debora bei Rehabilitanden mit chronischen Rückenschmerzen in der stationären verhaltensmedizinisch orthopädischen Rehabilitation (VMO) in Abhängigkeit von der sozialen Lage.. Rehabilitanden der Unterschicht wiesen in der Depressivität, Funktionskapazität und subjektiven Arbeitsfähigkeit generell signifikant schlechtere Werte im Vergleich zur Oberschicht auf. Zudem blieben positive Langzeiteffekte bei Rehabilitanden der Unterschicht eher aus. Dagegen verbesserten sich Rehabilitanden der Mittel- und Oberschicht insbesondere in der IG. Ferner zeigte sich, dass lediglich die IG langfristig in der subjektiven Arbeitsfähigkeit profitierte.. Die Studie belegt den Einfluss der sozialen Lage auf die psychophysische Gesundheit. Ferner wird eine soziale Ungleichheit im langfristigen Rehabilitationserfolg bei chronischen Rückenschmerzen nahegelegt, die durch die Gesundheitskompetenz vermittelt sein könnte. Somit sollten diese Aspekte bereits bei der Konzeption und insbesondere bei der Durchführung von psychologischen Gruppentrainings in der stationären medizinischen Rehabilitation bei chronischen Rückenschmerzen berücksichtigt werden.

Topics: Age Factors; Antipsychotic Agents; Chronic Pain; Clozapine; Cytochrome P-450 CYP1A2; Female; Follow-Up Studies; Functional Status; Germany; Health Literacy; Humans; Inpatients; Low Back Pain; Male; Patient Care Team; Psychological Distress; Rehabilitation; Return to Work; Schizophrenia; Self Efficacy; Sex Factors; Smoking; Social Class; Treatment Outcome

Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans.. Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics.. Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

Topics: Adult; Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Humans; Male; Mice; Prospective Studies; Schizophrenia; Weight Gain

Norwegian national guidelines recommend that clozapine be offered to patients with schizophrenia after two failed attempts with other antipsychotic drugs. One of the main objectives for the introduction of clinical pathways in mental health care is to provide an equal service to patients irrespective of where in the country they live. We wished to investigate the prescribing level of clozapine in various Norwegian counties.. We retrieved aggregated data from the Norwegian Prescription Database, the Norwegian Patient Registry and Statistics Norway on prescribing of clozapine, number of patients in contact with the specialist health service with the diagnosis schizophrenia, and population figures for 2016.. Nationwide in 2016, there were 50 users of clozapine per 100 000 inhabitants (95 % confidence interval (CI) 48-52). The number of users was highest in Troms county (76 (95 % CI 63-89) per 100 000 inhabitants) and lowest in Akershus county (38 (95 % CI 33-43) per 100 000 inhabitants). We found no significant correlation between the prescribing rate for clozapine and the proportion of the population in the county who were undergoing treatment for schizophrenia in the specialist health service.. Prescribing of clozapine varies among Norwegian counties and is not correlated with the proportion of the population who are undergoing treatment for schizophrenia in the specialist health service. Different levels of implementation of the national guidelines constitute a possible explanation for the geographic differences.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Databases, Factual; Drug Prescriptions; Drug Utilization; Female; Guideline Adherence; Humans; Male; Middle Aged; Norway; Practice Guidelines as Topic; Registries; Schizophrenia; Young Adult

Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period.. One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels.. From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide.. The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Weight; C-Peptide; Clozapine; Denmark; Fasting; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipid Metabolism; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Overweight; Placebos; Prediabetic State; Schizophrenia; Young Adult

Clozapine is the only evidence-based antipsychotic for treatment-resistant schizophrenia. However, it has considerable side effects, limiting its usability and reducing patients' adherence. One of the most common and distressing side effects is hypersalivation, which can be debilitating, stigmatizing and potentially dangerous through its association with aspiration pneumonia. There is a paucity of evidence guiding possible treatment strategies for hypersalivation. This study aims to examine the efficacy of hyoscine (scopolamine) for clozapine-induced hypersalivation. Fourteen inpatients diagnosed with treatment-resistant schizophrenia, treated with clozapine and suffering from hypersalivation were randomized to receive hyoscine 0.3 mg and placebo daily for 4 weeks each in a randomized, double-blind, placebo-controlled cross-over trial. The primary outcome was improvement in the Toronto Nocturnal Hypersalivation Scale. The secondary outcomes were change in the mass of the pillowcase, anxiety, depression and quality of life. Hypersalivation improved significantly with hyoscine over placebo when measured by the Toronto Nocturnal Hypersalivation Scale (odds ratio=0.21, 95% confidence interval: 0.16-0.28, P<0.001). No significant difference was observed in any of the secondary outcomes. This study showed a beneficial effect of hyoscine over placebo for clozapine-induced hypersalivation.

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Schizophrenia; Scopolamine; Sialorrhea

Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine.. Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS.. 26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p<0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group.. In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

Topics: Adult; Clozapine; Combined Modality Therapy; Drug Resistance; Female; Humans; Linear Models; Male; Prefrontal Cortex; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Transcranial Magnetic Stimulation; Treatment Outcome

This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia.. Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12.. Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (- 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; - 26 ± 76 vs - 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100).. In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. CLINICALTRIALS.. NCT00981526.

Topics: Adult; Antipsychotic Agents; Body Composition; Body Mass Index; Body Weight; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Insulin; Male; Middle Aged; Olanzapine; Schizophrenia; Telmisartan; Treatment Outcome; Triglycerides

Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population.. To evaluate the clinical effectiveness and cost-effectiveness of cognitive-behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome.. The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU).. Secondary care mental health services in five cities in the UK.. People with CRS aged ≥ 16 years, with an. Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services.. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs.. Cognitive-behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained.. Current Controlled Trials ISRCTN99672552.. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in

Topics: Adolescent; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Cognitive Behavioral Therapy; Cost-Benefit Analysis; Drug Resistance; Female; Humans; Male; Quality-Adjusted Life Years; Schizophrenia; Technology Assessment, Biomedical; Young Adult

Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia.. To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance.. Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used.. Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses.. Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase.. Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = -1.04; z = -0.59; P = .57), PANSS-positive (weighted β = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted β = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified.. Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance.. ClinicalTrials.gov identifier: NCT02164981.

Topics: Aged; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nitroprusside; Schizophrenia; Treatment Outcome

Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Middle Aged; Models, Biological; Schizophrenia; Uruguay

Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this patient group. However, little is known about the mechanisms underlying the assumed superiority of clozapine.. A total of 38 patients with DSM-IV schizophrenia (30 with and 8 without a DSM-IV CUD) and 20 healthy comparison subjects were included between April 2009 and June 2012. Patients were randomized to antipsychotic treatment with clozapine or risperidone. At baseline and after 4weeks of medication, brain response to cannabis-related, positive and neutral images was measured using functional MRI. Neural correlates of cue reactivity were assessed in the following regions of interest: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex and anterior cingulate cortex. Subjective craving was assessed using self-report questionnaires (OCDUS and MCQ).. At baseline, patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest. Clozapine treated patients reported a greater reduction in craving (F(1,28)=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients (T=3.94, pFWE=0.006). In addition, significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images.. These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission.. 'Nederlands trial register' (http://www.trialregister.nl), nr NTR1761, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1761.

Topics: Antipsychotic Agents; Brain; Brain Mapping; Clozapine; Comorbidity; Craving; Cues; Humans; Magnetic Resonance Imaging; Male; Marijuana Abuse; Medication Adherence; Risperidone; Schizophrenia; Treatment Outcome; Visual Perception; Young Adult

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Neuroprotective Agents; Schizophrenia

Numerous studies have demonstrated that fluvoxamine has considerable pharmacokinetic and pharmacodynamic interactions with clozapine. We conducted a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia.. We recruited 85 patients who received a DSM-IV diagnosis of schizophrenia. Eligible patients were randomized to receive fluvoxamine 50mg/day plus clozapine 100mg/day or clozapine 300mg/day. We studied metabolic parameters, psychopathology, and drug levels at baseline and 4, 8, and 12weeks after the intervention. Plasma levels of clozapine, norclozapine, clozapine N-oxide, and fluvoxamine were determined using high-performance liquid chromatography with ultraviolet detection.. No significant difference was observed in baseline characteristics between the two groups. Clozapine-fluvoxamine combined treatment significantly attenuated the increments in body weight, insulin resistance, and levels of insulin, glucose, and triglycerides compared with clozapine monotherapy. Both groups exhibited significant improvements in their Positive and Negative Syndrome Scale (PANSS) total and negative scores. The combined treatment group showed significant reduction in the PANSS general psychopathology scores compared with the monotherapy group. No difference was observed in the plasma clozapine level between the two groups. The monotherapy group showed higher levels of norclozapine and clozapine N-oxide than the combined group.. Compared with clozapine monotherapy, treatment with adjunctive fluvoxamine with clozapine for 12weeks can alleviate body weight gain and metabolic abnormalities in patients with schizophrenia, without sacrificing the clinical effect. Clinicians should interpret these findings cautiously considering the short duration of this study. The study was registered at www.clinicaltrials.gov (NCT01401491).

Topics: Antipsychotic Agents; Antisocial Personality Disorder; Body Weight; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fluvoxamine; Follow-Up Studies; Humans; Leukocytes; Male; Metabolic Diseases; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome

Topics: Adolescent; Adult; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Humans; Male; Middle Aged; Obesity; Pilot Projects; Schizophrenia; Weight Loss; Young Adult

This study assesses the risks and benefits of switching from two to one antipsychotic among participants on two non-clozapine oral antipsychotics, and among those on combinations involving either clozapine or an injectable antipsychotic. Ninety adult participants with schizophrenia or schizoaffective disorder were assigned to stay on polypharmacy or to switch to monotherapy. Half of these participants were receiving combinations of non-clozapine oral antipsychotics and half were receiving combinations involving either clozapine or an injectable antipsychotic. Participants were assessed every 60 days for one year. We examined differences in symptom and side effect trajectories as a function of group assignment and time for both medication groups. Participants who switched from two to one non-clozapine oral antipsychotic experienced significant increases in symptoms relative to stay participants. They also saw significant side effect benefits. Switch participants on combinations involving clozapine or an injectable antipsychotic did not differ over time from stay participants on either symptom or side effect measures. It appears that patients on these combinations can be safely switched to monotherapy. While there may be symptom related risks associated with switching patients on combinations of non-clozapine oral antipsychotics, there are significant health related benefits. Clozapine or injectable antipsychotic monotherapy are recommended options.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Substitution; Female; Humans; Male; Middle Aged; Polypharmacy; Psychotic Disorders; Risk Factors; Schizophrenia; Withholding Treatment

Omega-3 fatty acid (FA) supplementation has been reported to improve several cardio-metabolic risk factors. We aimed to assess the efficacy of omega-3 fatty acids on metabolic and inflammatory indices in patients with schizophrenia who were taking clozapine and sodium valproate. All patients were on a stable dose of 300-400mg of clozapine for 3 months. Subjects were randomized to treatment with either omega-3 fatty acid (4gr/day) or a placebo for 8 weeks. Height, weight, abdominal circumference, serum lipid profile, fasting blood glucose (FBG), and serum high sensitivity-C-reactive protein (hs-CRP) were determined at baseline and after 8 weeks of treatment. Fifty six subjects were recruited into the study. Patients with schizophrenia who were in the group receiving omega-3 FA capsules had an improvement in some anthropometric indices including weight, BMI, wrist and waist circumference, compared to the placebo group. Only changes in waist circumferences remained significantly different after adjustment for serum fasted TG. Our results showed omega-3 FA supplementation can improve some anthropometric indices in patients with schizophrenia who are taking clozapine pharmacotherapy.

Topics: Adult; Anthropometry; Antipsychotic Agents; Body Mass Index; Body Weight; C-Reactive Protein; Clozapine; Dietary Supplements; Double-Blind Method; Fasting; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Schizophrenia; Treatment Outcome; Triglycerides; Valproic Acid; Waist Circumference

Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of N-methyl-D-aspartate receptors, including inhibition of D-amino acid oxidase that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a D-amino acid oxidase inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine.. We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for 6 weeks' add-on treatment of 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive functions were also measured.. Both doses of sodium benzoate produced better improvement than placebo in the Scale for the Assessment of Negative Symptoms. The 2 g/day sodium benzoate also produced better improvement than placebo in PANSS-total score, PANSS-positive score, and Quality of Life Scale. Sodium benzoate was well tolerated without evident side effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS-total score and PANSS-positive score in the sodium benzoate group.. Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; D-Amino-Acid Oxidase; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Linear Models; Male; Middle Aged; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Sodium Benzoate; Taiwan; Treatment Outcome

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophils; Female; Humans; Leukocyte Count; Male; Middle Aged; Schizophrenia; Sex Characteristics; Sex Factors

Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation.. A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants.. Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds.. ACTRN12617001547336; Pre-results.

Topics: Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Metabolic Syndrome; Metformin; Obesity; Research Design; Schizophrenia; Secondary Prevention; Treatment Outcome; Weight Gain; Weight Loss

The long-term consequences of discontinuing antipsychotic medication after successful treatment of first-episode psychosis are not well studied. We assess the relation between early maintenance therapy decisions in first-episode psychosis and the subsequent clinical outcome at 10 years.. This is a 10 year follow-up study, spanning Sept 5, 2003, to Dec 30, 2014, of a randomised, double-blind trial in seven centres in Hong Kong in which 178 patients with first-episode psychosis with full positive symptom resolution after at least 1 year of antipsychotic treatment were given maintenance treatment (n=89; oral quetiapine 400 mg daily) or early treatment discontinuation (n=89; placebo) for 12 months. After the trial, patients received naturalistic treatment. Overall this cohort of patients will have received about 3 years of treatment before entering the follow-up phase of the study: about 2 years of maintenance treatment before study entry and 1 year of treatment in the trial. The primary outcome of this follow-up was the proportion of patients in each group (including those for whom direct follow-up was not available) with good or poor long-term clinical outcomes at 10 years, with poor outcome defined as a composite of persistent psychotic symptoms, a requirement for clozapine treatment, or death by suicide. The randomised trial was registered with ClinicalTrials.gov, number NCT00334035, and the follow-up study was registered with ClinicalTrials.gov, number NCT01926340.. Poor 10 year clinical outcome occurred in 35 (39%) of 89 patients in the discontinuation group and 19 (21%) of 89 patients in the maintenance treatment group (risk ratio 1·84, 95% CI 1·15-2·96; p=0·012). Suicide was the only serious adverse event that occurred in the follow-up phase (four [4%] patients in the early discontinuation group vs two [2%] in the maintenance group).. In patients with first-episode psychosis with a full initial response to treatment, medication continuation for at least the first 3 years after starting treatment decreases the risk of relapse and poor long-term clinical outcome.. Food and Health Bureau, Research Grants Council of Hong Kong, and AstraZeneca.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Female; Follow-Up Studies; Hong Kong; Humans; Male; Psychotic Disorders; Quetiapine Fumarate; Recurrence; Schizophrenia; Treatment Outcome; Young Adult

Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia.. We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual.. From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2·40, -4·79 to -0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event.. At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some.. National Institute for Health Research Technology Assessment programme.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Drug Resistance; Female; Humans; Male; Schizophrenia; Treatment Outcome

No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown.. This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual.. Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported.. For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation.. European Commission Seventh Framework Program.

Topics: Adolescent; Adult; Amisulpride; Antipsychotic Agents; Clozapine; Europe; Female; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome; Young Adult

To test the validity and sensitivity of the six-item version (PANSS-6) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) in treatment-resistant schizophrenia (TRS).. Using data from the clozapine phase (2E) of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, we investigated the following: (i) The scalability of PANSS-6 and PANSS-30; (ii) The correlation between PANSS-6 and PANSS-30 total scores; (iii) Whether PANSS-6 could identify cross-sectional symptom remission; and (iv) The efficacy of clozapine, olanzapine, risperidone and quetiapine in TRS using the 'speed of change' on PANSS-6 and PANSS-30 (change in total score per week) as outcome measures.. We found that (i) only PANSS-6 and not PANSS-30 was scalable; (ii) The correlation between PANSS-6 and PANSS-30 total scores was high (Spearman coefficient: 0.85), (iii) PANSS-6 accurately identified cross-sectional symptom remission as defined by the Andreasen et al. criteria; and (iv) The only antipsychotic that caused improvement (speed of change significantly lower than 0 during the first three months of treatment) was clozapine, both when using PANSS-6 (speed of change: -0.50 points/week; 95%CI: -0.84, -0.17) and PANSS-30 (speed of change: -1.41 points/week; 95%CI: -2.80, -0.02) as outcome measures.. PANSS-6 validly measures severity, remission and antipsychotic efficacy in TRS.

Topics: Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Humans; Olanzapine; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Quetiapine Fumarate; Reproducibility of Results; Risperidone; Schizophrenia; Sensitivity and Specificity

Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics.. We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales.. In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients.. These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

Topics: Adolescent; Adult; Antipsychotic Agents; Betahistine; Body Mass Index; Body Weight; Child; Clozapine; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult

Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.. To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.. This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.. Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.. The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.. Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.. Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.. clinicaltrials.gov Identifier: NCT01845259.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Outcome Assessment, Health Care; Overweight; Prediabetic State; Schizophrenia

For approximately one third of individuals treated for psychosis or schizophrenia, antipsychotic medications will have little or no therapeutic benefit. Clozapine remains the sole medication approved for treatment-resistant schizophrenia, and studies have demonstrated its superior efficacy in reducing psychotic symptoms.. Data were collected from the medical records of people who originally presented with a first-episode psychosis between 1995 and 1999 (N = 171). Data were obtained from first presentation up to December 31, 2013 or until the patient was discharged or transferred. Information on service use and physical health was gathered using a data collection template designed specifically for this audit.. Twenty-eight (16.3%) of the cohort were prescribed clozapine. Data were available for 24 individuals. Of this clozapine subsample, the mean age at baseline was 23.11 (SD = 4.58); 82.14% (n = 23) were male; and 82.14% (n = 23) had a baseline diagnosis of schizophrenia. The mean time to first trial of clozapine was 6.7 years. The mean number of antipsychotics prescribed before clozapine trial was 4.85. After the initiation of clozapine, the mean number of hospital admissions reduced from 6.04 per year to 0.88 per year.. Nearly 1 in 5 of the original cohort was considered to have a suboptimal response to trials of antipsychotic medication. The use of clozapine for treatment-resistant schizophrenia is underutilized, and better understanding of the barriers to prescribing clozapine is necessary given the implications for patient's quality of life and hospital admission rates. Physical health data further emphasizes the importance of physical health monitoring in this vulnerable population.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Female; Health Status; Hospitalization; Humans; Male; Patient Acceptance of Health Care; Psychotic Disorders; Schizophrenia; Young Adult

This study examined the effect of adjunctive telmisartan on psychopathology and cognition in olanzapine- or clozapine-treated patients with schizophrenia.. In a 12-week randomized, double-blind, placebo-controlled study, patients diagnosed with schizophrenia or schizoaffective disorder received either telmisartan (80 mg once per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS), and a neuropsychological battery was used to assess cognitive performance. Assessments for psychopathology and cognition were conducted at baseline and week 12.. Fifty-four subjects were randomized, and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). After 12-weeks of treatment, the telmisartan group had a significant decrease in PANSS total score compared withthe placebo group (mean ± SD: - 4.1 ± 8.1 vs. 0.4 ± 7.5, P = 0.038, SCohen's d = 0.57). There were no significant differences between the two groups in change from baseline to week 12 in PANSS subscale scores, SANS total score, or any cognitive measures (P > 0.100).. The present study suggests that adjunctive treatment with telmisartan may improve schizophrenia symptoms. Future trials with larger sample sizes and longer treatment durations are warranted.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Antipsychotic Agents; Benzimidazoles; Benzoates; Benzodiazepines; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Psychotic Disorders; Schizophrenia; Telmisartan

When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice.. The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia.. The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks.. The study was set in NHS multidisciplinary teams in adult psychiatry.. Eligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy.. Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks.. The primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale.. A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term.. The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants.. The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings.. EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876.. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in

Topics: Adult; Amisulpride; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Psychiatric Status Rating Scales; Quality-Adjusted Life Years; Schizophrenia; Sulpiride; Technology Assessment, Biomedical; Treatment Outcome

This study investigated the efficacy of scopolamine (an anticholinergic agent) ointment against clozapine-induced hypersalivation.. The patients enrolled in this study consisted of 10 clozapine-treated schizophrenia patients and 10 healthy adult men. A prospective, randomized, double-blind, crossover, placebo-controlled clinical trial was designed.. A total of 10 patients and 10 healthy adult men completed the study. No significant reduction in the saliva production of the clozapine-treated patients was observed; however, that of the healthy adult men decreased significantly.. Scopolamine ointment was not effective against clozapine-induced hypersalivation. A further study is necessary for confirming its effect.

Topics: Adult; Aged; Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Ointments; Outcome Assessment, Health Care; Pilot Projects; Prospective Studies; Schizophrenia; Scopolamine; Sialorrhea; Young Adult

While accumulating evidence suggests that vitamin D deficiency may be involved in the risk to develop schizophrenia and its outcome, there are no studies on vitamin D supplementation in this context. We sought to assess the effect of vitamin D supplementation on psychiatric, cognitive and metabolic parameters in chronic clozapine-treated schizophrenia patients.. This eight-week, randomized, double-blind, placebo-controlled clinical trial, recruited schizophrenia patients who had been maintained on clozapine treatment for at least 18weeks and had low levels of vitamin D (<75nmol/l) and total PANSS scores >70 (to ascertain the presence of residual symptoms). Patients were randomly allocated to either weekly oral drops of vitamin D (14,000IU) or placebo and subsequently assessed at two-week intervals for psychosis severity, mood, cognition and metabolic profile.. Twenty four patients were randomly assigned to vitamin D (aged 39.4±9.6years, 75% males) and the other 23 patients to the placebo arm (aged 42.5±11.2years, 60.9% males). After eight weeks, the vitamin D group exhibited a significant increase in vitamin D levels (31.4 vs -0.4nmol/l, p<0.0001). There was no significant effect of vitamin D on psychotic, depressive or metabolic parameters. However, in the vitamin D group, there was a trend towards improved cognition (effect size=0.17, significance lost following Bonferroni correction).. Vitamin D supplementation was associated with a trend towards improved cognition, but did not affect psychosis, mood or metabolic status. It is possible that the robust decrease in the PANSS scores in both groups may have obscured an effect of vitamin D supplementation.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Psychotic Disorders; Schizophrenia; Vitamin D

In a recent placebo-controlled, double-blind crossover trial (n = 52), significant beneficial effects on memory (d = 0.30) and negative symptoms (d = 0.29) were found after 12 weeks of memantine augmentation in patients with clozapine-refractory schizophrenia. In this open-label 1-year extension study we report the long-term effects and tolerability of memantine add-on therapy to clozapine.. Completers of the first trial who experienced beneficial effects during 12 weeks of memantine treatment received memantine for 1 year. Primary endpoints were memory and executive function using the Cambridge Neuropsychological Test Automated Battery, the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Severity Scale (CGI-S).. Of 31 randomized controlled trial completers who experienced beneficial effects from memantine, 24 received memantine for 1 year. The small improvement in memory found in the memantine condition in the placebo-controlled trial remained stable in the extension study. Executive function did not improve. After 26 weeks of memantine add-on therapy to clozapine, PANSS negative symptoms (r = 0.53), PANSS positive symptoms (r = 0.50) and PANSS total symptoms (r = 0.54) significantly improved. Even further significant improvement in all these measures was observed between 26 weeks and 52 weeks of memantine, with effect sizes varying from 0.39 to 0.51. CGI-S showed a non-significant moderate improvement at 26 weeks (r = 0.36) and 52 weeks (r = 0.34). Memantine was well tolerated without serious adverse effects.. In the 1-year extension phase the favourable effect of adjunctive memantine on memory was sustained and we observed further improvement of negative, positive and overall symptoms in patients with clozapine-treated refractory schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognitive Dysfunction; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Executive Function; Female; Follow-Up Studies; Humans; Male; Memantine; Memory Disorders; Middle Aged; Schizophrenia

Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose.. Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose.. Minor changes in median percentage values were observed for both s-clozapine (-8.4%) and s-norclozapine (+1.2%) across the 4-h time span. Maximum individual differences were 42.8% for s-clozapine and 38.4% for s-norclozapine. Compared to 12-h values, maximum median differences were 8.4% for s-clozapine and 7.3% for s-norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s-clozapine and 105.0% for s-norclozapine. The magnitude of s-clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis.. The impact of deviations in clozapine TDM sampling time, within the time span of 10-14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Female; Humans; Male; Middle Aged; Schizophrenia; Young Adult

To examine effects of different antipsychotic discontinuation strategies on clinical outcomes in patients with schizophrenia undergoing a switch to clozapine.. This pilot, 8-week, double-blind, randomized controlled trial was conducted from May 1999 to July 2004. Outpatients with a diagnosis of schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV and eligible for a switch to clozapine were included. Participants were randomly assigned to the immediate discontinuation (prior antipsychotics were discontinued at baseline) or gradual discontinuation (prior antipsychotics were reduced by 25% each week) group. For each group, clozapine was gradually increased to 300 mg/d at day 12, with this dose maintained for 3 weeks and thereafter adjusted as needed. Clinical outcome measures included the Brief Psychiatric Rating Scale (BPRS), UKU Side Effect Rating Scale, and extrapyramidal symptoms scales.. Thirty-three patients were enrolled; 15 and 18 patients were assigned to the immediate and gradual discontinuation groups, respectively. While significant improvements were observed in BPRS total scores after the switch to clozapine in both groups (P values < .001), no significant differences were found on any clinical outcome measures between the groups; however, additional analyses revealed a significant interaction between group and time for the UKU Psychic Side Effects subscale scores (P = .038).. This preliminary study demonstrated no statistically significant differences in efficacy or tolerability between immediate and gradual antipsychotic discontinuation strategies when switching to clozapine in patients with schizophrenia; however, due to the small sample size, larger-scale trials are needed to confirm these results.. ClinicalTrials.gov identifier: NCT02640300.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Substitution; Female; Humans; Male; Middle Aged; Pilot Projects; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The aim of this study is to evaluate the safety and effectiveness of rapid clozapine titration in patients with schizophrenia in hospital settings. We conducted a retrospective two-center cohort study to compare the safety and effectiveness of clozapine with different titration rates in treatment-refractory patients with schizophrenia. In the first center, clozapine was started at 25-50 mg followed by 50-100 mg as needed every 6 h on day 1, followed by increases of 50-100 mg/day. In the second center, titration was slower; clozapine initiated with 12.5-50 mg on day 1 followed by increases of 25-50 mg/day. The number of days between starting of clozapine until discharge was shorter in the rapid titration group (22.4 ± 8.72 vs 27.0 ± 10.5, p = 0.1). Number of days of total hospital stay were significantly shorter in the rapid titration group (29.6 ± 10.6 vs 41.2 ± 14.8, p = 0.002). Hypotension was more common in the rapid titration group and one patient had suspected myocarditis. Rapid clozapine titration appeared safe and effective. The length of stay following initiation of clozapine was shorter in the rapid-titration group, although this was not statistically significant. However starting clozapine earlier together with rapid titration has significantly shortened the length of hospital stay in patients with treatment refractory schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Female; Hospitalization; Humans; Length of Stay; Male; Schizophrenia; Young Adult

Increased body weight and hyperlipidemia caused by antipsychotics may be associated with improved antipsychotic efficacy in schizophrenia. If this association has a causal interrelationship via a genuine pathophysiological mechanism, then body weight loss in antipsychotic-treated patients would be accompanied by worsened psychopathology. This could have clinical implications.. To explore whether the decreased body weight in these patients is associated with a worsened psychopathology.. In our previously published study, a 16 week treatment period with add-on orlistat (but not placebo) resulted in body weight loss in male (but not female) clozapine- or olanzapine-treated overweight or obese patients. In the current study, we investigated whether body weight loss in those male patients could worsen psychosis. Changes in the Positive and Negative Syndrome Scale (PANSS) scores within groups and body weight changes and lipid profiles over the treatment period were analysed by the paired samples t-test. Between-group comparisons were analysed by the independent samples t-test.. Over the treatment period body weight decreased by 2.56 ± 3.25 kg from initial 106.02 ± 12.61 kg (p = 0.04) for the orlistat group, with no statistically significant changes for the placebo group. Lipid levels did not change in either group. The orlistat-induced weight decrease was not associated with worsening in the PANSS scores.. Weight loss was not associated with a worsening of psychosis. The interrelationship between the antipsychotic-induced weigh gain and improved schizophrenia psychopathology observed in earlier studies appears to be indirect. Orlistat treatment in our study did not worsen psychopathology in this population.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Humans; Lactones; Lipid Metabolism; Male; Middle Aged; Obesity; Olanzapine; Orlistat; Psychiatric Status Rating Scales; Psychopathology; Schizophrenia; Weight Loss

Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated.. Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin.. Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin.. These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.

Topics: Adolescent; Adult; Basic Helix-Loop-Helix Transcription Factors; Case-Control Studies; Circadian Rhythm; Clozapine; Humans; Hydrocortisone; Insulin; Male; Middle Aged; Nerve Tissue Proteins; Orexins; Period Circadian Proteins; Schizophrenia; Time Factors; Young Adult

Hypersalivation is a frequent, disturbing, and uncomfortable adverse effect of clozapine therapy that frequently leads to noncompliance. The aim of this study was to examine the efficacy of metoclopramide (dopamine D2 antagonist, antiemetic medication) as an option for management of hypersalivation associated with clozapine (HAC). A 3-week, double-blind, placebo-controlled trial was conducted in university-based research clinics from January 2012 to May 2014, on 58 inpatients treated with clozapine who were experiencing hypersalivation. The subjects were randomly divided into placebo and metoclopramide groups. The starting dose was 10 mg/d. Participants who did not respond were up-titrated 10 mg/d weekly to a total of 30 mg/d during the third week. The number of placebo capsules was increased accordingly up to 3 capsules per day. Primary outcome was the change from baseline to the end of study in the severity of hypersalivation as measured with the Nocturnal Hypersalivation Rating Scale and the Drooling Severity Scale. Secondary outcomes included Clinical Global Impression of Improvement scale and adverse effect scales. Significant improvement on the Nocturnal Hypersalivation Rating Scale was demonstrated in the metoclopramide group from the end of the second week (P < 0.004), and on the Drooling Severity Scale (P < 0.02) in the third week. Clinical Global Impression-Improvement scale scores revealed major improvement. Twenty subjects (66.7%) treated with metoclopramide reported significant decline or total disappearance of HAC in comparison to 8 patients (28.6%) who received placebo (P = 0.031). No adverse effects to metoclopramide were reported. Metoclopramide was found to be safe and effective for the treatment of HAC.

Topics: Adult; Antipsychotic Agents; Clozapine; Dopamine D2 Receptor Antagonists; Double-Blind Method; Humans; Metoclopramide; Middle Aged; Schizophrenia; Sialorrhea; Young Adult

Clozapine remains the only medication indicated for refractory schizophrenia. As new antipsychotic drugs become available, their efficacy compared to clozapine, particularly in moderately ill patients, is of great clinical interest. We compared risperidone, the first of these, to clozapine in partially responsive patients. Further, since participation of patients usually excluded from clinical trials is increasingly important, we broadened inclusion to a wider patient population.. We compared clozapine (n = 53) to risperidone (n = 54) in a randomized, double-blind, 29-week trial in schizophrenia patients (diagnosed using DSM-IV) at 3 research outpatient clinics. Randomization was stratified by "narrow" or "broad" inclusion criteria. The study was conducted between December 1995 and October 1999. Time to treatment discontinuation for lack of efficacy and time to 20% improvement in the Brief Psychiatric Rating Scale psychotic symptom cluster were the primary outcome measures.. There were no differences in all-cause discontinuation; clozapine-treated participants were significantly less likely to discontinue for lack of efficacy (15%) than risperidone-treated participants (38%) (Wilcoxon χ(2)1 = 6.10, P = .01). Clozapine resulted in significantly more global improvement (F2,839 = 6.07, P < .01) and asociality improvement (F2,315 = 6.64, P < .01) than risperidone. There was no difference in proportions meeting an a priori criterion of psychosis improvement (risperidone: 57%; clozapine: 71%). Significant adverse effect differences in salivation (F1 = 4.05, P < .05) (F1 = 12.13, P < .001), sweating (F1 = 5.07, P < .05), and tachycardia (F1 = 6.51, P < .05) favored risperidone.. Clozapine-treated partially responsive patients were less likely to discontinue treatment for lack of efficacy and improved more globally than those treated with risperidone, although psychotic symptoms did not differ. These findings suggest that clozapine should not be restricted to the most severely ill, treatment-refractory patients; it should be considered as an alternative for patients who have some response to other antipsychotics, but still experience troubling symptoms.

Topics: Brief Psychiatric Rating Scale; Clozapine; Comorbidity; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Resistance; Humans; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL) deficits likely related to degraded representations of reward values. However, the RL tasks used to date have required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30 demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action ("Go" or "NoGo") and the valence of the optimal outcome (reward or punishment-avoidance), such that all combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the reduction in Pavlovian bias was enhanced. The reduction in Pavlovian bias in SZ patients was accompanied by feedback processing differences at the time of the P3a component. The reduced Pavlovian bias in patients is suggested to be due to reduced fidelity in the communication between striatal regions and frontal cortex. It may also partially account for previous findings of poorer "Go-learning" in schizophrenia where "Go" responses or Pavlovian consistent responses are required for optimal performance. An attenuated P3a component dynamic in patients is consistent with a view that deficits in operant learning are due to impairments in adaptively using feedback to update representations of stimulus value.

Topics: Adult; Clozapine; Corpus Striatum; Event-Related Potentials, P300; Female; Frontal Lobe; Humans; Male; Middle Aged; Reinforcement, Psychology; Schizophrenia

Dysfunction of neuroplasticity due to N-methyl-d-aspartate (NMDA) receptor hypofunction may be a causal factor for memory and executive dysfunctioning in schizophrenia. Deregulation of NMDA transmission in the prefrontal cortex may also explain negative and positive symptoms. Clozapine augmentation with memantine targets altered NMDA receptor-mediated neurotransmission in schizophrenia and showed substantial beneficial effects on several symptom domains in a small proof-of-concept study. We evaluate effects of memantine add-on treatment to clozapine for memory and executive function, and negative and positive symptoms in schizophrenia.. Clozapine-treated patients with refractory schizophrenia were randomly assigned to 12 weeks of double-blind adjunctive treatment with memantine (n = 26) or placebo (n = 26). Crossover occurred after a 2-week placebo wash-out period. Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Side effects were assessed using the Liverpool University Neuroleptic Side-Effect Rating Scale.. When compared with placebo, memantine improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB (effect size = 0.30) and PANSS negative subscale score (effect size = 0.29). Side effects were mild and transient.. In patients with clozapine-treated refractory schizophrenia, memantine addition significantly improved verbal and visual memory and negative symptoms without serious adverse effects. These results justify further investigations on long-term memantine augmentation to clozapine in treatment-resistant schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognitive Dysfunction; Cross-Over Studies; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Humans; Male; Memantine; Memory Disorders; Middle Aged; Outcome Assessment, Health Care; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Physicians; Schizophrenia; Self Report

There is mounting evidence that schizophrenia risk variants influence response to antipsychotic medication. Common single nucleotide polymorphisms (SNPs) in or near the inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) gene have been repeatedly associated with schizophrenia and related psychiatric disorders in genome-wide association studies. Here, we provide the first study to assess the relevance of the ITIH3 rs2535629 SNP in response to antipsychotic medication.. The rs2535629 SNP was genotyped in N=256 patients receiving various antipsychotics for up to 26weeks. Treatment response was assessed using the Brief Psychiatric Rating Scale (BPRS) including its positive and negative subscales. Follow-up analyses were performed after stratifying for ethnicity and medication.. We found significant association of rs2535629 with improvement of negative symptoms in patients of European ancestry after six months of clozapine treatment (F1,87=8.8, pcorr=0.032). Patients homozygous for the minor A-allele showed the best improvement of negative BPRS scores. However, we observed no association between rs2535629 and changes in total BPRS score in the entire sample or the clozapine-treated subgroup.. Although there was no association of genotype with overall changes in BPRS scores, the greater improvement of negative symptoms in minor allele carriers indicates that rs2535629 may help to identify a subset of schizophrenia patients with better treatment response to clozapine. Therefore, our findings provide the first suggestive evidence that rs2535629 is relevant in antipsychotic response.

Topics: Adult; Alpha-Globulins; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Female; Follow-Up Studies; Genetic Association Studies; Homozygote; Humans; Male; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia; Treatment Outcome; White People

For around a third of people with a diagnosis of schizophrenia, the condition proves to respond poorly to treatment with many typical and atypical antipsychotics. This is commonly referred to as treatment-resistant schizophrenia. Clozapine is the only antipsychotic with convincing efficacy for people whose symptoms are considered treatment-resistant to antipsychotic medication. However, 30-40 % of such conditions will have an insufficient response to the drug. Cognitive behavioural therapy has been shown to be an effective treatment for schizophrenia when delivered in combination with antipsychotic medication, with several meta-analyses showing robust support for this approach. However, the evidence for the effectiveness of cognitive behavioural therapy for people with a schizophrenia diagnosis whose symptoms are treatment-resistant to antipsychotic medication is limited. There is a clinical and economic need to evaluate treatments to improve outcomes for people with such conditions.. A parallel group, prospective randomised, open, blinded evaluation of outcomes design will be used to compare a standardised cognitive behavioural therapy intervention added to treatment as usual versus treatment as usual alone (the comparator group) for individuals with a diagnosis of schizophrenia for whom an adequate trial of clozapine has either not been possible due to tolerability problems or was not associated with a sufficient therapeutic response. The trial will be conducted across five sites in the United Kingdom.. The recruitment target of 485 was achieved, with a final recruitment total of 487. This trial is the largest definitive, pragmatic clinical and cost-effectiveness trial of cognitive behavioural therapy for people with schizophrenia whose symptoms have failed to show an adequate response to clozapine treatment. Using a prognostic risk model, baseline information will be used to explore whether there are identifiable subgroups for which the treatment effect is greatest.. Current Controlled Trials ISRCTN99672552 . Registered 29(th) November 2012.

Topics: Adolescent; Adult; Antipsychotic Agents; Clinical Protocols; Clozapine; Cognitive Behavioral Therapy; Combined Modality Therapy; Cost-Benefit Analysis; Double-Blind Method; Drug Resistance; Female; Humans; Male; Quality-Adjusted Life Years; Schizophrenia; Treatment Outcome; Young Adult

Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ.. This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes.. This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine.. Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.

Topics: Acetylcysteine; Adolescent; Adult; Aged; Antipsychotic Agents; Australia; Clozapine; Double-Blind Method; Drug Resistance; Female; Follow-Up Studies; Free Radical Scavengers; Humans; Male; Middle Aged; New Zealand; Quality of Life; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Young Adult

Clozapine is the only medication licensed for the treatment of resistant schizophrenia in the UK. Although efficacious, a common and unpopular side effect of clozapine treatment is clozapine-induced hypersalivation (CIH), which can contribute to non-adherence. The standard treatment for CIH in the UK is hyoscine hydrobromide but this may aggravate cognitive deficits in patients with schizophrenia while glycopyrrolate may be an effective alternative with a more tolerable side effect profile. There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH.. This is a multicentre randomised, double-blind, placebo-controlled feasibility study of glycopyrronium bromide (glycopyrrolate) and hyoscine hydrobromide (hyoscine) in patients with clozapine-induced hypersalivation. We aim to recruit 42 patients who have been prescribed clozapine and are experiencing hypersalivation, and randomise them to one of three study arms (either hyoscine, glycopyrrolate or placebo). The primary outcome measures will be the participant recruitment and attrition rates, and the secondary outcome will be the metrics of the daytime hypersalivation measure. After a 1-week washout period (discontinuing CIH medication, if any), there will be a 4-week treatment period where participants will be titrated up to the maximum tolerated dose of hyoscine, glycopyrrolate or placebo. Measurements of daytime salivation, nocturnal salivation, cognition and side effects will be taken during home visits in week 2 and week 5. Information on salivation and side effects will also be taken through telephone calls in week 3 and week 4. To gather information on the experience of study participants, exit interviews will also be requested with all participants who drop out of the study and a sample of participants who complete the study.. There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH. There is promising evidence that glycopyrrolate may be more successful in the treatment of CIH causing fewer cognitive side effects. We propose to conduct a randomised placebo-controlled feasibility study of glycopyrrolate and hyoscine in the treatment of clozapine-induced hypersalivation to inform the design of a future efficacy trial.. Clinicaltrials.gov NCT02613494 , 23 November 2015.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clinical Protocols; Clozapine; Double-Blind Method; Feasibility Studies; Female; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Research Design; Salivation; Schizophrenia; Scopolamine; Sialorrhea; Time Factors; Treatment Outcome; United Kingdom; Young Adult

Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. The lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. This study was designed to determine whether metformin at 500 mg/d and 1000 mg/d is effective in improving the metabolic profiles of clozapine-treated patients with pre-existing metabolic abnormalities, and whether its effectiveness depends on metformin dosage.. In this 12-week, randomized, double-blind, placebo-controlled trial, metformin at 500 mg/d or 1000 mg/d was prescribed to clozapine-treated patients with schizophrenia who had pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at weeks 4, 8, and 12. The outcomes were any changes in metabolic traits.. Among the 96 clozapine-treated patients with schizophrenia screened for the trial, 55 patients with pre-existing metabolic abnormalities were randomly assigned to placebo (n = 18), metformin dosage at 500 mg/d (n = 18), and metformin dosage at 1000 mg/d (n = 19) groups. The body weight (BW) of patients in the metformin 1000 mg/d group significantly decreased, by a mean of 0.97 kg over the 12 week trial period. Moreover, patients in the metformin at 500 mg/d and 1000 mg/d groups had a significant decrease in body mass index (BMI) after 12 weeks, with the mean decrease being 0.70 and 0.50 kg/m2, respectively. No significant changes were observed in the other metabolic parameters of patients in the three groups.. Our results demonstrated that a low metformin dosage of either 500 mg/d or 1000 mg/d for 12 weeks slightly reduced the BW and BMI of clozapine-treated patients with pre-existing metabolic abnormalities. A longer period of treatment with a larger sample is warranted to determine the factors that influence the metformin treatment response.. ClinicalTrials.gov NCT02751307.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Schizophrenia; Treatment Outcome

Up to 70% of patients with treatment-resistant schizophrenia do not respond to clozapine. Pharmacological augmentation to clozapine has been studied with unimpressive results. The authors examined the use of ECT as an augmentation to clozapine for treatment-refractory schizophrenia.. In a randomized single-blind 8-week study, patients with clozapine-resistant schizophrenia were assigned to treatment as usual (clozapine group) or a course of bilateral ECT plus clozapine (ECT plus clozapine group). Nonresponders from the clozapine group received an 8-week open trial of ECT (crossover phase). ECT was performed three times per week for the first 4 weeks and twice weekly for the last 4 weeks. Clozapine dosages remained constant. Response was defined as ≥40% reduction in symptoms based on the psychotic symptom subscale of the Brief Psychiatric Rating Scale, a Clinical Global Impressions (CGI)-severity rating <3, and a CGI-improvement rating ≤2.. The intent-to-treat sample included 39 participants (ECT plus clozapine group, N=20; clozapine group, N=19). All 19 patients from the clozapine group received ECT in the crossover phase. Fifty percent of the ECT plus clozapine patients met the response criterion. None of the patients in the clozapine group met the criterion. In the crossover phase, response was 47%. There were no discernible differences between groups on global cognition. Two patients required the postponement of an ECT session because of mild confusion.. The augmentation of clozapine with ECT is a safe and effective treatment option. Further research is required to determine the persistence of the improvement and the potential need for maintenance treatments.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Cross-Over Studies; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Prospective Studies; Schizophrenia; Single-Blind Method; Treatment Outcome; Young Adult

Underuse of the antipsychotic clozapine for schizophrenia is an impediment to improving outcomes for patients. Because of its possible severe side effects, including granulocytopenia or even agranulocytosis, clozapine treatment entails regular WBC monitoring, which can be a major drawback for patients and practitioners. The HemoCue WBC DIFF system is a point-of-care device using capillary blood sampling which provides WBC counts with differentials, including granulocytes. We investigated if capillary sampling instead of conventional venous sampling might diminish the burden for patients and practitioners and motivate them to continue clozapine treatment. A randomized cross-over trial design was used to compare the two sampling methods. Patients׳ subjective experiences of various aspects of blood sampling were rated on a 10-cm visual analogue scale (VAS). Patients and practitioners were also asked if they had any preference for venous or capillary sampling and patients were asked if the sampling method influenced their motivation to continue clozapine treatment. Seventy-three patients were included in this study. Three dropped out before completion. The VAS ratings on all five aspects and the total burden experienced showed a consistent pattern favouring capillary blood sampling (p<0.001). This pattern was more pronounced for inpatients than for outpatients. Patients strongly preferred capillary testing (p<0.001). The method used moderately influenced their motivation for clozapine therapy. In this study patients tolerated capillary blood testing with a point-of-care device better than traditional venous sampling at a laboratory and practitioners also preferred it. Using this method might therefore boost clozapine prescription rates.

Topics: Adult; Antipsychotic Agents; Blood Specimen Collection; Capillaries; Clozapine; Cross-Sectional Studies; Female; General Practitioners; Humans; Male; Middle Aged; Pain Measurement; Point-of-Care Systems; Schizophrenia; Veins; Young Adult

The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n=49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n=19], quetiapine [n=15], or risperidone [n=16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. ≥6 on the CDSS), using mixed models.. No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p<.01 for the whole sample and p=.01 for those with an MDE), and comparable to olanzapine and risperidone.. The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE.

Topics: Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Depressive Disorder, Major; Double-Blind Method; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

This preliminary prospective study evaluated cardiac status in 15 treatment-resistant schizophrenia patients (aged 18-55 years) without evidence of cardiovascular disease. Patients underwent clinical assessment, blood tests, ECG, and echocardiography before and during clozapine treatment for 4 weeks as doses increased from 25 to 100 mg/day. Serum concentrations of high-sensitivity C-reactive protein, troponin-I, brain natriuretic peptide, and clozapine+norclozapine were assayed at week 3; ECG and echocardiography were repeated at week 4. At moderate serum drug concentrations (124 ng/ml), the heart rate increased by 10% and high-sensitivity C-reactive protein levels were slightly elevated, but troponin-I and brain natriuretic peptide levels were not elevated. Echocardiographic indices indicated declining left ventricular (LV) diastolic and systolic function in 60-80% of participants, with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index by 16-24% in 60-80% of participants and a decrease in the E/A ratio by 29% in 73% of participants - all uncorrelated with drug concentrations. Early treatment with moderate doses of clozapine was associated with subclinical but substantial decreases in LV functioning in surprisingly high proportions of participants. Studies with more participants, higher drug doses, and long-term follow-up are needed to confirm and determine the course of the observed abnormalities and to evaluate their relationship with rare clinical cardiotoxicity associated with clozapine.

Topics: Adolescent; Adult; Antipsychotic Agents; C-Reactive Protein; Clozapine; Drug Resistance; Echocardiography; Female; Heart Rate; Humans; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Schizophrenia; Treatment Outcome; Troponin I; Ventricular Function, Left; Young Adult

Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes.. Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23).. Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo.. Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Obesity-related genetic variants, including TMEM18 (rs6548238), SH2B1 (rs7498665), and GNPDA2 (rs10938397), have been shown to be associated with obesity in the general population. Our study aimed to test whether these genetic variants are associated with metabolic profiles and metformin treatment response in clozapine-treated schizophrenic patients. We recruited 107 clozapine-treated patients who were genotyped and measured their metabolic profiles. Fifty-five subjects, who had at least 1 metabolic abnormality in a range of measures, were subsequently randomized to a 24-week trial of metformin (n = 28) or placebo (n = 27). We examined the associations between TMEM18, SH2B1, GNPDA2 genetic variants and metabolic profiles at baseline in all patients and metabolic changes in the trial groups. We found a significant association between SH2B1 and blood pressure at baseline in all patients. In the metformin group, TMEM18 minor allele carriers had a greater reduction in insulin levels (P = 0.04). A significantly higher proportion of TMEM18 and GNPDA2 minor allele carriers (60% and 40%) lost more than 7% of their body weight after metformin treatment as compared with their homozygous counterparts (21.7% and 15.4%, P = 0.02 and 0.004, respectively).There were trends toward favorable metabolic changes in minor allele carrier groups. In the placebo group, no association between genetic variants and changes in metabolic profiles was found. In conclusion, the study results suggest that these genes might be associated with metabolic abnormalities and response to metformin in clozapine-treated patients with schizophrenia.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aldose-Ketose Isomerases; Alleles; Antipsychotic Agents; Clozapine; Double-Blind Method; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Membrane Proteins; Metabolic Diseases; Metformin; Middle Aged; Obesity; Schizophrenia

Difficulties with affect regulation and impulse control have a strong influence on violence. The objective of this study was to determine whether baseline depression and impulsivity predict aggression and whether they predict differential response to antiaggressive treatment. This is important, as we lack knowledge as to the selection of antipsychotics for the treatment of aggression.. Physically aggressive inpatients with schizophrenia who received an evaluation of depression and impulsivity at baseline were randomly assigned in a double-blind, parallel group, 12-week trial to clozapine, olanzapine, or haloperidol. Trait impulsivity was measured by the Barratt Impulsiveness Scale; depression by the Positive and Negative Syndrome Scale Depression factor. The number and severity of aggressive events, as measured by the Modified Overt Aggression Scale (MOAS), were the outcome measures.. Baseline depression and impulsivity predicted higher levels of aggression, as measured by the MOAS total score, over the 12-week treatment period across all 3 medication groups. In addition, there was a strong interaction effect between baseline depression/impulsivity and medication grouping in predicting MOAS score. In particular, when higher depression and impulsivity were present at baseline, patients on haloperidol presented with more aggression than patients on the other 3 medications.. Depression and impulsivity are important predictors of aggression and of differential response to antiaggressive treatment. This is most likely due to the medications' dissimilar neurotransmitter profiles. By identifying patients who will respond better to a given medication, we will be able to develop individualized strategies for the treatment of violent behavior.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Depression; Double-Blind Method; Female; Haloperidol; Humans; Impulsive Behavior; Male; Middle Aged; Olanzapine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Violence; Young Adult

The present 16-week double-blind, randomized, placebo-controlled trial was aimed to explore the efficacy of ziprasidone add-on pharmacotherapy on clinical symptoms and cognitive functioning in 40 schizophrenic patients (active group, n = 20; placebo group, n = 20) with residual symptoms (Brief Psychiatric Rating Scale mean [SD] baseline total score in active group vs placebo, 40.4 [5.9] vs 37.9 [6.8]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that ziprasidone augmentation of clozapine significantly reduced Positive and Negative Syndrome Scale "Negative" (P = 0.006, mean change [SD] in active group vs placebo, -2.7 [2.3] vs 1.1 [2.1], Cohen d = 1.7) and "General Psychopathology" (P = 0.009, mean change [SD] in active group vs placebo, -5.3 [3.8] vs -0.7 [2.0], Cohen d = 1.5). Regarding cognitive domains, ziprasidone was more effective than placebo in improving semantic fluency (P < 0.0001, mean change [SD] in active group vs placebo, 4.4 [3.5] vs -0.1 [4.1], Cohen d = 1.2). Ziprasidone had only a small effect on prolongation of heart-rate corrected QT interval (QTc) of the electrocardiogram, not significantly different from placebo (QTc milliseconds, mean [SD], week 16 in active group vs placebo, 408.17 [20.85] vs 405.45 [17.11], P = 0.321); within-group comparison revealed that QTc prolongation induced by ziprasidone was statistically significant (baseline vs week 16, P = 0.002). Ziprasidone added to clozapine was effective on negative and cognitive symptoms, although it may be proposed as a helpful treatment in schizophrenia, mainly for those patients who partially respond to clozapine monotherapy.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Electrocardiography; Female; Heart Rate; Humans; Italy; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Thiazoles; Time Factors; Treatment Outcome; Young Adult

Schizophrenia is associated with impaired sleep continuity. The second generation antipsychotics clozapine and olanzapine have been reported to improve sleep continuity but also to rarely induce restless legs syndrome (RLS). The aims of this randomized double-blind study were to compare the effects of clozapine and olanzapine on sleep and the occurrence of RLS. Therefore, polysomnographies were recorded and RLS symptoms were assessed in 30 patients with schizophrenia before and after 2, 4 and 6 weeks of treatment with either clozapine or olanzapine. Treatment with both antipsychotics increased total sleep time, sleep period time and sleep efficiency and decreased sleep onset latency. These changes were similar in both groups, occurred during the first 2 treatment weeks and were sustained. For example, sleep efficiency increased from 83% (olanzapine) and 82% (clozapine) at baseline to 95% at week 2 and 97% at week 6 in both treatment groups. Sleep architecture was differently affected: clozapine caused a significantly stronger increase of stage 2 sleep (44%) than olanzapine (11%) but olanzapine a significantly stronger increase of REM-sleep. Olanzapine caused an 80% increase of slow wave sleep whereas clozapine caused a 6% decrease. No patient reported any of 4 RLS defining symptoms at baseline. During treatment, 1 patient of each group reported at one visit all 4 symptoms, i.e. met the diagnosis of an RLS. In conclusion, sleep continuity similarly improved and sleep architecture changed more physiologically with olanzapine. Neither of the antipsychotics induced RLS symptoms that were clinically relevant.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Clozapine; Databases, Factual; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Polysomnography; Schizophrenia; Sleep Wake Disorders; Time Factors; Treatment Outcome; Young Adult

Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and are associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this comorbid group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. We compared the effects of clozapine and risperidone on attentional bias, subjective craving and associated regional brain activity in patients with schizophrenia and CUD. Overall, 36 patients with schizophrenia and 19 healthy controls were included. Patients were randomised to antipsychotic treatment with clozapine or risperidone. At baseline and after 4 weeks of medication use, regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging. Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop, while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop. A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop. These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone.

Topics: Adolescent; Adult; Antipsychotic Agents; Attentional Bias; Brain Mapping; Clozapine; Craving; Humans; Magnetic Resonance Imaging; Male; Marijuana Abuse; Netherlands; Predictive Value of Tests; Risperidone; Schizophrenia; Schizophrenic Psychology; Stroop Test; Time Factors; Treatment Outcome; Young Adult

Metabolic disturbances, obesity and life-shortening cardiovascular morbidity are major clinical problems among patients with antipsychotic treatment. Especially two of the most efficacious antipsychotics, clozapine and olanzapine, cause weight gain and metabolic disturbances. Additionally, patients with schizophrenia-spectrum disorders not infrequently consume alcohol. Glucagon-like peptide-1 (GLP-1) has shown to improve glycaemic control and reduce alcohol intake among patients with type 2 diabetes.. To investigate whether the beneficial effects of GLP-1 analogues on glycaemic control and alcohol intake, in patients with type 2 diabetes, can be extended to a population of pre-diabetic psychiatric patients receiving antipsychotic treatment.. Trial design, intervention and participants: The study is a 16-week, double-blinded, randomised, parallel-group, placebo-controlled clinical trial, designed to evaluate the effects of the GLP-1 analogue liraglutide on glycaemic control and alcohol intake compared to placebo in patients who are prediabetic, overweight (body mass index ≥27 kg/m(2)), diagnosed with a schizophrenia-spectrum disorder and on stable treatment with either clozapine or olanzapine.. The primary endpoint is the change in glucose tolerance from baseline (measured by area under the curve for the plasma glucose excursion following a 4 h 75 g oral glucose tolerance test) to follow-up at week 16. The secondary endpoints include changes of dysglycaemia, body weight, waist circumference, blood pressure, secretion of incretin hormones, insulin sensitivity and β cell function, dual-energy X-ray absorption scan (body composition), lipid profile, liver function and measures of quality of life, daily functioning, severity of the psychiatric disease and alcohol consumption from baseline to follow-up at week 16. Status: Currently recruiting patients.. Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations.. ClinicalTrials.gov: NCT01845259, EudraCT: 2013-000121-31.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clinical Protocols; Clozapine; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Olanzapine; Prediabetic State; Research Design; Schizophrenia

The present 12-week open-label uncontrolled trial was aimed to explore the efficacy of reboxetine add-on pharmacotherapy on clinical symptoms and cognitive functioning in 15 patients with schizophrenia with suboptimal response (mean [SD] Brief Psychiatric Rating Scale baseline total score, 32.2 [5.4]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that reboxetine at a dosage of 4 mg/d mildly reduced only depressive symptoms (Calgary Depression Scale for Schizophrenia: P = 0.035, Cohen d = 0.7), whereas worsening of performances on phonemic fluency (P = 0.012, Cohen d = 0.5) was observed. After Bonferroni correction, changes at the Calgary Depression Scale for Schizophrenia and at the Verbal Fluency Task were not further confirmed.The results obtained indicate that reboxetine seemed to be scarcely effective for reducing clinical symptoms in patients with schizophrenia who have had an incomplete clinical response to clozapine. Regarding cognitive functioning, in our sample, a trend to experience cognitive impairment in the examined domains was observed, as confirmed by a mild worsening of performances on cognitive tasks.Schizophrenia is a heterogeneous disorder with regard to pathophysiology; therefore, data reflecting the mean response of a sample of patients may fail to reveal therapeutic effects. More research is needed to better identify subgroups of patients with peculiar features, which may account for responsivity to experimental medications and augmentation strategies.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Drug Therapy, Combination; Female; Humans; Male; Morpholines; Pilot Projects; Reboxetine; Schizophrenia

Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many adverse effects are noted. Clinicians usually hesitate to switch from clozapine to other antipsychotics because of the risk of a re-emergence or worsening of the psychosis, although empirical studies are very limited. Zotepine, an atypical antipsychotic with a pharmacologic profile similar to clozapine, was found to be an effective treatment for patients with treatment-resistant schizophrenia in Japan. This 12-week study is the first prospective, randomized, and rater-blind study to investigate the efficacy and tolerability of switching from clozapine to zotepine. Fifty-nine patients with schizophrenia, who had taken clozapine for at least 6 months with a Clinical Global Impression-Severity score of at least 3, were randomly allocated to the zotepine and the clozapine groups. At the end of the study, 52 patients (88%) had completed the trial. The 7 withdrawal cases were all in the zotepine group. The final mean (SD) dose of zotepine and clozapine was 397.1 (75.7) versus 377.1 (62.5) mg/d, respectively. Patients in the zotepine group showed a significant increase in the Brief Psychiatric Rating Scale [mean (SD), 4.7 (8.7) vs -1.3 (6.3); P = 0.005], more general adverse effects as revealed by the Udvalg for Kliniske Undersogelser Rating Scale [mean (SD), 1.74 (3.9) vs -0.2 (2.8); P = 0.039], more extrapyramidal adverse effects as demonstrated by the Simpson and Angus Scale [mean (SD), 1.29 (3.5) vs 0.17 (2.1); P = 0.022], an increased use of propranolol (37.1% vs 0%, P < 0.0001) and anticholinergics (25.7% vs 0%, P = 0.008), and an increased level of prolactin (29.6 vs -3.8 ng/ mL, P < 0.0005), compared with the clozapine group. The results suggested that switching from clozapine to zotepine treatment should be done with caution.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Dibenzothiepins; Dose-Response Relationship, Drug; Drug Substitution; Humans; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Young Adult

Japan approved clozapine for treatment-resistant schizophrenia in June 2009. The aim of this study was to evaluate clozapine's efficacy and tolerability in Japanese patients. A twelve-week, single-arm clinical trial of clozapine in treatment-resistant schizophrenia inpatients, was conducted under real-world conditions using raters masked for type of antipsychotic. Thirty-eight patients were recruited, with 33 (86.8%) completing the trial. At week 12, clozapine was associated with significant improvement in the Positive and Negative Syndrome Scale (PANSS) total (p < 0.0001), PANSS positive (p < 0.0001), negative (p = 0.0055) and general subscale scores (p < 0.0001). Significant improvements occurred in all PANSS scores by week 4, the first post-baseline psychopathology rating. Altogether, 50.0% of patients showed ≥20% reduction in PANSS total score, 20.6% had ≥30% reduction and 14.7% had >40% reduction. Eighteen patients (47.4%) were discharged before week 12. However, all patients experienced ≥1 adverse event. Two of 38 patients (5.2%) dropped out due to moderate leucopenia and one of them developed agranulocytosis after stopping clozapine. However, both patients recovered. Eight adverse events (hypersalivation, fatigue, sedation, constipation, insomnia, nausea/vomiting, chest pain and leucopenia) were observed in 34-79% of patients. These findings suggest that clozapine is beneficial in Japanese treatment-resistant schizophrenia patients. However, attention should be paid to patients' adverse events.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Female; Humans; Male; Middle Aged; Schizophrenia; Treatment Outcome

Many studies have shown that metformin can decrease body weight and improve metabolic abnormalities in patients with schizophrenia. Whether or not the beneficial effects can be sustained after discontinuation of metformin needs to be evaluated. We conducted a 24-week randomized, double-blind, placebo-controlled study to evaluate the effect of metformin on metabolic features in clozapine-treated patients with schizophrenia and followed their body weight after stopping the intervention for at least 24 weeks.. The study was conducted between September 2008 and July 2011. We recruited patients with DSM-IV diagnosis of schizophrenia or schizoaffective disorder who had been taking clozapine for more than 3 months, were overweight or obese, or fulfilled at least 1 criteria of metabolic syndrome. Eligible patients were randomized to receive metformin 1,500 mg/d or placebo. We followed metabolic features at baseline and at weeks 2, 4, 8, 16, and 24 and rechecked body weight when the patients stopped the trial after at least 24 weeks.. A total of 55 subjects (28 in the metformin and 27 in the placebo group) were enrolled. There were no significant differences in all baseline characteristics between the 2 groups, except that patients in the metformin group had higher fasting plasma glucose levels (P = .03). After the 24-week intervention, body weight (P < .0001), body mass index (P < .0001), fasting plasma glucose (P < .0001), high-density lipoprotein cholesterol (P = .03), insulin level (P = .01), and homeostasis model assessment index (P = .02) had significant changes in the metformin group. At the end of the intervention, 8 patients (28.57%) lost more than 7% of their body weight in the metformin group. Mean body weight returned to baseline after patients stopped the intervention in the metformin group.. Metformin can significantly reduce body weight and reverse metabolic abnormalities in clozapine-treated patients with schizophrenia and preexisting metabolic abnormalities. However, the beneficial effects of metformin on body weight disappeared after discontinuing this medication.

Topics: Adult; Body Weight; Clozapine; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Metabolic Syndrome; Metformin; Middle Aged; Obesity; Overweight; Psychotic Disorders; Schizophrenia; Time Factors; Treatment Outcome

Long-term studies for patients with resistant schizophrenia are necessary to assess the effectiveness of combination strategies on persisting positive symptoms.. This multicenter, naturalistic, randomized, superiority study (ClinicalTrials.gov identifier: NCT00395915) aimed to compare clinical efficacy and tolerability of haloperidol versus aripiprazole as combination treatment with clozapine in patients with resistant schizophrenia.. One hundred six patients were followed up for 12 months. After 12 months, the proportion of patients who discontinued treatment was not significantly different between aripiprazole and haloperidol (37% vs 28%, respectively; P = 0.431). The change in the Brief Psychiatric Rating Scale score was similar in the aripiprazole and haloperidol groups (-7.0 vs -7.9, respectively; P = 0.389), whereas the tolerability total score decreased significantly more in the aripiprazole group (-7.2 vs -2.3; P = 0.008).. While the effectiveness of clozapine augmentation with a second antipsychotic agent is not clearly demonstrated yet, results from this study suggest that augmentation with aripiprazole offers no substantial benefit over haloperidol in efficacy. Aripiprazole was perceived more tolerable than haloperidol, but it is uncertain how this finding may translate into the real world of clinical practice.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Disease-Free Survival; Drug Resistance; Drug Therapy, Combination; Haloperidol; Humans; Italy; Kaplan-Meier Estimate; Linear Models; Multivariate Analysis; Piperazines; Proportional Hazards Models; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

In first-episode patients with psychosis, clozapine may be potentially valuable as an initial treatment seeking to limit early on clinical and cognitive deterioration. Nevertheless, until recently its restricted use has limited the study of this possibility. Our research group is developing a non-commercial, multicentric and open label study on the differential efficacy between clozapine and risperidone in first-episode schizophrenia. In this paper, we present the results related to clinical variables after a one-year follow-up. So far, we have recruited 30 patients diagnosed with schizophrenia or schizophreniform disorder with illness duration of less than two years. The patients had not received any previous treatment and they were randomized to treatment with clozapine or risperidone. Our results indicate that on average, patients on clozapine adhered to their original treatment for a longer time period than patients on risperidone. By last observation carried forward (LOCF) analysis, patients on clozapine and risperidone displayed similar clinical improvements, although marginally greater improvements in positive and total symptoms scores were found in the clozapine group. At the 12-month point we observed a marginal improvement in negative symptom scores in patients on clozapine. Subjective secondary effects, as measured with the Udvalg for KliniskeUndersøgelser (UKU) scale, correlated negatively with negative symptoms at follow-up. Our data, although preliminary, suggest that clozapine may have a slightly superior efficacy in the initial year of treatment of first-episode treatment-naïve patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Body Weight; Clozapine; Electrocardiography; Female; Follow-Up Studies; Glycemic Index; Humans; Lipid Metabolism; Male; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Time Factors; Treatment Outcome; Young Adult

The risks of antipsychotic drugs on metabolic syndrome (MS) present many challenges for psychiatrists.. To evaluate the effectiveness and influences on glucolipid metabolism in patients with schizophrenia and metabolic disorders switched from clozapine to ziprasidone.. Schizophrenic patients with metabolic syndrome who had been treated with clozapine for ≥ 2 years were enrolled in the open-label study. All the patients were switched to ziprasidone from clozapine and followed up for 24-week. The primary endpoints included body mass index (BMI), fasting glucose (FG), triglycerides (TG), HDL cholesterol (HDL-c) and systolic pressure (SP)/diastolic pressure (DP). Secondary endpoints included scores on the Positive and Negative Syndrome Scale (PANSS) and treatment emergent symptom scale (TESS).. A total of 213 cases satisfied the inclusion and exclusion criteria, but only 194 cases eventually completed the 24-week follow-up and were divided into ziprasidone group (n=68, complete substitution) and combined treatment group (n=126, partial substitution). In the ziprasidone group, TG at 4th and 24th week, BMI and HDL-c at 24th week were significantly improved (p < 0.05), while cognitive scores and total score of the PANSS at 4th and 24th week, negative factor, the factor of anxiety and depression at 24th week were significantly lower than those at the baseline (p < 0.05); In the combined group, cognitive factor scores (4 weekend, 24 weekends) and total score of PANSS (24 weeks) was significantly lower than baseline (p < 0.05). There was no significant difference in the TESS score (p > 0.05).. Ziprasidone completely or partially substituting clozapine can improve both glucolipid metabolism disorders, and cognitive disorders and affective disorders of schizophrenia.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol, HDL; Clozapine; Cognition Disorders; Female; Follow-Up Studies; Humans; Male; Metabolic Syndrome; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Thiazoles; Triglycerides

This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine-treated patients with schizophrenia.. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole-body dual-energy X-ray absorptiometry (DXA).. Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 ± 0.006 vs. -0.005 ± 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low-density lipoprotein (LDL) levels (-15.1 ± 19.8 vs. 4.4 ± 22.5 mg/dl, P = 0.019) and LDL particle numbers (-376 ± 632 vs. -36 ± 301 nm, P = 0.035). Further, there was a significant reduction in the lean mass (-1125 ± 1620 vs. 607 ± 1578 g, P = 0.011) measured by whole-body DXA scan in the aripiprazole group. All values were expressed as mean ± standard deviation, aripiprazole vs. placebo.. Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine-treated patients with schizophrenia.

Topics: Absorptiometry, Photon; Adult; Antipsychotic Agents; Aripiprazole; Body Composition; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glucose; Glucose Tolerance Test; Humans; Lipoproteins, LDL; Magnetic Resonance Spectroscopy; Male; Piperazines; Quinolones; Schizophrenia

Constipation is a common and potentially fatal side effect of clozapine treatment. Another important side effect of clozapine may also be significant weight gain. Orlistat is a weight-control medication that is known to induce loose stools as a common side effect. This study aimed to explore whether orlistat used to control clozapine-induced weight gain can simultaneously tackle clozapine-related constipation. In this 16-week randomized-controlled study, clozapine-treated patients received add-on orlistat (n=30) or add-on placebo (n=24). Colonic function was measured using the Bristol Stool Form Scale. There was a significant (P=0.039) difference in the prevalence of constipation in favor of orlistat over placebo in completers (n=40) at the endpoint. A decrease in the prevalence of constipation within the orlistat group (P=0.035) was observed (vs. no statistically significant changes in the placebo group). In clozapine-treated patients, orlistat may be beneficial not only for weight control but also as a laxative. As no established treatments for clozapine-induced constipation exist, orlistat can be considered for this population, although more studies are required.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Colon; Constipation; Cross-Sectional Studies; Diarrhea; Double-Blind Method; Finland; Humans; Incidence; Lactones; Laxatives; Obesity; Olanzapine; Orlistat; Overweight; Patient Dropouts; Prevalence; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Weight Loss

Several placebo controlled studies investigating lamotrigine augmentation of clozapine in schizophrenia patients with partial response have shown varying results. The aim of this study was to further investigate the efficacy and safety of this augmentation strategy, and its effect on the glutamatergic system through utilizing mismatch negativity (MMN) component of auditory event related potentials.. The study was designed to evaluate the efficacy and safety of lamotrigine augmentation of clozapine in a 12-week, double-blind, placebo-controlled, prospective, randomized design. Thirty-four patients diagnosed according to DSM-IV schizophrenia criteria and with partial response to clozapine were included. Patients were randomized to 25mg/day of lamotrigine or placebo, gradually increasing up to 200mg/day on the 6th week. The change in psychopathology was assessed with Positive and Negative Syndrome (PANSS), Calgary Depression (CDS) and Clinical Global Impression-Severity (CGI-S) scales. A neuropsychological test battery was administered and MMN measurements were also obtained at baseline and endpoint. Safety evaluation included physical examination, UKU Side Effect Rating Scale (UKU) assessment and serum drug level measurements.. No significant differences were found between the two treatment groups in PANSS Positive and General Psychopathology, CDS, neurocognitive test and UKU scores, as well as MMN measurements. PANSS Total, Negative and CGI-S scores showed significant improvement compared to lamotrigine in the placebo group.. This study did not show any benefit of augmentation of clozapine with lamotrigine in schizophrenia patients with partial response. The need for further investigation of other augmentation strategies of clozapine in partially responsive schizophrenia patients is evident.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Calcium Channel Blockers; Chi-Square Distribution; Clozapine; Cognition Disorders; Double-Blind Method; Drug Synergism; Electroencephalography; Evoked Potentials, Auditory; Female; Humans; Lamotrigine; Male; Middle Aged; Neuropsychological Tests; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Triazines; Young Adult

A substantial number of patients with treatment-resistant schizophrenia respond only partially to clozapine. Therefore, it has been common practice to use augmentation strategies to maximize clozapine's effect. But the efficacy of this strategy remains poorly established. We have conducted a randomized double-blind placebo controlled clinical trial in patients with schizophrenia currently receiving clozapine with partial response, and tested the efficacy of pimozide augmentation on positive and negative symptoms and also on neurocognitive measures.. Thirty-two outpatients enrolled in the clinical trial and 28 completed. Patients with adequate blood levels of clozapine were randomized to pimozide vs placebo and participated in the trial for 12 weeks receiving monthly assessments for Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS), and weekly assessments for electrocardiogram (EKG), and side effects. Neurocognitive tests measuring verbal fluency, working memory, motor and attention/executive function were obtained at study entry and end of the trial.. We found no significant effect of pimozide on BPRS total, psychosis and depression subscale items, SANS scores or QTc interval. Neurocognitive measures did not show significant improvement either.. In this well controlled clinical trial of patients with treatment-resistant schizophrenia currently receiving clozapine, pimozide augmentation was not an effective strategy to maximize the benefit for better control of positive and negative symptoms or improving neurocognitive function.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Double-Blind Method; Drug Synergism; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Pimozide; Schizophrenia; Treatment Outcome

Previous studies have suggested the utility of nonlinear complexity measures of heart rate variability (HRV) in evaluating the regulatory capacity of the neuroautonomic system. The purpose of the present study was to investigate the effects of clozapine on the nonlinear complexity measures of HRV in patients with treatment-resistant schizophrenia to find novel electrophysiological markers that indicate response to clozapine treatment. Forty patients with treatment-resistant schizophrenia were evaluated during 8 weeks of clozapine monotherapy. For nonlinear complexity measures of HRV, the approximate entropy (ApEn) and sample entropy (SampEn) values were obtained. The response rate to clozapine was 37.5%. The results of multivariate analysis of covariance revealed that the ApEn and the SampEn values of HRV at week 8 were significantly higher in the responders than in the nonresponders. Repeated-measures analysis of covariance showed a significant group by time interaction effect in the ApEn and SampEn indices. The responder group showed an increasing pattern of change in these complexity measures after administration of clozapine, whereas the nonresponder group showed a decreasing pattern of change. These results suggest that the nonlinear dynamic complexity measures of HRV, which indicate the irregularity and complexity of the biosystem, may be useful in evaluating the therapeutic changes of neuroautonomic function in schizophrenia. The response to clozapine treatment is expected to be more favorable when the plasticity of the neuroautonomic system reflected in the nonlinear complexity measures is high.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Electrocardiography; Female; Heart Rate; Humans; Logistic Models; Male; Multivariate Analysis; Nonlinear Dynamics; Predictive Value of Tests; Prospective Studies; Psychiatric Status Rating Scales; Republic of Korea; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

Clozapine, the most widely used option in treatment-resistant schizophrenia, has been shown to be superior to other antipsychotic medications in improving cognitive function in patients. However, the results have not been consistent and the mechanisms underlying this effect have not been elucidated. Thus, the purpose of the present study was to evaluate verbal and nonverbal cognition (using visuospatial processing tests) in patients treated with clozapine (initially treatment resistant) and those treated with other second-generation antipsychotics, relative healthy control subjects. Furthermore, we examined neural correlates of visuospatial processing in the three groups.. Twenty schizophrenia patients treated with clozapine (TR-C group), 23 patients stabilised with atypical antipsychotics other than clozapine (NTR group), and 21 healthy control participants completed a battery of verbal and visuospatial cognitive tests. In addition, participants underwent functional magnetic resonance imaging (fMRI) while performing one of the visuospatial tests (the mental rotation task). The fMRI data were analysed separately in each group using Statistical Parametric Mapping software (SPM5).. Overall, schizophrenia patients exhibited deficit on verbal and nonverbal processing relative to the healthy controls, but we observed some interesting differences between the two groups of patients. Specifically, the NTR group performed better than the TR-C group on the Block Design and the Raven's Progressive Matrices. With respect to brain function during mental rotation, the NTR group showed significant activations in regions of the temporal and occipital cortex, whereas the TR-C patients did not. The relative deactivations associated with the task were also more robust in NTR compared to the other group of patients, despite a similar performance.. Present results suggest better visuospatial processing in the NTR relative to the TR-C group. This difference could be attributed to the treatment resistance itself or a lack of beneficial effect of clozapine relative to other atypical antipsychotics in ameliorating nonverbal abilities. Future studies of the relationship between clozapine and cognition, as well as between treatment resistance and cognition, are warranted.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Cognition Disorders; Dibenzothiazepines; Drug Resistance; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia; Space Perception; Young Adult

Despite extensive experience with antipsychotic medications, we have limited capacity to predict which patients will benefit from which medications and for what symptoms. Such prediction is of particular importance for the proper treatment of violence. Our goal was to determine whether executive function predicts outcome of treatment for aggressive behavior and whether such prediction varies across medication groups.. Ninety-nine physically aggressive inpatients (aged 18-60 years) with schizophrenia or schizoaffective disorder (diagnosed according to DSM-IV) who completed tests of executive function were randomly assigned in a double-blind, parallel-group, 12-week trial to clozapine (n = 32), olanzapine (n = 32), or haloperidol (n = 35). The number and severity of aggressive events as measured by the Modified Overt Aggression Scale (MOAS) were the outcome measures. Psychopathology and medication side effects were also assessed. The study was conducted from 1999 to 2004.. Poor executive function predicted higher levels of aggression, as measured by MOAS scores over the 12-week period, in all 3 medication groups (F(1,98) = 222.2, P < .0001). There was, however, a significant interaction effect between medication grouping and executive function (F(1,98) = 15.32, P < .001): clozapine exerted an antiaggression effect even in the presence of executive dysfunction.. Executive function was a strong predictor of response to antiaggression treatment in all medication groups, but clozapine still retained clinical efficacy in the presence of poor executive functioning. Olanzapine was particularly efficacious in the absence of executive dysfunction. These findings have important implications for a targeted approach to the treatment of aggression in patients with schizophrenia.. clinicaltrials.gov Identifier: NCT01123408.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Executive Function; Female; Haloperidol; Humans; Male; Olanzapine; Predictive Value of Tests; Psychological Tests; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology; Tetrabenazine

We have previously shown that patients with schizophrenia treated with typical antipsychotics were impaired on the weather prediction probabilistic classification learning (PCL) task that relies on striatal function, and that similar patients treated with atypical antipsychotics were impaired on the Iowa gambling task (IGT) that depends on medial prefrontocortical function.. We tested the hypothesis that test performance of patients treated with risperidone will be more similar to those treated with typical rather than atypical antipsychotics.. Groups of schizophrenia patients treated with risperidone, olanzapine, clozapine or typical antipsychotics did not differ on the Positive and Negative Syndrome Scale or the Mini Mental State Exam (MMSE) but scored lower than controls on the MMSE. For the PCL task, patients treated with clozapine improved over trials while those treated with typical antipsychotics, olanzapine, or risperidone did not. For the IGT, patients treated with typical antipsychotics or risperidone improved over trials while those treated with clozapine or olanzapine did not.. Results generally supported the hypothesis that patients treated with risperidone perform more like those treated with typical antipsychotics than those treated with other atypical antipsychotics.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Decision Making; Female; Gambling; Humans; Learning; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

Sleep propensity at daytime has not been investigated in untreated patients with schizophrenia. Furthermore, while the antipsychotics clozapine and olanzapine are considered to frequently cause 'sleepiness' or 'sedation', this has not been objectified yet. Therefore, 30 patients with schizophrenia were included in this randomized, double-blind study. Sleep propensity was assessed before and after 2, 4 and 6 weeks of treatment with either clozapine or olanzapine using a Multiple Sleep Latency Test (MSLT); in the MSLT, sleep latencies of 5 nap opportunities of 20 min during daytime are averaged. In addition, the number of sleep onsets was recorded. Mean sleep latency in untreated schizophrenic patients was 16.2 ± 0.8 min at baseline. Both antipsychotics induced an increase of sleep propensity as indicated by a shortened sleep latency and more sleep onsets during the treatment period as compared to baseline. These effects were strongest in the morning. Four patients receiving clozapine and 3 patients receiving olanzapine reported subjective sleepiness, in all but one commencing in the first treatment week and persisting until study end. While the mean sleep latency during treatment was significantly shorter in these patients (12.3 ± 0.8 min) than in those without subjective sleepiness (14.9 ± 0.7 min), a short sleep latency was not necessarily associated with subjective sleepiness. In conclusion, mean sleep latency was >36% longer (i.e. sleep propensity was lower) in untreated patients with schizophrenia than in healthy subjects previously consistently reported. Furthermore, clozapine and olanzapine increased sleep propensity in schizophrenic patients. A minority of patients reported subjective sleepiness.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Clozapine; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Polysomnography; Psychiatric Status Rating Scales; Reaction Time; Schizophrenia; Sleep Stages; Statistics as Topic; Time Factors; Young Adult

To assess the cognitive effects of sertindole augmentation in clozapine-treated patients diagnosed with schizophrenia. Cognition is secondary outcome of the trial.. A 12-week, double-blinded, randomized, placebo-controlled, augmentation study of patients treated with clozapine. Participants were randomized 1:1 to receive 16 mg of sertindole or placebo as adjunctive treatment to clozapine.. Participants displayed substantial cognitive deficits, ranging from 1.6 standard deviation below norms at baseline to more than three standard deviations on tests of response readiness and focused attention. There were no significant differences between sertindole augmentation and placebo groups at study end. Correlation analysis of Positive and Negative Syndrome (PANSS) subscales, Global Assessment of Functioning subscale (GAF-F) and Clinical Global Impression (CGI) with 20 neurocognitive indices was conducted, but no significant correlations were found. Second, we tested change from baseline to endpoint for the PANSS, GAF-F, and CGI, vs. the concomitant changes in cognitive test performance, and found no significant correlations.. The clozapine-treated patients displayed marked cognitive deficits at baseline. Adding sertindole did not improve or worsen cognitive functioning, which is in line with previous negative studies of the effect on cognition of augmenting clozapine treatment with another antipsychotic drug.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Imidazoles; Indoles; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Schizophrenia

Clozapine augmentation with antipsychotic drugs is widely used despite sparse evidence supporting this strategy. Sertindole is a nonsedating atypical antipsychotic drug with low affinity for cholinergic receptors, which makes it potentially suitable for augmentation of clozapine. The study design was a 12-week, double-blind, randomized, placebo-controlled study including patients with International Statistical Classification of Diseases, 10th Revision schizophrenia (F20.0-F20.3) and treated with clozapine for at least 6 months who had not achieved sufficient response. Patients were randomized 1:1 to either sertindole 16 mg or placebo, and assessment was done at baseline and after 6 and 12 weeks. Assessment included the Positive and Negative Syndrome Scale, Clinical Global Impression, Udvalg for Kliniske Undersøgelser, World Health Organization Quality of Life Brief, Drug Attitude Inventory, fasting glucose, lipids, and electrocardiogram. Clozapine augmentation with sertindole was not superior to placebo regarding total score or subscale score of the Positive and Negative Syndrome Scale, Clinical Global Impression, World Health Organization Quality of Life Brief, or Drug Attitude Inventory. No increased adverse effects compared with placebo were found. Four patients randomized to sertindole experienced a significant worsening of psychosis, and 2 of them required psychiatric admission. Metabolic parameters were unchanged during the study, but augmentation of clozapine with sertindole was associated with a 12-millisecond (SD, 20-millisecond) QTc prolongation compared with 0 millisecond (SD, 20 milliseconds) in the placebo group (P < 0.03). Augmentation with sertindole showed no benefits compared with placebo. Psychiatrists should be aware that augmentation might not add any benefits for the patients and in some cases worsen psychosis.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Imidazoles; Indoles; Male; Middle Aged; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Treatment Outcome

Social cognition captures affect recognition, social cue perception, "theory of mind," empathy, and attributional style. The aim of our study was to assess social cognition in schizophrenia inpatients being treated with first-generation antipsychotic drugs (FGAs), n=28 (perphenazine and haloperidol, FGAs) or with second-generation antipsychotic drugs (SGAs), n=56 (olanzapine and clozapine, SGAs).. Eighty-four patients completed the Facial Expression Recognition Test, the Voice Emotion Recognition Test, the Short Recognition Memory Test for Faces, and the Reading the Mind in the Eyes Test. Patients also completed the Visual Object and Space Perception Test (VOSP) as a control task, which would not engage social cognition. The patients were compared with fifty healthy controls matched for age and gender.. There were no significant differences on social cognitive performance between the FGA- and SGA-treatment groups. Nor was olanzapine superior to clozapine, FGAs or both. However, patients treated with FGAs performed significantly worse on VOSP compared to both groups treated with SGAs, a 10% difference.. We cannot conclude that SGAs were associated with better social cognition than FGAs. However, there were small but significant advantages for SGAs in non-social visual processing function, as evaluated with the VOSP.

Topics: Adolescent; Adult; Affect; Antipsychotic Agents; Awareness; Benzodiazepines; Case-Control Studies; Clozapine; Cues; Discrimination, Psychological; Emotions; Facial Expression; Female; Haloperidol; Hospitalization; Humans; Linear Models; Male; Middle Aged; Olanzapine; Perphenazine; Psychotic Disorders; Retina; Schizophrenia; Schizophrenic Psychology; Social Behavior; Social Perception; Speech Perception; Theory of Mind; Visual Perception; Young Adult

There is evidence to suggest that clozapine is underutilized in treatment-refractory schizophrenia. Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a multi-phase, randomized comparative effectiveness trial for schizophrenia, were used to identify factors associated with choosing randomization to clozapine. Two pathways were available in phase 2 of CATIE: randomization to clozapine or an untried atypical antipsychotic (2E), or randomization to an untried atypical antipsychotic (2T). We examined the proportion of entrants who chose to enter phase 2E due to the lack of efficacy of the phase 1 treatment, along with their demographic and clinical characteristics. Only 31.2% who discontinued phase 1 for lack of efficacy entered phase 2E. In multivariable analysis, males showed significantly increased odds of choosing phase 2E (adjusted odds ratio (AOR) = 2.38; confidence interval (CI) = 1.20, 4.70) as did patients with higher Positive and Negative Syndrome Scale total scores (AOR = 1.01; CI = 1.00, 1.03), more inpatient days (AOR = 1.06; CI = 1.02, 1.10) and more outpatient visits, (AOR = 1.06; CI = 1.02, 1.11). More effort examining the decision-making process of patients and providers is needed in order to increase the utilization of this effective treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Olanzapine; Patient Acceptance of Health Care; Patient Dropouts; Patient Participation; Perphenazine; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Sex Characteristics

Studies have shown that insulin resistance is associated with cognitive impairment. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists improve insulin sensitivity. The purpose of this study was to evaluate the effect of rosiglitazone, a PPAR-γ agonist, on cognition in clozapine-treated patients with schizophrenia. In an eight-week double-blind, placebo-controlled pilot trial, clozapine-treated patients with schizophrenia were randomized to receive rosiglitazone (4mg/day) or placebo. A neuropsychological battery including the Digit Span subtest from the Wechsler Adult Intelligence Scale-III (WAIS-III), the verbal fluency test, the Hopkins Verbal Learning Test (HVLT), the Trail-Making Test (TMT) and the Wisconsin Card Sorting Test (WCST) was administered at baseline and week eight. Nineteen patients completed the study. There were no significant differences on any demographic or general clinical variables between the rosiglitazone group (n=9) and the placebo group (n=10). When baseline scores were controlled, there were no significant differences in change scores of cognitive performance over eight weeks between the two groups. In this pilot study, rosiglitazone had no cognitive benefit in clozapine-treated patients with schizophrenia. Future studies with longer treatment duration and larger sample size are needed to further explore the potential role of rosiglitazone in improving cognitive function in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Cognition Disorders; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Neuropsychological Tests; Pilot Projects; PPAR gamma; Rosiglitazone; Schizophrenia; Thiazolidinediones; Treatment Outcome

In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from 4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to 101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h, respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients regarding both the rate and extent of absorption.

Topics: Administration, Oral; Antipsychotic Agents; Biological Availability; Chromatography, High Pressure Liquid; Clozapine; Cross-Over Studies; Humans; Schizophrenia; Tandem Mass Spectrometry

To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.. Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.. A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.. Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

Topics: Adolescent; Adult; Antipsychotic Agents; Asian People; China; Clozapine; Drug Monitoring; Female; Humans; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Prospective Studies; Schizophrenia; Sex Factors; Smoking; Tissue Distribution; Young Adult

Clozapine is the most effective drug for schizophrenia. A suspension formulation of clozapine for patients who may have difficulty swallowing tablets was approved based on the 1996 US Food and Drug Administration (FDA) Guidance and has been launched in Australia, New Zealand and the UK. The objective of this study was to compare the bioequivalence of a new suspension formulation of clozapine with clozapine tablets (Clozaril(®)).. The steady-state bioequivalence of a 50-mg/mL clozapine suspension and Clozaril(®) tablets was compared under fasting and fed conditions in a randomized, multiple-dose, two-way crossover study, consistent with the 2005 FDA Bioequivalence Guidance. Adult patients with schizophrenia established on once-daily doses of clozapine were administered Clozaril(®) tablets or clozapine suspension for 11 days, then switched to the other formulation for the next 11 days. On days 10 and 11 of each period, fasted (day 10) and fed (day 11) pharmacokinetic profiles were obtained over 24 h.. Compared with the tablet formulation, point estimates for maximum plasma concentration (C(max)) and area under the plasma concentration-time curve during a dosage interval (τ) [AUCτ] for the suspension formulation were close to 100 %, and all 90 % confidence intervals (CIs) were between 80 % and 125 % under fasted (C(max) 99.91; 90 % CI 94.60, 104.70; AUC(τ) 99.55; 90 % CI 92.40, 100.70) and fed (C(max) 99.72; 90 % CI 93.70, 103.50; AUC(τ) 99.68; 90 % CI 93.40, 101.80) conditions. Food did not affect AUC(τ); however, C(max) was reduced by ~20 %, with a similar magnitude of change for both formulations. Safety/tolerability profiles were similar between the two formulations.. The tablet and suspension formulations are bioequivalent, with similar safety profiles, under fed and fasted conditions.

Topics: Administration, Oral; Adult; Analysis of Variance; Antipsychotic Agents; Area Under Curve; Chemistry, Pharmaceutical; Clozapine; Cross-Over Studies; Fasting; Female; Humans; Least-Squares Analysis; Male; Middle Aged; New Zealand; Postprandial Period; Schizophrenia; Suspensions; Tablets; Therapeutic Equivalency; Young Adult

This study was undertaken to examine if patients exhibit more pronounced metabolic abnormalities after 8-year treatment with clozapine or olanzapine than before, and also to investigate whether there exist any differences between long-term clozapine and olanzapine therapies regarding metabolic side- effects.. Fifty psychiatric outpatients diagnosed with schizophrenia or schizoaffective disorder and on treatment with clozapine or olanzapine were studied during 8 years. Fasting blood or serum samples for glucose, lipids, prolactin and antipsychotic drug concentrations were analyzed. In addition, body mass index was calculated.. More patients treated with olanzapine compared with those treated with clozapine ended with their medication, in most cases because of diabetes mellitus and/or hyperlipidemia, during the 8-year follow-up. Also more patients treated with olanzapine compared with those treated with clozapine developed manifest diabetes mellitus during the 8-year period. Prolactin levels were higher in the patients treated with olanzapine compared with in those treated with clozapine at study start, but there were no differences in the other parameters between the treatment groups at study start. In the patients remaining on their medication all 8 years, the glucose level increased over time in the clozapine group, but not in the olanzapine group, whereas body mass index and lipids were unchanged over time in both treatment groups.. Our findings point to that both olanzapine and clozapine long-term treatments cause development of hyperglycemia and/or hyperlipidemia. Furthermore, olanzapine long-term treatment seems to more often lead to development of manifest diabetes mellitus than long-term treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hyperlipidemias; Male; Metabolic Diseases; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia

The persistence of psychotic, affective, cognitive, and psychosocial symptoms despite medications is commonly observed in schizophrenic patients. The present study was a 24-week double-blind, randomized, placebo-controlled trial aimed to explore the efficacy of topiramate add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine. After clinical and cognitive assessments were randomly allocated to receive either up to 200 mg/day of topiramate or a placebo. A final sample of 43 patients completed the study. The results obtained indicate that topiramate appeared to be scarcely effective for reducing clinical symptomatology in schizophrenic patients who have had an incomplete clinical response to clozapine. Regarding cognitive functioning, in our sample a trend to experience cognitive impairment in the examined domains was observed, as the patients included in the topiramate groups expressed cognitive complaints partially confirmed by a mild worsening of performances on certain cognitive tasks. Schizophrenia is a heterogeneous disorder with regard to pathophysiology; therefore, data reflecting the mean response of a sample of patients may fail to reveal therapeutic effects. More research is needed to better identify subgroups of patients with peculiar features which may account for responsivity to experimental medications and augmentation strategies.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Cognition; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Schizophrenia; Topiramate; Treatment Outcome; Young Adult

To explore long-term effects of orlistat in adult clozapine- or olanzapine-treated patients with DSM-IV-diagnosed schizophrenia and overweight or obesity who tolerate orlistat.. Orlistat or placebo was added to clozapine or olanzapine in stable doses in a 16-week randomized controlled trial. Open-label orlistat was added to the antipsychotics during a 16-week extension phase for those completing the double-blind phase. No low-calorie diet or participation in behavioral programs was required. Body weight (primary outcome) and some metabolic parameters were measured prospectively. Analyses were performed for those completing both phases (ie, population differing from that reported earlier). The study was conducted from 2004 through 2005.. During the open-label phase, the 44 patients experienced mean ± SD body weight loss of -1.29 ± 3.04 kg, P = .007. During both phases, men (but not women) showed a weight loss of -2.39 ± 5.45 kg, P = .023. Some subgroups showed desirable changes in several metabolic parameters. Prolonged (32 weeks) orlistat treatment yielded no additional benefits as compared to short (16 weeks) treatment.. In clozapine- or olanzapine-treated overweight or obese patients able to take orlistat on a long-term basis, the drug, with no concomitant hypocaloric diet or behavioral interventions, caused moderate weight loss only in men. However, some metabolic benefits may be achieved independently of weight changes. In patients who do not respond to orlistat within the first 16 weeks, continuation treatment may provide no additional benefits.. controlled-trials.com Identifier: ISRCTN65731856.

Topics: Adult; Anti-Obesity Agents; Antipyretics; Benzodiazepines; Cholesterol; Cholesterol, LDL; Clozapine; Double-Blind Method; Female; Humans; Lactones; Male; Obesity; Olanzapine; Orlistat; Schizophrenia; Sex Factors; Treatment Outcome; Weight Loss

Previous publications demonstrated substitute benzamides as effective agents in treatment of clozapine-induced sialorrhea (CIS). The aim of this study was to compare efficacy of amisulpride and moclobemide (both from the substitute benzamide group) in controlling, or at least minimizing, CIS.. The study was designed as a 6-week, two-center, fixed-dose, comparison study of 400 mg/day of amisulpride versus 300 mg/day of moclobemide as an adjunctive treatment in 53 schizophrenia and schizoaffective disorder patients (diagnosed according to DSM-IV) suffering from CIS. The patients were treated with each medication during 2 weeks, followed by a washout period of 2 weeks. Primary outcome measures included the reduction in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Secondary outcomes included the Positive and Negative Syndrome Scale (PANSS), Manic State Assessment Scale, and Extrapyramidal Symptom Rating Scale (ESRS).. Both amisulpride and moclobemide were very effective in reducing CIS. Almost 74% of patients treated with amisulpride and 83% of patients treated with moclobemide showed some level of improvement on NHRS. Only in one patient treated with amisulpride, CIS worsened.. Both medications were safe and effective as treatment of CIS. Although moclobemide exceeded amisulpride in antisalivation activity, treatment of CIS with amisulpride leads to improvement in psychotic symptoms.

Topics: Adult; Aged; Amisulpride; Antipsychotic Agents; Clozapine; Cross-Over Studies; Female; Humans; Male; Middle Aged; Moclobemide; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Sialorrhea; Sulpiride

Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50-70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Double-Blind Method; Electroencephalography; Female; Humans; Male; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Schizophrenia; Statistics, Nonparametric; Transcranial Magnetic Stimulation

Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has been shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. To examine serum BDNF, two groups of chronically medicated DSM-IV SZ patients (n=44), on treatment with clozapine (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

Topics: Adult; Antipsychotic Agents; Brain-Derived Neurotrophic Factor; Clozapine; Female; Humans; Male; Schizophrenia

The simultaneous prescription of two or more antipsychotic drugs in combination is a common treatment strategy for those patients who have demonstrated a suboptimal response to clozapine; nevertheless, evidence suggesting potential advantages of combination treatment with clozapine plus one antipsychotic in terms of efficacy and tolerability are still sparse. The present 24-week double-blind, randomized, placebo-controlled trial of adjunctive aripiprazole to clozapine therapy in schizophrenia was aimed to explore the efficacy of aripiprazole add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 15 mg/day of aripiprazole or a placebo. A final sample of thirty-one patients completed the study. The results obtained indicate that aripiprazole added to stable clozapine treatment showed a beneficial effect on the positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenia patients. Regarding executive cognitive functions, aripiprazole augmentation of clozapine had no significant effects. The findings provide evidence that aripiprazole augmentation of clozapine treatment is well-tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy; further double-blind, placebo-controlled trials in a larger number of patients are required to evaluate the therapeutic potential of aripiprazole augmentation of clozapine.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Aripiprazole; Clozapine; Double-Blind Method; Drug Interactions; Female; Humans; Male; Piperazines; Quinolones; Schizophrenia; Time Factors

The differential effects of so-called 'first- and second generation' antipsychotic medications, when given in the first episode, on the long-term outcome of schizophrenia remain to be elucidated.. We compared the 9-year outcomes of individuals initially randomised to clozapine or chlorpromazine.. One-hundred and sixty individuals with treatment-naive, first episode schizophrenia or schizophreniform disorder in a mental health centre in Beijing, China were randomised to clozapine or chlorpromazine treatment for up to 2 years,followed by up to an additional 7 years of naturalistic treatment. The primary outcome was remission status for individuals in each group.. Individuals in both groups spent essentially equal amounts of time in each clinical state over the follow-up time period(remission, 78%; intermediate, 8%; relapse, 14%). There were no significant differences on other measures of illness severity. The clozapine group was more likely than the chlorpromazine group to remain on the medication to which they were originally assigned (26% v. 10%, P = 0.01). There were no significant differences between the two groups on other secondary efficacy outcomes.. These findings support the comparability in effectiveness between antipsychotic medications but with slightly greater tolerability of clozapine in the treatment of first-episode psychosis.

Topics: Adolescent; Adult; Antipsychotic Agents; China; Chlorpromazine; Clozapine; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Linear Models; Male; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Survival Analysis; Time Factors; Treatment Outcome; Young Adult

Previous studies investigated whether prolactin (PRL) serum level was a biomarker of antipsychotic response, schizophrenia symptomatology, and tardive dyskinesia. Most of the findings support that antipsychotic drugs modulate PRL levels but PRL is not a steady indicator. Recent results suggest a genetic effect of PRL and PRL receptor (PRLR) polymorphisms in PRL levels indicating that independently of antipsychotic therapy subjects could have altered PRL levels due to their genetic background.We evaluated whether PRL and PRLR variants were associated with treatment outcome and tardive dyskinesia. We observed no association of PRL/PRLR polymorphism with treatment response (best genotypic results include PRL rs849885 and PRLR rs4703509 permuted p=0.326). Regarding tardive dyskinesia, the major allele of PRL rs37364 was nominally associated with risk for tardive dyskinesia in the European ancestry sub-sample (permuted p=0.183). Although we reported no significant associations, it is definitely worthy of investigation to see if together (genetic variants in the PRL system and PRL serum measures) could be a reliable biomarker for antipsychotic response and TD prevalence. Our results suggest that more studies in this context are required to shed light in the molecular mechanisms underlying antipsychotic response and tardive dyskinesia occurrence.

Topics: Adult; Alleles; Antipsychotic Agents; Biomarkers; Clozapine; Dyskinesia, Drug-Induced; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Prolactin; Prospective Studies; Receptors, Prolactin; Schizophrenia; Treatment Outcome; White People; Young Adult

Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Double-Blind Method; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pimozide; Placebos; Psychotic Disorders; Schizophrenia

It has been proposed that a deficit of adenosinergic activity could contribute to the pathophysiology of schizophrenia. The authors undertook this study to further evaluate the level of adenosine deaminase (ADA) in patients with chronic schizophrenia treated with monotherapy of haloperidol, risperidone or clozapine and correlation between the ADA level with response to treatment.. The trial was a prospective, 8-week, double blind study of parallel groups of patients with chronic schizophrenia. Eligible participants in the study were 51 patients with chronic schizophrenia with ages ranging from 20 to 45 years. All participants were inpatients, in the active phase of illness, and met DSM-IV-TR criteria for schizophrenia. Patients were randomly allocated (17 patients in each group) to risperidone (6 mg/day) or haloperidol 15 mg/day or clozapine (300 mg/day). Serum ADA activity was measured at baseline and week 8.. The plasma levels of ADA in patients with chronic schizophrenia who received clozapine were significantly higher than patients who received haloperidol. In addition, response to treatment was positively correlated with plasma levels of ADA only in the clozapine group (r = 0.46 and p = 0.04).. The results indicate an increased activity of the enzyme ADA in the serum of schizophrenic patients being treated with clozapine and this increase may be correlated with clozapine's superior antipsychotic efficacy.

Topics: Adenosine; Adenosine Deaminase; Adult; Chronic Disease; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Prospective Studies; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

Early, effective treatment in first-episode schizophrenia is advocated, although evidence based on a systematic approach over multiple antipsychotic trials is lacking. Employing a naturalistic design, we examined response rates over 3 circumscribed antipsychotic trials.. Between June 2003 and December 2008, 244 individuals with first-episode schizophrenia or schizoaffective disorder according to DSM-IV criteria were treated at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, following an algorithm that moved them through 2 antipsychotic trials, followed by a trial with clozapine. For the first 2 trials, treatment consisted of risperidone followed by olanzapine, or vice versa; each trial consisted of 3 stages (low-, full-, or high-dose) lasting up to 4 weeks at each level and adjusted according to response/tolerability. Clinical response was defined as a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved) and/or a Brief Psychiatric Rating Scale Thought Disorder subscale score ≤ 6. Data were analyzed retrospectively, and publication of anonymized clinical data was approved by the Research Ethics Board of the Centre for Addiction and Mental Health in May 2003.. In trial 1, 74.5% of individuals responded, with rates significantly higher for olanzapine (82.1%, 115/140) versus risperidone (66.3%, 69/104; P = .005). With trial 2, response rate dropped dramatically to 16.6% but again was significantly higher for olanzapine (25.7%, 9/35) compared to risperidone (4.0%, 1/25; P = .04). Response rate climbed above 70% once more, specifically 75.0% (21/28), in those individuals who agreed to a third trial with clozapine.. Results confirm a high response rate (75%) to initial antipsychotic treatment in first-episode schizophrenia. A considerably lower response rate (< 20%) occurs with a second antipsychotic trial. Results here were specific to olanzapine and risperidone, suggesting clinical differences (ie, olanzapine more effective than risperidone). A subsequent trial with clozapine is clearly warranted, although it remains unclear whether outcome would be further enhanced if it were used earlier in the treatment algorithm.

Topics: Adolescent; Adult; Algorithms; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Female; Humans; Male; Olanzapine; Prospective Studies; Quetiapine Fumarate; Retrospective Studies; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

In recent years, several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics. While there has been some success, in general, results have not been compelling. Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression. Therefore, we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or olanzapine.. The study was a double-blind, placebo-controlled trial. All participants received the same psychosocial platform: a structured support and exercise group. People with schizophrenia or schizoaffective disorder, on olanzapine or clozapine, who had gained at least 7% of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week, randomized, parallel group, double-blind comparison of adjunctive atomoxetine or placebo.. Thirty-seven participants (20 atomoxetine, 17 placebo) were randomized and 26 participants (14 atomoxetine, 12 placebo; 70.2%) completed the study. There were no significant group differences in baseline BMI (atomoxetine: 34.5±4.9; placebo: 35.7±7.0) or weight (atomoxetine: 102.2±15.7 kg; placebo: 104.3±17.5 kg). Both treatment groups showed modest, not significant, trends in weight loss, averaging about 2 kg. Gender or baseline antipsychotic treatment did not modify treatment effects on weight. Secondary outcomes included neuropsychological assessments, symptom assessments (BPRS, SANS) and safety assessments. Of these, only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine.. Atomoxetine is not effective for weight loss in this population, but both olanzapine and clozapine participants can lose weight with structured group support and exercise.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Appetite Depressants; Atomoxetine Hydrochloride; Attention; Benzodiazepines; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Clozapine; Combined Modality Therapy; Diet, Reducing; Double-Blind Method; Exercise; Female; Humans; Life Style; Male; Maryland; Middle Aged; Neuropsychological Tests; Obesity; Olanzapine; Propylamines; Psychotic Disorders; Schizophrenia

This multisite study was conducted to compare the efficacy and tolerability of combination treatment with clozapine plus aripiprazole versus combination treatment with clozapine plus haloperidol in patients with schizophrenia who do not have an optimal response to clozapine. Patients continued to take clozapine and were randomly assigned to receive daily augmentation with aripiprazole or haloperidol. Physicians prescribed the allocated treatments according to usual clinical care. Withdrawal from allocated treatment within 3 months was the primary outcome. Secondary outcomes included severity of symptoms on the Brief Psychiatric Rating Scale and antipsychotic subjective tolerability on the Liverpool University Neuroleptic Side Effect Rating Scale. A total of 106 patients with schizophrenia were randomly assigned to treatment. After 3 months, we found no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups (13.2% vs 15.1%, P = 0.780). The 3-month change of the Brief Psychiatric Rating Scale total score was similar in the aripiprazole and haloperidol groups (-5.9 vs -4.4 points, P = 0.523), whereas the 3-month decrease of the Liverpool University Neuroleptic Side Effect Rating Scale total score was significantly higher in the aripiprazole group than in the haloperidol group (-7.4 vs -2.0 points, P = 0.006). These results suggest that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia compared with augmentation with haloperidol. However, an advantage in the perception of adverse effects with aripiprazole treatment may be meaningful for patients.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Brief Psychiatric Rating Scale; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Haloperidol; Humans; Male; Piperazines; Quinolones; Schizophrenia

A positive relationship between cholesterol levels and cognition has been reported in various human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol.. This was a double-blind randomized prospective 12-week study. Participants received a baseline evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were evaluated at the end of 12 weeks. A general cognitive index (GCI) derived from the cognitive battery was the primary variable.. 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There was a statistically and clinically significant positive association between change in cholesterol levels and change in GCI. This association was especially pronounced for verbal memory. There was no interaction between medication grouping and cholesterol level; the positive association was observable separately in each medication group. It was very robust and remained significant after we controlled for glucose and triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications, and pre-study antipsychotic medications.. Cholesterol levels show a strong association with cognition in schizophrenia in all medication groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core deficit of schizophrenia.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Clozapine; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Triglycerides; Young Adult

It is reported that 30% to 80% schizophrenia patients suffered from hypersalivation when taking clozapine. Some investigations of the use of formulas of traditional Chinese medicine (TCM) to treat clozapine-induced hypersalivation suggested their potential treatment effects. In these formulas, Suoquan Pill (SQP) and Wuling Powder (WLP) were suggested to have therapeutic effects in improving clozapine-induced hypersalivation.. A prospective, double-blind, randomized, placebo-controlled study will be conducted to test the therapeutic effects of SQP and WLP in relieving hypersalivation in patients taking clozapine. A total of 45 patients will be enrolled into this study with 15 in each treatment group. Patients will receive medication according to their assigned group. Either SQP 10 g per oral dose twice daily, WLP 10 g per oral dose twice daily or placebo powder 10 g per oral dose twice daily will be prescribed to the patients for 8 weeks. The Drooling Severity Scale, Nocturnal Hypersalivation Rating Scale and sialoscintigraphy will be used as the primary outcome measures; the Clinical Global Impressions Severity, the Positive and Negative Syndrome Scale, the Abnormal Involuntary Movement Scale, the Simpson-Angus Scale and the TCM constitutional scale will be used as the secondary outcome measures. It is hypothesized that SQP and WLP will have a beneficial effect in controlling clozapine-induced hypersalivation symptoms. It may also improve the life quality of psychotic patients by improving their mental status.. ClinicalTrials.gov (Identifier: NCT01045720).

Topics: Clozapine; Double-Blind Method; Drugs, Chinese Herbal; Humans; Phytotherapy; Placebos; Prospective Studies; Research Design; Schizophrenia; Sialorrhea

Sedation is a common side effect of clozapine treatment and may exacerbate metabolic consequences of poor diet and exercise habits that are common in patients with schizophrenia. Modafinil has been proposed as a treatment for clozapine-induced sedation and metabolic abnormalities.. To estimate the effect sizes and person-to-person variation in anthropometric measures, glucose and lipid metabolism, and diet on modafinil treatment for future randomized control trials.. A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted, adding modafinil up to 300 mg/day to stabilized schizophrenia outpatients receiving clozapine. Blood pressure, weight, BMI, laboratory assays, and dietary intake were tracked to monitor changes in metabolic markers.. Thirty-five participants were randomly assigned to treatment with study drug or placebo and were included in the analysis. Modafinil did not improve blood pressure, weight, BMI, glucose or lipid metabolism compared to placebo. Modafinil was well tolerated and did not worsen psychosis.. Results of this pilot trial do not support routine use of modafinil to counteract increased weight and metabolic diseases in patients taking clozapine. However, the effects of modafinil on weight and insulin regulation warrant further investigation with effect sizes of 0.4 to 0.6.

Topics: Adult; Analysis of Variance; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Weight; Clozapine; Double-Blind Method; Female; Follow-Up Studies; Humans; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Modafinil; Neuroprotective Agents; Retrospective Studies; Schizophrenia; Time Factors

The limitations of antipsychotics for treatment of schizophrenia have led to investigation of the usefulness of pharmacological augmentation strategies. Clinical studies have provided evidence for glutamate abnormalities in schizophrenia. Topiramate is an anticonvulsant drug with alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist properties; therefore, the objective of the present study was to explore the therapeutic efficacy of topiramate as an adjunctive medication in schizophrenia.. A 17 week, double-blind, placebo-controlled clinical trial was performed on 80 patients (25 - 65 years) from 2005 - 2007. All were hospitalized in Mashhad psychiatric hospitals with chronic DSM-IV-TR-diagnosed schizophrenia. All participants received up to 300 mg/day of clozapine. In addition, participants randomly received either topiramate (200 - 300 mg/day) or placebo gradually added to their ongoing treatment. Efficacy of medication was measured by administering Positive and Negative Syndrome Scale at baseline and weeks 4, 8, 12, and 17.. During the study, 5 patients from the placebo group and 12 participants from topiramate group were excluded. Clozapine and topiramate group showed significant decreases in all three subscales of PANSS values from baseline, with the maximum efficacy in week 12. However, after tapering topiramate, the general psychopathology sign was the only subscale that showed a significant difference. The clozapine and placebo group showed a significant decrease in all three subscales of PANSS values compared to baseline. The significant efficacy for all subscales was obtained at the end point. No significant differences in PANSS scores from baseline to end point were noted between case and control groups.. Augmentation of clozapine and topiramate did not significantly decline patterns in any of the three subscales of PANSS compared to the clozapine and placebo group. Irct ID: IRCT138904014236N1

Topics: Adult; Aged; Anticonvulsants; Antipsychotic Agents; Chemotherapy, Adjuvant; Chronic Disease; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Topiramate; Treatment Outcome

Antidepressant drugs have often been used as an augmentation strategy for those patients who have demonstrated a suboptimal response to clozapine. The present 16-week double-blind, randomized, placebo-controlled trial study aimed to explore the efficacy and tolerability of duloxetine add-on pharmacotherapy on clinical symptomatology and executive cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments, the patients were randomly allocated to receive, in a double-blind design, at a dose of 60 mg per day of duloxetine or a placebo. A final sample of 33 patients completed the study. The results obtained indicate that duloxetine added to stable clozapine treatment showed a beneficial effect on the negative and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. With regard to executive cognitive functions, duloxetine augmentation of clozapine had no significant effects. The findings provide evidence that duloxetine augmentation of clozapine treatment is safe and well tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy.

Topics: Adrenergic Uptake Inhibitors; Adult; Antidepressive Agents; Antipsychotic Agents; Clozapine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Duloxetine Hydrochloride; Executive Function; Female; Guidelines as Topic; Humans; Male; Middle Aged; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Thiophenes; Time Factors; Treatment Outcome; Young Adult

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genotype; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Prospective Studies; Risperidone; Schizophrenia; Single-Blind Method; Tumor Necrosis Factor-alpha; Weight Gain

This study prospectively assessed outcomes in a group of patients who were randomly switched from Clozaril to generic clozapine (Gen-Clozapine). The authors examined data from rating scales administered before the switch and at points after the switch. There were no statistically significant differences between the groups on any baseline measures, including psychiatric status and dose of medication. In the group of patients who were switched to the generic formulation, there was a significant increase in Global Assessment Scale scores by the end of the 6-month monitoring period. In the group of patients who remained on Clozaril, a significant decrease in the 32-item Behavior and Symptom Identification Scale scores was found at the end of the monitoring period. The results of this study suggest that clinical equivalence indeed followed bioequivalence when switching from Clozaril to Gen-Clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Drugs, Generic; Female; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Single-Blind Method; Therapeutic Equivalency; Treatment Outcome

Topics: Antipsychotic Agents; Brain-Derived Neurotrophic Factor; Clozapine; Dopamine Agents; Double-Blind Method; Drug Therapy, Combination; Humans; Memantine; Schizophrenia; Treatment Outcome

Antipsychotic drugs are the best means available for symptomatically treating individuals suffering from schizophrenia; however, there is a significant variability in clinical response to these psychotropic medications. Previous findings connect oxytocin (OXT) with schizophrenia and antipsychotic action. Therefore, we evaluated if OXT and OXT receptor (OXTR) genes might play a role in the symptom severity and clozapine treatment response in schizophrenia subjects. The rs2740204 variant in the OXT gene was significantly associated with treatment response (after 1000 permutations p=0.042) and nominally associated with negative symptoms in our sample. Furthermore, variants in the OXTR were nominally associated with severity of overall symptoms accessed using the Brief Psychiatric Rating Scale (rs237885, rs237887) as well as on the improvement of the positive symptoms (rs11706648, rs4686301, rs237899). Additional association studies in independent samples will be able evaluate whether OXT and OXTR genes are truly playing a role in the clozapine treatment outcome.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Oxytocin; Pharmacogenetics; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Receptors, Oxytocin; Schizophrenia; Statistics as Topic; Treatment Outcome

Clozapine-induced sialorrhea (CIS) is a subjective distressing adverse effect and occurs in 31%-57% of schizophrenic patients receiving clozapine therapy. Current pharmacotherapy on CIS has focused on anticholinergic agents, even though they may impair cognitive function. Previous case reports have suggested the benefit of glycopyrrolate or biperiden in treating this condition, but no randomized controlled trial has provided evidence. The objective of our study was to evaluate the efficacy and impact on cognition of glycopyrrolate and biperiden treatments for schizophrenic patients suffering from CIS.. Patients who satisfied the inclusion criteria entered a 12-week, randomized, double-blind, crossover, fixed-dose trial. The study consisted of two 4-week crossover phases, which were separated by a 4-week washout period. Sialorrhea and global cognitive function were assessed by using a Drooling Rating Scale (DRS) and the Mini Mental State Examination (MMSE), respectively.. Throughout the study, patients treated with glycopyrrolate or biperiden had significantly reduced DRS scores. Moreover, the DRS scores were significantly lower with glycopyrrolate treatment than with biperiden. In other respects, there were no significant differences in MMSE scores in patients treated with glycopyrrolate. However, we found a significant reduction in MMSE scores in patients treated with biperiden.. We provide evidence, for the first time, of the efficacy of glycopyrrolate and biperiden in the treatment of CIS. Furthermore, glycopyrrolate displays less impact on cognitive function. Consequently, glycopyrrolate can become a valid option for treating CIS. Observations from our study serve as a springboard for additional large-scale prospective trials.

Topics: Adult; Antipsychotic Agents; Biperiden; Clozapine; Cognition; Cross-Over Studies; Double-Blind Method; Female; Glycopyrrolate; Humans; Male; Mental Status Schedule; Middle Aged; Muscarinic Antagonists; Schizophrenia; Sialorrhea; Taiwan

Clozapine has been shown to be superior to typical neuroleptic drugs for treating positive symptoms in treatment-resistant (TR) schizophrenia. Long-term data from randomized clinical trials comparing clozapine with typical neuroleptics in non-TR schizophrenia are rare. We previously reported that clozapine was superior to typical neuroleptic drugs in some domains of cognition in recent onset non-TR schizophrenia. We now present data on psychopathology and quality of life from this randomized, flexibly dosed, 24-month study of clozapine vs. typical neuroleptics in non-TR schizophrenia patients. Both treatments produced significant improvement in measures of psychopathology, quality of life, and global function, with minor exceptions. There was no difference in extrapyramidal side effects between the patients treated with clozapine or typical neuroleptics. However, significantly more relapse/rehospitalization drop-outs occurred in the typical neuroleptic group. Two patients treated with typical neuroleptics, but none treated with clozapine, became non-responsive to treatment. Clozapine was associated with significantly greater weight gain. Clozapine and typical neuroleptic drugs appear to produce equivalent improvement in psychopathology in patients with non-TR schizophrenia. Clozapine may be more effective than typical neuroleptics for treatment retention and prevention of relapse, but it produces more severe metabolic side effects. These considerations should be taken into account in decisions of how best to utilize clozapine in the treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Suicide, Attempted; Time Factors; Treatment Outcome; Young Adult

Clozapine is associated with significant weight gain and metabolic disturbances. This multicentre, randomized study comprised a double-blind, placebo-controlled treatment phase of 16 wk, and an open-label extension phase of 12 wk. Outpatients who met DSM-IV-TR criteria for schizophrenia, who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or =2.5 kg while taking clozapine, were randomized (n=207) to aripiprazole at 5-15 mg/d or placebo, in addition to a stable dose of clozapine. The primary endpoint was mean change from baseline in body weight at week 16 (last observation carried forward). Secondary endpoints included clinical efficacy, body mass index (BMI) and waist circumference. A statistically significant difference in weight loss was reported for aripiprazole vs. placebo (-2.53 kg vs. -0.38 kg, respectively, difference=-2.15 kg, p<0.001). Aripiprazole-treated patients also showed BMI (median reduction 0.8 kg/m(2)) and waist circumference reduction (median reduction 2.0 cm) vs. placebo (no change in either parameter, p<0.001 and p=0.001, respectively). Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein (LDL) cholesterol. There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigator's Assessment Questionnaire scores favoured aripiprazole over placebo. Safety and tolerability were generally comparable between groups. Combining aripiprazole and clozapine resulted in significant weight, BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine. Improvements may reduce metabolic risk factors associated with clozapine treatment.

Topics: Adolescent; Adult; Aged; Aripiprazole; Body Mass Index; Body Weight; Chemotherapy, Adjuvant; Cholesterol; Clozapine; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Quinolones; Schizophrenia; Treatment Outcome; Young Adult

The role of leptin in atypical antipsychotic-induced metabolic dysfunction was explored by assessing the anthropometric and metabolic profile and the response to metformin (MET) of clozapine- (CLZ) treated schizophrenia patients according to their single nucleotide polymorphisms (SNPs) in the leptin promoter (LEP2548/GA) and leptin receptor (LEPR Q223R) genes.. Phase 1. Body mass index (BMI), waist circumference, serum glucose, HbA1C, lipids, leptin, cortisol, insulin resistance index (HOMA-IR), metabolic syndrome and the frequencies of SNPs were assessed in 56 CLZ-treated patients (78.6% males). Phase 2. Fifty two phase 1 subjects were randomly assigned to MET XR (n=23) (1000 mg/day) or placebo (n=29) for 14 weeks. Changes in anthropometric and biochemical variables were compared between the SNPs.. Phase 1. The QQ group displayed the lowest triglyceride levels (p<0.05). No other significant difference was observed. Phase 2. Change in anthropometric variables did not differ between the genotypes in any treatment group. After MET, glucose levels significantly increased in the GG group (p<0.05), whereas the HOMA-IR and the low density cholesterol significantly decreased in the QQ- but not in the (QR+RR) group (p<0.05). No differences were observed after placebo.. BW response to CLZ was not related to LEP- and LEPR-SNPs. The GG and (QR+RR) genotypes showed an unexpectedly opposite and blunted response to MET administration respectively.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Clozapine; Double-Blind Method; Female; Genotype; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metabolic Diseases; Metformin; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Leptin; Schizophrenia; Venezuela

To observe the effect of electroacupuncture (EA) in combination with small dose of clozapine on clinical symptoms of refractory schizophrenia patients so as to evaluate its validity and security.. Eighty schizophrenia patients were randomized into medication group and EA + medication group (n=40/group). Patients of medication group were treated with conventional oral administration of clozapine (50-100 mg/d to 200-500 mg/d, for 8 weeks) and those of EA + medication group treated by EA of Baihui(GV 20) and bilateral Taiyang (EX-HN 5) and oral administration of clozapine (50 mg/d to 100-150 mg/d). EA was given to the patients, 3 times a week for 8 weeks. Scores of the Positive and Negative Symptom Scale (PANSS) and the Untoward Effect Symptom Scale (TESS) were used to assess the therapeutic effect.. Following treatment, PANSS scores for positive symptoms and the common psychiatric symptoms of the medication and EA + medication groups all decreased evidently from the 2rd week on (P < 0.05, P < 0.01), and those of the negative symptoms reduced obviously from the 4th week on (P < 0.05). Comparison between two groups showed no significant differences in PANSS scores for positive and negative symptoms and the common psychiatric symptoms after the treatment (P > 0.05). But TESS score of EA+ medication group was evidently lower than that of medication group (P < 0.01), suggesting an apparently fewer untoward effects in EA + medication group. Of the two 40 cases in medication and EA+ medication groups, 6 (15%) and 5 (12.5%) were cured, 8 and 8 (20%) experienced marked improvement in their symptoms, 17 (42.5%) and 16 (40%) had an improvement, 9 (22.5%) and 11 (27.5%) failed, with the effective rates being 77.5% and 72.5% separately.. Both medication and EA+ medication can improve refractory schizophrenia patients'clinical symptoms, but the later has fewer untoward effects.

Topics: Adolescent; Adult; Clozapine; Combined Modality Therapy; Electroacupuncture; Female; Humans; Male; Middle Aged; Schizophrenia; Treatment Outcome; Young Adult

The large numbers of partial clozapine responders represent a major therapeutic challenge. Unfortunately, there are no clear data to support how best to treat these patients. This study examines the efficacy and safety of adjunctive risperidone in a well-defined treatment-resistant population optimally treated with clozapine. A total of 69 inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder entered a 16-week double-blind, placebo-controlled, randomized clinical trial. Of them, 33 participants were randomized to risperidone and 36 were randomized to placebo. There was no significant group difference in the predefined response criteria. There were modest group differences for Brief Psychiatric Rating Scale (BPRS) positive symptoms, which were significant in the completer analysis (F=5.70; df=1, 70.3; p=0.02; ES=0.27) but not the intent-to-treat (ITT) analyses (F=3.01; df=1, 77.5; p=0.09; ES=0.19). A similar pattern was found for the BPRS total score, with the completer analysis showing a significant improvement in the risperidone group (F=5.21; df=1, 64.9; p=0.03; ES=0.27), whereas the ITT analysis was not significant (F=3.52; df=1, 71.3; p=0.06; ES=0.22). In addition, there was a small, but significant, group difference for negative symptoms, as measured by the SANS total score, which favored the risperidone group (F=5.67; df=1, 78.7; p=0.02; ES=0.24). There were no significant group differences on safety measures, including neuropsychological test and extrapyramidal symptom scores. A significant elevation of prolactin in the risperidone group was observed. The study results suggest that adjunctive risperidone may have a modest benefit for treatment-resistant clozapine patients. The study results are discussed in the context of previous double-blind studies of adjunctive risperidone. (clinicaltrials.gov, trial number: NCT00056498).

Topics: Adult; Clozapine; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

To investigate whether applying advanced machine learning (ML) methodologies to pre-treatment electroencephalography (EEG) data can predict the response to clozapine therapy in adult subjects suffering from chronic schizophrenia.. Pre-treatment EEG data are collected in 23+14 schizophrenic adults. Treatment outcome, after at least one year follow-up, is determined using clinical ratings by a trained clinician blind to EEG results. First, a feature selection scheme is employed to select a reduced subset of features extracted from the subjects' EEG that is most statistically relevant to our treatment-response prediction. These features are then entered into a classifier, which is realized in the form of a kernel partial least squares regression method that performs response prediction. Various scales, including the positive and negative syndrome scale (PANSS) are used as treatment-response indicators.. We determined that a set of discriminating EEG features do exist. A low-dimensional representation of the feature space showed significant clustering into clozapine responder and non-responder groups. The minimum level of performance of the proposed prediction methodology, tested over a range of conditions using the leave-one-out cross-validation method using the original 23 subjects, with further testing in an independent sample of 14 subjects, was 85%.. These findings indicate that analysis of pre-treatment EEG data can predict the clinical response to clozapine in treatment resistant schizophrenia.. If replicated in a larger population, this novel approach to EEG analysis may assist the clinician in determining treatment-efficacy.

Topics: Adult; Antipsychotic Agents; Artificial Intelligence; Clozapine; Discrimination, Psychological; Electroencephalography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pilot Projects; Predictive Value of Tests; Psychiatric Status Rating Scales; Reproducibility of Results; Schizophrenia; Sensitivity and Specificity; Treatment Outcome

Clozapine represents the treatment of choice for refractory psychosis, although a significant number of individuals demonstrate suboptimal response to it as well, leading to clozapine augmentation strategies. A variety of agents have been investigated in this regard, including mood stabilizers, such as anticonvulsants. Within this group of medications, topiramate is unique in that it is associated with weight loss, making it an attractive option because of clozapine's notable risk for associated metabolic disturbance. A 12-week naturalistic, open study was carried out to examine the potential benefits of topiramate in clozapine-treated individuals with schizophrenia demonstrating a suboptimal clinical response. We were specifically interested in clinical symptoms, changes in metabolic parameters, and tolerability. A total of 20 subjects were enrolled, and 16 completed the study, including 5 individuals with type 2 diabetes. Topiramate augmentation led to a 14% improvement in total Brief Psychiatric Rating Scale scores (P = 0.0003), a 2.5% decrease in body weight (P = 0.015), and was generally well tolerated, paraesthesia being the most common side effect. These findings support topiramate as a viable augmentation strategy in clozapine partial responders, with evidence of both clinical and metabolic benefits.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Schizophrenia; Topiramate; Treatment Outcome; Weight Loss

Glutamate antagonists such as topiramate have been proposed based on the glutamate hypothesis of schizophrenia because its properties encourage its exploration and possible development as a medication for the treatment of schizophrenia. A randomised, double-blind, placebo-controlled clinical trial was performed on 18- to 45-year-old patients with schizophrenia. Baseline information including vital signs, height, weight, smoking status, demographic characteristics, (past) psychiatric history, medication history and medication-related adverse effects were collected. Patients were randomly assigned to a topiramate or placebo group. Efficacy of medication was measured by administering Positive and Negative Syndrome Scale (PANSS), and tolerability of treatment was recorded on day 0 (baseline), day 28 and day 56. PANSS values (95% confidence interval) at baseline, day 28 and day 56 in the topiramate group were 96.87 (85.37-108.37), 85.68 (74.67-96.70) and 76.87 (66.06-87.69), respectively; compared with 101.87 (90.37-113.37), 100.31 (89.29-111.32) and 100.56 (89.74-111.37) in the placebo group. General linear model for repeated measures analysis showed that topiramate has lowered PANSS values significantly compared with the placebo group. Similar significant decline patterns were found in all three subscales (negative, positive and psychopathology sign). Clinical response (more than 20% reduction in PANSS) was significantly higher in topiramate-treated subjects than controls (50% vs 12.5%). Topiramate can be an effective medication in controlling schizophrenic symptoms, considering its effect on negative symptoms and controlling antipsychotic-associated weight gain.

Topics: Adolescent; Adult; Anti-Obesity Agents; Anticonvulsants; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology; Topiramate; Weight Gain

Patients suffering from schizophrenic psychoses sometimes insufficiently respond to antipsychotic monotherapy and then combination approaches are preferred. We aimed in validating the add-on of ziprasidone and risperidone to clozapine, and we performed a randomised head-to-head trial. Patients with partial response to clozapine were randomly attributed to augmentation with ziprasidone (n = 12) or risperidone (n = 12). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Depression Scale (HAMD), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). Furthermore, several safety and tolerability measures were obtained. After six weeks, both groups showed significant reductions of positive and negative symptoms. In addition, affective state, psychosocial functioning and clozapine side effects improved without significant differences between the groups. Both approaches were well tolerated. However, the ziprasidone group experienced a small elongation of the QTc interval and a reduction of extrapyramidal symptoms. Patients under clozapine-risperidone therapy developed a rise of serum prolactin levels. The clozapine augmentation with ziprasidone or risperidone resulted in significant psychopathological improvements. The side effects differed between the treatment groups. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Long QT Syndrome; Male; Middle Aged; Piperazines; Prolactin; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Thiazoles; Treatment Outcome; Young Adult

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapine's and olanzapine's similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapine's differential effects on interleukin-6.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cytokines; Double-Blind Method; Female; Fever; Humans; Leptin; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Weight Gain

This study was to evaluate the relationship between clozapine and aPL in schizophrenia patients.. 163 Participants were evaluated: 37 unmedicated schizophrenia patients, 50 clozapine-treated schizophrenia patients and 76 age- and sex-matched healthy controls. A fasting blood sample was taken for serum aPL and serum clozapine level. Serum aPL were measured by ELISA technique and HPLC method was used for the determination of serum clozapine level.. The unmedicated schizophrenia patients showed higher IgG aCL level [mean+/-SD: 1.51+/-0.81 and 1.25+/-0.13 U, respectively (t=2.77, df=111, p<0.01)] and IgM aCL level [mean+/-SD: 1.53+/-0.54. and 1.33+/-0.15 U, respectively (t=-2.98, df=111, p<0.01)] compared with the healthy controls. The comparison of the clozapine-treated schizophrenia patients and the healthy controls showed significant difference in IgG aCL level [mean+/-SD: 1.74+/-0.90 and 1.25+/-0.13 U, respectively (t=-4.77, df=124, p<0.01)] and IgM aCL level [mean+/-SD: 1.62+/-0.83 and 1.33+/-0.15 U, respectively (t=-4.35, df=124, p<0.01)]. In clozapine-treated schizophrenia patients, the results of Pearson correlation coefficients showed that there was a significant positive relationship between serum IgM aCL and serum clozapine level (r=0.461, p<0.01), and serum IgG aCL were significantly correlated with serum IgM aCL (r=0.279, p<0.05). Stepwise multiple regression analysis was performed with various characteristics, such as duration of medication, daily dose and serum clozapine level as candidate factors for serum aCL (IgG and IgM isotypes) in clozapine-treated schizophrenia patients. Only serum clozapine level was able to enter into the regression model of IgM aCL (Model R(2)=0.212, p<0.05).. A higher serum clozapine level is associated with an increased aPL in schizophrenia patients.

Topics: Adult; Antibodies, Antiphospholipid; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Schizophrenia; Young Adult

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes.. Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments.. Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33-41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall).. Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Chronic Disease; Clozapine; Dibenzothiazepines; Female; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Perphenazine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

Clozapine is associated with significant weight gain. However, it is still debatable whether the majority of weight gain occurs in the early phase of treatment or if weight gain is a persistent side effect. The inconsistent results in previous outpatient studies may be due to many confounding factors, such as variations in drug adherence, diet content, activity level and environmental factors. The objective of this study was to investigate long-term weight changes in hospitalized Chinese schizophrenic patients treated with clozapine.. Patients were admitted at the largest mental hospital in Taiwan and had routine monthly body weight monitoring during the study period. Retrospective chart reviews were conducted to obtain demographic data, age at which clozapine treatment was initiated, and weight changes after the initiation of clozapine treatment.. The study sample consisted of 349 hospitalized schizophrenic patients, including 204 males (58.8%), with an average age at clozapine initiation of 38.6+/-9.3 and an average clozapine dosage of 318+/-9.3 mg/day. Body weight increased over time, and reached a plateau at month 42. Younger age at clozapine initiation (P=0.0038) and lower baseline body mass index (BBMI) (P<0.0001) were associated with more weight gain. The patients with BBMI<25 gained significantly more weight (10.98+/-8.48 kg) compared to patients with BBMI>or=25 (1.17+/-13.29 kg) (P=0.004).. Similar to reports on Caucasians, clozapine-associated weight gain in Chinese patients reached a plateau at month 42. Younger patients with normal BBMI were associated with higher risk of weight gain.

Topics: Adult; Antipsychotic Agents; Asian People; Body Mass Index; Clozapine; Cohort Studies; Female; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Schizophrenia; Weight Gain

The primary purpose of this 8-week double-blind, placebo-controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine-treated subjects with schizophrenia with insulin resistance.. Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI.. Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non-significant improvement in SG (0.016 +/- 0.006-0.018 +/- 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 +/- 2.8-7.8 +/- 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low-density lipoprotein cholesterol (LDL-C) particle number (987 +/- 443-694 +/- 415, effect size = 0.30, P = 0.04).. Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cholesterol, LDL; Clozapine; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Placebos; Rosiglitazone; Schizophrenia; Thiazolidinediones

The second-generation antipsychotic agents clozapine and olanzapine have been associated with weight gain and increased lipid and glucose blood levels. Since some of the neurotransmitters that are impaired in aggressive patients are involved in lipid/glucose metabolism, aggressive patients may represent a subgroup with a differential profile of adverse metabolic reactions to these medications. The goal of this study was to assess the effects of clozapine and olanzapine in comparison to the first-generation agent haloperidol on these metabolic parameters in aggressive patients with schizophrenia.. 110 inpatients with schizophrenia and a history of physical assaults were included in a randomized double-blind 12-week study. Fasting glucose, cholesterol and triglycerides were collected at baseline and at the end of the study. Ninety-three patients provided blood samples at baseline and at least at one point after randomization to clozapine (N=34), olanzapine (N=31) or haloperidol (N=28).. There were significant differences among the three medication groups in weight gain and in increases in blood lipids and glucose. Patients on haloperidol showed no increase on any of these parameters. Patients on olanzapine gained the most weight, but patients on clozapine had the greatest increases in cholesterol, triglyceride, and glucose. An effect of ethnicity was observed, as African-American patients were more likely to develop metabolic abnormalities than other ethnic groups, especially on clozapine.. In this prospective randomized trial, clozapine and olanzapine were associated with weight gain. Clozapine was associated with increases in both lipids and glucose. This effect was most prominent in the African-American patients.

Topics: Adult; Aggression; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Clozapine; Double-Blind Method; Ethnicity; Female; Haloperidol; Humans; Inpatients; Lipid Metabolism; Male; Middle Aged; Olanzapine; Prospective Studies; Schizophrenia; Weight Gain; Young Adult

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Weight; Clozapine; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Italy; Lipids; Male; Middle Aged; Patient Compliance; Piperazines; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Thiazoles; Young Adult

This study sought to examine the effect of ziprasidone on olanzapine or clozapine-associated medical morbidity such as insulin resistance, diabetes mellitus (DM) and impaired fasting glucose, obesity, and hyperlipidemia in patients with schizophrenia or schizoaffective disorder.. This was a 6-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in 21 schizophrenia or schizoaffective patients with DM, impaired fasting glucose, or insulin resistance.. Ten olanzapine-treated subjects and 11 clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week 6, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative, or depressive symptoms. QTc significantly increased at week 2 but not at week 6.. The addition of 160 mg/day of ziprasidone was well tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperglycemia; Insulin Resistance; Male; Middle Aged; Morbidity; Olanzapine; Piperazines; Schizophrenia; Thiazoles; Time Factors

The prototypical atypical antipsychotic agent, clozapine, is more efficacious for refractory schizophrenia than the 'typical' antipsychotics, but the mechanism underlying this enhanced efficacy is still under investigation. Since 2002, at least 22 association studies have shown that the DTNBP1 can be associated with the risk for schizophrenia. We hypothesized that DTNBP1 might also influence the response to antipsychotic treatments. This study aimed to investigate the relationship between the DTNBP1 and the effects of clozapine and haloperidol on refractory schizophrenia.. Patients with refractory schizophrenia were assigned to clozapine (n=85) or haloperidol (n=96) and followed for 3 months. Symptom improvement was evaluated by Positive and Negative Syndrome Scale score. Six markers at DTNBP1 and 38 ancestry-informative markers were genotyped in all participants. The relationships between the effects of antipsychotics and the diplotypes, haplotypes, genotypes, and alleles of DTNBP1 were tested by analysis of covariance, analysis of variance, and t-test.. Patients with diplotype ACCCTC/GTTGCC, genotypes T/T+T/C, or allele T of marker rs742105 (P1333) have better response to clozapine (0.005< or =P< or =0.049), and patients with diplotype ACCCTC/GCCGCC, genotype A/G, or allele A of marker rs909706 (P1583) have better response to haloperidol (0.007< or =P< or =0.080) in European-Americans, African-Americans, and/or the combined sample; European-American patients with diplotype ACCCTC/GCCGCC have worse response to clozapine on positive symptoms (P=0.011).. This study shows that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine and the typical antipsychotic haloperidol. Participants with different DTNBP1 diplotypes, haplotypes, genotypes, or alleles might have different responses to these antipsychotics.

Topics: Antipsychotic Agents; Black or African American; Carrier Proteins; Clozapine; Double Bind Interaction; Dysbindin; Dystrophin-Associated Proteins; Genetic Variation; Genotype; Haloperidol; Haplotypes; Humans; Schizophrenia; Treatment Outcome; White People

One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.. The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.. The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.

Topics: Antipsychotic Agents; Aripiprazole; Clinical Protocols; Clozapine; Drug Resistance; Drug Therapy, Combination; Government Regulation; Haloperidol; Humans; Italy; Piperazines; Prospective Studies; Quinolones; Research Design; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Most antipsychotics are thought to have an effect on D(2) and D(3) receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([(11)C]-(+)-PHNO), the first agonist radioligand with higher affinity for D(3) than D(2) receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D(2) receptor and on D(3) vs D(2) receptor subtypes.. To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D(2) and D(3) receptors by comparing the [(11)C]-(+)-PHNO and [(11)C]raclopride binding in the D(3) receptor-rich (globus pallidus and ventral striatum) and D(2) receptor-rich (caudate and putamen) regions.. Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D(3) receptor-preferring agonist) vs placebo on the increased [(11)C]-(+)-PHNO signal observed in the globus pallidus of patients.. Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.. Twenty-three patients with schizophrenia and 23 healthy controls.. Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride.. The antipsychotic-treated patients showed high occupancies with both [(11)C]-(+)-PHNO and [(11)C]raclopride in the dorsal striatum, with [(11)C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [(11)C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [(11)C]raclopride. This unblocked [(11)C]-(+)-PHNO signal was displaced by a single dose of pramipexole.. Antipsychotics block both the high- and low-affinity states of the D(2) receptors across the brain, but antipsychotic treatment does not block the [(11)C]-(+)-PHNO signal in the D(3) receptor-rich regions, despite the ongoing D(2) receptor blockade. This [(11)C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D(3) receptor-preferring agonist. The radiotracer [(11)C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzodiazepines; Benzothiazoles; Binding, Competitive; Carbon Radioisotopes; Caudate Nucleus; Clozapine; Dopamine Agonists; Dopamine Antagonists; Double-Blind Method; Female; Globus Pallidus; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Olanzapine; Oxazines; Positron-Emission Tomography; Pramipexole; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia

Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration.. In a double-blind, parallel group protocol, 61 patients (94.4% with schizophrenia) receiving clozapine (196.8+/-132 mg daily, range: 25-500) for more than 3 consecutive months (86.5+/-40.6 months, range: 4-168) were randomly allocated to extended release MET (n=31; 500 to 1000 mg daily) or placebo (n=30) group for 14 weeks. The BW, the body mass index, waist circumference, serum glucose, insulin, lipids, glycated hemoglobin (HBA1c), leptin and cortisol, and the HOMA-IR index were assessed at baseline, and weeks 7 and 14.. MET was well tolerated and the mental state was not impaired during the study. The protocol was completed by all the placebo subjects and by 24 MET-treated patients. In a complete analysis at week 14, without including data of the 7 dropouts, the MET group lost -1.87+/-2.9 kg, whereas the placebo group had a stable BW: 0.16+/-2.9 kg, p=0.01 for the between group comparisons (effect size: 0.70). Leptin levels also tended to decrease after MET (p=0.08). Insulin and the triglyceride-HDL-C ratio significantly decreased (p<0.05, effect size 0.59 and 1.99 respectively) and the HDL-C significantly increased (p=0.001, effect size 0.95) after MET.. MET improves metabolic control during prolonged clozapine administration.

Topics: Adult; Anthropometry; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol, HDL; Clozapine; Double-Blind Method; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Schizophrenia; Statistics, Nonparametric; Waist Circumference

The aim of our study was to evaluate the effects of low doses of clozapine in flexible regime in comparison with haloperidol and chlorpromazine in long term.. The naturalistic study was prospective, active-controlled with 325 adult outpatients of both genders (140 females), with mean year age of 34.8 (range 21-57), suffering from chronic schizophrenia. The first onset of illness was at the mean of 27.9 years (range 17-38), and subjects had the mean year age of 4.1+/-0.5 previous relapses. The patients were allocated to receive haloperidol (105 subjects, dose range 2-15 mg), chlorpromazine (n=105, 100-400 mg) or clozapine (n=115, 75-600 mg). The scores of psychometric instruments (GWB, PANSS, CGI) were regularly assessed during 5 year period.. The sixty-six responders were included in per-protocol analysis: 12, 10 and 16 with positive and 7, 6 and 15 with negative schizophrenic syndrome in haloperidol, chlorpromazine and clozapine group, respectively. The statistically significant differences in all psychometric scores was found, for both schizophrenic syndromes, favoring clozapine. The distribution of eighteen different types of adverse events, which we noted, were significantly different among treatment groups ( chi2=315.7, df=34, p<0.001). Clozapine was safer and had fewer adverse effects (average of 0.9 adverse events per patient) than haloperidol (2.7) and chlorpromazine (3.2).. Clozapine, in low doses of flexible regime, in long term (five years) showed better effectiveness in chronic schizophrenics with positive and negative symptoms than typical antipsychotics.

Topics: Adult; Antipsychotic Agents; Chlorpromazine; Clozapine; Drug Administration Schedule; Female; Haloperidol; Humans; Male; Prospective Studies; Schizophrenia; Time Factors; Treatment Outcome

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or= 80, and CGI-S score >or= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Weight; Clozapine; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Italy; Lipids; Male; Middle Aged; Patient Compliance; Piperazines; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Thiazoles; Young Adult

ABCB1 is a transmembrane transporter that is expressed in excretory organs (kidneys and liver), in intestine mucosa and on the blood-brain barrier. Because of the particular distribution of the protein, the activity of ABCB1 may significantly affect drug pharmacokinetics during absorption and distribution. Of note, several SNPs of ABCB1 are known and many of them affect transporter activity and/or expression. In this view, changes in the pharmacokinetics of drugs that are ABCB1 substrates could be clinically relevant and the evaluation of ABCB1 SNPs should deserve particular attention. Therefore, the aim of the present study was to investigate the possible association between ABCB1 polymorphisms and clozapine plasma levels in psychotic patients.. c.1236C>T (exon 12), c.2677G>T (exon 21) and c.3435C>T (exon 26) SNPs of ABCB1 were evaluated by PCR techniques, while plasma levels of clozapine and norclozapine were measured by HPLC in 40 men (aged, 47.6 +/- 16.6 years, median: 42 years) and 20 women (aged 40.7 +/- 11.4 years, median: 38 years) 1 month after the start of clozapine administration.. A total of three SNPs were in Hardy-Weinberg equilibrium, with a calculated frequency of the wild-type alleles of 0.54, 0.55 and 0.45 for SNPs on exons 12, 21 and 26, respectively. Patients with c.3435CC or c.2677GG genotypes had significantly lower dose-normalized clozapine levels than those who were heterozygous or TT carriers. More interestingly, c.3435CC patients (15 subjects) needed significantly higher daily doses of clozapine (246 +/- 142 mg/day) compared with the remaining 24 CT and 21 TT patients (140 +/- 90 mg/day) in order to achieve the same clinical benefit.. c.3435CC patients require higher clozapine doses to achieve the same plasma concentrations as CT or TT patients, and ABCB1 genotyping should be considered as a novel strategy that should improve drug use.

Topics: Adult; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clozapine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gene Frequency; Haplotypes; Humans; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia

Patients with schizophrenia often suffer from cognitive deficits and negative symptoms that are poorly responsive to antipsychotics including clozapine. Clozapine-induced sedation can worsen cognition and impair social and occupational functioning.. To evaluate the efficacy, tolerability, and safety of modafinil for negative symptoms, cognition, and wakefulness/fatigue in DSM-IV-diagnosed schizophrenia patients treated with clozapine.. A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted between September 2003 and September 2007, adding modafinil up to 300 mg/d to stabilized schizophrenia outpatients receiving clozapine. Psychopathology, cognition, and wakefulness/fatigue were assessed with standard rating scales.. Thirty-five patients were randomly assigned to treatment with study drug and included in the analysis. Modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared to placebo. Modafinil was well tolerated and did not worsen psychosis.. Results of this pilot trial do not support routine use of modafinil to treat negative symptoms, cognitive deficits, or wakefulness/fatigue in patients on clozapine. However, given our limited power to detect a treatment effect and the clear possibility of a type II error, larger trials are needed to resolve or refute a potential therapeutic effect of uncertain magnitude.. clinicaltrials.gov Identifier: NCT00573417.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzhydryl Compounds; Central Nervous System Stimulants; Clozapine; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Fatigue; Female; Humans; Male; Middle Aged; Modafinil; Neuropsychological Tests; Pilot Projects; Placebos; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Wakefulness

Clozapine-induced hypersalivation (CIH) occurs in up to 57% of treated patients and can be the source of considerable subjective distress. Previous open-label studies suggest that sublingual ipratropium bromide may be effective in treating CIH.. We conducted a randomized, double-blind, placebo-controlled crossover trial to evaluate the efficacy of ipratropium in 20 individuals with CIH between September 2006 and August 2007. This study was 5 to 6 weeks in duration, based on the participants' clozapine blood-monitoring schedule, and it consisted of two 2-week crossover phases separated by a 1- or 2-week washout period. Primary outcome measures included the reduction in the Toronto Nocturnal Hypersalivation Scale (TNHS) and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. Secondary outcomes included visual analog scales assessing hypersalivation severity (VAS-S) and distress (VAS-D).. No significant reduction in CIH was found on the TNHS (P = .379), CGI-S (P = .266), or CGI-I (P = .599). Moreover, no difference was noted between study groups on the VAS-S (P = .969) and VAS-D (P = .527). There was no difference in the number of CIH responders at the conclusion of the 2-week placebo (40%, n = 8) and ipratropium (45%, n = 9) study phases (45%, n = 9) according to the TNHS. Randomization order did not have a significant effect on TNHS, CGI-S, or CGI-I scores. Tolerability was comparable between groups, with dry mouth occurring in 1 placebo group subject and 2 ipratropium group subjects.. Despite the reports of some preliminary studies that ipratropium is an efficacious treatment for CIH, ipratropium failed to demonstrate significant clinical effect in comparison to placebo. Further research should explore the efficacy of other locally acting anticholinergic agents or other classes of medications.. clinicaltrials.gov Identifier: NCT00381589.

Topics: Adolescent; Adult; Aged; Cholinergic Antagonists; Clozapine; Cross-Over Studies; Double-Blind Method; Female; Humans; Ipratropium; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Sialorrhea; Surveys and Questionnaires; Treatment Outcome

The purpose of this study was to investigate the effect of clozapine on regional cerebral blood flow (rCBF) and its relationship with response to treatment. In addition, we aimed to study the influence of clozapine on proton magnetic resonance spectroscopy ((1)H-MRS) findings in the dorsolateral prefrontal cortex (DLPFC) in a subgroup of patients. Psychopathology, neurocognitive functioning, and SPECT imaging of 22 patients were assessed at the baseline and 8 weeks after the initiation of clozapine treatment. In 10 of these patients intermediate-echo (TE: 135 ms) single-voxel (1)H-MRS was also performed at the baseline and after 8 weeks. Clozapine treatment increased the right frontal (superior and medial)/caudate perfusion ratio in the whole group, while it increased bilateral frontal (superior and medial)/caudate perfusion ratios in treatment responders. In addition, percentage changes in left and right frontal (superior and medial)/caudate perfusion ratios compared to the baseline were higher in treatment responders than in non-responders. The improvement in attention was related to the increase in percentage change in the right frontal (superior and medial)/caudate perfusion ratio, while the improvement in verbal fluency was related to the increase in percentage changes in both right and left frontal (superior and medial)/caudate perfusion ratios and to right frontal (superior and medial)/thalamus perfusion. Baseline frontal (superior and medial)/thalamus perfusion could explain 32% of the variability of percentage improvements in psychopathology. (1)H-MRS showed that the baseline PANSS general psychopathology score was inversely correlated with the baseline NAA/Cre ratio. An increased NAA/Cre ratio in DLPFC after 8 weeks of clozapine treatment was also revealed by (1)H-MRS. Our SPECT imaging results suggest the presence of an imbalance in fronto-striato-thalamic circuitry that changes with clozapine, especially in the responders, while (1)H-MRS results indicate a supportive effect of clozapine on neuronal integrity.

Topics: Adult; Antipsychotic Agents; Brain; Brain Mapping; Cerebrovascular Circulation; Clozapine; Electrons; Female; Humans; Magnetic Resonance Spectroscopy; Male; Psychiatric Status Rating Scales; Regional Blood Flow; Schizophrenia; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Young Adult

Glutamate deregulation may be involved in the neuropathology of schizophrenia, mainly through N-methyl-d-aspartate (NMDA) receptor dysfunction. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a weak nonselective NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to clozapine in patients with refractory schizophrenia.. In this double-blind, placebo-controlled study, outpatients with refractory schizophrenia according to DSM-IV clinical criteria were randomly assigned, from March 2005 to February 2008, to receive either 20 mg/d memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. The primary outcome measure was the total score on the 18-item Brief Psychiatry Rating Scale (BPRS) and BPRS subscales of positive and negative symptoms. Secondary outcomes were global severity of disease as measured by the Clinical Global Impressions scale (CGI), cognition as assessed by the Mini-Mental State Examination (MMSE), and extrapyramidal symptoms as assessed by the Simpson-Angus Scale (SAS).. Twenty-one participants completed the study and were used in the analysis. Significant improvement (P < .01) on the total BPRS score, its subscales of positive (effect size [ES] = -1.38) and negative (ES = -3.33) symptoms, the CGI score (ES = 1.56), and the MMSE score was observed with memantine as compared with placebo. No significant changes in extrapyramidal symptoms were observed.. Memantine add-on to clozapine therapy was associated with improvement in negative and positive symptoms in refractory schizophrenia patients.. clinicaltrials.gov Identifier: NCT00757978.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Double-Blind Method; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Humans; Male; Memantine; Middle Aged; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The use of cognitive-behavior therapy (CBT) in addition to antipsychotic regimen to treat persistent psychotic symptoms of schizophrenia is growing. The aim of this study was to compare the efficacy of CBT to a befriending (BF) control group in patients with schizophrenia who are refractory to clozapine. Twenty-one patients completed the 21-week trial. In comparison with the control group, the CBT group showed a significant improvement in the General Psychopathology and total score of the Positive and Negative Syndrome Scale, as well as an improvement of Quality of Life scale. The improvement in psychopathology persisted at 6-month follow-up assessment.

Topics: Adult; Clozapine; Cognitive Behavioral Therapy; Drug Resistance; Follow-Up Studies; Humans; Middle Aged; Schizophrenia; Schizophrenic Psychology; Young Adult

The present study explores sweet stimuli effects on hunger and negative alliesthesia in patients treated with antipsychotic drugs and controls. Those phenomena were examined in relation to previous weight gain, eating and weight-related cognitions and type of sweet stimuli: aspartame or sucrose. Alliesthesia is delayed in participants who gained weight regardless of cross group differences. A similar reduction of hunger was observed after the intake of two kinds of sweet stimuli (aspartame or sucrose) whereas alliesthesia measures were not affected. Whereas atypical antipsychotic drug-induced weight gain is linked to delayed satiety, the phenomenon is similar in magnitude in non-psychiatric controls who gained weight.

Topics: Adult; Antipsychotic Agents; Aspartame; Benzodiazepines; Carbonated Beverages; Clozapine; Dibenzothiazepines; Double-Blind Method; Food Preferences; Humans; Hunger; Male; Middle Aged; Olanzapine; Pleasure; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Sucrose; Surveys and Questionnaires; Sweetening Agents; Taste; Time Factors; Young Adult

Although one third to one half of refractory schizophrenic patients responds to clozapine, however, there are few evidences currently that could predict clozapine response before the use of the medication. The present study aimed to train and validate artificial neural networks (ANN), using clinical and pharmacogenetic data, to predict clozapine response in schizophrenic patients. Five pharmacogenetic variables and five clinical variables were collated from 93 schizophrenic patients taking clozapine, including 26 responders. ANN analysis was carried out by training the network with data from 75% of cases and subsequently testing with data from 25% of unseen cases to determine the optimal ANN architecture. Then the leave-one-out method was used to examine the generalization of the models. The optimal ANN architecture was found to be a standard feed-forward, fully-connected, back-propagation multilayer perceptron. The overall accuracy rate of ANN was 83.3%, which is higher than that of logistic regression (LR) (70.8%). By using the area under the receiver operating characteristics curve as a measure of performance, the ANN outperformed the LR (0.821+/-0.054 versus 0.579+/-0.068; p<0.001). The ANN with only genetic variables outperformed the ANN with only clinical variables (0.805+/-0.056 versus 0.647+/-0.066; p=0.046). The gene polymorphisms should play an important role in the prediction. Further validation of ANN analysis is likely to provide decision support for predicting individual response.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Computer Simulation; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Drug Therapy, Computer-Assisted; Female; Humans; Male; Middle Aged; Models, Biological; Neural Networks, Computer; Outcome Assessment, Health Care; Pattern Recognition, Automated; Pharmacogenetics; Schizophrenia; Treatment Outcome

The focus of this study was the systematic evaluation of the clinical effects of the extract of ginkgo biloba (EGb) as an adjunct to the atypical antipsychotic clozapine in the treatment of refractory schizophrenia. In a placebo-controlled study, 42 patients with chronic, treatment-resistant schizophrenia, who were maintained on optimal doses of clozapine, were administered either 120 mg/day of EGb (N=20) or placebo (N=22) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms were completed biweekly. The use of EGb as an adjunct to clozapine was effective in decreasing negative symptoms, but not positive and overall psychopathology symptoms. EGb produced a mean 7.9+/-7.0 point reduction in the total Scale for the Assessment of Negative Symptoms score compared with a mean 1.8+/-3.5 point reduction in the placebo group (P=0.034). These preliminary data suggested that EGb was found useful for enhancing the effect of clozapine on negative symptoms in patients with treatment-resistant schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Ginkgo biloba; Humans; Male; Phytotherapy; Plant Extracts; Schizophrenia

There is evidence that major psychiatric disorders such as schizophrenia (SZ) are associated with deregulation of synaptic plasticity with downstream alterations of neurotrophins. NT3 is an important neurotrophin in the central nervous system, and performs key biological functions, such as promoting the survival, differentiation, and plasticity of neurons. NT3 has a central role in the early neuronal development; enhancing the survival of dopaminergic neurons, suggesting possible involvement in the physiopathology of dopamine related neuropsychiatric disorders such as SZ. Variations in the NT3 gene increase the risk of SZ. Three groups of chronically medicated DSM-IV patients with SZ, on treatment with clozapine (n=12), haloperidol (n=12), risperidone (n=12) and 10 healthy controls had 5 ml blood samples collected by venipuncture. NT3 serum levels were assessed using sandwich-ELISA and were significantly lower in SZ patients (p<0.005) when compared to either controls. These findings suggest that the NT3 signaling system may play a role in the pathophysiology of SZ and might be related to the course of illness or to treatment variables. Longitudinal studies are warranted.

Topics: Adult; Antipsychotic Agents; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Enzyme-Linked Immunosorbent Assay; Haloperidol; Humans; Longitudinal Studies; Male; Middle Aged; Neurotrophin 3; Phlebotomy; Risperidone; Schizophrenia

Schizophrenia is associated with various abnormalities in the immune system. Suppression of inflammatory cytokines by cigarette smoke is well-established. The purpose of this study was to determine any differences in cytokine profiles in smokers and nonsmokers with schizophrenia and whether there were any relationships among altered cytokine profiles and psychopathological symptoms.. Serum interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha levels were measured in 96 male inpatients with DSM-IV schizophrenia: 66 smokers and 30 nonsmokers. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS).. The positive PANSS symptoms were lower in smokers than nonsmokers, while the negative symptoms were lower in those who smoked more cigarettes. Cytokine levels were positively correlated: IL-2 level with IL-6 and IL-6 with both IL-8 and TNF-alpha. Both IL-2 and IL-6, but not IL-8 or TNF-alpha, were significantly lower in smokers than nonsmokers (p < 0.002; p < 0.01). Lower IL-2 levels correlated with fewer negative symptoms and with smoking more cigarettes.. The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be associated with nicotine-induced suppression of some inflammatory cytokines.

Topics: Age Factors; Antipsychotic Agents; Chronic Disease; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Drug Administration Schedule; Humans; Interleukins; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Smoking; Smoking Cessation; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Few studies have examined prediction of schizophrenia outcome in relation to brain magnetic resonance imaging measures. In this study, remission status at the time of discharge was examined in relation to admission cortical thickness for childhood-onset schizophrenia probands. We hypothesized that total, frontal, temporal, and parietal gray matter thickness would be greater in patients who subsequently remit.. The relation between admission cortical brain thickness on magnetic resonance imaging and remission status at the time of discharge an average of 3 months later was examined for 56 individuals (32 males) ages 6 to 19 diagnosed with childhood-onset schizophrenia. Cortical thickness was measured across the cerebral hemispheres at admission. Discharge remission criteria were adapted from the 2005 Remission in Schizophrenia Working Group criteria.. Patients remitted at discharge (n = 16 [29%]) had thicker regional cortex in left orbitofrontal, left superior, and middle temporal gyri and bilateral postcentral and angular gyri (p < or = .008).. Our results provide neuroanatomic correlates of clinical remission in schizophrenia and evidence that response to treatment may be mediated by these cortical brain regions.

Topics: Adolescent; Age of Onset; Antipsychotic Agents; Cerebral Cortex; Child; Clozapine; Combined Modality Therapy; Dominance, Cerebral; Double-Blind Method; Drug Therapy, Combination; Family Therapy; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Milieu Therapy; Occupational Therapy; Organ Size; Outcome Assessment, Health Care; Parietal Lobe; Patient Discharge; Schizophrenia; Schizophrenic Psychology; Temporal Lobe

A recent 12-week controlled comparison demonstrated the superiority of clozapine to "high-dose" olanzapine in adolescents with treatment-refractory schizophrenia. In the present study, the authors conducted a 12-week, open-label, follow-up study to examine changes in lipid and glucose metabolism in youths maintained on clozapine and to determine whether patients who were previously randomized to high-dose olanzapine (up to 30 mg/day) responded to clozapine.. Thirty three (14 clozapine, 19 olanzapine) (85%) of 39 patients were available for the present 12-week, open-label extension study. Extended safety data using an intention-to-treat analysis from the 14 subjects treated with clozapine for a total of 24 weeks are presented. In addition, we report the clinical outcomes for 10 of 19 olanzapine-treated patients who were switched after 12 weeks to clozapine due to treatment nonresponse. Clinical response was defined as a decrease of 30% or more in total Brief Psychiatric Rating score from week 12 and a Clinical Global Impression-Improvement rating of 1 (very much improved) or 2 (much improved).. The incidence of hypertriglyceridemia (defined as fasting triglycerides >125 mg/dL) (10/14 = 71%) and the incidence of "prediabetes" (defined as fasting blood glucose > or =100) (4/14 = 29%) at week 24 in the clozapine-treated subjects were notable. Seven (70%) of 10 of young patients with schizophrenia who failed treatment with "high-dose" olanzapine were found to respond to a 12-week, open-label clozapine trial.. Clinicians and caregivers need to be aware of potential metabolic adverse events of long-term clozapine treatment. Adolescents with a poor response to olanzapine may do better on clozapine.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertriglyceridemia; Lipid Metabolism; Male; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The present study examined the ability of the International Suicide Prevention Trial (InterSePT) Scale for Suicidal Thinking (ISST) and the Calgary Depression Scale (CDS) to predict suicide attempts or hospitalizations to prevent attempts (referred to as Type 1 events) during the InterSePT trial [Meltzer, H.Y., Alphs, L., Green, A.I., Altamura, A.C., Anand, R., Bertoldi, A., Bourgeois, M., Chouinard, G., Islam, M.Z., Kane, J., Krishman, R., Lindenmayer, J.P., Potkin, S., 2003. Clozapine treatment for suicidality in schizophrenia. Archive of General Psychiatry 60, 82-91]. The primary goal of this analysis was to determine if the ISST and CDS ratings indicated that the raters, an unblinded (UP) and a blinded psychiatrist (BP) using the ISST, and a blinded rater using the CDS, were able to identify those patients who had a Type 1 event. The ratings of patients adjudged to have experienced a Type 1 event (Group 1) were compared with patients who did not (Group 2). The ISST and the CDS ratings obtained 2-8 weeks prior to a Type 1 event (Pre-1) and Pre-2, the rating immediately prior to Pre-1, obtained 2-12 weeks before Pre-1, were analyzed to test the hypothesis that the difference between Pre-2 and Pre-1 ratings for the Group 1 patients was significantly greater than the difference in the comparable ratings for Group 2 patients. The prediction that patients with Type 1 events would show greater worsening in ISST and CDS ratings between Pre-2 and Pre-1 than the Group 2 patients was confirmed. However, the sensitivity and specificity of a worsening in ratings was not sufficient to provide definitive warning of an impending Type 1 event. Other characteristics of the patients with Type 1 events provide additional warning: e.g. overall higher ratings on these scales, slower improvement in suicidality during treatment, and previous number of suicide attempts. These results indicate that the ISST and CDS may provide some additional information that can assist clinical decision making regarding suicidal risk in patients with schizophrenia or schizoaffective disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Observer Variation; Olanzapine; Personality Inventory; Psychiatric Status Rating Scales; Psychometrics; Psychotic Disorders; Reproducibility of Results; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Single-Blind Method; Suicide; Suicide Prevention; Suicide, Attempted; Thinking

The purpose of this study was to compare the effects of olanzapine, clozapine, and haloperidol on neurocognitive function in schizophrenic patients who present with documented episodes of physical aggression and to determine whether change in cognitive function is related to aggression. One hundred physically aggressive schizophrenic inpatients were assigned to a randomized, double-blind, parallel-group, 12-week treatment, and received cognitive evaluations at baseline. There were 33, 34, and 33 subjects in the clozapine, olanzapine, and haloperidol groups, respectively. They were administered a battery of tests assessing psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. A general cognitive index was derived from the above battery. The overall score on the Modified Overt Aggression Scale was used to measure the number and severity of the aggressive events. Psychiatric symptoms and side effects were also assessed. The improvement in the general cognitive index differed significantly among the 3 treatment groups, with olanzapine being superior to both haloperidol and clozapine. Further analyses revealed significantly greater improvement with olanzapine in several cognitive domains. Furthermore, improvement in the general cognitive index was significantly associated with a decrease in aggression in the olanzapine group but not in the other 2 medication groups. In violent schizophrenic patients, olanzapine treatment is associated with better cognitive functioning relative to haloperidol and clozapine. This improvement in neurocognitive function is associated with a decrease in aggressive behavior. As clozapine markedly reduced aggression, there may be different pathways for the antiaggressive effect of olanzapine and that of clozapine.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Violence

To assess the effectiveness of aripiprazole in the treatment of patients with psychotic symptoms in the emergency psychiatric setting.. We considered all patients admitted to a psychiatric intensive care unit of a general hospital in a two year-period, treated with at least one dose of aripiprazole. We measured 1) the rate of cases starting aripiprazole who did not change antipsychotic in the course of hospitalization; 2) the rate of cases who were concurrently treated with another antipsychotic; 3) the CGI Improvement score.. In 63 cases, aripiprazole was started on admission. Forty-nine (77.7%) of these cases were treated with aripiprazole also on discharge. Among the 63 cases who started aripiprazole on admission, 22 (34.9%) were concurrently treated with another antipsychotic. Among the 53 cases discharged with aripiprazole, 15 (28.3%) were concurrently treated with another antipsychotic. Of the 49 cases treated with aripiprazole both on admission and on discharge, 24 cases were much improved, 11 cases moderately improved, 10 cases mildly improved, and 4 cases were not improved at the CGI Improvement Score.. Aripiprazole should be considered as first line treatment in some patients affected by psychotic disorders visited in the emergency psychiatric setting.

Topics: Acute Disease; Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Drug Therapy, Combination; Emergency Services, Psychiatric; Female; Humans; Intensive Care Units; Male; Middle Aged; Piperazines; Psychiatric Department, Hospital; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Severity of Illness Index; Treatment Outcome

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was -0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dioxoles; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychomotor Performance; Risperidone; Sample Size; Schizophrenia; Schizophrenic Psychology

The present study evaluated the effectiveness and safety of clozapine versus "high-dose" olanzapine in treatment-refractory adolescents with schizophrenia.. Children, ages 10-18 years, who met DSM-IV criteria for schizophrenia and who were resistant or intolerant to at least two antipsychotic drugs were randomized to receive 12 weeks of double-blind flexibly dosed treatment with clozapine (n = 18) or "high-dose" olanzapine (up to 30 mg/day) (n = 21). The primary efficacy measure was response (improvement), defined as a decrease of 30% or more in total Brief Psychiatric Rating Scale score from baseline and a Clinical Global Impression Scale improvement rating of "1" (very much improved) or "2" (much improved).. Significantly more clozapine-treated adolescents met response criteria (66%) compared with olanzapine-treated subjects (33%). Clozapine was superior to olanzapine in terms of reduction of the psychosis cluster scores and negative symptoms from baseline to end point. However, both treatments were associated with significant weight-gain and related metabolic abnormalities.. This double-blind randomized comparison of two second-generation antipsychotic drugs for treatment-refractory adolescents with schizophrenia supports clozapine as the agent of choice. The development of interventions to limit weight gain and metabolic side effects are needed to enhance the risk-benefit profile for both study treatments.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Benzodiazepines; Child; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Recent data have suggested few differences in the cognitive effects of antipsychotic medications. However, assessment of such effects can be complex, due to a number of factors. Clozapine has previously shown greater clinical and lesser cognitive benefits than other atypicals. This study compared the cognitive benefits of clozapine and ziprasidone in schizophrenia patients (n=130) with a history of either failure to respond to or intolerance of previous adequate antipsychotic treatments.. Patients were randomized (double-blind) to either clozapine or ziprasidone in a single country (Italy), multi-site trial. The cognitive assessments examined episodic memory (RAVLT), executive functioning (Stroop test), and processing speed (Trail-making test (TMT) Parts A and B).. Analyses found statistically significant within-group improvements for ziprasidone in learning and delayed recall on the RAVLT and on TMT Parts A and B. Clozapine-treated patients improved on the RAVLT, but not on the TMT. A composite cognitive score improved from baseline in both groups, but the improvements were significantly larger in the ziprasidone group (p=.029).. These results indicated that cognitive functioning improved following treatment with ziprasidone in patients with a history of either treatment resistance or intolerance, and that the effects are comparable or greater than those observed with clozapine. One interpretation of these findings is that clozapine treatment interferes with the performance benefits associated with practice.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Double-Blind Method; Drug Resistance; Drug Tolerance; Female; Humans; Italy; Male; Memory Disorders; Neuropsychological Tests; Piperazines; Placebos; Schizophrenia; Schizophrenic Psychology; Thiazoles; Trail Making Test; Treatment Outcome

Only limited data are available on the effectiveness of augmented antipsychotics to clozapine therapy in chronic schizophrenia. We conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of augmentation with the atypical neuroleptic amisulpride to clozapine in a small sample group of patients.. 16 patients with the DSM-IV diagnosis of chronic schizophrenia and partially responsive to clozapine participated in this pilot study. Patients on a steady dose of clozapine randomly received either clozapine and amisulpride 400 mg/day (n=7) or clozapine and amisulpride 600 mg/day (n=6) or clozapine and placebo for 6 weeks (n=3). Efficacy measures were BPRS, CGI, GAF and MADRS score. Side effects and prolactin levels were obtained. Primary outcome measure were BPRS score changes.. The beneficial effect of augmented amisulpride at a daily dose of 600 mg was observed in the mean scores of secondary outcome measures, as assessed by GAF, CGI and MADRS. Measures of primary objectives failed to improve significantly. No reduction in BPRS total score was achieved due to lack of power of the study, whereas the BPRS subscore "activity" had a tendency to improve. Amisulpride was more beneficial in a higher than a lower dose. No severe side-effects occurred, but tremor, bradykinesia, akathisia and elevated prolactin levels were recorded.. Augmented amisulpride improved the global outcome of patients suffering from chronic schizophrenia in this pilot study and tended to be a helpful treatment option in cases of partial or non-responsiveness to clozapine. Limitations emerge from the small sample size and lack of power. Further investigation requires a larger number of patients to be included.

Topics: Adolescent; Adult; Aged; Amisulpride; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Pilot Projects; Schizophrenia; Sulpiride

Clozapine, despite its side-effect burden, has been considered to be the drug of choice for patients with schizophrenia whose psychotic symptoms fail to respond adequately to other anti-psychotic drugs. There are conflicting data concerning the potential utility of olanzapine in treatment-resistant schizophrenia at doses beyond the 10- to 20-mg/day range that has proven to be effective for most nonrefractory patients with schizophrenia.. The main objective of this study was to compare the efficacy and tolerability of high-dose olanzapine (target dose, 25-45 mg/day) and clozapine (300-900 mg/day) in patients with schizophrenia or schizoaffective disorder who had failed to respond adequately to prior treatment with other antipsychotic drugs.. This 6-month, randomized, double-blind, parallel-group study compared the efficacy and tolerability of olanzapine (mean dose, 34 mg/day; N = 19) or clozapine (mean dose, 564 mg/day; N = 21) in patients with treatment-resistant schizophrenia or schizoaffective disorder, diagnosed according to DSM-IV criteria. Outcome measures included psychopathology, cognitive performance (as assessed with a comprehensive neuropsychological test battery), and tolerability. The study was conducted between May 2000 and December 2003.. Robust and significant (mostly p < .001) improvement in multiple measures of psychopathology, mainly between 6 weeks and 6 months of treatment, was found in both treatment groups, with no significant difference between the 2 treatments except for the Global Assessment of Functioning score, which favored clozapine (p = .01). Improvement in some domains of cognition was significant-and equivalent for both drugs, as well. Nonsignificantly different improvement in Verbal List Learning-Immediate Recall (p < .05), Controlled Word Association Test (p < .05), and Digit Symbol Substitution Test (p < .001) was found. There were no significant differences in extrapyramidal symptoms. Weight gain was significantly (p = .01) greater with olanzapine.. Olanzapine, at higher than customary doses, demonstrated similar efficacy to clozapine in treatment-resistant schizophrenia and schizoaffective disorder in this study. However, the small sample size precludes definitively concluding that the 2 treatments are equivalent, at these doses, in treatment-resistant schizophrenia. The metabolic side effects of olanzapine are a limitation in its use.. ClinicalTrials.gov identifier NCT00179231.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Time Factors; Treatment Outcome; Weight Gain

It has been previously demonstrated that unmedicated persons with schizophrenia have deficits in cortical inhibition (CI) as indexed with transcranial magnetic stimulation (TMS). This inhibition is largely mediated by cortical GABAergic mechanisms. It has also been demonstrated that these inhibitory deficits may be normalized with the use of atypical antipsychotic medications. The purpose of this study, therefore, was to examine the effects of clozapine on TMS measures of CI and to compare these effects to unmedicated persons with schizophrenia and healthy subjects. We used two TMS inhibitory paradigms: short interval intra-cortical inhibition (SICI) and the cortical silent period (CSP) to evaluate CI in 10 clozapine-treated persons with schizophrenia, 6 unmedicated persons with schizophrenia and 10 healthy subjects. Clozapine-treated persons with schizophrenia had significantly longer CSPs compared with healthy subjects and unmedicated persons with schizophrenia. There were no significant differences in SICI between groups, however, the severity of psychotic symptoms was correlated with reduced SICI across all persons with schizophrenia. Our findings suggest that clozapine treatment is associated with greater CI in persons with schizophrenia and this increase may be related to potentiation of cortical GABAergic receptor mediated inhibitory neurotransmission. Our results also confirm previous findings suggesting that deficits in CI are related to the severity of psychotic symptoms in persons with schizophrenia.

Topics: Adult; Antipsychotic Agents; Cerebral Cortex; Clozapine; Electroencephalography; Electromyography; Evoked Potentials, Motor; Female; Humans; Male; Motor Cortex; Neural Inhibition; Psychiatric Status Rating Scales; Psychotic Disorders; Receptors, GABA; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission; Transcranial Magnetic Stimulation

This study compared the bioequivalence of FazaClo (clozapine orally disintegrating tablets) 100 mg to Clozaril (clozapine standard oral tablets) 100 mg after multiple doses in patients with schizophrenia.. This was a randomized, open-label, multiple-dose study in which patients with schizophrenia received FazaClo or Clozaril 100 mg twice daily for 5 days before crossing over to the alternate therapy. Blood samples were obtained at regular intervals during and after the completion of treatment, and standard pharmacokinetic parameters were calculated. Safety and patient satisfaction with FazaClo were also assessed.. Thirty-six patients were enrolled, of whom 33 completed the study and 30 were included in the steady-state analyses. All pharmacokinetic parameters for clozapine and desmethylclozapine (the major metabolite of clozapine) were similar between FazaClo and Clozaril in both the completer and steady-state populations. Geometric mean values for steady-state maximum and minimum concentrations and area under the plasma concentration-time curve for FazaClo were all within 95-105% of those for Clozarilwell within the range considered by the US FDA as acceptable for bioequivalence (80-125%). Patients also expressed a high level of satisfaction with the FazaClo orally disintegrating tablet formulation.. FazaClo produced pharmacokinetic profiles almost identical to those of Clozaril. This should provide clinicians with reassurance that patients who receive FazaClo will achieve plasma drug concentrations similar to those produced by the same daily dose of Clozaril, and that no cross-titration is necessary when switching from one of these clozapine formulations to the other.

Topics: Administration, Oral; Adolescent; Adult; Antipsychotic Agents; Area Under Curve; Clozapine; Cross-Over Studies; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Generic; Female; Half-Life; Humans; Intestinal Obstruction; Intestine, Small; Male; Metabolic Clearance Rate; Middle Aged; Patient Dropouts; Patient Satisfaction; Schizophrenia; Sweating; Tablets; Therapeutic Equivalency

Inadequate response to clozapine poses a substantial problem in the pharmaco-therapy of refractory schizophrenia. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia.. Patients with DSM-IV schizophrenia who had a history of treatment failure or partial response to long-term clozapine treatment were recruited. A total of 62 patients with either a baseline Brief Psychiatric Rating Scale (BPRS) score of at least 35 or more than 2 Schedule for Assessment of Negative Symptoms (SANS) global rating item scores of at least 3 were randomly assigned to double-blind augmentation treatment with either aripiprazole (5-30 mg/day) or placebo over 8 weeks. The primary outcome measure was change in BPRS total score from baseline. The study was conducted between December 1, 2005, and December 10, 2006.. There was no significant difference in the primary outcome measure between the 2 groups. In secondary analyses, improvement was significantly greater with aripiprazole treatment than with placebo for negative symptoms assessed by both the BPRS negative symptom sub-scale and the SANS total score but not for positive symptoms. Prolactin and triglyceride levels were significantly lower in the aripiprazole group than in the placebo group. No significant differences between the 2 groups were observed in adverse effects, including extrapyramidal symptoms and serum glucose levels.. Although aripiprazole augmentation of clozapine did not lead to a significant improvement of total symptom severity in schizophrenia, a favorable change in the negative symptom domain was observed.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Brief Psychiatric Rating Scale; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperazines; Quinolones; Schizophrenia; Severity of Illness Index; Surveys and Questionnaires

This study evaluated the association of neurocognition and symptoms with measures of social and occupational functioning in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).. CATIE was an 18-month study of individuals with schizophrenia. Symptoms of 1,386 patients were measured with the positive syndrome scale of the Positive and Negative Syndrome Scale (PANSS) and a PANSS negative symptom scale that eliminated items that most overlap with measures of community functioning or neurocognition. The Heinrichs-Carpenter Quality of Life Scale, which a rater completes on the basis of the patient's self-report, and recent employment were used to assess community functioning. Hierarchical regression analyses and mixed models tested the association of neurocognition and symptoms with social/occupational functioning as well as changes in these measures during treatment.. Both symptoms and neurocognition were associated with quality of life in bivariate correlation analyses. Symptoms contributed more to the incremental explained variance in quality of life than did neurocognitive functioning, but both kinds of measures were significantly related to quality of life. In an analysis including only the positive syndrome scale, the increased explained variance in quality of life was about equal to that associated with neurocognition. Neurocognition and both symptom measures were independently associated with quality of life in the cross-sectional mixed-model analysis. Changes in neurocognition and both symptom measures during treatment were also significantly associated with change in the quality of life.. Both psychotic symptoms and neurocognitive deficits appear to contribute independently to decreased quality of life in schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Brain; Clozapine; Cognition Disorders; Cost-Benefit Analysis; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Quality of Life; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

The aim of this study was to investigate whether augmentation of clozapine with aripiprazole improves clinically significant residual symptoms in stabilized outpatients with chronic schizophrenia.. Twenty seven stabilized outpatients meeting criteria for chronic schizophrenia, who had residual symptoms despite clozapine treatment, were assigned to receive oral aripiprazole (15 mg/day) for a period of 16 weeks. Patients remained on clozapine (100-900 mg/day) for at least 12 months, prior to study initiation. Symptoms assessments were made with the Positive and Negative Symptom Scale (PANSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Examination (MMSE), at baseline and at weeks 4, 8, 12, and 16. The Quality of Life Scale (QLS) was administered at baseline and at week 16.. There was a statistically significant improvement in the mean scores for PANSS (p<0.05), PANSS negative (p<0.001), MADRS (p<0.05), MMSE (p<0.01), and QLS (p<0.05), but not for PANSS positive (p>0.05). Extrapyramidal side effects (as assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale) did not vary significantly at any point of the study. No statistically significant change was observed in prolactin levels and body weight. Results were similar for the intention-to-treat (n=27) and completer (n=23) groups.. Aripiprazole augmentation in a group of chronic schizophrenic outpatients treated with clozapine led to a substantial improvement in clinically significant residual symptoms, such as negative-depressive symptoms, cognitive impairment and quality of life, without worsening the side effect burden.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Synergism; Female; Follow-Up Studies; Humans; Male; Middle Aged; Outpatients; Pilot Projects; Piperazines; Psychiatric Status Rating Scales; Psychometrics; Quinolones; Schizophrenia; Time Factors

This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine-associated weight gain.. This was a 12-week double-blind, placebo controlled, randomized trial of sibutramine for weight loss in obese clozapine-treated schizophrenia or schizoaffective disorder subjects.. Ten patients were enrolled into the placebo group and 11 patients into the sibutramine group. There were no significant baseline differences between the two groups on age, gender, education, ethnicity, diagnosis, weight, body mass index (BMI), and blood pressure. At week 12, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, Hba1c, fasting glucose, or cholesterol levels.. Sibutramine treatment did not show significant weight loss compared with placebo in clozapine-treated patients with schizophrenia or schizoaffective disorder. Further research with a larger sample size and longer follow-up duration is warranted.

Topics: Adult; Anthropometry; Antipsychotic Agents; Appetite Depressants; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Clozapine; Cyclobutanes; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Hemoglobins; Humans; Male; Obesity; Psychotic Disorders; Schizophrenia; Weight Gain

Risperidone augmentation of clozapine in refractory schizophrenia has theoretical but only inconsistent support from clinical trials.. To examine if adding risperidone to stable yet symptomatic schizophrenia outpatients on optimized clozapine monotherapy improves psychopathology.. We conducted a double-blind placebo-controlled parallel-group trial of a fixed dose of 4 mg/day risperidone added for 6 weeks in 24 outpatients with schizophrenia.. Subjects who received risperidone showed a non-significant decrease in PANSS total score. The PANSS disorganized thought subscale improved significantly (beta=-3.3079, p=0.047).. Our trial does not support the routine addition of risperidone to clozapine in refractory schizophrenia patients. However, much larger trials are needed to conclusively settle the question of added efficacy from this combination.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Female; Humans; Male; Mass Screening; Middle Aged; Prolactin; Risperidone; Schizophrenia

This study examined the relative effects of the second-generation antipsychotic drugs and an older representative agent on psychosocial functioning in patients with chronic schizophrenia.. Consenting patients were enrolled in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. In phase 1, patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. Clozapine was included for patients who chose this pathway after discontinuing phase 1 due to inefficacy; all other patients received another second-generation antipsychotic. Psychosocial functioning was assessed using the Quality of Life Scale.. Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains.. All antipsychotic treatment groups in all phases made modest improvements in psychosocial functioning. There were no differences among them after 6, 12, or 18 months. More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions.

Topics: Adaptation, Psychological; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Dibenzothiazepines; Follow-Up Studies; Health Status; Humans; National Institute of Mental Health (U.S.); Olanzapine; Patient Dropouts; Perphenazine; Piperazines; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Thiazoles; Treatment Outcome; United States

Based on the evidence that lamotrigine added to clozapine in refractory schizophrenic patients has reported promising results, the present 24-week double-blind, randomized, placebo-controlled trial had the aim to explore the efficacy of lamotrigine add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 200 mg/day of lamotrigine or a placebo. A final sample of fifty-one patients completed the study. The results obtained indicate that lamotrigine added to stable clozapine treatment showed a beneficial effect on the negative, positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. Regarding cognitive functions, improvement was observed in some explored areas, such as attentional resistance to interference, verbal fluency and executive functioning. The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Attention; Brief Psychiatric Rating Scale; Clozapine; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Humans; Lamotrigine; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triazines

Topics: Adolescent; Adult; Aged; Alkaloids; Antipsychotic Agents; Chlorpromazine; Cholinesterase Inhibitors; Clozapine; Drug Resistance; Drug Synergism; Female; Humans; Male; Middle Aged; Risperidone; Schizophrenia; Sesquiterpenes

Thirteen outpatients with chronic but stable schizophrenia received donepezil and placebo augmentation of their maintenance antipsychotic medication regimen. Each subject received in a randomized, counterbalanced order 1) donepezil 5 mg for 6 weeks then donepezil 10 mg for six weeks and 2) placebo donepezil for 12 weeks. Serial ratings of the Positive and Negative Symptom Scale (PANSS) [Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13(2): 261-276] were performed by a trained rater blind to the donepezil order and condition: at baseline, 12 weeks and 24 weeks. On donepezil as compared to baseline or placebo, there was a significant improvement in PANSS negative scores (p=.018, n=13). These results are discussed with respect to other studies using cholinesterase inhibitors as an augmentation strategy in schizophrenia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cholinesterase Inhibitors; Clozapine; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Olanzapine; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Three patients underwent fMRI during a word generation task before and after successful treatment of auditory hallucinations with rTMS and were compared to four control subjects. There was a significant increase and more normal task related brain activation in brain areas involved in language processing including left temporoparietal cortex after rTMS treatment.

Topics: Adult; Amisulpride; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Female; Functional Laterality; Hallucinations; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parietal Lobe; Reaction Time; Schizophrenia; Sulpiride; Temporal Lobe; Transcranial Magnetic Stimulation; Treatment Outcome

Patients with schizophrenia treated with clozapine often gain weight. This study evaluated the effects of dietary control and physical activity among obese inpatients with schizophrenia being treated with clozapine.. Fifty-three clozapine-treated obese patients with schizophrenia in a veterans hospital in eastern Taiwan who had a body mass index greater than 27 (weight divided by height in meters squared) and who were taking clozapine were randomly assigned to a study group of 28 or a control group of 25. The study group was placed on a diet that reduced calorie intake by 200 to 300 kcal per day (to 1,300 to 1,500 kcal per day for women and to 1,600 to 1,800 kcal per day for men) and a six-month regimen of regular physical activity in which participants used approximately 600 to 750 kcal per week (level walking and walking on stairs for 60 minutes three days per week). Anthropometric, metabolic, and hormonal parameters were measured after three and six months by using anthropometry, an enzyme autoanalyzer, immunoassay, and enzyme-linked immunosorbent assay.. Compared with the control group, the study group showed a significant decrease in body weight, body mass index (5.4% reduction), waist circumference (3.3 cm), and hip circumference (3.3 cm) after three months and after six months. Triglyceride and insulin-like growth factor-binding protein-3 (IGFBP-3) decreased significantly only after six months.. A program of dietary control and regular physical activity can significantly reduce body weight and improve metabolic profiles of insulin, triglyceride, and IGFBP-3 among obese inpatients taking clozapine for the treatment of schizophrenia.

Topics: Adult; Anthropometry; Antipsychotic Agents; Body Mass Index; Clozapine; Diet, Reducing; Exercise; Female; Follow-Up Studies; Hospitalization; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Male; Middle Aged; Obesity; Schizophrenia; Taiwan; Triglycerides; Veterans

Weight gain is a problem commonly encountered with antipsychotic treatment and has become more apparent with increasing use of the newer atypical antipsychotics. The adipocyte-derived hormone, leptin, has been associated with body weight and energy homeostasis, and abnormal regulation of leptin could play a role in weight gain induced by antipsychotics. We investigated whether a leptin gene promoter variant affected weight gain after long-term treatment with clozapine in chronic schizophrenia. Leptin G2548A polymorphism was genotyped in 102 Chinese Han inpatients with chronic schizophrenia treated with clozapine. Weight gains, expressed as change in body mass index (BMI), were monitored after long-term clozapine treatment. We found a significant relationship between the 3 leptin G/A genotypes and mean BMI gain (F(2,99) = 3.35, P = 0.039, r(2) = 0.09). Moreover, genotype had a strong effect on BMI gain in male (P = 0.004, r(2) = 0.16), but not in female patients (P > 0.05). Thus, variation in the leptin gene may be a risk factor for weight gain in male patients with schizophrenia on long-term clozapine treatment.

Topics: Antipsychotic Agents; Asian People; Body Mass Index; China; Chronic Disease; Clozapine; Female; Genotype; Humans; Leptin; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Promoter Regions, Genetic; Schizophrenia; Weight Gain

A limitation in the use of classic neuroleptic drugs is the eventual appearance of extrapyramidal symptoms. Some studies, mainly based on experimental situations, have related these symptoms with a defect in the mitochondrial electron transport chain (ETC), especially with complex I (CI). One of the advantages of the "atypical" neuroleptics is a lower incidence of movement disorders. We studied peripheral blood mononuclear cells from naive schizophrenic patients (n = 25) and patients under chronic treatment with 1 "typical" neuroleptic (haloperidol, n = 15) or 1 "atypical" neuroleptic (risperidone, n = 23; or clozapine, n = 21). Patients were on standard clinical situation, on treatment for at least 28 months, and did not present signs or symptoms of extrapyramidal dysfunction. Absolute enzyme activities of ETC complexes I to IV were spectrophotometrically quantified, and oxygen consumption with substrates of different complexes was measured polarographically. As an indirect measure of oxidative damage, we quantified membrane lipid peroxidation through the loss of cis-parinaric acid fluorescence. We found differences among groups when comparing the activity of CI, which was decreased in patients receiving neuroleptics, either assessed enzymatically or through oxygen consumption. This effect was lower for atypical neuroleptics than for haloperidol. Haloperidol was also associated with a significant increase of peripheral blood mononuclear cell membrane peroxidation. We conclude that antipsychotics given at clinical standard doses, either typical or atypical, inhibit CI of the ETC. It remains to be established if this finding in a nontarget tissue for antipsychotics may account for the lower incidence of movement disorders observed in patients on atypical agents.

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Electron Transport; Electron Transport Complex I; Female; Haloperidol; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Neuroleptic Malignant Syndrome; Risperidone; Schizophrenia

Atypical antipsychotics (SGA) have the propensity to induce weight gain.. The aim was to evaluate early changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels.. We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study.. Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University.. Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months.. At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals.. Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Body Weight; Clozapine; Female; Ghrelin; Glucose Tolerance Test; Hormones; Human Growth Hormone; Humans; Insulin; Male; Metabolic Networks and Pathways; Neurosecretory Systems; Peptide Hormones; Risperidone; Schizophrenia; Weight Gain

Several lines of evidence suggest that clozapine is more effective than both first- and second-generation antipsychotic drugs in treatment-resistant schizophrenia (TRS). However, clinicians appear to be hesitant to prescribe this drug. It would therefore be extremely valuable if predictors of response to clozapine could be identified. The aim of this study was to evaluate the predictive factors of clinical responses to clozapine in a group of Turkish patients with TRS.. This was a 16-week uncontrolled open study carried out among 97 TRS patients (80 males and 17 females; DSM-IV diagnosis). All patients fulfilled the criteria for refractory schizophrenia according to the UK guidelines for the National Institute of Clinical Excellence (NICE). After all previous antipsychotic medications had run their course, the patients were started on clozapine according to a standardized titration and dosage schedule. Psychopathology was evaluated before the initiation of clozapine therapy and once every 4 weeks using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment for Positive Symptoms, and the Scale for the Assessment of Negative Symptoms.. Of the TRS patients on clozapine, 55.7% achieved a clinical response, defined as at least a 20% decrease in BPRS. We observed a favorable effect of clozapine on both positive and negative symptoms. Logistic regression analysis showed that a good clozapine response was more likely when schizophrenia began at a later age, when negative symptoms were severe, and when patients had an early response at 4 weeks.. A combination of demographic, baseline clinical, and acute treatment response variables may accurately predict response to clozapine in TRS. Priority should be given to initiating clozapine at the earliest phase of TRS, especially for patients with evident negative symptoms.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Female; Humans; Logistic Models; Male; Middle Aged; Probability; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Turkey

Investigators have reported that weight gain attributed to clozapine is associated with its clinical response. However, weight gain is a nonspecific physiological variable that, in itself, does not explain the mechanism underlying this relation. Alternatively, other biological variables that are often associated with weight gain, such as serum lipids, may assist in explaining this observation. The primary objective of this study was to determine whether an increase in serum lipids is associated with improvement in schizophrenia symptoms during steady state treatment with clozapine.. The data for this study represent a subset of data from a randomized, double-blinded trial that evaluated subjects with schizophrenia who demonstrated a poor treatment response to clozapine. While continuing their clozapine therapy, subjects were randomly assigned to receive either risperidone 3 mg daily or placebo for 8 weeks. This course of treatment was followed by an optional (open-label) 18 weeks of augmentation with risperidone. In the present study, we included all subjects from the previously reported trial who had fasting lipid analyses and Positive and Negative Syndrome Scale (PANSS) scores from days 7 and 63 (n = 55). For the primary analyses, we used multiple regression to examine the association between serum lipid concentrations and PANSS scores, after controlling for weight.. The analyses showed that the change in serum lipid concentration predicted change in symptoms over that of change in weight. Specifically, an increase in serum triglyceride concentration was associated with a decrease in the total PANSS score (p = 0.037). In addition, an increase in either serum total cholesterol concentration (p = 0.007), serum triglyceride concentration (p = 0.017) or their combined effect (p = 0.010) was associated with a decrease in PANSS negative subscale scores.. Elevation of serum lipids is associated with an improvement in schizophrenia symptoms in subjects treated with clozapine. Although the mechanism is unclear, serum lipids may play a role in influencing clozapine's therapeutic activity.

Topics: Antipsychotic Agents; Body Weight; Clozapine; Data Interpretation, Statistical; Double-Blind Method; Humans; Lipids; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triglycerides

To study the therapeutic effects on auditory hallucinations refractory to clozapine with 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied on the left temporoparietal cortex.. Eleven patients with schizophrenia (DSM-IV) experiencing auditory hallucinations (unresponsive to clozapine) were randomly assigned to receive either active of rTMS (N = 6) or sham stimulation (N = 5) (with concomitant use of clozapine) using a double-masked, sham-controlled, parallel design. A total of 160 minutes of rTMS (9600 pulses) was administered over 10 days at 90% motor threshold. The study was conducted from January 2003 to December 2005.. There was a reduction in hallucination scores in both groups, which persisted during follow-up in the active group for the items reality (p = .0493) and attentional salience (p = .0360). Both groups showed similar patterns of symptomatic changes on subscales (negative symptoms, general psychopathology) and total scores of the Positive and Negative Syndrome Scale, Clinical Global Impressions scale, and Visual Analog Scale.. Active rTMS in association with clozapine can be administered safely to treat auditory hallucinations, although its clinical utility is still questionable. No significant clinical effects were observed in the sample studied, possibly because it was too small and/or due to its high refractoriness.

Topics: Adult; Clozapine; Demography; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Resistance; Female; Hallucinations; Humans; Male; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Transcranial Magnetic Stimulation; Treatment Outcome

: Lamotrigine previously was found to attenuate ketamine-induced behavioral changes and, in 2 placebo-controlled trials, to improve psychosis when added to antipsychotic medication. We sought to evaluate the potential role of lamotrigine augmentation in schizophrenia patients resistant to atypical antipsychotic medication.. : Two multicenter, randomized, double-blind, 12-week, parallel-group trials were conducted to compare flexibly dosed lamotrigine (100-400 mg/d) with placebo as add-on treatment in schizophrenia patients with stable, residual psychotic symptoms. The primary end point was changed in Positive and Negative Syndrome Scale total score at week 12.. : Two hundred seventeen patients were enrolled in study 1 and 212 in study 2; completion rates in the intent-to-treat samples were 71% and 74%, respectively, and did not differ between treatment groups. Overall, mean Positive and Negative Syndrome Scale total scores improved in both studies and did not differ between treatment groups. In study 1, the Scale for Assessment of Negative Symptoms total score and Clinical Global Impression improved more with placebo than with lamotrigine; in study 2, the cognitive composite score improved more with lamotrigine than with placebo.. : Results from these 2 studies do not support the use of lamotrigine as an adjunct to atypical antipsychotics in patients with refractory psychosis. It is unclear why positive results from previous lamotrigine trials were not replicated. The positive effect of lamotrigine on cognition in one trial, while of uncertain significance, may merit further study.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Female; Humans; Lamotrigine; Male; Middle Aged; Patient Compliance; Patient Dropouts; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Suicide, Attempted; Treatment Outcome; Triazines

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale 0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale 0-6: clozapine, 36.6 +/- 8.8 to 15.9 +/- 13.7; olanzapine, 36.7 +/- 9.9 to 19.1 +/- 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 +/- 0.6 to 2.5 +/- 1.5; olanzapine, 4.5 +/- 0.6 to 2.3 +/- 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Appetite; Benzodiazepines; Blood Pressure; Body Mass Index; Bulimia; Clozapine; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Fatigue; Female; Heart Rate; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Sialorrhea; Treatment Outcome; Weight Gain

The development of therapeutic strategies for cognitive dysfunction remains one of the primary goals in the treatment of schizophrenia. The pharmacodynamic profile of mirtazapine, an antidepressant that enhances noradrenergic and serotonergic transmission, is based on a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism. Mirtazapine shares some pharmacological similarities with that of clozapine. This 8-week open label trial aimed to discover whether the addition of 30 mg mirtazapine could potentiate the effects on cognition of an ongoing stabilized clozapine therapy in 15 persons who met the criteria for chronic schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). Mirtazapine adjunction was well tolerated and induced a significant improvement in cognitive performance, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph, 1998) total score and by the subscales for immediate and delayed memory (p<.01). Since Hamilton Depression Rating Scale (HAM-D; Hamilton, 1967), Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962), and Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1989) scores at Week 8 did not show significant differences from baseline, the improvements in the effects of clozapine on cognition observed after the addition of mirtazapine seemed to be a direct rather than an indirect action of this drug (e.g., via mood or other psychopathological symptoms). These findings suggest a potential role for mirtazapine as a useful strategy to augment the efficacy of clozapine in the treatment of cognitive dysfunctions in chronic schizophrenia.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Cognition; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Drug Synergism; Female; Humans; Male; Mianserin; Mirtazapine; Schizophrenia; Time Factors

Topics: Analysis of Variance; Antipsychotic Agents; Case-Control Studies; Clozapine; Functional Laterality; Genetic Predisposition to Disease; Guanidines; Hippocampus; Humans; Receptors, N-Methyl-D-Aspartate; Reference Values; Schizophrenia; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

Explore relationships between 12 dopamine D2 gene variants and quantitative measures of positive and negative symptom response following clozapine treatment in two treatment refractory or intolerant populations (Caucasian and African-American).. Subjects included 97 Caucasian and 35 African-American DSM-III-R or DSM-IV schizophrenics and were genotyped by 5'-exonuclease fluorescence assays. Genotype, allele +/- and haplotype groups were compared on Brief Psychiatric Rating Scale (BPRS) overall, positive (BPOS) and negative symptom subscales (BNEG) using analysis of variance.. In Caucasians, no significant associations were found for any individual polymorphisms or haplotypes. In African-Americans, the TaqIB B2 (T) allele and rs1125394 allele 1 (A), and a two-marker haplotype containing these two alleles were associated with improvement in overall BPRS and BPOS response.. Variability in clozapine response is still not fully understood and likely involves multiple factors. This study suggests that D2 receptor gene variants may be among such factors.

Topics: Adult; Alleles; Antipsychotic Agents; Black or African American; Clozapine; Demography; Female; Gene Frequency; Genetic Variation; Haplotypes; Humans; Linkage Disequilibrium; Male; Psychiatric Status Rating Scales; Receptors, Dopamine D2; Schizophrenia; Treatment Outcome; White People

The purpose of the present study was to compare the subjective response and attitude towards antipsychotic treatment between schizophrenic patients receiving clozapine and those receiving risperidone. Ninety-four outpatients who had been on a stable drug dosage were evaluated (clozapine group: n=57, mean dose=254.1 mg/day; risperidone group: n=37, mean dose=3.0 mg/day). Subjective response to antipsychotic treatment was assessed using the Drug Attitude Inventory (DAI). The two treatment groups had a positive total mean score, indicating that both groups had a positive subjective view of drug treatment. The proportion of subjects who had a positive total score was not different between the two groups. In subscale scores, multivariate analysis revealed that clozapine group tended to have a higher score on the subjective positive response subscale (P=0.06). The scores of subjective negative response or attitude to medication subscales were not different between groups. In conclusion, there was no marked difference between stabilized outpatients taking clozapine and risperidone in terms of subjective response and attitude towards antipsychotic treatment. Considering that subjects treated with clozapine were treatment resistant patients, equal DAI score might indicate a more favorable subjective experience of clozapine. Further prospective studies on subjective response to various atypical agents are required to obtain valuable insight into how best to use these drugs from the patient's perspective.

Topics: Adult; Antipsychotic Agents; Attitude; Chi-Square Distribution; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Multivariate Analysis; Outpatients; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Surveys and Questionnaires; Time Factors

The beneficial effect of sulpiride augmentation of clozapine therapy for treatment-resistant schizophrenia patients is enhanced by its antisalivatory effect on clozapine-induced hypersalivation (CIH). Amisulpride, similar to sulpiride, is a substitute benzamide derivative with higher selective binding to the D2/D3 dopamine receptor. We hypothesized that add-on amisulpride would also be beneficial in controlling CIH. In a randomized, double-blind, placebo-controlled cross-over study, 20 clozapine-treated schizophrenia (DSM-IV criteria) inpatients with CIH were randomly initially assigned to add-on amisulpride (nine patients; 400 mg/day up-titrated from 100 mg/day over 1 week) or placebo (11 patients). Primary outcome was change in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Other measures included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression scale (CGI) and Simpson-Angus Scale (SAS). Mean NHRS indices were considerably lower with amisulpride (1.79 +/- 1.25) than with placebo (2.63 +/- 1.33) [F(1,38) = 5.36, P < 0.05]. With amisulpride treatment, there was a significant improvement on the negative symptoms subscale of the PANSS [F(3,57) = 3.76, P < 0.05], but not on the SAS, CGI or other subscales of the PANSS (all F < 1). Short-term amisulpride augmentation has a strong ameliorating effect on CIH. A long-term, large-scale study with a broader dose range is warranted to evaluate the stability of this effect across time.

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Placebos; Schizophrenia; Sialorrhea; Sulpiride

We conducted this 6-week open-label trial to examine the effects of adjunctive aripiprazole in clozapine-treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia.. Ten clozapine-treated subjects received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. Eighty percent were male, the mean age was 38.7 +/- 8.9 years and the mean clozapine dose was 455 +/- 83 mg daily.. There was a significant decrease in weight (P = 0.003), body mass index (P = 0.004), fasting total serum cholesterol (P = 0.002) and total triglycerides (P = 0.04) comparing baseline to study endpoint. There was no significant change in total Positive and Negative Syndrome Scale scores.. This combination may be useful for clozapine-associated medical morbidity and must be studied in placebo-controlled double-blind randomized trials to determine efficacy and safety.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Aripiprazole; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Clozapine; Community Mental Health Centers; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Quinolones; Schizophrenia; Triglycerides

There is strong evidence that oxygen free radicals may play an important role in the pathophysiology of schizophrenia. Impaired antioxidant defense and increased lipid peroxidation have been previously reported in drug-naïve, first episode and chronically medicated schizophrenic patients using typical neuroleptics. We measured serum SOD and TBARS in two groups of chronic medicated DSM-IV schizophrenic patients, under haloperidol (n = 10) or clozapine (n = 7) and a group of healthy controls (n = 15). Serum SOD and TBARS were significantly higher (p = 0.001) in schizophrenic patients (7.1 +/- 3.0 and 3.8 +/- 0.8) than in controls (4.0 +/- 1.6 and 2.5 +/- 0.7). Among patients, serum TBARS was significantly higher (p = 0.008) in those under clozapine (4.4 +/- 0.7) than in those under haloperidol treatment (3.4 +/- 0.7). For SOD levels the difference between groups was not found. It is reasonable to argue that the difference found in TBARS levels might be due to the course of the disease, instead of medication. Further investigation on the role of oxidative tonus and lipid peroxidation in different schizophrenia subtypes and different outcome patterns in this disorder is warranted. Additionally it could also address questions concerning a possible oxidant/antioxidant imbalance in schizophrenia.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Female; Haloperidol; Humans; Male; Middle Aged; Schizophrenia; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The treatment of schizophrenia with multiple antipsychotic drugs is common, but the benefits and risks are not known.. In a randomized, double-blind study, we evaluated patients with schizophrenia and a poor response to treatment with clozapine. The patients continued to take clozapine and were randomly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale (PANSS). The secondary outcomes included cognitive functioning.. A total of 68 patients were randomly assigned to treatment. In the double-blind phase, the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups. There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment (P=0.38). The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 (95 percent confidence interval, -7.3 to 7.0). The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P=0.02 for the comparison between the two groups in the change from baseline). The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group (16.2 vs. 1.8 mg per deciliter [0.90 vs. 0.10 mmol per liter], P=0.04). The incidence and severity of other side effects did not differ between the two groups.. In this short-term study, the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia. (ClinicalTrials.gov number, NCT00272584).

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Failure

There is an ongoing debate over whether atypical antipsychotics are more effective than typical antipsychotics in the treatment of schizophrenia. This naturalistic study compares atypical and typical antipsychotics on time to all-cause medication discontinuation, a recognized index of medication effectiveness in the treatment of schizophrenia.. We used data from a large, 3-year, observational, non-randomized, multisite study of schizophrenia, conducted in the U.S. between 7/1997 and 9/2003. Patients who were initiated on oral atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine, or ziprasidone) or oral typical antipsychotics (low, medium, or high potency) were compared on time to all-cause medication discontinuation for 1 year following initiation. Treatment group comparisons were based on treatment episodes using 3 statistical approaches (Kaplan-Meier survival analysis, Cox Proportional Hazards regression model, and propensity score-adjusted bootstrap resampling methods). To further assess the robustness of the findings, sensitivity analyses were performed, including the use of (a) only 1 medication episode for each patient, the one with which the patient was treated first, and (b) all medication episodes, including those simultaneously initiated on more than 1 antipsychotic.. Mean time to all-cause medication discontinuation was longer on atypical (N = 1132, 256.3 days) compared to typical antipsychotics (N = 534, 197.2 days; p < .01), and longer on atypicals compared to typicals of high potency (N = 320, 187.5 days; p < .01), medium potency (N = 140, 213.5 days; p < .01), and low potency (N = 74, 208.7 days; p < .01). Among the atypicals, only clozapine, olanzapine, and risperidone had significantly longer time to all-cause medication discontinuation compared to typicals, regardless of potency level, and compared to haloperidol with prophylactic anticholinergic treatment. When compared to perphenazine, a medium-potency typical antipsychotic, only clozapine and olanzapine had a consistently and significantly longer time to all-cause medication discontinuation. Results were confirmed by sensitivity analyses.. In the usual care of schizophrenia patients, time to medication discontinuation for any cause appears significantly longer for atypical than typical antipsychotics regardless of the typical antipsychotic potency level. Findings were primarily driven by clozapine and olanzapine, and to a lesser extent by risperidone. Furthermore, only clozapine and olanzapine therapy showed consistently and significantly longer treatment duration compared to perphenazine, a medium-potency typical antipsychotic.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bias; Clozapine; Drug Administration Schedule; Episode of Care; Female; Follow-Up Studies; Humans; Male; Olanzapine; Outcome Assessment, Health Care; Perphenazine; Proportional Hazards Models; Research Design; Risperidone; Schizophrenia; Time Factors; Treatment Outcome; United States

Schizophrenic outpatients (n=102) whose condition had stabilized with clozapine (CLZ) therapy and were being maintained on CLZ were followed for 1 year. Clinical status and concentrations of serum clozapine (CLZ) and its metabolite norclozapine (NCLZ) were evaluated periodically or when relapse occurred. Relapse was defined as a significant exacerbation of psychotic symptoms or hospitalization. Thirty-three patients relapsed and 69 did not. Relapse patients displayed significantly lower serum concentrations of CLZ and a sum of CLZ and NCLZ at endpoint than non-relapses (CLZ: 162 ng/ml vs. 237 ng/ml, p<0.001; CLZ+NCLZ: 225 ng/ml vs. 301 ng/ml, p<0.001). When all subjects were pooled together, a significant inverse correlation was observed between percent increase in the total score on the Brief Psychiatric Rating Scale (BPRS) from baseline and serum levels of CLZ alone (r=0.404, p<0.001) and the sum of CLZ and NCLZ (r=0.364, p<0.001). Relapses and non-relapses were well separated by a threshold CLZ serum concentration of 200 ng/ml with a sensitivity of 73% and a specificity of 80%. The threshold value represented about a 40% lower serum CLZ level than concentration achieved in acute treatment. Survival analysis showed a similarity of the relapse risk over time defined by the CLZ serum threshold and by symptomatic criteria. These results suggest that effective relapse prevention may require maintenance of patients at CLZ serum concentrations above 200 ng/ml and above 60% of the acute-phase level during long-term maintenance treatment of schizophrenia.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Recurrence; Schizophrenia; Statistics as Topic; Time Factors

There is good evidence that clozapine is more efficacious than first-generation antipsychotic drugs in resistant schizophrenia. It is less clear if clozapine is more effective than the other second-generation antipsychotic (SGA) drugs. A noncommercially funded, pragmatic, open, multisite, randomized controlled trial was conducted in the United Kingdom National Health Service (NHS). Participants were 136 people aged 18-65 with DSM-IV schizophrenia and related disorders whose medication was being changed because of poor clinical response to 2 or more previous antipsychotic drugs. Participants were randomly allocated to clozapine or to one of the class of other SGA drugs (risperidone, olanzapine, quetiapine, amisulpride) as selected by the managing clinician. Outcomes were assessed blind to treatment allocation. One-year assessments were carried out in 87% of the sample. The intent to treat comparison showed no statistically significant advantage for commencing clozapine in Quality of Life score (3.63 points; CI: 0.46-7.71; p = .08) but did show an advantage in Positive and Negative Syndrome Scale (PANSS) total score that was statistically significant (-4.93 points; CI: -8.82 to -1.05; p = .013) during follow-up. Clozapine showed a trend toward having fewer total extrapyramidal side effects. At 12 weeks participants who were receiving clozapine reported that their mental health was significantly better compared with those receiving other SGA drugs. In conclusion, in people with schizophrenia with poor treatment response to 2 or more antipsychotic drugs, there is an advantage to commencing clozapine rather than other SGA drugs in terms of symptom improvement over 1 year.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Depressive Disorder; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology

To determine how the use of the newer, so called atypical antipsychotic medications, effects the pharmacoeconomic treatment burden of schizophrenia and related conditions and to provide a clear comparison of the costs and risks associated with these atypical drugs.. In this 2-year, open-label, prospective study, resource utilization (RU) data were collected on 160 patients with these conditions. A comparison between risks and costs was performed by combining the generalized CNOMSS data on both economic factors and risk assessments.. The main findings of the study were that the total adjusted 1- and 2-year costs were lowest for quetiapine. Drug acquisition costs were lowest for risperidone for both the 1- and 2-year cohorts. Clozapine use was predictably associated with the highest overall and medication costs at both 1 and 2 years.. Treatment with risperidone or quetiapine was associated with the lowest overall costs when compared with olanzapine or clozapine.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Canada; Clozapine; Cohort Studies; Cost of Illness; Cost-Benefit Analysis; Dibenzothiazepines; Drug Costs; Female; Health Care Surveys; Health Resources; Humans; Male; Olanzapine; Prospective Studies; Psychotic Disorders; Quetiapine Fumarate; Risk Assessment; Risperidone; Schizophrenia

When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]).. Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation.. For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cross-Over Studies; Dibenzothiazepines; Drug Monitoring; Drug Resistance; Eosinophilia; Female; Follow-Up Studies; Humans; Male; Olanzapine; Piperazines; Prospective Studies; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.. The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.. One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.. After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.. This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Clozapine; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Olanzapine; Prospective Studies; Risperidone; Schizophrenia; Sulpiride; Triglycerides; Waist-Hip Ratio

To compare the short-term curative effect of clozapine (CZ) and its combination with electroacupuncture (EA) in treating schizophrenia.. Ninety schizophrenia patients were randomly divided into two groups equally: the EA group treated with combination of CZ (200 - 300 mg/d in mean) and EA, and the CZ group treated with CZ alone. The effects of treatment were evaluated with PANSS, CGI and TESS before and at the 2th, 4th, 6th and 8th weekend of the treatment.. The initiation of effect in the two groups was the same, the total effective rate was 75% in the EA group and 73% in the CZ group. However, somatic complaint was lower and compliance was higher in the EA group than that in the CZ group respectively.. With the effect equal to CZ, combination of CZ and EA shows higher compliance in treating schizophrenia, which would be beneficial in the later stage treatment for consolidation.

Topics: Acupuncture Therapy; Adolescent; Adult; Clozapine; Combined Modality Therapy; Electroacupuncture; Female; Humans; Male; Middle Aged; Schizophrenia

Worldwide, conventional antipsychotic medication continues to be used extensively, and tardive dyskinesia (TD) remains a serious complication. The primary objective of the present study was to compare the efficacy of EPA versus placebo in reducing symptoms of TD.. This was a 12-week, double-blinded, randomized study of ethyl-EPA 2g/day versus placebo as supplemental medication, in patients with schizophrenia or schizoaffective disorder, with established TD.. Eighty-four subjects were randomized, of whom 77 were included in the analysis. Both the EPA and placebo groups displayed significant baseline to endpoint improvements in Extrapyramidal Symptom Rating Scale dyskinesia scores, but there were no significant between-group differences (p=0.4). Response rates (>or=30% improvement in TD symptoms) also did not differ significantly between EPA-treated subjects (45%) and placebo-treated subjects (32%) (p=0.6). However, a post-hoc linear mixed model repeated measures analysis of variance indicated an effect for treatment group and duration of TD. The EPA-treated patients had significantly greater mean reductions in dyskinesia scores initially, although this was not sustained beyond 6 weeks.. This trial failed to demonstrate an anti-dyskinetic effect for ethyl-EPA 2g/day on the primary efficacy measure. However, a modest and transient benefit is suggested in patients with more recent onset of TD. The lack of clear-cut efficacy could be explained on the basis of the dose of EPA being too low, the study being underpowered, TD being too chronic in the majority of cases, differences in dietary fatty acid intake, or that EPA lacks an anti-dyskinetic action.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Double-Blind Method; Dyskinesia, Drug-Induced; Eicosapentaenoic Acid; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia

To determine the clinical and cost-effectiveness of different classes of antipsychotic drug treatment in people with schizophrenia responding inadequately to, or having unacceptable side-effects from, their current medication.. Two pragmatic, randomised controlled trials (RCTs) were undertaken. The first RCT (band 1) compared the class of older, inexpensive conventional drugs with the class of new atypical drugs in people with schizophrenic disorders, whose current antipsychotic drug treatment was being changed either because of inadequate clinical response or owing to side-effects. The second RCT (band 2) compared the new (non-clozapine) atypical drugs with clozapine in people whose medication was being changed because of poor clinical response to two or more antipsychotic drugs. Both RCTs were four-centre trials with concealed randomisation and three follow-up assessments over 1 year, blind to treatment.. Adult mental health settings in England.. In total, 227 participants aged 18-65 years (40% of the planned sample) were randomised to band 1 and 136 (98% of the planned sample) to band 2.. Participants were randomised to a class of drug. The managing clinician selected the individual drug within that class, except for the clozapine arm in band 2. The new atypical drugs included risperidone, olanzapine, quetiapine and amisulpride. The conventional drugs included older drugs, including depot preparations. As in routine practice, clinicians and participants were aware of the identity of the prescribed drug, but clinicians were asked to keep their participating patient on the randomised medication for at least the first 12 weeks. If the medication needed to be changed, the clinician was asked to prescribe another drug within the same class, if possible.. The primary outcome was the Quality of Life Scale (QLS). Secondary clinical outcomes included symptoms [Positive and Negative Syndrome Scale (PANSS)], side-effects and participant satisfaction. Economic outcomes were costs of health and social care and a utility measure.. Recruitment to band 1 was less than anticipated (40%) and diminished over the trial. This appeared largely due to loss of perceived clinical equipoise (clinicians progressively becoming more convinced of the superiority of new atypicals). Good follow-up rates and a higher than expected correlation between QLS score at baseline and at follow-up meant that the sample as recruited had 75% power to detect a difference in QLS score of 5 points between the two treatment arms at 52 weeks. The recruitment to band 2 was approximately as planned. Follow-up assessments were completed at week 52 in 81% of band 1 and 87% of band 2 participants. Band 1 data showed that, on the QLS and symptom measures, those participants in the conventional arm tended towards greater improvements. This suggests that the failure to find the predicted advantage for new atypicals was not due to inadequate recruitment and statistical power in this sample. Participants reported no clear preference for either class of drug. There were no statistically significant differential outcomes for participants entering band 1 for reasons of treatment intolerance to those entering because of broadly defined treatment resistance. Net costs over the year varied widely, with a mean of 18,850 pounds sterling in the conventional drug group and 20,123 pounds sterling in the new atypical group, not a statistically significant difference. Of these costs, 2.1% and 3.8% were due to antipsychotic drug costs in the conventional and atypical group, respectively. There was a trend towards participants in the conventional drug group scoring more highly on the utility measure at 1 year. The results for band 2 showed an advantage for commencing clozapine in quality of life (QLS) at trend level (p = 0.08) and in symptoms (PANSS), which was statistically significant (p = 0.01), at 1 year. Clozapine showed approximately a 5-point advantage on PANSS total score and a trend towards having fewer total extrapyramidal side-effects. Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals (p < 0.05). Net costs of care varied widely, but were higher than in band 1, with a mean of 33,800 pounds sterling in the clozapine group and 28,400 pounds sterling in the new atypical group. Of these costs, 4.0% and 3.3%, respectively, were due to antipsychotic drug costs. The increased costs in the clozapine group appeared to reflect the licensing requirement for inpatient ad. For band 1, there is no disadvantage in terms of quality of life and symptoms, or associated costs of care, over 1 year in commencing conventional antipsychotic drugs rather than new atypical drugs. Conventional drugs were associated with non-significantly better outcomes and lower costs. Drug costs represented a small proportion of the overall costs of care (<5%). For band 2, there is a statistically significant advantage in terms of symptoms but not quality of life over 1 year in commencing clozapine rather than new atypical drugs, but with increased associated costs of care. The results suggest that conventional antipsychotic drugs, which are substantially cheaper, still have a place in the treatment of patients unresponsive to, or intolerant of, current medication. Further analyses of this data set are planned and further research is recommended into areas such as current antipsychotic treatment guidance, valid measures of utility in serious mental illness, low-dose 'conventional' treatment in first episode schizophrenia, QLS validity and determinants of QLS score in schizophrenia, and into the possible financial and other mechanisms of rewarding clinician participation in trials.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Female; Humans; International Classification of Diseases; Male; Middle Aged; Patient Satisfaction; Quality of Life; Schizophrenia; Treatment Outcome

Violent behavior of patients with schizophrenia prolongs hospital stay and interferes with their integration into the community. Finding appropriate treatment of violent behaviors is of primary importance.. To compare the efficacy of 2 atypical antipsychotic agents, clozapine and olanzapine, with one another and with haloperidol in the treatment of physical assaults and other aggressive behaviors in physically assaultive patients with schizophrenia and schizoaffective disorder.. Randomized, double-blind, parallel-group, 12-week trial. Physically assaultive subjects with schizophrenia or schizoaffective disorder who were inpatients in state psychiatric facilities were randomly assigned to treatment with clozapine (n = 37), olanzapine (n = 37), or haloperidol (n = 36).. Number and severity of physical assaults as measured by the Modified Overt Aggression Scale (MOAS) physical aggression score and the number and severity of all aggressive events as measured by the MOAS overall score. Psychiatric symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS).. Clozapine was superior to both olanzapine and haloperidol in reducing the number and severity of physical assaults as assessed by the MOAS physical aggression score and in reducing overall aggression as measured by the MOAS total score. Olanzapine was superior to haloperidol in reducing the number and severity of aggressive incidents on these 2 MOAS measures. There were no significant differences among the 3 medication groups in improvement of psychiatric symptoms as measured by the PANSS total score and the 3 PANSS subscales.. Clozapine shows greater efficacy than olanzapine and olanzapine greater efficacy than haloperidol in reducing aggressive behavior. This antiaggressive effect appears to be separate from the antipsychotic and sedative action of these medications.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome; Violence

Agonists at the N-methyl-D-aspartate (NMDA)-glycine site (D-serine, glycine, D-alanine and D-cycloserine) and glycine transporter-1 (GlyT-1) inhibitor (N-methylglycine, or called sarcosine) both improve the symptoms of stable chronic schizophrenia patients receiving concurrent antipsychotics. Previous studies, however, found no advantage of D-serine, glycine, or D-cycloserine added to clozapine. The present study aims to determine the effects of sarcosine adjuvant therapy for schizophrenic patients receiving clozapine treatment.. Twenty schizophrenic inpatients enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/day) which was added to their stable doses of clozapine. Measures of clinical efficacy and side-effects were determined every other week.. Sarcosine produced no greater improvement when co-administered with clozapine than placebo plus clozapine at weeks 2, 4, and 6. Sarcosine was well tolerated and no significant side-effect was noted.. Unlike patients treated with other antipsychotics, patients who received clozapine treatment exhibit no improvement by adding sarcosine or agonists at the NMDA-glycine site. Clozapine possesses particular efficacy, possibly related to potentiation of NMDA-mediated neurotransmission. This may contribute to the clozapine's unique clinical efficacy and refractoriness to the addition of NMDA-enhancing agents.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Glycine Plasma Membrane Transport Proteins; Humans; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Sarcosine; Schizophrenia; Time Factors; Treatment Outcome

Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment.. To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious.. Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up.. National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge.. Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics.. After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13).. The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms.. Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1).. While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events.

Topics: Adolescent; Age of Onset; Antipsychotic Agents; Benzodiazepines; Child; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

Olanzapine is structurally similar to clozapine but has not been shown at routine doses to share the superiority of clozapine to traditional antipsychotics in treatment-resistant patients. Olanzapine, however, has been increasingly used in higher doses as clinicians attempt to find a more tolerable therapy for those refractory to conventional agents. This study examined the relationship of high-dose olanzapine plasma concentrations to symptoms, adverse effects, smoking, and gender. Thirteen patients participated in a double blind 16-week crossover study (8 weeks each arm) of olanzapine (50 mg/day) compared to clozapine (450 mg/day). Women had significantly higher plasma olanzapine levels than men at each time point in each arm (weeks 4, 6, and 8). At 8 weeks women had a steady-state olanzapine level of 278 +/- 62 ng/ml while men had a steady-state level of 127 +/- 47 ng/ml (p = 0.005). At week 4, olanzapine levels tended to be higher in those who had been on clozapine previously (205 ng/ml) compared to those who received olanzapine in the first arm (105 ng/ml). Cigarette intake was negatively correlated to olanzapine plasma concentrations (week 8: r = -0.86, p < 0.05). Plasma levels were significantly higher in those experiencing constipation (176 vs. 82 ng/ml; p = 0.022). Plasma levels of olanzapine were not associated with symptom response and anticholinergic effects were seen at greater frequency with higher olanzapine concentrations. In conclusion, this study reports plasma olanzapine levels at high fixed doses of olanzapine (50 mg/day) in relation to side effects, symptoms, smoking, and gender.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Constipation; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Olanzapine; Risk Factors; Schizophrenia; Severity of Illness Index; Sex Characteristics; Sex Factors; Smoking; Time Factors; Treatment Outcome; Vision Disorders; Xerostomia

This study aimed to assess the lipid-lowering properties of omega-3 fatty acids (also known as n-3 polyunsaturated fatty acids) in a group of patients taking clozapine.. Twenty-eight persons suffering from schizophrenia or schizoaffective disorder and currently taking clozapine participated in an open-label single-arm trial. Participants received supplements of 10 g of fish oil (containing 1.8 g of eicosopentaenoic acid and 1.2 g of docosahexaenoic acid) for a period of 28 days. Plasma lipids were measured on days 0 and 28.. This study demonstrated high rates of lipid abnormalities in the participants. Participants taking omega-3 fatty acids demonstrated a statistically significant reduction in mean serum triglyceride levels of 22%. There was an associated increase in total cholesterol (6.6%) and low-density lipoprotein cholesterol (22%). Common side-effects included fishy burps or breath, but no serious side-effects or interactions where observed.. Omega-3 fatty acids may be of value in patients taking clozapine and who have elevated serum triglyceride levels. Limitations of the study, practical implications and directions for future research are discussed.

Topics: Adult; Antipsychotic Agents; Cholesterol; Cholesterol, LDL; Clozapine; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Female; Humans; Hyperlipidemias; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Treatment Outcome; Triglycerides

Metabolic side effects have been found earlier during treatment with second-generation antipsychotics. Among those disturbances serum lipids are less investigated. We conducted a prospective, open study in schizophrenia patients in order to compare body weight and serum lipids during treatment with amisulpride, ziprasidone, clozapine or olanzapine over a period of 4 weeks. Body mass index, total cholesterol and triglycerides increased in patients treated with clozapine and olanzapine whereas high-density lipoprotein cholesterol decreased in those patients. In patients treated with amisulpride or ziprasidone, we found a decrease in body mass index and total cholesterol whereas high-density lipoprotein cholesterol increased. Our results indicate that treatment with ziprasidone and amisulpride is more favourable than treatment with clozapine and olanzapine with respect to the risk to induce weight gain and hyperlipidaemia. These results are important with regard to the increased risk for cardiovascular complications in patients with schizophrenia.

Topics: Adolescent; Adult; Aged; Amisulpride; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Clozapine; Humans; Lipids; Middle Aged; Olanzapine; Piperazines; Prospective Studies; Schizophrenia; Sulpiride; Thiazoles; Time Factors; Triglycerides

The effect of lamotrigine on the steady-state plasma concentrations of the atypical antipsychotics clozapine, olanzapine, and risperidone was investigated in patients with schizophrenia or bipolar disorder stabilized on chronic treatment with clozapine (200-500 mg/day; n = 11), risperidone (3-6 mg/day; n = 10) or olanzapine (10-20 mg/day; n = 14)). Lamotrigine was titrated up to a final dosage of 200 mg/day over 8 weeks, and pharmacokinetic assessments were made at baseline and during treatment weeks 6 and 10, at lamotrigine dosages of 100 and 200 mg/day respectively. The plasma concentrations of clozapine, norclozapine, risperidone, and 9-hydroxy-risperidone did not change significantly during treatment with lamotrigine. The mean plasma concentrations of olanzapine were 31 +/- 7 ng/mL at baseline, 32 +/- 7 ng/mL at week 6, and 36 +/- 9 ng/mL at week 10, the difference between week 10 and baseline being statistically significant (P < 0.05). Adjunctive lamotrigine therapy was well tolerated in all groups. These findings indicate that lamotrigine, at the dosages recommended for use as a mood stabilizer, does not affect the plasma levels of clozapine, risperidone, and their active metabolites. The modest elevation in plasma olanzapine concentration, possibly due to inhibition of UGT1A4-mediated olanzapine glucuronidation, is unlikely to be of clinical significance.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Drug Interactions; Female; Humans; Lamotrigine; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Triazines

Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting.. In 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared.. Fifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1-6 (n=0), 7-12 (n=13), 13-19 (n=18) and >or=20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01).. A daily consumption of 7-12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Chromatography, High Pressure Liquid; Clozapine; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Female; Humans; Inpatients; Male; Mass Spectrometry; Metabolic Clearance Rate; Middle Aged; Nursing Homes; Olanzapine; Schizophrenia; Smoking

To determine if prolactin levels are associated with glucose-insulin homeostasis in antipsychotic-treated patients with schizophrenia.. Prolactin levels and glucose homeostasis (quantified using oral glucose tolerance testing, insulin measurement, and homeostasis model assessment) were measured in 15 patients with elevated prolactin levels secondary to antipsychotic treatment of schizophrenia (mean age, 30.4 years; SD, 5.3 years). The effect of reducing prolactin levels by switching patients' antipsychotic treatment to clozapine was ascertained by performing the measures before and after the switch to clozapine.. There was no significant correlation between prolactin and glucose-insulin measures at baseline. There was a large reduction in prolactin (593 mIU/L) after switching to clozapine, but this was not associated with changes in glucose-insulin measures.. Prolactin is not a significant determinant of glucose-insulin homeostasis in patients taking antipsychotics for schizophrenia. There was no benefit from lowering prolactin levels using clozapine. This could be because prolactin does not have a major effect on glucose homeostasis or that the effects of prolactin reduction are countered by clozapine.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Clozapine; Follow-Up Studies; Glucose Tolerance Test; Homeostasis; Humans; Hyperprolactinemia; Insulin; Prolactin; Research Design; Schizophrenia; Time Factors; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

Atypical antipsychotic drugs produce improvement in some domains of cognition as well as psychopathology in patients with schizophrenia. However, the effect of combinations of atypical antipsychotic drugs on cognitive function is unknown. The aim of this study was to compare the effect of risperidone or placebo on cognitive function in patients with schizophrenia who were previously treated with clozapine monotherapy.. This prospective, randomized, double-blind, placebo-controlled, 6-week study included 30 patients with DSM-IV schizophrenia. Patients whose psychopathology was no more than partially responsive to clozapine treatment were randomly assigned to receive adjunctive treatment with risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Cognitive test scores for verbal learning and memory, verbal fluency, attention, executive function, verbal working memory, and motor function were the primary outcome measures. Secondary outcome measures included assessment of psychopathology, extrapyramidal side effects, and global functioning. Data were collected between November 2001 and July 2003.. Significant improvement was found in both treatment groups in a variety of cognitive measures, but there was significantly greater improvement in the placebo-augmented group on measures of initial learning acquisition and attention. The improvement in cognition was not correlated with improvement in psychopathology. There were significant correlations between improvement in verbal working memory, verbal learning and memory, and attention and quality of life and global functioning in the placebo-augmented but not the risperidone-augmented group.. Adjunctive treatment with risperidone for 6 weeks in patients with schizophrenia who had received chronic treatment with clozapine does not significantly improve cognitive function.

Topics: Adult; Antipsychotic Agents; Attention; Clozapine; Cognition; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Memory; Middle Aged; Prospective Studies; Quality of Life; Risperidone; Schizophrenia; Treatment Outcome

Kurz et al. conducted the first study of the intra-individual variability of clozapine plasma concentrations but did not take into account the effect of smoking and co-medication. As patients were receiving varying doses, Kurz et al. standardized plasma levels by using a plasma level/dose/kg ratio. In 15 patients, the mean coefficient of variation (CV) was 53% (S.D. = 21). In this new study, plasma clozapine and norclozapine concentrations were measured every 2 weeks in 47 patients randomized to 100, 300, or 600 mg/day for 16-week double-blind clozapine trials under controlled conditions (stable smoking, limited co-medication and absence of caffeinated beverages). For 100, 300 and 600 mg/day, the respective mean CVs for plasma clozapine concentrations were 23% (S.D. = 14), 19% (S.D.= 11) and 18% (S.D. = 8). For the combined concentrations of clozapine and norclozapine, the respective mean CVs were 20% (S.D. = 13), 16% (S.D. = 9) and 15% (S.D. = 7). Under 100 mg/day, the mean CV for clozapine concentrations was significantly higher for heavy smokers than non-heavy smokers (32%, S.D. = 3 vs. 19%, S.D. = 8) (p = 0.03). Studies of CVs in other environments are needed. Clozapine CVs may be important in order to understand the importance of variations around the therapeutic range and to interpret drug interactions above the usual noise of measuring plasma concentrations.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Schizophrenia; Severity of Illness Index; Smoking; Time Factors

To evaluate the effectiveness of clozapine on aggressive behavior for treatment-refractory adolescents (age range 8.5-18) with schizophrenia (295.x) at Bronx Children's Psychiatric Center.. Clozapine treatment was administered in an open-label fashion using a flexible titration schedule. The frequency of administration of emergency oral and injectable medications and the frequency of seclusion events 3 months immediately before and from 12 to 24 weeks of clozapine treatment (when optimal clozapine levels were achieved) were compared.. Twenty clozapine-treated children (mean +/- SD dose at week 24, 476 +/- 119 mg) were included. A statistically significant decrease in the frequency of the administration of emergency oral medications, the administration of emergency injectable medications, and seclusion events was found in adolescents during weeks 12 to 24 of clozapine treatment compared with their baseline condition before clozapine initiation.. These preliminary data indicate the benefits of clozapine treatment in adolescents with treatment-refractory schizophrenia for aggressive behaviors. Although open data limit conclusions from this study, it is important that there was a clinically significant improvement in aggressive behaviors that enabled patients to be discharged to a less restrictive setting. Additional controlled clinical trials of clozapine are needed in treatment-refractory children and adolescents.

Topics: Adolescent; Aggression; Antipsychotic Agents; Child; Clozapine; Female; Humans; Male; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia.. In a randomized, double-blind, placebo-controlled 12-week trial, 40 patients unresponsive or partially responsive to clozapine monotherapy received a steady dose of clozapine combined with either placebo (N=20) or up to 6 mg/day of risperidone (N=20). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), among other measures. Movement disorders were assessed with the Simpson-Angus Rating Scale.. From baseline to week 6 and week 12, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo. The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo. Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12. Clozapine/risperidone treatment did not induce additional weight gain, agranulocytosis, or seizures compared with clozapine/placebo treatment.. In patients with a suboptimal response to clozapine, the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia. The combination appears to be safe and well tolerated. Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Placebos; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

This randomized double-blind multicenter trial evaluated the effects of olanzapine vs. clozapine on subjective well-being, quality of life (QOL) and clinical outcome.. The primary objective was to demonstrate non-inferiority of olanzapine, mean dosage 16.2 +/- 4.8 (5-25 mg/day) vs. clozapine, mean dosage 209 +/- 91 (100-400 mg/day) regarding improvement on the 'Subjective Well-Being under Neuroleptic Treatment' (SWN) Scale after 26 treatment weeks in 114 patients with schizophrenia. Secondary outcome parameters included: Munich QOL Dimension List (MLDL), Positive and Negative Symptom Scale (PANSS), Clinical Global Impression (CGI).. SWN scores improved significantly in both groups, olanzapine was non-inferior to clozapine (group difference 3.2 points in favor of olanzapine; 95% CI: 4.2;10.5). MLDL-satisfaction, PANSS and CGI-S improved similarly, olanzapine yielded a higher CGI Therapeutic Index. Individual SWN and PANSS changes correlated only moderately (r = -0.45).. Olanzapine was non-inferior to clozapine. The lack of a marked correlation between PANSS and SWN improvements indicates that patients and psychiatrists perceive treatment differently.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Brief Psychiatric Rating Scale; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Quality of Life; Schizophrenia; Severity of Illness Index; Treatment Outcome

Several open trials and case studies have reported beneficial effects following the addition of risperidone for partial responders to clozapine. The purpose of this study was to carry out a placebo-controlled, randomized, double-blind trial of the efficacy, safety, and tolerability of adjunctive treatment with risperidone in patients with schizophrenia partially responsive to clozapine.. In this 6-week double-blind study, 30 patients with DSM-IV schizophrenia who had partial response to clozapine despite being treated for a mean of 32 months were randomly assigned to risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale, the Clinical Global Impressions-Severity of Illness scale, the Global Assessment of Functioning scale, and the Quality of Life Scale. A variety of safety and tolerability measures were also obtained. Data were collected between November 2001 and July 2003.. Significant improvement was noted in both groups on a variety of measures of psychopathology, but there was significantly greater improvement in the placebo-treated patients on the primary outcome measure, the PANSS positive symptom subscale. There were no significant differences between the treatment groups regarding extrapyramidal symptoms, weight gain, vital signs, serum clozapine levels, and QTc interval. The only side effect significantly more severe in risperidone-treated compared to placebo-treated patients was sedation. The patients treated with risperidone developed significant increases in plasma prolactin levels.. Adjunctive risperidone treatment in schizophrenia patients partially responsive to clozapine does not significantly improve psychopathology or quality of life compared to placebo in a 6-week period.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Humans; Placebos; Prolactin; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms. The aim of the present study was to determine if glycine, or its ratio to serine, a precursor of glycine, predicts change in negative symptoms in subjects with schizophrenia during treatment with clozapine, an atypical antipsychotic drug with multiple effects on glutamatergic activity. Plasma levels of glycine, serine, and their ratio, were measured in 44 patients with schizophrenia who were subsequently treated with clozapine. Baseline glycine levels or glycine/serine ratios predicted the Scale for the Assessment of Negative Symptoms - Sum of the Global Scales and Avolition-Apathy after 6 wk of clozapine treatment. These results indicate the association of these amino acid measures with response to clozapine in terms of negative symptoms in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Female; Glycine; Humans; Male; Middle Aged; Predictive Value of Tests; Psychiatric Status Rating Scales; Regression Analysis; Schizophrenia; Schizophrenic Psychology; Serine

The purpose of this investigation was to evaluate the effects of clozapine and risperidone on spatial working memory in patients with schizophrenia.. Spatial working memory performance was evaluated at baseline and after 17 and 29 weeks in 97 patients with schizophrenia participating in a multisite trial.. Compared with baseline performance while receiving conventional antipsychotic medication, risperidone improved, and clozapine worsened, spatial working memory performance.. The differential effects of these medications on spatial working memory may be due to the anticholinergic effects of clozapine and prefrontal dopamine-enhancing effects of risperidone.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Diagnosis, Computer-Assisted; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Memory; Memory Disorders; Middle Aged; Neuropsychological Tests; Prefrontal Cortex; Psychomotor Performance; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Space Perception

Depressive symptoms are found at any stage of schizophrenia, and antidepressant medication may be beneficial. Selective serotonin reuptake inhibitor antidepressants have been considered safe in schizophrenia but in combination with clozapine, that is widely used in chronic treatment-resistant schizophrenia, remarkable pharmacokinetic interactions can occur causing an elevation in clozapine plasma levels. To investigate this further, the plasma levels of clozapine were measured in 11 schizophrenic male patients with depressive symptoms who were administered both clozapine and venlafaxine. Low to moderate doses of venlafaxine did not seem to have any significant effect on clozapine plasma levels.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Cyclohexanols; Depression; Humans; Male; Middle Aged; Schizophrenia; Venlafaxine Hydrochloride

Topics: Adult; Analysis of Variance; Clozapine; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Glycine; Humans; Male; Middle Aged; Refractory Period, Psychological; Schizophrenia; Schizophrenic Psychology

This study investigated the effect of clozapine on working memory in 15 subjects with schizophrenia, using an event related potential paradigm designed to separate components reflecting working memory updating from components related to target detection and response. Compared to matched controls and prior to treatment with clozapine, subjects with schizophrenia had N1, P3 and Late Slow Wave abnormalities indicating impairment in early stimulus evaluation and subsequent working memory functions. Treatment with clozapine was associated with normalization of the P3 and Late Slow Waves, indicating improvement in working memory updating and executive processing. There was also a partial normalization of N1 amplitude, suggesting improvement in early stimulus evaluation.

Topics: Adult; Antipsychotic Agents; Biperiden; Clozapine; Electroencephalography; Evoked Potentials; Female; Humans; Male; Memory, Short-Term; Middle Aged; Muscarinic Antagonists; Neuropsychological Tests; Psychomotor Performance; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Haloperidol; Humans; Nursing Assessment; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

To compare the bioavailability of two clozapine formulations (100 mg Clozaril tablet from Novartis Pharmaceuticals UK Ltd., UK, as a Reference formulation and 100 mg Cloril tablet from Atlantic Laboratories Corp., Ltd., Thailand, as a Test formulation). The present study was conducted under real-life conditions in schizophrenic patients using a steady-state, multiple-dose, randomized crossover design to avoid the risk of adverse effects in healthy volunteers and pharmacokinetic difference between single and multiple-dose of the drug.. The subjects received 100 mg bid of either the Reference formulation or the Test formulation for 7 days. At day-7 of each study phase, blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h after drug administration. Plasma was separated and stored at -80 degrees C until assay. The plasma concentration of clozapine was determined by high performance liquid chromatography. Pharmacokinetic parameters were calculated from the observed plasma-concentration time profiles. The bioequivalence between the two formulations was assessed by calculating individual peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC(0-12 h)) ratios.. All subjects well tolerated both clozapine formulations. No serious side effects were reported. The Tmax, terminal half-life and the total plasma clearance of clozapine (uncorrected for bioavailability) observed in the present study were comparable to those observed in other previous reports. All of the pharmacokinetic parameters investigated in the present study calculated from the subjects after administration of Test and Reference formulations were close. The 90% confident interval for the ratio of means for the lnCmax (0.9784-1.0622) and lnAUC(0-12h) (0.9559-1.0441) are within the guideline range of bioequivalence (0.80 to 1.25).. The result demonstrated that the Test formulation was bioequivalent to the Reference formulation (Clozaril) when orally administered in schizophrenic patients, in terms of both the rate and extent of absorption.

Topics: Adolescent; Adult; Analysis of Variance; Chemistry, Pharmaceutical; Clozapine; Cross-Over Studies; Humans; Male; Middle Aged; Schizophrenia; Tablets; Therapeutic Equivalency

McEvoy et al.'s study in 1999, which used cotinine levels but had limited power, suggested that clozapine treatment may be associated with a mild smoking decrease (particularly when plasma clozapine levels are > 150 ng/ml). Some naturalistic studies also suggest that clozapine treatment may be associated with a mild smoking decrease. The present study included 38 schizophrenic daily smokers from a double-blind clozapine trial. Five analyses were tested for significant decreases in plasma cotinine levels from a haloperidol baseline to: (1) the end of clozapine trials regarding clozapine doses (100, 300 or 600 mg/day), (2) the end of the clozapine trial where the highest plasma clozapine level was achieved, (3) the end of the clozapine trial where a clozapine level in the 150-450 ng/ml range was achieved, (4) the end of the first clozapine trial regardless of clozapine dose, and (5) the end of the last clozapine trial in the study. The first and straightforward analysis by dose showed no clozapine effects on smoking. The second and the third analyses (an attempt to mimic the design by McEvoy et al. [McEvoy, J.P., Freudenreich, O., Wilson, W.H., 1999. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol. Psychiat. 46, 125-129.]) also indicated that there was not a significant effect of clozapine on smoking. The fourth and five analyses were also negative. None of the five analyses in our clozapine trial demonstrated that clozapine had major effects on smoking. This study cannot rule out that in some subjects, clozapine treatment may be associated with a small decrease in smoking. New prospective longitudinal studies using repeated cotinine and clozapine levels are needed to explore whether clozapine may reduce smoking in some patients.

Topics: Adult; Antipsychotic Agents; Biomarkers; Clozapine; Cotinine; Double-Blind Method; Female; Haloperidol; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Sex Characteristics; Smoking; Time Factors

We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m2) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Clozapine; Female; Ghrelin; Humans; Leptin; Longitudinal Studies; Male; Peptide Hormones; Prospective Studies; Schizophrenia; Schizophrenia, Catatonic; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Weight Gain

Clozapine has shown superior efficacy in treatment of refractory schizophrenia, but its use is limited by emergent side-effects. Among other adverse effects, sialorrhea is a troublesome side-effect, its stigmatizing nature results in poor treatment compliance. Several hypotheses have been put forward in the etiology of clozapine-induced sialorrhea. 2 adrenergic antagonism is hypothesized to be involved in its pathophysiology, based on the response to clonidine and lofexidine. Oral clonidine (50 to 100 g/day) was tried on 12 stable outpatients of schizophrenia maintained on clozapine. Wet area over the pillow as reported by the patients was recorded at baseline and at 4 weeks of treatment along with the subjective response after the treatment. Most of the patients reported a decrease in sialorrhea without any adverse events. We describe encouraging results in an open case series of oral clonidine for clozapine-induced sialorrhea.

Topics: Adrenergic alpha-Agonists; Adult; Antipsychotic Agents; Clonidine; Clozapine; Female; Humans; Male; Middle Aged; Schizophrenia; Sialorrhea

While several new methods that account for noncompliance or missing data in randomized trials have been proposed, the dual effects of noncompliance and nonresponse are rarely dealt with simultaneously. We construct a maximum likelihood estimator (MLE) of the causal effect of treatment assignment for a two-armed randomized trial assuming all-or-none treatment noncompliance and allowing for subsequent nonresponse. The EM algorithm is used for parameter estimation. Our likelihood procedure relies on a latent compliance state covariate that describes the behavior of a subject under all possible treatment assignments and characterizes the missing data mechanism as in Frangakis and Rubin (1999, Biometrika 86, 365-379). Using simulated data, we show that the MLE for normal outcomes compares favorably to the method-of-moments (MOM) and the standard intention-to-treat (ITT) estimators under (1) both normal and non-normal data, and (2) departures from the latent ignorability and compound exclusion restriction assumptions. We illustrate methods using data from a trial to compare the efficacy of two antipsychotics for adults with refractory schizophrenia.

Topics: Algorithms; Antipsychotic Agents; Biometry; Clozapine; Computer Simulation; Data Interpretation, Statistical; Haloperidol; Humans; Likelihood Functions; Models, Statistical; Odds Ratio; Patient Compliance; Randomized Controlled Trials as Topic; Reproducibility of Results; Schizophrenia; Sensitivity and Specificity; Statistics as Topic; Treatment Outcome

Antipsychotic medications may reduce hostile and aggressive behavior in schizophrenia. This study compared the effectiveness of antipsychotics in the treatment of aggression.. The Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study compares the effectiveness of antipsychotic treatments in practice setting. Schizophrenia outpatients who initiated or changed to a new antipsychotic are followed in this non-interventional, prospective observational study for up to 3 years, with 6-months data now available on the entire cohort (N=7655). The presence or absence of verbal or physical hostility/aggression was assessed retrospectively for the period of 6 months before enrollment, and prospectively in the period of 6 months after enrollment (the study treatment period). At baseline, patients in five monotherapy treatment groups (combined N=3135) were prescribed one of the treatments: clozapine, olanzapine, quetiapine, risperidone, or haloperidol, and had complete data.. Hostile/aggressive behavior was reduced during the treatment period. Olanzapine and risperidone were significantly superior to haloperidol and to clozapine in this respect. These results remained essentially unchanged when adjusting for baseline imbalances in age, gender, age of onset, and substance abuse.. As monotherapy, both olanzapine and risperidone were superior to haloperidol and clozapine in reducing aggression. The relative lack of effectiveness of clozapine may be specific to this study population.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Cohort Studies; Dibenzothiazepines; Female; Haloperidol; Hostility; Humans; Male; Olanzapine; Outpatients; Prospective Studies; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Lamotrigine; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triazines

To assess treatment discontinuation and concomitant use of other antipsychotics among individuals initiated on olanzapine or risperidone for the treatment of schizophrenia.. Using data from the Quebec health insurance plan and the Quebec database for hospitalization, we conducted a population-based cohort study of patients for whom a first claim for olanzapine or risperidone was submitted between 1 January 1997 and 31 August 1999. Included were 6405 patients with schizophrenia whom we followed from the date of the first claim for olanzapine or risperidone either to discontinuation date, end of eligibility for the drug plan, 365 days, date of moving out of the province, or date of death. We used Cox regression models to compute hazards ratios (HRs) of having the treatment discontinued and logistic regression models to compute odds ratios (ORs) among persisting patients of having any concomitant antipsychotic prescription. All models were adjusted for age, sex, schizophrenia disorder, comorbidity, region, beneficiary type, substance use disorder, and prior hospitalization for mental illness.. Compared with risperidone users (n = 2718), discontinuation rates were lower for olanzapine users (n = 3687; HR = 0.79; 95%CI, 0.74 to 0.84). The odds of receiving any concomitant antipsychotic prescription did not differ statistically between olanzapine and risperidone users (OR 0.85; 95%CI, 0.71 to 1.01).. The study results suggest that new users of olanzapine were less likely to discontinue their initial treatment than were new users of risperidone, although discontinuation was high in both groups. Among those who persisted, concomitant use of other antipsychotics did not differ between olanzapine users and risperidone users.

Topics: Adult; Aged; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Clozapine; Cohort Studies; Dibenzothiazepines; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Olanzapine; Population Surveillance; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Time Factors

Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with (15)O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n=6) and normal volunteers (NVs) (n=12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1). Rest, (2). sensory motor control (SMC) task, and (3). decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n=5) and/or clozapine (n=5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol- and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidol-treated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

Topics: Acoustic Stimulation; Adult; Antipsychotic Agents; Auditory Perception; Brain Mapping; Clozapine; Female; Frontal Lobe; Gyrus Cinguli; Haloperidol; Humans; Male; Oxygen Radioisotopes; Psychomotor Performance; Reaction Time; Regional Blood Flow; Schizophrenia; Tomography, Emission-Computed

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Weight; Clozapine; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia

Several case reports described neurotoxic side-effects in the course of a combined clozapine-lithium treatment. Here we report on the safety and efficacy of this combination in a sample of 44 hospital patients. Medical records were retrospectively audited and a subsample of 23 patients was re-assessed. Mean total duration of combined treatment was 23.5 months. The combination (indications: prophylaxis; treatment of affective symptoms or aggression/excitement; augmentation of neuroleptic efficacy) was rated effective in 84% and adverse events were reported in 64% of the patients. Notably, most of the adverse events were benign and transient. However, 8 patients (18%) developed transient neurological adverse events that were genuinely novel in only 3 patients (7%) and coincided with high dosage of medication or high plasma levels or serotonergic (antidepressant) co-medication. Our data suggest that combined clozapine-lithium treatment may appear to be safe and effective when administered within a moderate therapeutic dose range and without serotonergic co-medication or other substances interfering with clozapine metabolism.

Topics: Adult; Aged; Antimanic Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Lithium; Male; Middle Aged; Myoclonus; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

The objective of this study was to demonstrate a multivariate health state approach to analyzing complex disease data that allows projection of long-term outcomes using clustering, Markov modeling, and preference weights.. We studied patients hospitalized 30 to 364 days with refractory schizophrenia at 15 Veterans Affairs medical centers.. We conducted a randomized clinical trial comparing clozapine, an atypical antipsychotic, and haloperidol, a conventional antipsychotic.. Health status instruments measuring disease-related symptoms and drug side effects were administered in face-to-face interviews at baseline, 6 weeks, and quarterly follow-up intervals for 1 year. Cost data were derived from Veterans Affairs records supplemented by interviews. K-means clustering was used to identify a small number of health states for each instrument. Markov modeling was used to estimate long-term outcomes.. Multivariate models with 7 and 6 states, respectively, were required to describe patterns of psychiatric symptoms and side effects (movement disorders). Clozapine increased the proportion of clients in states characterized by mild psychiatric symptoms and decreased the proportion with severe positive symptoms but showed no long-term benefit for negative symptoms. Clozapine dramatically increased the proportion of patients with no movement side effects and decreased incidences of mild akathisia. Effects on extrapyramidal symptoms and tardive dyskinesia were far less pronounced and slower to develop. Markov modeling confirms the consistency of these findings.. Analyzing complex disease data using multivariate health state models allows a richer understanding of trial effects and projection of long-term outcomes. Although clozapine generates substantially fewer side effects than haloperidol, its impact on psychiatric aspects of schizophrenia is less robust and primarily involves positive symptoms.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cluster Analysis; Cross-Sectional Studies; Data Interpretation, Statistical; Double-Blind Method; Haloperidol; Humans; Models, Statistical; Outcome and Process Assessment, Health Care; Principal Component Analysis; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; United States; United States Department of Veterans Affairs

Recent reports implicate clozapine in heart rate variability, QTc prolongation, torsade de pointes and sudden death at therapeutic doses, even in physically healthy patients. This study aims to examine whether autonomic (vital) signs are correlated with clozapine dose titration and blood levels of clozapine and nor-clozapine during clozapine therapy.. Thirty-seven consecutive patients with diagnosis of schizophrenia treated with clozapine were included in this prospective longitudinal study. The study was restricted to only the first 8 weeks of treatment. After obtaining informed consent, serum concentrations of clozapine and nor-clozapine were determined weekly at trough, as doses were administered q12h and adjusted according to clinical guidelines for clozapine use. Autonomic signs including BP (supine and erect), pulse (supine and erect) and temperature were monitored daily each morning before and one hour after the morning's dose of clozapine was administered.. We calculated analyses of covariance (ANCOVAs) to evaluate the changes in vital signs parameters, from baseline to week 8, with clozapine variables as covariates (i.e, the dose of clozapine, as well as the levels of serum clozapine and nor-clozapine). The blood pressure and pulse did not change significantly (p<0.01) from baseline to weeks 8. The temperature was inversely related to clozapine dose (p<0.003). Higher nor-clozapine to clozapine ratios were associated with higher BP measures (p=0.002). The magnitude of these relationships is weak (r<0.30).. There is a tendency to autonomic dysregulation during clozapine use. This has cardiac function implications, justifying cautious dose adjustment with frequent monitoring of vital signs.

Topics: Analysis of Variance; Antipsychotic Agents; Blood Pressure; Body Temperature; Clozapine; Drug Administration Schedule; Drug Monitoring; Female; Heart Rate; Humans; Longitudinal Studies; Male; Prospective Studies; Schizophrenia

Prolactin levels are elevated to varying degrees by antipsychotics. Prolactin elevations may result in sexual and other adverse effects, and they may be related to antipsychotic effects. We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level, to explore the relation between clinical effects and prolactin level, and to determine the relationship between plasma levels of antipsychotics and prolactin level.. Treatment-resistant patients (133 men, 24 women) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind, randomized, 14-week trial comparing clozapine (N = 40), olanzapine (N = 39), risperidone (N = 41), and haloperidol (N = 37). Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5, 8, 10, 12, and 14 during the trial. Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale. Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available. Data were gathered from June 1996 to December 1999.. Risperidone caused significant elevation of prolactin levels (p <.05) that appeared to be dose-dependent. Clozapine and olanzapine were associated with decreases of prolactin, whereas haloperidol led to a minor, nonsignificant increase. Plasma olanzapine and prolactin levels were correlated. Prolactin levels were not related to clinical improvement or extrapyramidal side effects.. Antipsychotics show major differences in their effects on prolactin, and risperidone has clearly the most robust effect.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Prolactin; Risperidone; Schizophrenia; Sexual Dysfunction, Physiological

The analysis of heart rate variability (HRV) has proven to be useful in evaluating the neuroautonomic dysfunctions associated with various clinical conditions. The purpose of this study was to investigate the linear and non-linear dynamic measures of HRV, and to evaluate their relationship with the psychotic symptom severity, in clozapine-treated schizophrenic subjects. Fifty schizophrenic patients treated with clozapine as monotherapy and 50 normal control subjects were evaluated for HRV analysis. The HRV measurements were obtained from a 30-min resting electrocardiogram (ECG). The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). In the patient group, the complexity and symbolic dynamics measures as well as the time and frequency domain measures of HRV were significantly lower than in the control group (P<0.01). The intermediate-term fractal scaling component value was significantly higher in the patient group (P<0.01). The PANSS total score and the positive symptom subscale score had significant negative correlations with the sample entropy (SampEn) value (P<0.01). In conclusion, schizophrenic patients treated with clozapine had markedly different heart rate dynamics compared to normal control subjects. The severity of psychotic symptoms was associated with the SampEn value, suggesting that the non-linear complexity measure might be useful in assessing the neuroautonomic dysfunction in schizophrenia.

Topics: Adult; Antipsychotic Agents; Case-Control Studies; Clozapine; Electrocardiography; Female; Heart Rate; Humans; Male; Nonlinear Dynamics; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time Factors

The purpose of this investigation was to evaluate the effects of clozapine and risperidone on social skill and problem solving in patients with schizophrenia.. The Wisconsin Card Sorting Test and the Maryland Assessment of Social Competence were administered at baseline, week 17, and week 29 of a multisite clinical trial.. Despite evidence of clinical improvement with both medications, there was virtually no medication effect on either social competence or problem solving.. These findings underscore the circumscribed nature of symptomatic improvement in the broader spectrum of clinical outcomes and suggest that new-generation medications may not be expected to produce substantial changes in social role functioning or social problem-solving capacity in the community. The generalizability of the findings should be viewed cautiously because of the low power of this trial, and replication is warranted.

Topics: Adult; Clozapine; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Neuropsychological Tests; Problem Solving; Risperidone; Schizophrenia; Severity of Illness Index; Social Behavior

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Lamotrigine; Male; Risk Assessment; Schizophrenia; Severity of Illness Index; Treatment Outcome; Triazines

Subject of the study is the analysis of the impact of antipsychotic medication on the incidence and the costs of inpatient treatment in patients with schizophrenia.. In a prospective longitudinal study with 5 points of measurement incidence and the costs of inpatient treatment, the type of antipsychotic medication, as well as the clinical and social characteristics of 307 outpatients with the diagnosis of schizophrenia (ICD 10 F 20.0) were assessed over a period of 2.5 years. The impact of antipsychotic medication on the incidence of inpatient treatment was analysed by means of a random-effect logit model. The impact of antipsychotic medication on the costs of inpatient treatment was analysed by means of a random-effect tobit model. Selection effects were controlled by means of propensity scores.. Patients who received antipsychotic treatment with conventional, new atypical or depot neuroleptics had a lower incidence of inpatient treatment and caused lower costs in comparison to patients without antipsychotic treatment. The same effect was found for patients who received a combined treatment with conventional and depot neuroleptics. No effects were found for clozapine or for a combination treatment with conventional and atypical neuroleptics. No significant differences between the effects of conventional, new atypical or depot-neuroleptics were found.. The application of neuroleptic medication in schizophrenia treatment generally reduces the incidence and the costs of inpatient treatment. An extension of the use of clozapine or new atypical neuroleptics to all patients with schizophrenia will not generally improve the treatment effectiveness regarding to the incidence and the costs of inpatient treatment.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Female; Germany; Health Expenditures; Hospital Costs; Humans; Male; Middle Aged; National Health Programs; Patient Readmission; Psychiatric Status Rating Scales; Schizophrenia

Hypersalivation is known as a frequent, disturbing, and socially stigmatizing side effect of therapy with the atypical antipsychotic clozapine. It has been shown that the addition of the anticholinergic pirenzepine is able to reduce clozapine-induced hypersalivation, probably by blocking M4-receptors. Nevertheless, a pharmacokinetic interaction between both compounds cannot be excluded.. In this pilot study, 29 schizophrenic patients (ICD-10; 51.7 % female; age: 36.7 +/- 8.7 years [mean +/- SD]) were included. Serum concentrations of clozapine and its pharmacologically active metabolite N-desmethylclozapine were determined under steady-state conditions by automated HPLC with UV detection before and after addition of pirenzepine for 3 days.. Significantly fewer patients reported hypersalivation after addition of pirenzepine (69 % vs. 34.5 %, P = 0.002). No significant differences of clozapine and N-desmethylclozapine serum levels before (329 +/- 181 ng/ml and 218.0 +/- 123.4 ng/ml, respectively) and 3 days after (336 +/- 215 ng/ml and 235.9 +/- 164.4 ng/ml, respectively) addition of pirenzepine were found. In three patients, however, clozapine serum levels increased; this was probably unrelated to pirenzepine.. In conclusion, treatment of clozapine-induced hypersalivation with pirenzepine is a recommendable combination with low risk of additional side effects.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pilot Projects; Pirenzepine; Schizophrenia; Sialorrhea; Spectrophotometry, Ultraviolet

Attentional deficits have been implicated in the pathophysiology of auditory hallucinations in schizophrenia. Since the latency of the P300 component of event-related potentials (ERPs) is considered to be a sensitive measure of stimulus classification speed, while its amplitude-a measure of attentional resource allocation when memory updating is engaged, the present study focuses on the comparison of P300 between healthy subjects and schizophrenic patients experiencing auditory hallucinations and treated with clozapine and olanzapine.. The auditory P300 was assessed during the anticipatory period of a short memory test, in 16 male hallucinated schizophrenic patients and 13 male normal subjects matched for age and educational level. The patients were reexamined under identical conditions when their hallucinations had resolved following treatment with clozapine (8 patients) and olanzapine (8 patients).. The patients with hallucinations exhibited significantly reduced P300 amplitude at leads Fp1, F3, (C3-T5)/2, F4, Cz and Fz, when compared to the normal controls and at leads Fp1, F3, F4, (C4-T6)/2, C4, P4, Cz and Fz when compared to themselves during the remission phase. However logistic regression models revealed that the most important leads, differentiating the patient group before treatment either with the healthy controls, or with itself after treatment, were that at the left temporoparietal and at the left prefrontal area. Memory performance of the patient group, even after treatment and in spite of its significant improvement, remained significantly less than that of healthy controls. both antipsychotic agents had similar effects on the p300 amplitude and memory performance.. These findings indicate that auditory hallucinations in schizophrenia manifest abnormal aspects of attention, mediated by a distributed network involving or affecting the left temporoparietal and left prefrontal area. Additionally, the present study points to an improvement of attentional function in schizophrenic patients experiencing auditory hallucinations, both in the clozapine group but also in the olanzapine group.

Topics: Adult; Antipsychotic Agents; Attention; Benzodiazepines; Case-Control Studies; Clozapine; Event-Related Potentials, P300; Hallucinations; Humans; Male; Memory, Short-Term; Neuropsychological Tests; Olanzapine; Psychiatric Status Rating Scales; Reaction Time; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Resistance, Multiple; Humans; Schizophrenia; Treatment Outcome

The development of therapeutic strategies to effectively treat negative symptoms remains one of the primary goals in the treatment of schizophrenia. Mirtazapine is the first of a new class of dual action compounds, the noradrenergic and specific serotonergic antidepressants (NaSSa), whose activity is related to the enhancement of noradrenergic and serotonergic transmission by a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism, respectively. This study was a 8-week double-blind, randomized, placebo-controlled trial of 30 mg adjunctive mirtazapine to clozapine therapy in 24 patients with DSM-IV schizophrenia. The main finding at the end of the trial was a significant reduction on the Scale for the Assessment of Negative Symptoms (SANS) total scores in the mirtazapine group compared to placebo (P<0.01) with a significant improvement on the SANS subscales avolition/apathy and anhedonia/asociality. The Brief Psychiatric Rating Scale total score at week 8 showed superiority of mirtazapine over placebo. These findings suggest a potential role for mirtazapine as an augmentation strategy in the treatment of negative symptoms of schizophrenia.

Topics: Adrenergic alpha-Antagonists; Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Synergism; Female; Humans; Male; Mianserin; Middle Aged; Mirtazapine; Psychiatric Status Rating Scales; Receptors, Serotonin, 5-HT2; Receptors, Serotonin, 5-HT3; Schizophrenia; Serotonin Antagonists; Time Factors; Treatment Outcome

There has been considerable support for the observation that atypical antipsychotics have a broader range of therapeutic effects than traditional antipsychotics. We are exploring whether this expanded clinical efficacy can also be seen in patients with treatment-resistant schizophrenia.. The subjects were 157 treatment-resistant inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week double-blind trial and rated with a standard measure of clinical antipsychotic efficacy (Positive and Negative Syndrome Scale [PANSS]). Factor analysis at baseline and endpoint together with changes in 5 PANSS-derived factors were examined. Data were gathered from June 1996 to December 1999.. The underlying PANSS factor structure, as indicated by the factor loadings, was essentially identical at baseline and endpoint. At baseline, the excitement factor was followed by the positive, negative, cognitive, and depression/anxiety factors, explaining 49.4% of the total variance. At endpoint, the positive factor was followed by the negative, excitement, cognitive, and depression/anxiety factors, explaining 55.5% of the total variance. The endpoint data indicated statistically significant (p <.05) improvements over time on the positive factor for all 3 atypicals, but not for haloperidol. The negative factor showed significant improvement for clozapine and olanzapine, with significant worsening for haloperidol. Clozapine, olanzapine, and risperidone were superior to haloperidol on the negative factor, while clozapine was also superior to risperidone. The cognitive factor showed significant improvement for all atypicals, as did the depression/anxiety factor. Only clozapine showed improvement on the excitement factor and was superior to both haloperidol and risperidone.. Treatment with atypical antipsychotics did not substantially change the underlying PANSS 5-factor structure. However, antipsychotic treatment with all 3 atypical medications was associated with significant improvements on 3 of 5 syndromal domains (positive, cognitive, and depression/anxiety) of schizophrenia. Clozapine and olanzapine also showed improvement on the negative factor. Only clozapine was associated with improvement on the excitement domain. This finding confirms that atypicals are associated with improvement of an expanded spectrum of symptoms in treatment-resistant patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Factor Analysis, Statistical; Female; Haloperidol; Humans; Male; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Amisulpride; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Drug Therapy, Combination; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Sulpiride; Treatment Outcome

The changes of theta activity (3.5-7 Hz) in the quantitative electroencephalography (QEEG) and serum clozapine levels and their correlation with clinical response, measured by the Positive and Negative Syndrome Rating Scale (PANSS) for schizophrenia, were examined prospectively in 16 patients suffering from schizophrenia during 18 weeks of clozapine (CLO) treatment.. Evaluations were performed on five occasions: before the initiation of CLO treatment at baseline and after 1, 3, 10, and 18 weeks of treatment. Doses of CLO starting from 50 mg/day were determined on the basis of clinical response. In the PANSS subscales for positive and negative symptoms, a significant (P < 0.05) improvement was observed after the first week, and in the subscale for general symptoms, improvement was seen after three weeks of treatment with CLO. A significant increase in theta power (P < 0.01) was found after three weeks of CLO treatment in the electrodes over the fronto-central scalp area, most distinctly in the midline.. After three weeks we observed significant inverse correlations between the theta power increase and the changes in PANSS subscales for negative (P < 0.01) and positive (P < 0.05) symptoms, and after 10 weeks, between the theta power increase and the change in PANSS subscales for general (P < 0.05) and positive (P < 0.05) symptoms. After 18 weeks a trend of inverse correlation between the PANSS subscales for general and negative symptoms and the right and midline theta power increase was observed, but not with regard to positive symptoms. There were trends, but no significant correlations, between CLO treatment response and serum CLO levels.. These findings indicate that the change in the theta frequency in QEEG and particularly in the midline electrodes over the fronto-central scalp area might be a more sensitive indicator for the evaluation of CLO treatment adequacy than the serum CLO level.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Evaluation; Electroencephalography; Female; Humans; Longitudinal Studies; Male; Neurologic Examination; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Statistics, Nonparametric; Time Factors; Treatment Outcome

Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome.. In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001.. Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings.. The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.

Topics: Adolescent; Adult; Aged; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Olanzapine; Psychotic Disorders; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; Treatment Outcome

Weight gain, a common adverse effect of clozapine, may impair health and affect patient compliance during treatment with this agent. The aim of this study was to investigate the relationship between genetic variants of the adrenergic beta3 receptor (ADRB3) and the G-protein beta3 subunit (GNB3) and clozapine-induced body weight change (BWC). Eighty-seven treatment-resistant schizophrenic patients were weighed before and after 4 months of clozapine treatment, with the subjects gaining an average of 2.6 kg in body weight. No statistically significant relationship was demonstrated for the investigated ADRB3 Trp64Arg and the GNB3 C825T polymorphisms in terms of BWC post-treatment, suggesting these two polymorphisms do not play a significant role in clozapine-induced BWC. Further exploration of other genetic variants implicated in clozapine-induced BWC is important, however, in order to predict and reduce clozapine-associated weight gain.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Female; GTP-Binding Proteins; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Adrenergic, beta-3; Schizophrenia; Weight Gain

Cognitive dysfunction in schizophrenia has been demonstrated to be dependent, in part, on dopaminergic activity. Clozapine has been found to improve some domains of cognition, including verbal memory, in patients with schizophrenia.. This study tested the hypothesis that plasma homovanillic acid (pHVA) levels, a peripheral measure of central dopaminergic activity, would predict the change in memory performance in patients with schizophrenia treated with clozapine.. Twenty-seven male patients with schizophrenia received clozapine treatment for 6 weeks. Verbal list learning (VLL)-Delayed Recall (VLL-DR), a test of secondary verbal memory, was administered before and after clozapine treatment. Blood samples to measure pHVA levels were collected at baseline.. Baseline pHVA levels were negatively correlated with change in performance on VLL-DR; the lower baseline pHVA level was associated with greater improvement in performance on VLL-DR during treatment with clozapine. Baseline pHVA levels in subjects who showed improvement in verbal memory during clozapine treatment ( n=13) were significantly lower than those in subjects whose memory performance did not improve ( n=14).. The results of this study indicate that baseline pHVA levels predict the ability of clozapine to improve memory performance in patients with schizophrenia.

Topics: Adult; Clozapine; Homovanillic Acid; Humans; Male; Memory; Predictive Value of Tests; Psychomotor Performance; Schizophrenia

Cognitive and psychomotor impairments are a core feature of most patients with schizophrenia and may have an important influence on driving ability. The present study investigated the effects of neuroleptic monotherapy on psychomotor functions related to car driving skills in schizophrenic patients. Consecutively admitted schizophrenic inpatients (n = 120) were tested under steady state plasma level conditions before discharge to outpatient treatment. Patients met the International Classification of Diseases, Tenth Revision criteria for schizophrenia. The study followed a naturalistic nonrandomized design. Data were collected with the computerized Act & React Testsystem and were analyzed according to medication, severity of illness, and age. Only 32.5% of the schizophrenic inpatients passed the tests without major impairments. Patients treated with atypical neuroleptics or clozapine showed a better test performance on skills related to driving ability when compared with patients on typical neuroleptics. Differences were most pronounced in measures of divided attention, stress tolerance, and attention. Data also suggest that treatment with clozapine had an overall positive impact on measures of reactivity and stress tolerance. These results show that even under steady state pharmacologic conditions psychomotor functions of most schizophrenic patients partly remitted must be considered as impaired. To evaluate these effects, a systematic neuropsychologic examination is recommended.

Topics: Adolescent; Adult; Antipsychotic Agents; Automobile Driving; Clozapine; Female; Flupenthixol; Humans; Male; Middle Aged; Psychomotor Performance; Schizophrenia; Schizophrenic Psychology; Visual Perception

The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Haloperidol; Humans; Olanzapine; Psychiatric Status Rating Scales; Psychometrics; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

Increasing evidence suggests that the cholinergic system is involved in the pathogenesis of schizophrenia. Donepezil, a central cholinesterase inhibitor, improves psychotic symptomatology in demented patients, however, evidence for its role in the management of active psychosis in schizophrenia remains limited. An 18-week double blind cross-over study was conducted in which eight patients were randomly assigned to either donepezil (5 mg/day for the first 4 weeks and 10 mg/day for the following 4 weeks) or placebo as augmentation treatment to clozapine. After this initial phase, there was a 2-week washout period of the study medication after which the same regimen was crossed over at the same dose and for the same period (8 weeks). No significant difference was noted in the total positive and negative symptom scale scores when donepezil was compared with placebo (16.7%+12.97% vs 3.20%+13.94% respectively, p = 0.18). However, three patients improved (>15%) in the total PANSS scores (37.03%, 16.6% and 25.33%) during the donepezil treatment phase, while only one patient improved (20.87%) during the placebo phase. No differences were noted in the Calgary depression scale (p = 0.305), Simpson Angus scale (p = 0.374), clinical global impression-improvement scale (p = 0.23) and clinical global impression-severity of illness scores (p = 0.116). Although this preliminary study failed to demonstrate a clear effect of donepezil augmentation in clozapine treated chronic schizophrenia patients, it seems that the subtle positive effect of donepezil observed in some of our patients should encourage further investigation in a larger sample of this patient subpopulation.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indans; Male; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome

This report examines whether the gains associated with changing to clozapine are greater for people who have been intolerant of first generation antipsychotic medications versus those who have been treatment-nonresponsive to previous agents. We examined data from an open-label, randomized trial that compared clozapine to usual care with first generation agents (n = 227). While most patients (n = 173, 76%) entered that study because they were nonresponsive to at least two first generation antipsychotic medications (treatment nonresponsive [TNR]), 24 percent (n = 54) were eligible because they experienced intolerable side effects (treatment intolerant [TI]). Significantly more TI patients discontinued their clozapine trial during the 2-year study compared to TNR patients, and TI patients taking clozapine were more likely to develop agranulocytosis or severe leukopenia. However, TI patients who remained on clozapine showed significant reductions in problematic behaviors and greater movement toward independent living situations than TNR patients. Clinicians should give serious consideration to offering clozapine and other second generation antipsychotic medications to patients who have demonstrated intolerance to first generation antipsychotic medications.

Topics: Adult; Antipsychotic Agents; Brain; Brief Psychiatric Rating Scale; Clozapine; Drug Resistance; Female; Humans; Male; Schizophrenia; Time Factors; Treatment Outcome

Few studies have examined gender differences in the propensity to gain weight on clozapine. Weight gain increases risk for many medical illnesses and is of particular concern for people with schizophrenia who are more overweight than the general population. Long-stay patients in Connecticut state hospitals were randomly assigned to switch to open-label treatment with clozapine (n = 138) or to continue receiving first generation (conventional) antipsychotic medications (n = 89). Using survival and random regression models, we examined percentage of body weight gained during 2 years for patients assigned to clozapine versus those who continued taking first generation antipsychotic medications. We also examined the impact of gender on weight gain. Patients who switched to clozapine gained a greater percentage of weight (13 pounds, 7%) than did patients remaining on first generation medications (5 pounds, 4%) at the end of 2 years. Normal-weight patients on clozapine were more likely to become obese (body mass index [BMI] > or = 30). Patients gained weight whether they switched to clozapine or remained on first generation antipsychotic medications, but weight gain was significantly greater (1 BMI unit) in the clozapine-treated group, particularly among women.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Obesity; Schizophrenia; Severity of Illness Index; Time Factors; Weight Gain

Schizophrenia is characterized by high suicide risk and low awareness of disorder. Although awareness has benefits for medication compliance and clinical outcome, it is unclear how it may relate to suicide risk in this population.. This multicenter investigation assessed awareness and suicide-related behavior in 980 patients with schizophrenia or schizoaffective disorder. Patients were followed over 2 years and assessed by blinded raters for suicide-related events.. Awareness of psychiatric condition at baseline was associated with increased risk of suicide events over the follow-up. This effect was mediated by depression and hopelessness levels. By contrast, changes in awareness associated with treatment decreased the risk of suicide.. Although some patients may become depressed after acknowledging the clinical handicaps of their disorder, treatment-related changes in awareness are generally associated with a positive outcome relative to suicide risk. The complex interactions and mediation effects of these clinical variables require careful monitoring.

Topics: Adult; Antipsychotic Agents; Awareness; Benzodiazepines; Clozapine; Comorbidity; Depressive Disorder; Female; Health Status; Humans; Male; Middle Aged; Olanzapine; Proportional Hazards Models; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; Treatment Outcome

Treatment options are very limited for individuals with schizophrenia resistant to clozapine. We tested the hypothesis that amisulpride augmentation would lead to an improvement in these patients.. This was an open non-randomized study. Thirty-three patients with sub-optimal response to clozapine were commenced on amisulpride in addition to clozapine. Clinical status was evaluated at baseline, 3 and 6 months using the Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Calgary Depression Scale, Calgary Anxiety Scale and various side effect rating scales.. Twenty-eight subjects completed 6 months treatment on clozapine and amisulpride. There was a statistically significant improvement in the mean scores for PANSS, SANS and GAS at follow-up and no significant changes in side effect ratings.. Co-administration of amisulpride, in a group of patients partially or non-responsive to clozapine, may lead to a substantial improvement in positive and negative symptoms, without worsening the side effect burden.

Topics: Amisulpride; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Schizophrenia; Sulpiride

Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Humans; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Pyridines; Receptor, Serotonin, 5-HT1A; Schizophrenia; Serotonin Antagonists; Time Factors

We report the results of a double-blind, randomized prospective trial on D2 and 5-HT2 receptor occupancy and the clinical effects of olanzapine versus clozapine in a sample of neuroleptic-refractory schizophrenic patients. Receptor occupancy was evaluated in different cortical areas and in basal ganglia using [18F] fluoro-ethyl-spiperone ([18F] FESP) and positron emission tomography (PET). A total of 15 neuroleptic-free patients completed the study undergoing a baseline and a post-treatment PET scan (olanzapine, nine patients, one female; clozapine, six patients, three female) 8 weeks after starting treatment. PET data were analysed both by regions of interest and on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM96). Olanzapine and clozapine induced a similar and significant inhibition of [18F] FESP binding index in the cortex. In the basal ganglia, receptor occupancy was significantly higher with olanzapine than with clozapine (p=0.0018). By contrast, no differences in receptor occupancy were detected at the level of the pituitary gland. Clinical outcomes, in particular a full extra pyramidal tolerability, were similar. In this sample of neuroleptic-refractory schizophrenic patients, olanzapine and clozapine showed a different pattern of occupancy of D2-like receptor despite a common lack of extrapyramidal side-effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain; Clozapine; Double-Blind Method; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Prospective Studies; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Spiperone

In vitro, animal studies and acute short-term clinical studies suggest clozapine releases prolactin but the effect is much smaller than that of typical antipsychotics. Repeated early morning trough measures of plasma clozapine and prolactin levels on each subject were studied during the course of a double-blind dose-response clozapine study. After a 4-week 10 mg/day haloperidol trial and a one-week washout, treatment- refractory schizophrenics were successively randomized to 100, 300,or 600 mg/day of clozapine for a 16- week treatment. The statistical analyses included 35 subjects (19 females and 16 males). The within-subject correlation of prolactin levels was 0.32 with clozapine levels and 0.75 with haloperidol levels. An increment of 100 ng/ml in clozapine level yielded an average increment of 0.45 ng/ml of prolactin levels in females and of 0.15 ng/ml in males. An increment of 1 ng/ml in haloperidol level yielded an average increment of 2.6 ng/ml of prolactin levels in females and of 1.5 ng/ml in males. At least one fourth of patients demonstrated a significant and strong (r > 0.6) correlation between clozapine and prolactin levels. This study suggests that clozapine has effects on prolactin levels but effects are small and may be more evident in some individuals, particularly females.

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Domperidone; Double-Blind Method; Female; Humans; Longitudinal Studies; Male; Middle Aged; Prolactin; Review Literature as Topic; Schizophrenia; Sex Characteristics

This study aims at identifying potential predictors of clinical response and functional outcome in 101 neuroleptic-refractory patients with a DSM-III-R diagnosis of schizophrenia (N = 34), schizoaffective disorder (N = 30) or bipolar disorder with psychotic features (N = 37), naturalistically treated with clozapine over a 48-month period. The "clinical response" and "functional outcome" criteria were respectively defined a priori as: a reduction of at least 50 % in the Brief Psychiatric Rating Scale total score in one evaluation with respect to baseline; and a Global Assessment of Functioning Scale score of at least 50. Several clinical and socio-demographic variables were assessed at baseline and only the diagnosis of bipolar disorder was significantly related with the clinical response. Variables significantly related with the functional outcome were female gender, university education and early age at onset.

Topics: Age of Onset; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cross-Over Studies; Demography; Educational Status; Female; Follow-Up Studies; Humans; Male; Outcome Assessment, Health Care; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Regression Analysis; Retrospective Studies; Schizophrenia; Severity of Illness Index; Time Factors; Treatment Outcome

This open label study describes the efficacy of electroconvulsive therapy (ECT) as adjunctive treatment in clozapine nonresponders suffering from schizophrenia.. The results of clozapine and ECT treatment in 11 clozapine nonresponders suffering from schizophrenia are reported in terms of remission and relapse.. Eight patients had a remission with this combination treatment. After remission of symptoms five patients had a relapse. Three of the five patients who relapsed had a second successful ECT course and remained well with maintenance ECT and clozapine. No evidence for adverse effects was found.. Adjunctive ECT can be efficacious in clozapine nonresponders suffering from schizophrenia.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

Suicidal behavior in patients with psychotic disorders represents a seriously undertreated life-threatening condition. The International Suicide Prevention Trial (InterSePT) is the first large-scale, prospective study designed to evaluate the potential of antipsychotic medications to reduce suicidal behaviors in patients with schizophrenia or schizoaffective disorder who are known to be at high risk for suicide. The unique challenges to study design and the solutions identified for the InterSePT study are described. These challenges included defining suicidal behavior in patients with psychosis, endpoint selection, determination of analytic strategy, and development of scales to assess suicidal behavior. Given the life-threatening nature of suicidal behavior, ethical considerations required that the design minimize suicide attempts and deaths. While the study focused primarily on treatment of suicide, opportunities were used to collect data in related areas of interest, including suicide risk factors, other efficacy measures (e.g., Positive and Negative Syndrome Scale, Covi Anxiety Scale, Calgary Depression Scale), adverse events, pharmacoeconomics, and pharmacogenetics. Because of the complexity of the design issues, a steering committee, suicide monitoring board, and publication committee were established to assist with their management.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Research Design; Risk Factors; Schizophrenia; Suicide Prevention; Treatment Outcome

A Suicide Monitoring Board (SMB) evaluated putative events of suicidal behavior to determine whether they should be counted as outcome data (endpoints) in the International Suicide Prevention Trial (InterSePT) study. The InterSePT study compared clozapine and olanzapine prospectively, on reduction of suicidality in schizophrenia and schizoaffective disorder. SMB members, blinded to patient identification, evaluated packages of clinical information and the forms used to summarize the putative events and their context. The SMB members met regularly by international teleconference to discuss ratings they found problematic and to achieve consensus. Exactly 243 of the 980 patients enrolled (24.8%) were considered to have experienced 577 suicidal events. Of these events, 483 (83.7%) were confirmed by the SMB as real or valid endpoints. Before the consensus discussions, acceptable levels of agreement (K = 0.52) were reached among the SMB members regarding ratings considered as valid suicidal events; agreement increased (K = 0.64) when consensus ratings and those of on-site psychiatrists also blinded to treatment were also included. This article discusses our experience of evaluating schizophrenia patients for suicidality in general and in particular from reviewing chart information. The process of making clinical judgments regarding the seriousness of suicidal behavior in schizophrenia patients and their suicidal risk warrants further study.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Endpoint Determination; Female; Humans; Male; Medical Records; Olanzapine; Reproducibility of Results; Schizophrenia; Suicide Prevention; Treatment Outcome

Some, but not all, previous studies have indicated that weight gain is associated with greater improvement in psychopathology during clozapine treatment. Possible reasons for the inconsistent results include failure to adjust for initial body weight and level of psychopathology, differences in trial duration, outcome measures, reliability of assessment, concomitant medications and clozapine dosage. The purpose of this study was to test the hypothesis that clozapine-induced weight gain is related to antipsychotic efficacy at 6 weeks and 6 months after adjusting for initial body weight and severity of illness.. Weight and psychopathology were determined in 74 patients with schizophrenia or schizoaffective disorder at baseline and after 6 weeks and 6 months of open treatment with clozapine monotherapy. The primary measures of psychopathology were the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms subscales, Schedule for Assessment of Negative Symptoms (SANS), Schedule for Assessment of Positive Symptoms (SAPS) and Global Assessment of Function Scale (GAFS).. Significant improvement in the key measures of psychopathology was noted at 6 weeks and 6 months. Mean weight gains at 6 weeks and 6 months were 3.7+/-5.7 S.D. and 7.3+/-7.9 S.D. kg, respectively, with the increase between 6 weeks and 6 months being significant. Age, but not gender, initial body weight, clozapine dosage or plasma levels predicted weight gain at both time points. At 6 weeks and 6 months, after adjustment for age, initial weight and level of psychopathology, the percentage change in weight significantly predicted the improvement in the BPRS Total and Positive symptoms subscale, the SANS Global score, as well as other measures of psychopathology.. Increase in weight with clozapine predicted improvement in psychopathology. This suggests that effects of clozapine on neurotransmitters which influence weight gain, e.g. 5-HT(2C) and 5-HT(1a) antagonism, in association with individual variations in these receptors and others molecules, e.g. peptides and transporters, due to polymorphisms or post-translational editing of mRNAs, may also contribute to the improvement in psychopathology.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Weight; Clozapine; Female; Humans; Male; Prospective Studies; Regression Analysis; Schizophrenia; Schizophrenic Psychology; Sex Factors; Time Factors; Weight Gain

We examined the effects of long-term clozapine treatment, concurrent treatment with beta-adrenergic antagonists, and clozapine-induced weight gain on serum glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for schizophrenia or schizoaffective disorder, participated in a 10-week, double-blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine trial, and had available serum glucose and lipid levels. Weight and glucose, and lipid laboratory values were measured at the baseline and throughout the double-blind and year-long study. There were significant increases in serum triglyceride, total cholesterol, and glucose levels during the course of clozapine treatment. There were no significant changes in high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had additive effects on changes in the total cholesterol and triglycerides, with propranolol having the most pronounced effects. Propranolol and atenolol had no significant effect on the serum glucose levels. There were significant correlations between the triglyceride and HDL level changes and clozapine-associated weight gain during the study. There were no significant correlations between the change in serum total cholesterol, LDL, or glucose and weight gain. Clozapine therapy has adverse effects on glucose and lipid homeostasis, with clozapine-induced changes in serum glucose likely due to the inherent pharmacological properties of clozapine. Concurrent beta-adrenergic receptor antagonist treatment may have an additive effect on serum lipids, and clozapine-associated weight gain also plays a modest role in triglyceride increases.

Topics: Adrenergic beta-Antagonists; Adult; Analysis of Variance; Antipsychotic Agents; Atenolol; Blood Glucose; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Haloperidol; Humans; Lipids; Male; Propranolol; Psychotic Disorders; Schizophrenia; Statistics, Nonparametric; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Synergism; Fluphenazine; Haloperidol; Humans; Middle Aged; Schizophrenia; Treatment Outcome

Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients.. A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of "much worsening of suicidality" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved.. Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P =.03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P =.03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P =.01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P =.01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P =.73).. Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Patient Dropouts; Pirenzepine; Psychotic Disorders; Risk Factors; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Suicide; Suicide Prevention; Suicide, Attempted; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Pilot Projects; Psychiatric Status Rating Scales; Schizophrenia

A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (P < 0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT(2A), and 5HT(2C) polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (P < 0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype.

Topics: Adult; Alleles; Antipsychotic Agents; Brain; Clozapine; Female; Genotype; Humans; Male; Predictive Value of Tests; Receptors, Dopamine D1; Schizophrenia; Tomography, Emission-Computed

The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors' goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial.. One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period.. One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22).. In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Hospitalization; Humans; Hypercholesterolemia; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Prospective Studies; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

To compare plasma and red-cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders.. Plasma and red-cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations.. Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups.. Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life threatening cardiac side-effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.

Topics: Adult; Antipsychotic Agents; Clozapine; Erythrocytes; Female; Humans; Male; Mood Disorders; Schizophrenia; Selenium; Serotonin Antagonists

Patients with chronic schizophrenia (DSM-IV criteria) often receive depot antipsychotic medications to assure longer administration and better compliance with their treatment regimen. This study evaluated whether patients stabilized on depot antipsychotic medication could be successfully transitioned to oral olanzapine.. In a 3-month open-label study, 26 clinically stable patients with schizophrenia taking depot antipsychotics for over 3 years were randomly assigned to continue on their current depot dose or to switch to oral olanzapine. Clinical ratings (Positive and Negative Syndrome Scale [PANSS], Global Assessment of Functioning [GAF] scale, and Clinical Global Impressions [CGI] scale) and side effect parameters (Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia Scale, AMDP-5 scale, vital signs, and weight) were obtained monthly.. Oral olanzapine patients (N = 13) demonstrated significant clinical improvement over the depot control group (N = 13) from baseline to 3-month endpoint (PANSS total, p =.012; PANSS general, p =.068; PANSS negative, p =.098; CGI-Improvement, p =.007; CGI-Severity, p =.026; GAF, p =.015). Side effect rating scales showed no statistical differences between the 2 groups (AIMS, Barnes Akathisia Scale, AMDP-5, vital signs). The depot control group showed no statistical superiority in any measure except weight change (p =.0005). After 3 months, all olanzapine patients preferred olanzapine to their previous depot medications and chose to continue on olanzapine treatment.. Clinicians may expect clinical improvement when switching chronically psychotic patients from traditional depot antipsychotic drugs to oral olanzapine. Switching may be completed within a 4-week period with relative compliance being maintained and patients preferring oral olanzapine to their previous depot medications.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Olanzapine; Patient Compliance; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperazines; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome; Weight Gain

The aim of the study was to investigate patterns of the P600 component of event-related potentials (ERPs) elicited during a working memory test in 16 male schizophrenic patients experiencing auditory hallucinations before and after treatment with clozapine and olanzapine, and 13 male normal subjects matched for age and educational level. Before treatment, patients showed significantly reduced P600 amplitudes on the right parietal region compared with controls, and when in remission also showed significantly reduced P600 amplitudes located on the right parietal and temporofrontal areas, compared both to themselves before treatment and to normal controls. The patient's memory performance before and after treatment remained significantly lower than that of healthy controls. These findings may indicate that auditory hallucinations in schizophrenia are associated with impaired synchronization of the processes related to target detection, as reflected by the P600. The present study also casts doubts regarding the cognitive sparing effect of atypical antipsychotics, despite the fact that they mediate symptom improvement.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain; Clozapine; Cognition; Double-Blind Method; Evoked Potentials, Auditory; Hallucinations; Humans; Male; Memory; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Reference Values; Schizophrenia; Schizophrenic Psychology

To report clinical findings resulting from a switch from branded to generic clozapine.. Twenty patients diagnosed with schizophrenia were followed in this naturalistic outpatient study. The Positive and Negative Syndrome Scale (PANSS), Beck Anxiety Inventory (BAI), Abnormal Involuntary Movement Scale, and the Movement Disorder Assessment were used to assess differences in the clinical status of patients before and after switching from Clozaril to generic clozapine (Mylan Pharmaceuticals). Results were analyzed by means of the paired t-test and by calculation of the percent change in mean scores. A clinically significant change as measured by the PANSS was defined as a +/- 20% change in mean scores at final evaluation. The design was open-label and non-blinded.. At the final evaluation, the t-test revealed no significant differences between branded and generic clozapine for the total PANSS, the positive symptom, negative symptom, and the general psychopathology subscales of the PANSS, and the BAI. There were no clinically significant changes for any measure.. In this small group of patients with schizophrenia, no deterioration in clinical status in several domains was noted after changing from branded to generic clozapine. This finding is consistent with pharmacologic data suggesting bioequivalence of the 2 products. Results, however, must be interpreted cautiously due to the lack of optimal study controls and small sample size.

Topics: Adolescent; Adult; Antipsychotic Agents; Area Under Curve; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Therapeutic Equivalency; Treatment Outcome

There is a lack of controlled trials examining the effectiveness of electroconvulsive therapy (ECT) combined with olanzapine or risperidone in treatment-resistant schizophrenia (TRS). The authors conducted a prospective, open, controlled trial of ECT in TRS in a long-term psychiatric rehabilitation unit in Hong Kong. Thirty patients with TRS from an inpatient psychiatric rehabilitation unit participated in this study. All subjects were resistant to a host of antipsychotic medications given singly or in different combinations. In addition, they were also resistant to or they refused clozapine treatment. Fifteen patients completed a course of ECT consisting of 8-20 sessions. Fifteen patients who refused ECT formed the control Subjects were assessed at baseline, 1 week, 1 month, and 2 months after their last ECT. Assessment instruments included the Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Rating Scale (HDRS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Clinical Global Impression (CGI), CGI Severity of Illness [CGI(SOI)], CGI Global Improvement [CGI(GI)], Nurses' Observation Scale for Inpatient Evaluation (NOSIE-30), and occupational therapists' rating of the subjects' functioning with respect to work (OT-W), social (OT-S), and leisure (OT-L) activities. In comparison with the control group, the ECT group showed statistically significant improvement only in the GAS and CGI at each posttreatment evaluation. There was a trend for ECT to reduce positive and negative symptoms, although the rate of improvement did not reach statistically significant levels. ECT augmentation of risperidone and olanzapine is of marginal efficacy compared to reports of the greater augmentation of these antipsychotics with other agents.

Topics: Adult; Analysis of Variance; Clozapine; Drug Therapy, Combination; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Statistics, Nonparametric

The purported advantages of second-generation or "atypical" antipsychotics relative to first-generation antipsychotics have not been examined in patients with a first episode of schizophrenia. This flexible-dose study examined efficacy and safety in a randomized, double-blind, 52-week trial, comparing chlorpromazine (CPZ) and clozapine (CLZ) in treatment naive patients experiencing their first episode of schizophrenia. In all, 160 inpatients with first-episode schizophrenia or schizophreniform disorder were randomized to CPZ or CLZ and followed them for 52 weeks or until dropout. The primary efficacy measure was time to first remission and proportion of time remaining in remission. The analysis was supplemented by comparisons on a profile of clinical symptoms and side effects. Of these first-episode patients, 80% achieved remission within 1 year (79% CPZ, 81% CLZ). The Kaplan-Meier estimated median time to first remission was 8 weeks for CLZ vs 12 weeks for CPZ (chi(2)(1)=5.56, p=0.02). Both the rate of first achieving remission and the odds for being in remission during the trial were almost doubled for the CLZ group in comparison with the CPZ group. At 12 weeks, CLZ was superior on many rating scale measures of symptom severity while CPZ was not superior on any. These symptom differences remained significant when controlling for EPS differences. By 52 weeks many of the symptom differences between groups were no longer significantly different. Generally, CLZ produced fewer side effects than CPZ, particularly extrapyramidal side effects. There was no significant difference between treatments in weight change or glucose metabolism. For each prior year of untreated psychosis, there was a 15% decrease in the odds of achieving remission (OR=0.85; CI 0.75-0.95). A high proportion of first-episode patients remitted within 1 year. We detected no difference in the proportion of first-episode patients receiving CLZ or CPZ that achieved remission. However, first-episode patients receiving CLZ remitted significantly faster and remained in remission longer than subjects receiving CPZ. While the CLZ group showed significantly less symptomatology on some measures and fewer side effects at 12 weeks, the two treatment groups seemed to converge by 1 year. Longer duration of untreated psychosis was associated with lower odds of achieving remission.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Chlorpromazine; Clozapine; Female; Follow-Up Studies; Humans; Male; Schizophrenia

The aim of this study was to evaluate the long-term efficacy and safety of clozapine in patients with treatment-resistant schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features.. 101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34); schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with psychotic features (N = 37) were naturalistically treated with clozapine at flexible doses over a 48-month period. Data were collected from 1994 to 2000. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness scale total predicted scores over time were estimated with random-effects regression models. Time to response to clozapine, defined as 50% reduction of BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier method. Survival curves were compared using the log-rank test.. The BPRS total predicted score halved its baseline value in 3 months for bipolar disorder patients, in 6 months for schizoaffective disorder patients, and in 24 months for schizophrenia patients. The proportion of subjects who satisfied the criterion for response to clozapine after 48 months of follow-up was significantly (p <.01) higher in the schizoaffective and bipolar disorder groups (90.0% and 83.8%, respectively) than in the schizophrenia group (64.7%). Baseline scores on the Global Assessment of Functioning (GAF) showed low levels of psychosocial and occupational functioning in all 3 groups. After 48 months of treatment, GAF scores showed a functional improvement in all 3 groups, with significantly (p <.01) greater improvement in the bipolar disorder group compared with the other groups.. The findings of this study confirm the efficacy and safety of clozapine for treatment-resistant patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Patients with schizoaffective disorder and those with bipolar disorder show greater clinical improvement than those with schizophrenia. Patients with bipolar disorder have the shortest time to response and the highest psychosocial and occupational functioning levels. Patients with schizoaffective disorder have the lowest treatment discontinuation rate.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Brief Psychiatric Rating Scale; Clozapine; Female; Follow-Up Studies; Humans; Male; Patient Dropouts; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Survival Analysis; Treatment Outcome

Clozapine has been shown to improve verbal declarative memory and other cognitive functions in chronic schizophrenia. This raises the possibility that additional adjunctive manipulations might improve memory further. In this study, we hypothesized that glucose, which improves memory in a variety of conditions, including schizophrenia, would improve memory more than saccharin in a group of patients stabilized on clozapine. Twelve outpatients with schizophrenia who received treatment with clozapine participated in a double-blind, counterbalanced, crossover study. Subjects received beverages containing either glucose or saccharin on one occasion, and then the other beverage about a week later. Fifteen minutes after ingesting the beverage, subjects received a brief battery of neuropsychological tests to assess verbal declarative memory, attention, and executive functions. Blood glucose levels were assessed at baseline, and at 15 and 50 min after beverage ingestion. The main findings were that retention of a list of words was improved in the glucose condition, while performance on a complex test of sustained vigilance declined after glucose ingestion. These findings provide evidence that glucose improves declarative memory in patients with schizophrenia who were treated with clozapine, and underscore the possibility of developing effective protocols to reduce cognitive dysfunctions in the disorder. They also highlight the need to explore the extent to which glucose modulates nonmemory cognitive functions such as attention, and to understand more generally how glucose availability and regulation influence cognition.

Topics: Adult; Antipsychotic Agents; Attention; Clozapine; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Glucose Solution, Hypertonic; Humans; Male; Mental Recall; Middle Aged; Neuropsychological Tests; Saccharin; Schizophrenia; Schizophrenic Psychology; Verbal Learning; Wechsler Scales

In light of the efficacy of newer antipsychotic agents and the possibility that drug withdrawal may negatively affect subsequent drug response, concern has arisen that the use of placebo in schizophrenia research may be unethical. This study examines the effect size of symptom exacerbation during drug washout with placebo and the effects of drug washout on the efficacy of subsequent drug treatment.. Fifty patients with treatment-resistant schizophrenia hospitalized on a research unit participated in a double-blind longitudinal study of the effects of drug washout after chronic treatment with a typical antipsychotic and before prospective treatment with clozapine. Brief Psychiatric Rating Scale (BPRS) scores were analyzed to examine drug effects and effect sizes for baseline treatment with a typical antipsychotic (>6 months treatment), drug washout with placebo (mean=34 days), early treatment with clozapine (mean=42 days, mean dose=345.0 mg/day), and optimal clozapine treatment (mean=83 days, mean dose=450.5 mg/day).. Patients' BPRS total, positive, and negative symptom scores significantly increased during placebo washout, compared with baseline treatment, and significantly decreased with administration of clozapine, compared with placebo washout and baseline treatment. However, 30% of patients showed some symptom improvement during placebo washout. The effect sizes for the BPRS total score were 0.63 for baseline treatment versus placebo washout, 1.10 for optimal clozapine treatment versus placebo washout, and 0.82 for optimal clozapine treatment versus baseline treatment.. Symptom exacerbation induced by drug withdrawal in patients with treatment-resistant schizophrenia did not impede subsequent responsiveness to clozapine. The effect size for clozapine, compared with typical antipsychotics, suggests that the drug-washout longitudinal design is useful for establishing a drug-free baseline and for investigating drug response, while requiring relatively few subjects.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Data Interpretation, Statistical; Double-Blind Method; Drug Resistance; Female; Humans; Longitudinal Studies; Male; Research Design; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; Treatment Outcome

The safety and tolerability of clozapine combined with lithium were investigated because of potential additive risks as well as frequent usage in clinical practice. Ten hospitalized schizophrenic and 10 schizoaffective patients receiving clozapine maintenance therapy with partial therapeutic response were studied in a randomized controlled trial. CGI and PANSS outcome ratings were employed and a cognitive battery was administered at baseline and after 4 weeks of lithium and placebo administration. Barnes and UKU side effect ratings and laboratory safety data were obtained. Combined lithium-clozapine treatment was well tolerated except for reversible neurotoxic reactions in two schizophrenic patients. Safety measures showed no significant variations, even during lithium toxicity. Total WBC and absolute granulocyte counts increased with lithium and declined with placebo. Schizoaffective patients improved with lithium on CGI and PANSS total and negative symptom scales and the cognitive measures, whereas schizophrenic patients did not. Lithium added to clozapine in treatment regimens for hospitalized, treatment-resistant, schizoaffective patients appears to afford potential benefit without harmful effects; for schizophrenic patients, however, it did not afford improvement but posed a risk of lithium toxicity.

Topics: Adult; Analysis of Variance; Clozapine; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Middle Aged; Psychotic Disorders; Schizophrenia

Schizophrenia patients are known to manifest widespread, multifaceted cognitive deficits. There is now an increasing emphasis on the critical importance of cognitive deficits for the functional outcome in schizophrenia. Typical antipsychotics, although effective in reducing positive symptoms of the illness, have not shown much effect on cognitive functions. Atypical antipsychotics have shown promise of improving some cognitive functions.. This naturalistic study aimed to determine whether olanzapine and clozapine improve cognitive functioning in a sample of 48 patients with chronic schizophrenia who had either failed to show sufficient clinical improvements or suffered from distressing side effects with conventional antipsychotics and were switched to either olanzapine or clozapine for clinical reasons and, if so, whether the two drugs produce similar or different cognitive effects.. All patients completed a comprehensive battery of neuropsychological tests designed to index executive functioning, verbal learning, verbal and visual and memory, attention, working memory, and psychomotor speed at: (i) baseline, (ii) after 6 weeks and (iii) after 6 months of treatment with olanzapine or clozapine.. From the initial 48 patients who remained on olanzapine ( n=16) or clozapine ( n=14) for the entire duration with continuous participation, 30 provided data for this study. There were improvements over time (i.e. from baseline through 6 weeks to 6 months) in both treatment groups on verbal fluency, verbal learning and verbal and visual memory measures.. The findings indicate similar beneficial effects of olanzapine and clozapine on verbal learning and memory measures in patients showing a favourable clinical response to these drugs.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Female; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Olanzapine; Pirenzepine; Problem Solving; Schizophrenia; Time Factors; Treatment Outcome

The study was designed to assess the predictive relationship between brain structure volume and positive and negative symptom response to clozapine and haloperidol.. Partially responsive outpatients with schizophrenia who participated in a 10-week, parallel-group, double-blind comparison of clozapine and haloperidol and who had an available magnetic resonance imaging scan were included in the current study. Prefrontal gray and white matter, hippocampal, and caudate volumes were manually measured. The Scale for the Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS) were used to assess symptom changes. The Simpson-Angus Rating Scale was used to assess extrapyramidal symptoms.. Twenty-two patients randomly assigned to clozapine and 23 patients assigned to haloperidol met study entry criteria. There were significant interactions between treatment and right prefrontal gray matter volume for BPRS total score and SANS total score. There were no significant treatment-by-brain structure interactions for BPRS positive symptom items. Right prefrontal gray matter volume was also related to differential treatment effects for the BPRS subscales of anxiety/depression and hostility and the Simpson-Angus Rating Scale akathisia item.. These results suggest that there is a differential interaction among clozapine and haloperidol, brain structure, and treatment response. Partially responsive patients with larger brain volumes may be more likely to experience the benefits of clozapine treatment, but they may be more vulnerable to side effects and experience a subsequent worsening of their symptoms when treated with haloperidol.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Brief Psychiatric Rating Scale; Caudate Nucleus; Clozapine; Double-Blind Method; Female; Functional Laterality; Haloperidol; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Prefrontal Cortex; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

This article examines the ways in which changes in the treatment environment and in measurement perspectives can affect the evaluation of cost-effectiveness of new medications. In three studies we reexamined data from a clinical trial of haloperidol and clozapine conducted from 1993 to 1996. The results of the studies are as follows: Study 1 found that clozapine treatment was associated with significantly reduced inpatient costs, and increased outpatient costs, suggesting that as systems use less inpatient care and more outpatient care, more effective medications may increase, rather than decrease, costs in sicker patients. Study 2 found that while provider assessments and standard measures favored clozapine over haloperidol, patient responses showed little evidence of a clinical advantage for clozapine and a less favorable side-effect profile. Study 3 found that while annual drug costs in the published trial were estimated to be dollars 4,545 for a full year of clozapine treatment, atypical antipsychotic costs in 2000 were estimated to range from dollars 1,254 to dollars 3,016 in the Department of Veterans Affairs system, and from dollars 2,221 to dollars 8,147 in the private sector. In conclusion, cost-effectiveness, as evaluated in studies like CATIE, will increasingly need to be tied to service system contingencies, environments, and evaluation perspectives.

Topics: Adult; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Female; Haloperidol; Humans; Male; Schizophrenia; Surveys and Questionnaires; Veterans

Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide.. This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events.. Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinson's, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present.. This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Proportional Hazards Models; Prospective Studies; Psychotic Disorders; Research Design; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide

This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics. In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders. Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Double-Blind Method; Humans; Muscarinic Antagonists; Psychiatric Status Rating Scales; Quinuclidinyl Benzilate; Receptors, Muscarinic; Schizophrenia

The risk of suicide for schizophrenia patients is 20 to 50 times higher than that for the general population. Long-term treatment with clozapine, an atypical antipsychotic, has been shown to reduce the rate of suicide by 80% to 85%. The goal of the present study was to examine whether clozapine's effect on the reduction of suicidal behavior in chronic schizophrenic patients could be due to a reduction in impulsive-aggressive behavior.. 44 patients with chronic DSM-IV schizophrenia were treated with clozapine or haloperidol decanoate in an open prospective 6-month trial. Changes in measures of suicidality, impulsiveness, aggression, depressed mood, and positive and negative symptoms were assessed at baseline and at 6 months.. The clozapine-treated group (N = 18) had a significantly greater reduction on all outcome measures compared with the haloperidol decanoate-treated group (N = 26). Only in the clozapine-treated group did the reduction in measures of suicidality correlate significantly with a reduction in impulsiveness and aggression. The reductions in suicidality and impulsive aggression were not significantly correlated with reductions in depressed mood or positive and negative symptom scores in either group.. These data suggest that the reduction in suicidality following long-term clozapine treatment may be related to a reduction in impulsiveness and aggression.

Topics: Adolescent; Adult; Aggression; Antipsychotic Agents; Chronic Disease; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Disruptive, Impulse Control, and Conduct Disorders; Drug Administration Schedule; Female; Haloperidol; Humans; Male; Middle Aged; Schizophrenia; Suicide, Attempted

It is well established that the combination of psychopharmacological treatment and psychosocial interventions, such as psychotherapy, family orientation and occupational therapy (OT), represent the best strategy for treating patients with schizophrenia. However, in terms of treatment-resistant schizophrenia (TRS) almost only psychopharmacological treatments are available and psychosocial interventions such as OT had not proved to be effective. The aim of this study is to investigate if OT is effective when added to a psychopharmacological treatment in TRS.. Two groups of patients with TRS were compared: The experimental group (EG) received psychopharmacological treatment with clozapine plus sessions of occupational therapy (OT) and the control group (CG) received only clozapine. The Scale for Interactive Observation in Occupational Therapy (EOITO) was employed to evaluate the outcome. The duration of the study was 6 months and patients were rated at baseline and monthly totaling 7 assessments. EOITO was independently applied by two occupational therapists with high reliability rates (Kappa=0.90, p=0.001). Repeated measures of analyses of variance and the evaluation of the standardized effect sizes were used for statistical analyses.. The EG showed that the OT intervention was effective along the whole period of observation, mainly from the 4th month to the end of the study.. In patients with TRS the combination of OT and clozapine showed to be more effective than the use of clozapine alone. OT may represent an additional therapeutic option for patients with TRS.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Occupational Therapy; Schizophrenia; Treatment Failure

Increased serotonergic activity is discussed as an important pathogenetic factor in schizophrenia. Further support for this hypothesis is difficult to obtain due to the lack of valid indicators of the brain's serotonin system. A great deal of evidence discovered through human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. The LDAEP is a measure of auditory cortex activity, reflecting increase or decrease of auditory evoked potential amplitudes with increasing tone loudness, which is probably modulated by the serotonergic innervation there. This is true only for the LDAEP of the primary auditory cortex, since this region is more highly innervated by serotonergic fibers than the secondary auditory cortex. The LDAEP (N1/P2 component) of 25 inpatients with schizophrenia free of medication and 25 healthy controls matched by age and gender, were recorded. Using dipole source analysis, the LDAEP of primary (tangential dipole) and this of secondary auditory cortex (radial dipole) was separately analyzed. Following a 4-week treatment with the 5-HT(2) antagonists clozapine or olanzapine, patients were once again studied. The LDAEP of the primary, but not of the secondary auditory cortex, was significantly weaker in the patients with schizophrenia than in healthy volunteers, indicating enhanced serotonergic neurotransmission. After treatment with the 5-HT(2) antagonists, the LDAEP (of the right hemisphere) tended to be increased, indicating normalization of serotonergic function in the patients with schizophrenia. These results suggest that the loudness dependence of primary auditory cortex evoked activity is well suitable to assess serotonergic dysfunction in schizophrenia.

Topics: Adult; Antipsychotic Agents; Auditory Cortex; Benzodiazepines; Clozapine; Double-Blind Method; Electroencephalography; Evoked Potentials, Auditory; Female; Humans; Loudness Perception; Male; Olanzapine; Psychiatric Status Rating Scales; Reference Values; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Synaptic Transmission

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Middle Aged; Olanzapine; Schizophrenia; Treatment Outcome

Clozapine is an effective atypical antipsychotic drug applied in the treatment of resistant schizophrenia. The drug is mainly metabolized by cytochrome P-450 (CYP) enzymes especially the isozyme CYP1A2. Remarkably, the effective dosage varies widely among patients, making it necessary to individualize drug therapy with clozapine. The explanation for dosage variation may be differences in drug metabolism, and more specifically of CYP1A2 activity. This study is aimed at determining to what extent variability in clozapine dose can be explained by pharmacokinetic (PK) factors and more specifically by CYP1A2 activity in effectively treated psychiatric patients. In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated. For calculation of the pharmacokinetic parameters of clozapine, population PK software based upon Bayesian analysis was used. Caffeine clearance was estimated with the paraxanthine/caffeine ratio and served as estimate of CYP1A2 activity.A significant linear relationship was found between the clozapine dose and clozapine clearance (R: 0.71; P<0.05), whereas no relationship was found between clozapine dosage and clozapine serum trough concentration. Moreover, individual caffeine and clozapine clearances were found to be significantly related (R: 0.62; P<0.05) as were clozapine dose per kg body weight and P/C mol ratio (R: 0.44; P<0.05). We conclude that CYP1A2 activity is an important determinant of the variability of effective clozapine doses in psychiatric patients.

Topics: Adult; Algorithms; Antipsychotic Agents; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Female; Humans; Male; Middle Aged; Phenotype; Phosphodiesterase Inhibitors; Psychiatric Status Rating Scales; Schizophrenia; Xanthines

Topics: Algorithms; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Guanidines; Humans; Image Processing, Computer-Assisted; Radiopharmaceuticals; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Tomography, Emission-Computed, Single-Photon

There are some reports that classical neuroleptics may lead to osteoporosis or reduced bone mineral density (BMD). However, there is no adequate information about the effects of atypical neuroleptics on BMD. The aim of this study was to measure BMD in schizophrenic patients taking classical and atypical neuroleptics, compared to healthy controls. Seventy-five patients with schizophrenia (40 taking classical neuroleptics [CN], 35 taking atypical neuroleptics [AN]) and 20 healthy controls (HC) were included in the study. Spine (L1-L4) BMD was measured by dual-energy X-ray absorptiometry. ANOVA showed that BMD was higher in HC than AN and CN. In addition, there was a negative correlation between the duration of neuroleptic treatment and BMD and the duration of the illness. These findings suggest that atypical neuroleptics may be safer than the classical neuroleptics in terms of reduced BMD.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Bone Density; Clopenthixol; Clozapine; Female; Fluphenazine; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Risperidone; Schizophrenia