clozapine and Psychotic-Disorders

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

The current comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) in treating Parkinson's Disease Psychosis (PDP) are not entirely understood.. To evaluate comparative efficacy, safety, and acceptability of AAPs in patients with PDP.. We conducted a systematic review and a network meta-analysis to compare the efficacy, safety, and acceptability of pimavanserin, quetiapine, olanzapine, clozapine, ziprasidone, and risperidone. We estimated relative standardized mean differences (SMDs) for continuous outcomes and odds ratios (OR) for binary outcomes, with their respective 95% confidence intervals (CIs).. We included 19 unique studies evaluating AAPs in a total of 1,242 persons with PDP. Based on Clinical Global Impression Scale for Severity, pimavanserin (SMD, -4.81; 95% CI, -5.39, -4.24) and clozapine (SMD, -4.25; 95% CI, -5.24, -3.26) significantly improved symptoms compared with placebo. Also, compared to placebo, pimavanserin (OR, 1.16; 95% CI, 1.07, 1.24) significantly improved psychotic symptoms based on Scale for Assessment of Positive Symptoms for Parkinson's Disease Psychosis/Hallucinations and Delusions scores. In comparison to placebo, clozapine (SMD, -0.69; 95% CI, -1.35, -0.02), pimavanserin (SMD, -0.01; 95% CI, -0.56, 0.53), and quetiapine (SMD, 0.00; 95% CI, -0.68, 0.69) did not impair motor function per Unified Parkinson's Disease Rating scale. Based on Mini-Mental State Examination scale, quetiapine (SMD, 0.60; 95% CI, 0.07, 1.14) significantly impaired cognition compared to placebo.. In patients with PDP, pimavanserin and clozapine demonstrated significant improvement in psychosis without affecting motor function. With quetiapine being associated with a significant decline in cognition and despite not impairing motor function, our findings suggest that it should be avoided in patients with PDP and reduced cognitive abilities.

Topics: Antipsychotic Agents; Clozapine; Humans; Network Meta-Analysis; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate

Patients with chronic psychosis on prolonged antipsychotic therapy may present with paroxysmal dystonia along with an exacerbation of their psychotic symptoms: paroxysmal dystonia and psychotic exacerbations (PDPE). The interindividual variability in the clinical presentations of PDPE can pose challenges in its diagnosis and treatment. The objectives of this work are to (i) discuss this rare phenomenon through a series of 10 patients and a relevant literature review, (ii) conceptualize its neurobiological underpinnings, and (iii) explore the preliminary treatment approaches for its management. Acute stress and/or a dysfunctional gamma-aminobutyric acid (GABA) ergic or dopaminergic system may be implicated in the pathogenesis of PDPE. The episodes respond acutely to parenteral benzodiazepines, while long-term management can be achieved by reducing antipsychotic doses, switching to clozapine or using central GABA enhancers. This article is the first attempt at conceptualizing and exploring treatment options for the rare condition PDPE and intends to guide future research in this regard.

Topics: Antipsychotic Agents; Clozapine; Dystonia; gamma-Aminobutyric Acid; Humans; Psychotic Disorders

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

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 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

Over half of Parkinson's disease (PD) patients develop psychotic symptoms, and PD psychosis (PDP) is associated with significant distress to patients, caregiver burden, and impairs quality of life. Pharmacological therapy is limited to atypical antipsychotics.. This review will summarize efficacy but will focus on the safety of antipsychotics for treating PDP, and in particular the off-target safety issues including cognitive impairment, sleep disturbance, cardiovascular effects, and motor function.. Pimavanserin is the only medication approved in the US for treating PDP, however clozapine is also considered efficacious. Despite lack of substantial evidence for efficacy, quetiapine is commonly used to treat PDP. Despite the effectiveness of pimavanserin and clozapine for treating PDP, a need exists for additional pharmacological agents that are effective for PDP while providing an acceptable safety and tolerability profile. Medications to treat PDP should avoid worsening motor function, and also minimize sleep disturbances, cognitive impairment, cardiovascular effects, and other non-motor safety concerns. A neutral effect or reduction in mortality risk associated with PD and PDP would be ideal, and low rate of discontinuation due to AEs is desirable. Lastly, medications that can be used safely in combination with other pharmacological agents is essential.

Topics: Antipsychotic Agents; Clozapine; Delusions; Hallucinations; Humans; Parkinson Disease; Psychotic Disorders; Quality of Life

Comorbid disorders often occur in psychoses from the schizophrenia spectrum and are an additional burden for patients' quality of life, render treatment and rehabilitation prognosis more difficult and can also contribute to suicidal ideation. Specifically, obsessive-compulsive syndrome (OCS) and OC disorder (OCD) have been reported.. What is known about the epidemiology and pathogenesis and which conclusions can be drawn regarding the diagnostics and treatment?. This review evaluated current reports on comorbid OCS during different stages of psychotic disorders, starting with the at-risk mental state (ARMS) via the first manifestation and up to chronic courses. The focus was on pharmacological and psychotherapeutic consequences.. Patients with ARMS suffer much more often from OCS than the general population. The prevalence is even higher in patients with a first manifestation of psychosis. During the chronic courses ca. 30% of patients are affected by comorbid OCS and 12% fulfill the diagnostic criteria of a OCD. The pathogenesis can most likely be explained by a genetic disposition in the glutamatergic system, shared structural and functional abnormalities of cortical and subcortical structures, pharmacological influences and psychosocial stressors.. Clozapine and other antipsychotics may induce or aggravate OCS in a dose-dependent manner. In order to alleviate symptoms clozapine should be reduced to a minimally sufficient level. This can be attempted through combination, for example with dopaminergic antipsychotics. In general, serotonergic antidepressants can be added. Cognitive behavioral therapy should be offered to every patient with comorbid OCS. For future research multimodal longitudinal studies investigating the efficacy of interventions and aimed at the subjective level will be important.. HINTERGRUND: Komorbide Störungen treten bei Psychosen aus dem schizophrenen Formenkreis häufig auf und belasten die PatientInnen zusätzlich in der Lebensqualität, erschweren Therapie und Rehabilitationsprognose und können auch zur Suizidalität beitragen. Dazu gehört das Auftreten obsessiv-kompulsiver Syndrome (OCS) bzw. einer Zwangsstörung (OCD).. Was ist bekannt über Epidemiologie und Pathogenese, welche Konsequenzen ergeben sich für Diagnostik und Therapie?. Die Literatur wurde in Hinblick auf OCS bei psychotischen Störungen, beginnend im „at risk mental state“ (ARMS) über die Erstmanifestation bis zum chronischen Verlauf evaluiert. Besondere Schwerpunkte lagen auf pharmakologischen und psychotherapeutischen Konsequenzen.. Obsessiv-kompulsive Syndrome treten beginnend mit dem ARMS deutlich häufiger auf als in der Allgemeinbevölkerung. Die Prävalenz ist bei Erstmanifestation noch höher und im chronischen Verlauf sind ca. 30 % der PatientInnen betroffen. Die Diagnose einer komorbiden OCD wird im chronischen Verlauf bei 12 % der PatientInnen gestellt. In der Pathogenese müssen genetische Disposition im glutamatergen System, gemeinsame kortikale und subkortikale Strukturen und Funktionen, pharmakologische Einflüsse und psychosoziale Stressoren bedacht werden.. Wenn eine Induktion oder Verstärkung der OCS durch Antipsychotika wie Clozapin vorliegt, sollte als kausale Therapie eine Clozapin-Dosisreduktion angestrebt werden. Dies kann durch Kombination z. B. mit dopaminergen Antipsychotika versucht werden. Allgemein können serotonerge Antidepressiva augmentiert werden. In jedem Fall komorbider OCS bei Psychose soll kognitive Verhaltenstherapie angewandt werden. Für die Forschung werden Studien sinnvoll sein, die an der subjektiven Ebene ansetzen und engmaschig longitudinal Verläufe und Therapieeffekte darstellen.

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Humans; Obsessive-Compulsive Disorder; Psychotic Disorders; Quality of Life

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

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

Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates.. We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons.. One hundred twocountries were included, from Europe (. Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

Topics: Antipsychotic Agents; Australia; Clozapine; Humans; Neutropenia; Psychotic Disorders

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

We present a rare case of Acute Interstitial Nephritis (AIN) that occurred following a re-trial of clozapine in a 56-year-old lady with schizoaffective disorder. On initial trial of clozapine, this patient felt generally unwell with respiratory symptoms. Her inflammatory markers were raised and her renal function showed a mild, transient deterioration which normalised on the day of cessation of clozapine. Two years later, clozapine was re-trialled due the refractory nature of her psychiatric symptoms. She subsequently developed renal failure and AIN was confirmed by renal biopsy. Renal function improved after cessation of clozapine; however, she never fully regained normal renal function.

Topics: Clozapine; Female; Humans; Male; Middle Aged; Nephritis, Interstitial; Psychotic Disorders

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

Aggression is a major problem within psychiatry. During the recent years, a lot of research has been done, but many clinical decisions are still not evidence-based.. This article describes three studies of the thesis 'Aggression in Psychiatry'. The overarching goal was to contribute to the current knowledge on aggression with clinically relevant results. The three studies described in this article are focused on psychotic disorders.. The first study is a survival analysis with data from a 6-year follow-up study. The second study is focused on associations between aggression and clinical factors and the effect of antipsychotics on aggression in first episode psychosis patients. The third study is a meta-analysis focused on the effectiveness of typical versus atypical antipsychotics on aggression.. The yearly incidence of aggression in patients with psychotic disorders is around 2%. Patients with symptoms such as impulsivity, but also childhood trauma are at risk for aggression. Amisulpride appears effective against aggression during the first weeks of treatment. In patients with more persistent aggression, clozapine is most effective.. Aggression is complex and heterogeneous. More research is needed, but with the findings of these three studies, we contribute to the current knowledge of aggression and treatment options.

Topics: Aggression; Antipsychotic Agents; Clozapine; Follow-Up Studies; Humans; Psychotic Disorders

Objectives Individuals with first-episode psychosis (FEP) are poorly represented in clinical trials leading to drug approval. As a result, there is a relative paucity of empirical data to guide the psychopharmacological treatment of these youths. This article provides a synthesis of this literature, informed by the authors' clinical experience in treating FEP over the past 25 years. Methods This selective review of the literature focuses on the psychopharmacological treatment of FEP and includes both randomized trials and observational studies. It is organized around the following themes for FEP: response and remission rates; relapse rates; specifics regarding susceptibility to adverse events; comparisons of efficacy, safety and relapse prevention among various molecules and dosage forms; recommendations for duration of treatment; approach to treatment resistance; and use of clozapine. For each of these themes, research data are interpreted and supplemented by commentary based on the authors' clinical experience, with a strong focus on the individual's recovery. Results Symptom remission is achieved in approximately 75% of individuals during the initial treatment of a FEP, its maintenance being a very strong predictor of functional recovery. The rate of psychotic relapse during the three years following a FEP is about 60%, the problem of adherence to treatment being the main cause of these relapses. The FEP population is distinguished by a greater propensity for adverse events, including weight gain and extrapyramidal reactions. With the exception of treatment-resistant FEP, no clear difference has been demonstrated in the efficacy of the various molecules, but they do differ in their adverse events profile and formulations. As such, the use of long-acting injectable antipsychotics (LAIs) is superior to oral agents in preventing relapse. While the guidelines recommend continued treatment for 18 months after remission is achieved, these recommendations are based on empirical data that are still unclear, necessitating the use of a shared-decision approach with the patient and his/her family. In the group of people who do not achieve a satisfactory response after two trials of antipsychotics, clozapine is effective in up to 80% of people. Conclusions The FEP population is characterized by a high response rate, relapses frequently related to non-adherence to treatment, and increased susceptibility to adverse events. Tailoring pharmacological treatment for FEP

Topics: Adolescent; Antipsychotic Agents; Clozapine; Female; Humans; Male; Psychopharmacology; Psychotic Disorders; Recurrence

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Topics: Animals; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperprolactinemia; Metabolic Syndrome; Psychotic Disorders; Risk Factors

Disturbed eating behaviours have been widely reported in psychotic disorders since the early 19th century. There is also evidence that antipsychotic (AP) treatment may induce binge eating or other related compulsive eating behaviours. It is therefore possible that abnormal eating patterns may contribute to the significant weight gain and other metabolic disturbances observed in patients with psychosis. In this scoping review, we aimed to explore the underlying psychopathological and neurobiological mechanisms of disrupted eating behaviours in psychosis spectrum disorders and the role of APs in this relationship. A systematic search identified 35 studies that met our eligibility criteria and were included in our qualitative synthesis. Synthesizing evidence from self-report questionnaires and food surveys, we found that patients with psychosis exhibit increased appetite and craving for fatty food, as well as increased caloric intake and snacking, which may be associated with increased disinhibition. Limited evidence from neuroimaging studies suggested that AP-naïve first episode patients exhibit similar neural processing of food to healthy controls, while chronic AP exposure may lead to decreased activity in satiety areas and increased activity in areas associated with reward anticipation. Overall, this review supports the notion that AP use can lead to disturbed eating patterns in patients, which may contribute to AP-induced weight gain. However, intrinsic illness-related effects on eating behaviors remain less well elucidated, and many confounding factors as well as variability in study designs limits interpretation of existing literature in this field and precludes firm conclusions from being made.

Topics: Antipsychotic Agents; Appetite; Brain; Bulimia; Case-Control Studies; Clozapine; Craving; Diet Surveys; Energy Intake; Feeding Behavior; Food Preferences; Humans; Hunger; Neuroimaging; Olanzapine; Psychotic Disorders; Reward; Satiation; Self Report; Snacks; Weight Gain

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

Clozapine is an alternative antipsychotic medication used to control symptoms of schizophrenia and to reduce risks of suicidal behavior in patients who did not adequately respond to standard medication. Due to severe side effects including cardiomyopathy and myocarditis its clinical use is limited.. A 31-year-old man of east European descent presented to the emergency medical department with fatigue, shortness of breath and chest pain. Due to a schizoaffective disorder he was treated with clozapine and lithium. Echocardiography revealed severely impaired left ventricular systolic function. After exclusion of coronary artery disease by coronary angiography an endomyocardial biopsy was performed according to the guidelines. This confirmed the clinically suspected toxic cardiomyopathy. Therefore, antipsychotic treatment was immediately changed and state of the art heart failure medication was started resulting in a clear improvement of left ventricular function.. In patients treated with clozapine or lithium and clinical signs of heart failure, toxic cardiomyopathy should be considered.

Topics: Adult; Antipsychotic Agents; Biopsy; Cardiomyopathies; Chest Pain; Clozapine; Dyspnea; Echocardiography; Fatigue; Heart; Humans; Male; Myocardium; Psychotic Disorders; Treatment Outcome

While the majority of individuals with a first episode of psychosis (FEP) achieve symptomatic remission with the appropriate treatment, there is a small but significant proportion who do not achieve remission of symptoms despite adequate treatment with at least two antipsychotic medications (termed treatment resistance). Clozapine is indicated in individuals who fulfil the criteria for treatment-resistant schizophrenia, however, despite it being the most effective antipsychotic medication, there can be delays in the commencement of clozapine in eligible patients.. A systematic search was performed to identify articles reporting either the time taken to commence clozapine (or delays) in eligible individuals or articles reporting barriers to the commencement of clozapine. The initial search generated 5588 articles and of these, 18 were eligible.. 13 studies described delays in commencing clozapine and five studies reported on the barriers to the commencement of clozapine. The duration of delay from when an individual was deemed eligible for clozapine treatment to the time of clozapine commencement ranged from 19.3 weeks to 5.5 years. In addition, the duration of illness prior to clozapine initiation ranged from 1.1 to 9.7 years. It was found that some clinicians were more inclined to prescribe antipsychotic polypharmacy or doses higher than recommended than to prescribe clozapine.. Delays in commencing clozapine have been consistently demonstrated. Early intervention for psychosis services are the ideal settings to identify individuals with persistent positive psychotic symptoms and commence clozapine if indicated.

Topics: Antipsychotic Agents; Clozapine; Health Services Accessibility; Humans; Psychotic Disorders; Time-to-Treatment

Electroconvulsive therapy is an established treatment for symptoms of psychosis and is currently recommended for use in patients who are experiencing an acute exacerbation of positive symptoms or who have had catatonia. There is also evidence to suggest that electroconvulsive therapy can be a safe, effective treatment in first episode psychosis, such as schizophrenia spectrum disorders, particularly in treatment-resistant patients. Other forms of neuromodulation (transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, deep brain stimulation) have less of an evidence base to support their use and are not formally indicated for the treatment of psychosis.

Topics: Adolescent Psychiatry; Antipsychotic Agents; Clozapine; Deep Brain Stimulation; Electroconvulsive Therapy; Humans; Psychotic Disorders; Transcranial Direct Current Stimulation

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

Psychosis is a common problem for people treated for Parkinson's disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required.. This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine. Treatment with second generation antipsychotic drugs and cholinesterase inhibitors are also reviewed.. Clozapine and pimavanserin have proven efficacy for Parkinson's disease psychosis (PDP), without impairing motor function. In clozapine's favor are its antipsychotic benefits seen within 1 week and its effectiveness in improving tremor in PD. However, this is counterbalanced by the need for blood monitoring, despite the extremely low doses used, and sedation. Pimanvanserin is well tolerated, without sedation or other significant side effects. Its onset of benefit, however takes 4-6 weeks. While quetiapine is also frequently used, its efficacy is not supported by double blinded, randomized trials.

Topics: Antipsychotic Agents; Clozapine; Dopamine; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Urea

To summarize and evaluate the existing literature regarding medications to treat Parkinson's disease (PD) psychosis.. MEDLINE (1946 to March 2017), EMBASE (1980 to March 2017), CINAHL (1982 to March 2017), and PsychInfo (1887 to March 2017) were searched using the following terms: Parkinson disease, Parkinson's disease, psychotic disorders, psychosis, delusions, and hallucinations.. The search was limited to randomized controlled trials (RCTs) reporting human outcomes. Data extracted included the following: study design, population, setting, intervention, control, outcomes related to psychosis and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of 235 studies were included; 11 articles reported comparisons between active drug and placebo, whereas 5 compared clozapine and an active comparator. Placebo-controlled trials demonstrated benefit for clozapine (n = 2) and pimavanserin (n = 2), with no firm benefits observed for quetiapine (n = 4) or olanzapine (n = 3). Comparative studies demonstrated improved efficacy in symptom scores when clozapine or comparator agent (n = 2, quetiapine; n = 1, olanzapine; n = 1, risperidone; and n = 1, ziprasidone) was assessed alone. However, no comparator data suggest that one agent is better than another, and none are yet available for pimavanserin. Overall risk of bias across all studies was moderate to high.. Despite lack of rigor in study designs, published data to date suggest that clozapine and pimavanserin should be considered drugs of choice to treat PD psychosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Evidence-Based Medicine; Humans; Olanzapine; Parkinson Disease; Piperazines; Piperidines; Practice Guidelines as Topic; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Thiazoles; Urea

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

Topics: Antipsychotic Agents; Autistic Disorder; Child; Child Behavior Disorders; Clozapine; Humans; Male; Psychotic Disorders; Treatment Outcome

Research and development of early intervention (EI) services for first-episode psychosis have brought much-needed transformation of service delivery for this serious mental disorder to many jurisdictions. The effectiveness of the EI model of service delivery is contingent on timely access to all evidence-informed treatment interventions, including a rational approach to pharmacotherapy. In this perspective paper, we present a brief review of the well-established effectiveness of clozapine in patients who clearly show lack of response to regular antipsychotic therapy. We concentrate, in particular, on the need to identify eligibility for clozapine therapy very early on following failure of treatment on 2 antipsychotic medications. We suggest that attention to the low use of clozapine in the very early phase of treatment of psychosis may be of particular value, as the response to clozapine at this stage is likely to produce larger benefits in other domains of outcomes because of the greater retention of patients' personal and social agency.

Topics: Antipsychotic Agents; Canada; Clozapine; Humans; Psychotic Disorders

The objective of this study was to perform a systematic review and meta-analysis of studies reporting the impact of clozapine on hospital use in people with a psychotic illness.. PubMed, EMBASE, PsycINFO and the Cochrane Schizophrenia Group Trials Register were systematically searched from inception to 12 October 2016. We included all trials and observational studies, except case reports.. Thirty-seven studies were included. Clozapine significantly reduced the proportion of people hospitalised compared to control medicines (RR = 0.74; 95% CI: 0.69-0.80, P < 0.001, 22 studies, n = 44 718). There were significantly fewer bed days after clozapine treatment compared to before clozapine treatment in both controlled (MD = -34.41 days; 95% CI: -68.22 to -0.60 days, P = 0.046, n = 162) and uncontrolled studies (MD = -52.86 days; 95% CI: -79.86 days to -25.86 days, P < 0.001, n = 2917). Clozapine and control medicines had a similar time to rehospitalisation (-19.90 days; 95% CI: -62.42 to 22.63 days, P = 0.36).. Clozapine treatment reduced the number of people hospitalised and the number of bed days after treatment compared with before treatment. Clozapine has the potential to reduce acute hospital use among people with treatment refractory schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Female; Hospitalization; Humans; Male; Observational Studies as Topic; Psychotic Disorders; Randomized Controlled Trials as Topic; Treatment Outcome

Electronic cigarettes are becoming increasingly popular and therefore psychiatrists are being confronted more and more frequently by this relatively new phenomenon. We discuss the case of a patient who switched from traditional cigarettes to electronic cigarettes and thereupon had a significant increase in the clozapine serum level. The increased level led to considerable side-effects and, as a result, the patients clozapine dosage had to be reduced. In theory, a rise in the clozapine serum level is to be expected after such a switch. However, since electronic cigarettes have not been on the market for very long, psychiatrists need to be aware of the risks and dangers that can arise as a result of exceptionally high clozapine levels.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Electronic Nicotine Delivery Systems; Humans; Male; Middle Aged; Psychotic Disorders; Smoking; Smoking Cessation

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

Topics: Antipsychotic Agents; Clozapine; Heart; Humans; Male; Myocarditis; Psychotic Disorders; Young Adult

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 is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life-threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (≤2 months) myocarditis ranges from <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Cardiomyopathies; Cardiotoxicity; Clozapine; Drug Monitoring; Humans; Psychotic Disorders

Psychotic symptoms are present in up to 50% of patients with Parkinson's disease. These symptoms have detrimental effects on patients' and caregivers' quality of life and may predict mortality. The pathogenesis of psychotic symptoms in Parkinson's disease is complex, but the use of dopaminergic medications is one of the risk factors. The treatment of psychotic symptoms in Parkinson's disease is complicated due to the ability of antipsychotic medications to worsen motor symptoms. The efficacy of clozapine in the treatment of psychosis in patients with Parkinson's disease has been confirmed in several clinical trials; however, the adverse effects and the necessity of blood count monitoring are the reasons why the use of this drug is challenging. The studies on safety and efficacy of other antipsychotics conflicting results. The use of antipsychotics in these patients is also associated with increased mortality. Psychotic symptoms in Parkinson's disease per se are also proven predictors of mortality. Thus it is necessary to treat psychotic symptoms but the choice of an antipsychotic should be based on careful risk/benefit assessment. Pimavanserin as a novel therapeutic option with more favorable adverse effects profile is now available for this indication, but careful postmarketing monitoring is necessary to establish the true picture of this drug's long-term safety and efficacy.

Topics: Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Psychotic Disorders; Quality of Life; Risk Factors; Treatment Outcome

Psychosis in Parkinson's disease (PD) is one of the greatest determinants of nursing home placement and caregiver stress. Traditionally associated with medications with dopaminergic effect, it has now been linked to other medications and other stressors e.g. systemic illnesses. The development of hallucinations in a PD patient can herald the onset of dementia and usually predicts increased mortality risk. Medication reduction in PD psychosis usually reduces the symptoms; however, this comes at the cost of worsening motor function. If gradually decreasing the patient's medications does not resolve the psychosis, the treatment of choice is an atypical antipychotic. Though only clozapine has level A recommendation for this indication, other atypicals like quetiapine continue to get used for this purpose on account of the logistics involved with clozapine use. Cholinesterase inhibitors are also increasingly being used for PD psychosis on account of the association with dementia. The treatment of PD psychosis is an unmet need in PD management and search for suitable agents constitutes an active area of research in PD.

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Humans; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate

Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease (PD) patients treated with dopaminergic drugs, and is associated with high morbidity and mortality. It also correlates with depression and dementia, and can contribute to considerable caregiver stress and burnout. While symptoms can be relieved by decreasing doses or number of anti-PD medications, this may lead to an unacceptable worsening of motor function. When general medical or psychiatric conditions have been ruled out, and decreasing dopaminergic agents is not effective in treating psychosis, therapies include atypical antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is effective but is associated with a poor side-effect profile and the necessity for frequent blood draws. Clinicians prefer quetiapine for its theoretically better safety profile, although there is no evidence for efficacy in treating psychosis. All atypical antipsychotics are associated with increased mortality in this patient population. Cholinesterase inhibitors can ameliorate psychosis symptoms. The serotonin 5-HT

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Humans; Molecular Targeted Therapy; Neurotransmitter Agents; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Urea

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

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Administration Routes; Dyskinesia, Drug-Induced; Humans; Paliperidone Palmitate; Psychotic Disorders

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

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

Clozapine is the only licensed medication for treatment-resistant schizophrenia. The metabolism of clozapine is affected by multiple pharmacokinetic interactions, so the co-administration of adjunct medications can have a significant clinical effect. The anti- tuberculosis medication rifampicin is a potent inducer of the cytochrome P450 system and therefore can cause a reduction in the plasma concentration of clozapine. There is limited clinical evidence regarding co-administration of these medications; in particular there is a lack of data regarding the effect on plasma clozapine levels, which is the key factor determining clinical efficacy. This is clinically relevant given evidence of an increased risk of tuberculosis in patients with schizophrenia.. We present a case of a 28 year old British man with a diagnosis of schizoaffective disorder who presented with persistent psychotic symptoms. He developed a systemic inflammatory condition, diagnosed as tuberculosis, and was commenced on a six month course of treatment that included rifampicin. This case presents comprehensive data to illustrate the effect on clozapine plasma levels of a complete course of tuberculosis therapy.. This case report provides guidance to clinicians in managing drug interactions between clozapine and rifampicin to enable safe and effective treatment. The co-administration of these medications is likely to increase as the existing underuse of clozapine is recognised whilst the incidence of tuberculosis increases.

Topics: Adult; Antibiotics, Antitubercular; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Humans; Male; Psychotic Disorders; Rifampin; Treatment Outcome; Tuberculosis

Psychosis is three times more common in people with an intellectual disability than in those without an intellectual disability. A low intelligence quotient (IQ) is a defining characteristic for intellectual disability and a risk factor for poor outcome in psychosis. Clozapine is recommended for treatment-resistant psychosis. The effect of psychotropic medication can be different in people with intellectual disability; for example, they may be more prone to side effects. People with an intellectual disability and psychosis form a special subgroup and we wanted to examine if there is randomised controlled trial (RCT) data in this population to support the use of clozapine.. To determine the effects of clozapine for treating adults with a dual diagnosis of intellectual disability and psychosis.. We searched CENTRAL, Ovid MEDLINE, Embase and eight other databases up to December 2014. We also searched two trials registers, the Cochrane Schizophrenia Group's Register of Trials, and contacted the manufacturers of clozapine.. RCTs that assessed the effects of clozapine, at any dose, for treating adults (aged 18 years and over) with a dual diagnosis of intellectual disability and psychotic disorder, compared with placebo or another antipsychotic medication.. Three review authors independently screened all titles, abstracts and any relevant full-text reports against the inclusion criteria.. Of the 1224 titles and abstracts screened, we shortlisted 38 full-text articles, which we subsequently excluded as they did not meet the inclusion criteria. These studies were not RCTs. Consequently, no studies are included in this Cochrane review.. There are currently no RCTs that assess the efficacy and side effects of clozapine in people with intellectual disabilities and psychoses. Given the use of clozapine in this vulnerable population, there is an urgent need for a RCT of clozapine in people with a dual diagnosis of intellectual disability and psychosis to fill the evidence gap.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Intellectual Disability; Psychotic Disorders

Topics: Antipyretics; Body Weight; Carbohydrate Metabolism; Clozapine; Humans; Lipid Metabolism; Psychotic Disorders

Psychosis is a major psychiatric problem that often occurs at the interface of psychiatry and the neurological specialty of movement disorders. Psychotic syndromes are common in treated movement disorder patients, and almost all antipsychotic drugs produce movement disorders. There is little published data on psychosis in movement disorders aside from Parkinson's disease (PD).. In this review, we focus primarily on PD, in which about 30% of treated patients have visual hallucinations and 5-10% have paranoid delusions; dementia with Lewy bodies, a variant of PD in which dementia occurs early and psychotic symptoms are common; Huntington's disease (HD), an inherited disorder that causes behavioral problems, frequently including psychosis; and tardive dyskinesia (TD), a group of movement disorder syndromes caused by antipsychotic drugs. All articles were reviewed in each of the more common movement disorders and indexed in PubMed with keywords including psychosis, psychotic symptoms, antipsychotics, hallucinations and delusions.. Although there are no approved drugs for treating psychotic symptoms in any of the movement disorders, pimavanserin, a 5-HT2A inverse agonist, is thought likely to gain approval in 2015 for treating PD psychosis. We present evidence that clozapine is currently the drug of choice for treating psychosis in patients with parkinsonism; however, blood monitoring requirements make it difficult to use. The choice of treatment of hyperkinetic disorders such as HD and the TD disorders depends on the clinical scenario.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Movement Disorders; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

Insufficient treatment of psychosis often manifests as violent and aggressive behaviors that are dangerous to the patient and others, and that warrant treatment strategies which are not considered first-line, evidence-based practices. Such treatment strategies include both antipsychotic polypharmacy (simultaneous use of 2 antipsychotics) and high-dose antipsychotic monotherapy. Here we discuss the hypothesized neurobiological substrates of various types of violence and aggression, as well as providing arguments for the use of antipsychotic polypharmacy and high-dose monotherapy to target dysfunctional neurocircuitry in the subpopulation of patients that is treatment-resistant, violent, and aggressive. In this review, we focus primarily on the data supporting the use of second-generation, atypical antipsychotics both at high doses and in combination with other antipsychotics.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brain; Clozapine; Dibenzocycloheptenes; Drug Therapy, Combination; Heterocyclic Compounds, 4 or More Rings; Humans; Impulsive Behavior; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Polypharmacy; Psychotic Disorders; Quetiapine Fumarate; Receptors, Dopamine D2; Risperidone; Thiazoles; Violence

Parkinson's disease (PD) affects 10 million people worldwide. Half will develop psychosis, the majority experiencing hallucinations rather than delusions. Emergence of psychosis increases the likelihood of institutionalization and mortality. Where pharmacological treatment is warranted, options are limited. Most currently licensed atypical antipsychotics are ineffective or worsen motor symptoms in people with PD. This review of provides an overview of the current landscape of treatments and the opportunities in emerging research. Clozapine is the only licensed antipsychotic with proven efficacy, although the associated side effects limit its use. With recent advances in understanding the role of serotonin, rational drug design approaches have delivered a novel pharmacological treatment with recently proven efficacy in clinical trials of people with PD and psychosis. Pimavanserin represents an important addition to treatment.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Design; Humans; Parkinson Disease; Psychotic Disorders; Serotonin

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

Tardive syndromes (TS) arise from long term exposure to dopamine receptor blocking agents. Clozapine has been considered to have low risk of causing new onset TS and is considered as a treatment option in patients with TS.. This review evaluates the usefulness of clozapine in patients with TS and occasional reports of clozapine causing TS.. Electronic searches were carried out using the search engines of PUBMED, Science direct and Google Scholar databases. All reports describing use of clozapine in management of TS, monitoring of TS while on clozapine and onset of TS after initiation of clozapine were identified.. Fifteen trials and 28 case series/case reports describe the use of clozapine in TS. Most of these reports show that clozapine is useful in patients with TS, in the dose range of 200-300 mg/day and the beneficial effect is seen within 4-12 weeks of initiation. One case series and two case reports described clozapine withdrawal emergent dyskinesias suggesting a masking role of clozapine. One trial, three case series and two case reports describe beneficial effects of clozapine on long standing neurological syndromes. There is relatively less literature (2 trials and 15 case series/reports) describing the emergence of TS with clozapine.. Evidence of beneficial effects of clozapine in TS is greater than its role in causation/worsening of TS. Hence, clozapine should be considered in symptomatic patients who develop TS while receiving other antipsychotics. Further research on mechanism of TS and clozapine effect on TS is required.

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

To review the literature to examine the use of clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with clozapine.. MEDLINE was searched in December 2010 using the following keywords: 'clozapine levels', 'clozapine and toxicity', 'clozapine and death', 'clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual.. The literature reported significant variation in clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given clozapine level. The lowest effective clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels.. The exact range of clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable.

Topics: Antipsychotic Agents; Autopsy; Cause of Death; Clozapine; Humans; Psychotic Disorders

Weight gain as a result of atypical anti-psychotic treatment is a common issue with different atypical anti-psychotic treatments causing differing magnitudes of weight gain. Although differing amounts of weight gain result from different atypical agents little is known about the temporal course of weight gain in anti-psychotic treatment. Specifically is the time course of weight gain comparable across different agents. Therefore this article reviews the temporal course of weight gain for three common atypical anti-psychotics namely; clozapine, olanzapine and risperidone. It is evident that all three of these agents exhibit similar although at distinct magnitudes temporal courses of weight gain. That is an initial rapid increase from baseline to 3 months (stage 1), a steady increase from 3 months to 18 months (stage 2) and a plateau after this point (stage 3) with continued anti-psychotic treatment. It is postulated that each of these stages of weight gain result from distinct neural mechanisms. The hypothesized neural correlates for each stage of weight gain are reviewed and discussed. The article concludes with recommendations for future research.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Nervous System Physiological Phenomena; Olanzapine; Psychotic Disorders; Risperidone; Time Factors; Weight Gain

Psychosis, a frequent complication in Parkinson's disease (PD), contributes significantly to morbidity, mortality, nursing-home placement and quality of life. Medication side effects, issues of trial design and negative outcomes have limited clinical advances of new treatments for PD psychosis. Evidence-based medicine maintains clozapine as the most effective antipsychotic in PD without motor worsening, despite risk of agranulocytosis. Safe, effective treatments that improve psychosis without exacerbating parkinsonism are urgently needed.. This article reviews the: i) phenomenology of PD psychosis, ii) pharmacological rationale for antipsychotics in PD; iii) clinical trials of antipsychotics in PD; iv) novel research strategies such as neuroimaging, genetics and animal models; and v) associated challenges in studying and treating PD psychosis. Preparation of this review included an extensive literature search using PubMed.. Management of PD psychosis is complex. Challenges pertaining to study design, rating scales, subject recruitment and completion have limited PD psychosis treatment trials. Novel research strategies focus on nondopaminergic systems and incorporate neuroimaging, genetic associations and animal models. These strategies also have challenges but have the potential to enhance our understanding of PD psychosis and advance the development of agents that can ultimately be tested in well-designed, randomized, controlled trials.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Psychotic Disorders; Randomized Controlled Trials as Topic

Parkinson's disease (PD) patients often develop psychotic symptoms that severely affect quality of life and limit the use of medications to ameliorate motor symptoms. Psychotic symptoms are a major cause for nursing home placement. While these symptoms do not always require treatment, they often do but antipsychotic drugs all share the common pharmacological mechanism of blocking dopamine D2 receptors which may worsen motor problems in this very vulnerable population. Double blind, placebo controlled trials (DBPCT) have shown that clozapine is effective at controlling the psychotic symptoms at doses far below those used in schizophrenia, without worsening motor function, even improving tremor. DBPCT have demonstrated that olanzapine worsens motor function without improving psychosis. Quetiapine has been shown in DBPCT to be free of motor side effects in PD patients but not effective, whereas many open label studies have indicated that quetiapine is effective. The other atypical have been the subjects of conflicting open label reports. The effects of the atypicals in PD psychosis is reviewed.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Evidence-Based Medicine; Humans; Olanzapine; Parkinson Disease; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic

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

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

The effectiveness and tolerability of switching patients' therapy from brand-name to generic clozapine are reviewed.. Clozapine is the most effective treatment for patients with refractory psychotic disorders and is also effective for reducing suicidal and violent behavior in this same population. Generic versions of clozapine are widely used. However, possible differences in pharmacokinetic profiles between branded and generic clozapine, and the potential risks of medication changes in severely ill but stable patients, may result in apprehension about converting from branded to generic clozapine. Articles, abstracts, and clinical presentations that compared clinical outcomes between Clozaril (Novartis Pharmaceuticals, East Hanover, NJ) and generic forms of clozapine in patients with primary psychotic disorders, bipolar disorder, or related conditions were identified via a computerized search of the medical literature. Thirteen relevant reports, mostly uncontrolled observational studies or chart reviews, described the effects of switching from brand-name to generic clozapine in 966 patients. The majority of patients tolerated conversion without worsening of symptoms or adverse effects, increased intensive service utilization, or medication adjustment. Clinical deterioration was described in a case review and in one randomized, controlled study.. Available literature supports the effectiveness and safety of generic clozapine formulations in patients who previously were stable during treatment with brand-name clozapine. The risk of poor outcome after conversion to a generic clozapine formulation appears to be low but difficult to predict. Patients should be closely monitored during the first one to three months after conversion from one formulation to another.

Topics: Antipsychotic Agents; Clozapine; Drugs, Generic; Humans; Psychotic Disorders; Therapeutic Equivalency

To examine the pharmacokinetic implications and potential clinical effects of tobacco smoking cessation in patients on stable clozapine or olanzapine treatment.. A literature search of MEDLINE (1950-November 2009) and EMBASE (1980-November 2009) was conducted using the search terms smoking, tobacco, cigarette, cannabis, smoking cessation, cytochrome P450, antipsychotic, clozapine, and olanzapine. In addition, reference lists from publications identified were searched manually.. English-language articles and human studies were identified, yielding 111 returns. Articles that reported clinical outcomes following smoking cessation were selected. Pharmacokinetic data for these drugs were reviewed and articles that provided relevant background information were also included.. Pharmacokinetic studies have demonstrated more rapid clearance of olanzapine and lower clozapine and norclozapine (desmethylclozapine) concentrations in smokers compared to nonsmokers. These studies also found that smokers require higher doses of these agents than nonsmokers. There are case reports of adverse clinical outcomes following smoking cessation in patients being treated with olanzapine and clozapine. Reports that included serum concentrations consistently found elevations following smoking cessation, and dosage reductions of 30-40% were required to achieve pre-cessation concentrations. Worsening psychiatric symptoms, somnolence, hypersalivation, extreme fatigue, extrapyramidal effects, and seizures have all been reported following smoking cessation in this patient group.. Pharmacists need to be aware of potential risks associated with smoking cessation in patients stabilized on clozapine or olanzapine. Toxicity as a result of recent smoking reduction or cessation may be a reason for hospital admission. For hospitalized patients, pharmacists should obtain information concerning smoking status, including cessation attempts. Nonspecific signs and symptoms of elevated clozapine or olanzapine concentrations should be considered in relation to clinical status while the patient is hospitalized. Measurement of baseline serum clozapine concentrations and/or empiric dosage adjustment in patients expected to have a prolonged hospital stay with forced smoking cessation may be appropriate.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia, Paranoid; Smoking Cessation

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

Women who are pregnant and who have a history of psychosis are commonly managed with antipsychotic medications. The evidence regarding the use of antipsychotics in pregnancy has been insufficient to provide adequate support for this practice and is a concern for clinicians and women alike. This review presents literature surrounding the use of antipsychotic medications in pregnancy, providing an overview of the historical and contemporary perspectives which influence clinicians prescribing practices. Data were sourced from Medline, CINAHL, PsycINFo, using the terms antipsychotics with pregnancy and psychosis or schizophrenia. This was expanded to include the most common atypical antipsychotics: olanzapine, risperidone, clozapine, quetiapine, ziprasidone and aripiprazole. Literature was found reporting the use of antipsychotic medications in pregnancy since the introduction of antipsychotics in the 1950s, comprising mainly of authors' reviews of the literature, case studies, retrospective reports, drug company registries and more recently a prospective comparative study. This review identifies that the literature provides no clear answer for clinicians as to the risk associated with the use of antipsychotics in pregnancy. To this effect, recently in Australia, the National Register of Antipsychotic Medications in Pregnancy was established to prospectively collect information regarding outcomes for mother and baby, when antipsychotic medications have been used during pregnancy.

Topics: Abnormalities, Drug-Induced; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes, Gestational; Dibenzothiazepines; Female; Humans; Infant, Newborn; Olanzapine; Piperazines; Pregnancy; Pregnancy Complications; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles

Treatment with clozapine can affect the heart, leading to serious complications such as myocarditis and cardiomyopathy. When in their early stages both illnesses are difficult to diagnose; this can have serious consequences. Recent analyses of clozapine data suggest that particularly myocarditis is possibly more common than has been assumed hitherto.. To determine the frequency of these complications and to find out what diagnostic tests are available and whether it is necessary or possible to adjust current guidelines on these complications.. The relevant literature was consulted via PubMed, Embase Psychiatry and Psycinfo on the basis of the keywords 'clozapine' and 'myocarditis', 'cardiomyopathy' and 'heart failure'.. Studies showed that the incidence of myocarditis varied from 0.015 to 1.3%. Cardiomyopathy was the subject of fewer studies, one study reported an incidence of 0.022%. More than 50% of the cases of myocarditis developed during the first few weeks of treatment, the average time being about 15 days. For an early diagnosis it is important to monitor the patient's symptoms carefully, especially during the first four weeks following the start of medication. Monitoring should include laboratory tests and electrocardiography. Echocardiography and MRI can be useful additions to the diagnostic process.. Early diagnosis of myocarditis is important because it is a serious condition. Timely recognition of subclinical myocarditis could possibly prevent later complications such as cardiomyopathy. Clinical guidelines are proposed on the basis of the literature.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Female; Humans; Male; Middle Aged; Myocarditis; Prevalence; Psychotic Disorders

Metabolic syndrome and cardiovascular diseases are important causes of morbidity and mortality among patients with severe mental illnesses. Atypical or second-generation antipsychotics (SGAs) are associated with obesity and other components of metabolic syndrome, particularly abnormal glucose and lipid metabolism. This review aims to provide a summary of recent evidence on metabolic risks associated with SGAs, current recommendations for metabolic monitoring, and efficacy of treatment options currently available.. Studies have identified younger, antipsychotic-naive patients with first-episode psychosis as a population vulnerable to adverse metabolic effects from SGAs. These patients gained more weight and developed evident lipid and glucose abnormalities as soon as 8-12 weeks after treatment initiation. Findings are more striking among children and adolescents. The differential effects of various SGAs are well described, with clozapine and olanzapine associated with the highest metabolic risk. In addition to behavioral therapy, emerging data suggest that pharmacological therapy, most notably metformin, is efficacious in the treatment and possibly prevention of SGA-associated metabolic derangements.. More data have become available on the burden from metabolic complications associated with SGAs. New and effective treatment options are required in the near future to improve cardiovascular health in this susceptible population.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Clozapine; Humans; Metabolic Syndrome; Metformin; Obesity; Olanzapine; Practice Guidelines as Topic; Psychotic Disorders; Severity of Illness Index; Weight Gain

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

Hallucinations and psychosis are common in patients with Parkinson's disease (PD), with reported prevalences of up to 48% and 80%, respectively. However, few randomized, double-blind, placebo-controlled trials evaluating the treatment options have appeared in the literature. The studies that have been published were complicated by lack of agreement on the diagnosis of psychosis in PD, poor completion rates, mixed populations that included dementia, and other issues. Several reviews, guidelines, and consensus statements have sought to establish standards for treating these symptoms of PD. In 2006, the American Academy of Neurology (AAN) published a practice guideline (based on articles published up to 2004) for management of depression, psychosis, and dementia in patients with PD. Since then, a number of relevant studies have been published.. The purpose of this article was to review data that have appeared in the literature since publication of the AAN guideline regarding the management of hallucinations and psychosis in PD.. A literature search of the PubMed, CINAHL, and PsychInfo databases was conducted for human studies published in English from January 2004 to June 2010. All clinical studies were included except case reports and case series. Studies with <20 participants were also excluded. Search terms included psychosis, hallucinosis, hallucination, delusion, Parkinson, atypical antipsychotic, neuroleptic, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone.. Thirteen studies were included in the review: 3 studies of clozapine, 7 studies of quetiapine, 2 head-to-head trials comparing quetiapine and clozapine, and 1 noncomparative trial of clozapine or quetiapine interventions. Most of the studies included participants with a mean age in the early to mid 70s and a mean duration of PD typically >10 years.. Results of the identified studies suggested that patients with PD might benefit from long-term clozapine therapy. Results of the quetiapine studies were conflicting. However, no statistically significant difference in effectiveness was found between quetiapine and clozapine in comparative trials. The significance of the differences in treatment responses between patients with dementia and those without dementia remains unclear, and it was not possible to draw conclusions for or against other atypical antipsychotics because of insufficient evidence. Further studies are needed to address the methodologic issues in the current trials and to assess safety issues in larger cohorts.

Topics: Aged; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Comorbidity; Delusions; Dementia; Depression; Dibenzothiazepines; Disease Progression; Guidelines as Topic; Hallucinations; Humans; Middle Aged; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Research Report; Risperidone

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

Akathisa is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics. This review examines the recent literature relevant to second-generation antipsychotic (SGA)-induced akathisia.. Recent studies using large databases clearly indicate that extrapyramidal side effects, in particular akathisia, do occur with the SGAs, although the frequency is not as high as with the conventional antipsychotics. Risk factors include use of high doses, high potency SGAs, or combinations of SGAs with other psychotropic drugs, bipolar depression, palliative care settings, and comorbid substance abuse in psychosis. The dopamine hypothesis remains plausible for understanding the pathophysiology of akathisia. There is emerging evidence that mirtazapine may be useful in the treatment of acute akathisia.. Even though akathisia is less prevalent with SGAs than with the first-generation drugs, it remains clinically important and all clinicians should be conversant with its recognition and management.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Prevalence; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk Factors; Risperidone; Sulpiride; Thiazoles

In patients with a psychotic disorder, substance abuse is a major problem. Substance abuse is associated with changes in dopaminergic neurotransmission of dopamine D1 and D2 receptors. Differences in efficacy between antipsychotics on substance abuse could be explained by differences in D2 receptor occupancy rate, differences in dissociation rate of the dopamine D2 receptor and differences in D1/D2 receptor occupancy ratio. Since clozapine and risperidone show a maximal difference in these properties, we review the effect of these antipsychotics on substance abuse. The results suggest a superior effect of clozapine for the long-term treatment of substance abuse. This could support the hypothesis that low occupancy of the dopamine D2 receptor, a high dissociation rate and a high D1/D2 receptor ratio is related to efficacy on substance abuse. The results of this review suggest that clozapine could be considered as the medication of first choice in treating patients with substance use disorder.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Receptors, Dopamine D1; Receptors, Dopamine D2; Risperidone; Substance-Related Disorders

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

The management of patients with first-episode psychosis (FEP) is a difficult, but challenging task. Early and efficient treatment may influence long-term clinical outcome. Atypical antipsychotics (A-AP) are commonly prescribed in this population, but few data exist to establish their appropriate usage in the management of FEP. Our purpose is to review the literature and to summarize current data on the prescription of A-AP in FEP.. Studies assessing efficacy or safety of A-AP in FEP were identified by searches in Medline (up to April 2006). The following nine drugs were considered for this review: clozapine, olanzapine, risperidone, amisulpride, aripiprazole, quetiapine, ziprasidone, zotepine, and sertindole.. Only four A-AP (clozapine, quetiapine, olanzapine, and risperidone) were evaluated as treatment of FEP. All of them show the same efficacy as conventional antipsychotics (C-AP). Clozapine has no benefit over C-AP in the treatment of naive patients. It entails a high rate of treatment discontinuation because of the need for regular white blood cell monitoring explained by the risk of agranulocytosis. Hence, clozapine may not be a first-line treatment of FEP. Tolerance to quetiapine and olanzapine is better than C-AP regarding extrapyramidal side effects, but weight gain induced by these two A-AP may be very disabling in a young population. Considering results from head-to-head comparative studies, olanzapine may be more effective than risperidone when an affective component is associated with the FEP symptomatology, but more data are needed to demonstrate this point. Risperidone is a relatively well-tolerated compound when it is prescribed at doses lower than 4 mg/d. It is the only A-AP that showed greater efficacy than C-AP to prevent relapse in patients with FEP. Unfortunately, information regarding the preventive efficacy of the other A-AP are lacking.. Further studies, particularly longer-term studies, are needed to explore the impact of A-AP prescription in FEP on the course of psychotic disorders. The common use of A-AP as treatment of FEP is justified by a relatively better tolerance compared to C-AP, and by the hypothesis-not demonstrated-of a better effect on long-term outcome.

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

Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly effective atypical antipsychotic in schizophrenic patients. Although this adverse reaction has been well known for almost 30 years, only few genetically based determinants can be identified to date. Furthermore, owing to rare occurrence, specific clinical course and complexity of pathomechanisms of antipsychotic-induced agranulocytosis, only a few of the findings met the criteria of replication. The most promising susceptibility genes for CiA include genes involved in the human leukocyte antigen system and in specific metabolizing enzyme systems. However, complex idiosyncratic drug reactions such as CiA are considered to be determined by multiple, possibly interacting genetic variations, rather than by a single causative variant.

Topics: Agranulocytosis; Animals; Clozapine; Genetic Linkage; Genetic Variation; Humans; Psychotic Disorders

Treatment resistance is considered a challenging problem of antipsychotic pharmacotherapy. In such cases, combination approaches are commonly used, for instance the add-on of aripiprazole to clozapine. This review aims at giving an overview of the present knowledge on this strategy. We performed a keyword-based screening of databases (including November 2007) and evaluated the data in a systematic manner. The courses of 94 patients were reported in 11 publications. At a mean dosage of 20.5 mg/day, aripiprazole achieved clinical improvement of psychotic symptoms and facilitated a dose reduction of clozapine from 476.7 to 425.1 mg/day. In parallel, clozapine serum levels decreased from 611 to 523 ng/ml. No pharmacokinetic interactions were reported, and clozapine-induced side effects ameliorated. However, single cases of extrapyramidal side effects occurred. The combination of clozapine and aripiprazole follows a neurobiological rationale and appears to be effective and tolerable. The results of placebo-controlled trials might allow further insight into the benefits and risks of this strategy.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Humans; Piperazines; Psychotic Disorders; Quinolones; Randomized Controlled Trials as Topic; Weight Loss

Psychosis due to dopamimetic treatment is a difficult problem in patients with Parkinson's disease (PD). The aim of this structured review with meta-analysis was to evaluate which neuroleptic drugs can efficiently be used to treat drug-induced psychosis (DIP) in Parkinson's disease. Electronic databases were screened for the key words Parkinson's disease and psychosis. Only 7 trials with a satisfactory allocation concealment and data reporting were included into the study. Two trials compared low-dose clozapine versus placebo with a significantly better outcome for clozapine regarding efficacy and motor functioning. In one trial clozapine was compared against quetiapine showing equivalent efficacy and tolerability. However, in two placebo controlled trials quetiapine failed to show efficacy. In two further placebo controlled trials olanzapine did not improve psychotic symptoms and significantly caused more extrapyramidal side effects. Based on randomized trial-derived evidence which is currently available, only clozapine can be fully recommended for the treatment of DIP in PD. Olanzapine should not be used in this indication.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Data Interpretation, Statistical; Dibenzothiazepines; Dopamine; Dopamine Agents; Humans; Olanzapine; Parkinson Disease; Psychotic Disorders; Quality Assurance, Health Care; Quetiapine Fumarate; Randomized Controlled Trials as Topic

Clozapine is an important antipsychotic agent that has a unique profile of clinical benefits, but that has also been associated with several serious and potentially life-threatening safety concerns. In order to minimise the impact of haematological adverse events, health professionals treating patients with clozapine are currently required to register their patients on a centrally administered data network and to conform to strict protocols. The consensus statement documented in this article extends existing protocols by recommending monitoring of patients treated with clozapine for additional adverse effects during treatment. This consensus statement reflects the current practice at five major public psychiatric hospitals in Victoria, Australia, for the monitoring and management of clozapine-related adverse events, and has been implemented at these sites because of emerging safety concerns associating clozapine with cardiovascular and metabolic adverse effects.

Topics: Agranulocytosis; Antipsychotic Agents; Australia; Clozapine; Consensus; Diabetes Mellitus; Humans; Hyperlipidemias; Neutropenia; Population Surveillance; Psychotic Disorders; Weight Gain

Psychosis may be seen with several movement disorders. As pharmacological treatments can sometimes worsen movement disorders, psychosis in these situations can be complex for clinicians to manage. This review covers the management of psychosis in three different movement disorders: Parkinson's disease, dementia with Lewy bodies and Huntington's disease.

Topics: Antipsychotic Agents; Clozapine; Haloperidol; Humans; Huntington Disease; Lewy Body Disease; Parkinson Disease; Patient Education as Topic; Psychotic Disorders; Risperidone

Clozapine-induced hypersalivation (CIH) is a significant side effect affecting about one-third of patients treated with clozapine. CIH can be stigmatizing, can affect quality of life, and can result in discontinuation of clozapine treatment. The purpose of this review is to provide an understanding of CIH, specifically, its pathophysiology, measurement, and the evidence for CIH treatment alternatives.. We searched MEDLINE from 1980 to June 2006 for all reported pharmacologic treatment studies related to CIH. We identified additional references by a manual search of the bibliographies of retrieved articles.. Several studies reported improvement of CIH with both selective and nonselective anticholinergic medications. However, with the exception of local anticholinergic agents such as ipratropium bromide and atropine eye drops, potential systemic adverse effects limit the effectiveness of this class of medications. Open-label studies of clonidine, an alpha2 antagonist, suggest that it may be beneficial in managing CIH. Other pharmacologic treatments, such as amisulpride and botulinum toxin, may be useful in refractory CIH cases.. Although few randomized controlled trials were found in the literature, this review highlights potential treatment alternatives for this common and disabling cause of hypersalivation. Prompt and effective treatment of CIH may assist with treatment tolerability, adherence, and outcomes in patients with treatment-refractory schizophrenia. Information on funding and support and author affiliations appears at the end of the article.

Topics: Clozapine; Humans; Psychotic Disorders; Sialorrhea; Stereotyping

Compared with the first-generation, or "typical" antipsychotic drugs, second-generation or atypical antipsychotics cause fewer extrapyramidal (motor) problems, but they pose new challenges, as they often contribute to metabolic disturbances such as weight gain, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus. Patients taking atypical antipsychotics should be monitored for glycemic and cardiovascular risk factors and should receive treatment for such problems as they arise.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Humans; Olanzapine; Psychotic Disorders; Risk Factors; Risperidone; Weight Gain

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Aripiprazole; Cholinesterase Inhibitors; Clozapine; Controlled Clinical Trials as Topic; Dibenzothiazepines; Humans; Lewy Body Disease; Male; Parkinson Disease; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Quinolones

To examine the evidence that discontinuation of long-term antipsychotic medication, including clozapine, may provoke a psychotic episode.. Databases were searched and citations scrutinised.. Evidence for a rapid onset psychosis (supersensitivity psychosis) following clozapine withdrawal was found and weaker evidence that this might occur with some other antipsychotic drugs. Some cases were reported in people without a psychiatric history. It appears that the psychosis may be a feature of drug withdrawal rather than the re-emergence of an underlying illness, at least in some patients. Meta-analyses of withdrawal studies have suggested that antipsychotic discontinuation may also increase the risk of relapse over and above the risk because of the underlying disorder, but not all individual studies show this effect. Mechanisms may relate to brain adaptations to long-term drug use but data are sparse.. These effects require further urgent research. Interventions to reduce morbidity after drug withdrawal need to be developed.

Topics: Antipsychotic Agents; Clozapine; Humans; Long-Term Care; Psychoses, Substance-Induced; Psychotic Disorders; Recurrence; Risk Factors; Substance Withdrawal Syndrome

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

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

With other atypical antipsychotics now available, having predictors of clozapine response would be of considerable value, offering clinicians guidance in their decision as to when, and if, a trial of clozapine is warranted.. The aim was to review existing evidence regarding identified predictors and markers of clozapine response.. Relevant studies were identified through PUBMED searches (1975-June 2004) and cross-referencing of reviews and included studies. The data were summarized under two main categories: clinical (general, neurological, cognitive/neuropsychological, clozapine levels) and biological (biochemical, endocrine, genetic, metabolic, morphological, dopamine D2 receptor occupancy). 'Reliable' predictors/markers were defined a priori as those with support of at least two independent reports that addressed overall response, with no contradictory findings to date. 'Potential' predictors/markers had the support of a single report that addressed overall response and at least one other evaluating treatment outcome but not directly addressing response status.. Higher baseline clinical symptoms and functioning in the previous years and low cerebrospinal homovanillic acid/5-hydroxyindoleacetic acid levels were identified as reliable. Three potential measures were identified: reduction of frontal cortex metabolic activity, reduction of caudate volume, and improvement in P50 sensory gating.

Topics: Animals; Antipsychotic Agents; Biomarkers; Clozapine; Humans; Neuropsychological Tests; Psychotic Disorders

Behavioural symptoms such as anxiety, depression and psychosis are common in Parkinson's disease (PD), and dementia occurs in about 90% of the patients. These symptoms can be more disabling than the motor dysfunction and they negatively impact quality of life, increase caregiver distress and are more frequently associated with nursing home placement. Depression can be treated with counselling and pharmacotherapy. Tricyclic antidepressants or selective serotonin reuptake inhibitors are widely used, but there is still need for controlled clinical trials. Management of psychosis in PD is complex and includes elimination of identifiable risk factors, reduction of polypharmacy and administration of atypical neuroleptics, which can alleviate psychotic symptoms without worsening motor functions. Clozapine is the best documented atypical neuroleptic shown to be effective against psychosis in PD patients. Cholinesterase inhibitors may prove additional benefit in psychotic PD patients. Recent evidence from small double-blind and open-label trials suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.

Topics: Antipsychotic Agents; Anxiety Disorders; Cholinesterase Inhibitors; Clozapine; Dementia; Depressive Disorder; Humans; Mental Disorders; Parkinson Disease; Psychotic Disorders

Conventional antipsychotic drugs, used for a half century to treat a range of major psychiatric disorders, are being replaced in clinical practice by modern "atypical" antipsychotics, including aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone among others. As a class, the newer drugs have been promoted as being broadly clinically superior, but the evidence for this is problematic. In this brief critical overview, we consider the pharmacology, therapeutic effectiveness, tolerability, adverse effects and costs of individual modern agents versus older antipsychotic drugs. Because of typically minor differences between agents in clinical effectiveness and tolerability, and because of growing concerns about potential adverse long-term health consequences of some modern agents, it is reasonable to consider both older and newer drugs for clinical use, and it is important to inform patients of relative benefits, risks and costs of specific choices.

Topics: Antipsychotic Agents; Clozapine; Humans; Nervous System Diseases; Psychotic Disorders

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Diabetes Mellitus; Humans; Muscle, Skeletal; Myocarditis; Neutropenia; Psychotic Disorders; Risk Factors; Seizures; Weight Gain

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 authors presents the state of knowledge on the prevalence and proposed mechanisms leading to weight gain during treatment with atypical antipsychotics. A short review on the therapeutic approaches is also supplied.

Topics: Antipsychotic Agents; Body Weight; Clozapine; Dibenzothiazepines; Humans; Hyperlipidemias; Leptin; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Thiazoles; Weight Gain

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

Lewy body dementia, also referred to as dementia with Lewy bodies (DLB), is a neurodegenerative disorder now considered to be the second most common cause of dementia after Alzheimer's disease. Postmortem findings suggest that DLB accounts for 20% to 34% of all dementia cases and is often underdiagnosed. Salient features of DLB include fluctuations in cognition, perceptual abnormalities (e.g., visual hallucinations), and mild parkinsonism. Other symptoms include frequent falls, nighttime agitation, and depression. DLB symptomatology can be partly explained by the extensive destruction of dopaminergic and acetylcholinergic pathways caused by neurodegeneration. For this reason, DLB patients are especially vulnerable to the antidopaminergic and anticholinergic actions of most conventional antipsychotics, which makes treatment of the psychotic symptoms of DLB extremely difficult. Patients are particularly sensitive to developing extrapyramidal symptoms (EPS) and also to the potentially fatal complication of neuroleptic sensitivity, which affects approximately 50% of DLB patients. Therefore, a need exists for antipsychotic drugs with less propensity to induce EPS and reduced affinity for dopamine and acetylcholine receptors. Here we review studies evaluating the efficacy and tolerability of atypical antipsychotics for the treatment of psychoses associated with DLB. Olanzapine appears to be poorly tolerated, and risperidone has been associated with high risk of neuroleptic malignant syndrome. Clozapine use remains controversial because of its potent anticholinergic action and risk of agranulocytosis. Quetiapine has been shown to reduce psychiatric manifestations of DLB without causing neuroleptic sensitivity or increasing EPS. Hence, quetiapine is an attractive candidate for the treatment of psychoses in DLB and other dementias.

Topics: Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Controlled Clinical Trials as Topic; Dibenzothiazepines; Humans; Lewy Body Disease; Olanzapine; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Treatment Outcome

The literature continues to highlight the debate on the ethics and merits of trials sponsored by the pharmaceutical industry. This study attempts to determine the prevalence and outcomes of industry-sponsored trials involving clozapine, risperidone, or olanzapine.. We searched the literature from January 1, 1990, to December 31, 2001, to capture all eligible clinical trials involving clozapine, risperidone, or olanzapine. The primary outcome measured was the clinical outcome of industry-sponsored studies. Secondary outcome measures included the following parameters: disclosure of any sponsorship and financial support, author(s) employed by the industry, use of comparator drug(s) within the trial, sample size, blinding, and use of placebo.. The database comprised 372 articles. Of these trials, 124 (33.3%) were sponsored by the pharmaceutical industry. In general, trials sponsored by Eli Lilly or Janssen had better research design than trials not funded by the pharmaceutical industry. With regard to authorship, more trials funded by Eli Lilly (74.6%) were coauthored by an employee of the company, compared with trials funded by either Janssen (23.3%) or Novartis/Sandoz (5.6%). Further, more trials sponsored by Eli Lilly reported positive outcomes (92.1%), compared with Janssen-sponsored trials (88.4%) and Sandoz/Novartis-sponsored trials (72.2%). No negative results were reported in any of the industry-funded trials.. One-third of the published clinical trials involving clozapine, risperidone, or olanzapine were funded by their respective manufacturer. The reported outcomes of the sponsored trials highly favour the manufacturer's product.

Topics: Benzodiazepines; Clinical Trials as Topic; Clozapine; Drug Industry; Humans; Olanzapine; Outcome Assessment, Health Care; Psychotic Disorders; Risperidone

Visual hallucinations (VHs) occur frequently in Parkinson's disease (PD). VHs occur more frequently in elderly patients with longer duration of illness, cognitive impairment, and sleep disturbances. The relationship between the use of antiparkinsonian drugs and VHs is complicated, but most drugs used to treat parkinsonian motor symptoms induce VHs and psychosis in some PD patients. The "continuum hypothesis" proposing that medication-induced psychiatric symptoms in PD begin with drug-induced sleep disturbances, followed by vivid dreams, with progression to hallucinatory and delusional experiences has been challenged. In some patients, VHs may represent intrusion of REM sleep-related imagery into wakefulness. Improving REM sleep abnormalities in PD (e.g., stimulants, anticholinesterase inhibitors) is one strategy now being tested to improve VHs in PD.

Topics: Antiparkinson Agents; Cholinesterase Inhibitors; Clozapine; Dopamine Agents; Dreams; Hallucinations; Humans; Parkinson Disease; Polysomnography; Psychotic Disorders; Sleep Deprivation; Sleep Disorders, Intrinsic; Sleep, REM

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risperidone; Serotonin Antagonists; Thiazoles; Treatment Outcome; United States

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Controlled Clinical Trials as Topic; Dementia; Dibenzothiazepines; Humans; Olanzapine; Parkinson Disease; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles; Treatment Outcome

Central criteria for the definition of atypical antipsychotics are antipsychotic efficacy and minimal or none extrapyramidal symptoms (EPS). This last criterium is of importance in the differentiation with the traditional antipsychotics. Of the four atypical antipsychotics which are discussed here, clozapine is the most atypical. The best proof is its good efficacy in the treatment of Parkinson psychosis with minimal adverse effects on motor function. Clozapine is the best choice for this indication. At this moment there is not enough evidence available concerning quetiapine. Risperidon and olanzapine give more Dopamine2-occupancy with higher doses and can evoke EPS, but this is still less compared to the traditional antipsychotics. All four atypical drugs cause less tardive dyskinesia. Atypical antipsychotics are not well studied in the treatment of elderly patients with functional psychosis. However the available information and the literature on the treatment of young adults makes it probable that the atypical antipsychotics are at least as effective in the elderly as the traditional antipsychotics. The median daily doses are lower for elderly than for younger patients. Risperidon has been proven effective in the treatment of agressive behaviour in dementia. Atypical antipsychotics have their 'own' adverse effects. Those which have the most impact in the elderly are discussed.

Topics: Aged; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Parkinson Disease; Psychotic Disorders; Receptors, Dopamine D2; Treatment Outcome

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

Awareness of the metabolism of second-generation antipsychotics by the cytochrome P450 (CYP) system can inform the clinician about how to avoid and manage drug-drug interactions involving these enzymes. Clozapine is metabolized primarily by CYP1A2, with additional contributions by CYP2C19, CYP2D6 and CYP3A4. Risperidone is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Olanzapine is metabolized primarily by CYP1A2 and to a lesser extent by CYP2D6. Quetiapine and ziprasidone are metabolized by CYP3A4. At the usual clinical doses, these drugs appear not to significantly affect the metabolism of other medications. There is, however, a lack of in vivo metabolic data, especially for the 3 newest second-generation antipsychotics: olanzapine, quetiapine and ziprasidone.

Topics: Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme System; Humans; Liver; Psychotic Disorders

Psychotic symptoms are seen in numerous psychiatric illnesses afflicting the elderly. This article reviews the efficacy of the pharmacologic management of psychotic symptoms in primary psychotic disorders, affective disorders, and neurodegenerative disorders.. A comprehensive literature review.. Evidence to support the use of pharmacologic interventions to manage psychotic symptoms in elderly patients afflicted with primary psychotic disorders and affective disorders is limited by the absence of randomized, placebo-controlled trials (RCTs). The use of low-dose clozapine is supported by RCTs in Parkinson's disease. The efficacy of risperidone and olanzapine for the treatment of psychotic symptoms has been demonstrated by large RCTs in Alzheimer's disease.. There is evidence of the efficacy of antipsychotic medications to manage psychotic symptoms in elderly patients. However, the absence of published evidence from RCTs in primary psychotic and affective disorders, and the limited evidence in the neurodegenerative illnesses, is notable.

Topics: Aged; Alzheimer Disease; Benzodiazepines; Bipolar Disorder; Clozapine; Depressive Disorder; Drug Administration Schedule; Humans; Lewy Body Disease; Olanzapine; Parkinson Disease; Pirenzepine; Psychotic Disorders; Risperidone

Drug-induced iatrogenic hallucinations and psychosis occur in about 30% of Parkinson's disease (PD) patients and are the single most important precipitant for nursing home placement, which carries a grave prognosis. In addition, parkinsonism is a frequent accompaniment to the more common dementing syndromes, Alzheimer's disease (AD), vascular dementia, and dementia with Lewy bodies (DLB). The five most recent antipsychotic drugs approved by the Food and Drug Administration in the United States have been marketed as "atypical" antipsychotics (AA) due to their relative freedom from extrapyramidal symptoms when used in schizophrenia patients. The use of these newer antipsychotic drugs in PD and other parkinson-sensitive populations represents the most stringent test to their freedom from motor side effects. To date, clozapine, risperidone, olanzapine, and quetiapine have been studied in parkinson-vulnerable populations. This article reviews the data and highlights the differences that these four drugs have on motor function. It also emphasizes the challenges in evaluating the available data on the motor effects of AA, especially on the non-PD elderly and cognitively impaired population. Suggestions are made for future research to improve the interpretability of these studies.

Topics: Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Clozapine; Dementia, Vascular; Dibenzothiazepines; Hallucinations; Humans; Iatrogenic Disease; Lewy Body Disease; Olanzapine; Parkinson Disease; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone

Currently, tardive dyskinesia (TD) remains an important clinical problem. The average prevalence is estimated at 30%. The appearance of antipsychotics has opened new paths. The extrapyramidal profile of these molecules is more favorable than that of conventional neuroleptics. In order to assess their prophylactic as well as curative potential, we reviewed the literature concerning four of these atypical antipsychotics: clozapine, risperidone olanzapine and amisulpride. Clozapine seems to induce fewer cases of TD than the conventional neuroleptics, and has a specific therapeutic effect. However, the risk of agranulocytosis reduces the possibility of utilisation. Risperidone appears to be an effective therapy, but several authors report cases of TD during treatment. Furthermore, larger studies and longer follow-ups are necessary to confirm the efficiency of olanzapine and amisulpride. Further studies and observations are still necessary before drawing any conclusion for these new atypical antipsychotic actions. They are doubtlessly promising, but we cannot ignore the notion of risk-benefit; regular monitoring and listening to the subjective experience of the patients must remain uppermost in the choice of therapy.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Prevalence; Psychotic Disorders; Risperidone; Sulpiride

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

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

Priapism is a prolonged, usually painful, and persistent penile erection not usually associated with sexual stimuli, resulting from a disturbance in the normal regulatory mechanisms that initiate and maintain penile flaccidity. This infrequent adverse event of antipsychotic medication use requires emergency evaluation and has potentially serious long-term sequelae including erectile dysfunction. Clinicians prescribing antipsychotic medications should be aware of this rare but serious adverse event.. A computerized search, using the MEDLINE database (1966-summer 2000), located cases of priapism associated with most conventional antipsychotics as well as with clozapine, risperidone, and olanzapine. The search included no restrictions on languages. Keywords included priapism combined with antipsychotic agents and the names of the currently available atypical antipsychotics. Twenty-nine publications were located using these parameters. Additional publications were reviewed for general background on pathophysiology, evaluation, and management. The quality of the evidence reviewed is limited by the observational and uncontrolled nature of case reports, case series. and review articles.. Psychotropic-induced priapism is currently believed to be caused by the alpha1-adrenergic antagonism of these medications. Detumescence is sympathetically mediated, and alpha1-adrenergic antagonism (within the corpora cavernosa) inhibits detumescence. The propensity of individual antipsychotics to induce priapism can presumably be estimated on the basis of alpha1adrenergic blockade affinities. Of the conventional antipsychotics, chlorpromazine and thioridazine have the greatest alpha1-adrenergic affinity and have been most frequently reported to be associated with priapism. Of the atypical antipsychotics, risperidone has greater alpha1-adrenergic affinity, although 3 of the 5 currently U.S. Food and Drug Administration (FDA)-approved atypicals have been reported to be associated with priapism.. Virtually all antipsychotic medications have been reported to rarely cause priapism due to their alpha-adrenergic antagonism. This adverse event should be considered a urologic emergency. Clinicians should be familiar with this infrequent serious adverse event of antipsychotic medications.

Topics: Antipsychotic Agents; Benzodiazepines; Circadian Rhythm; Clozapine; Erectile Dysfunction; Female; Forensic Psychiatry; Humans; Male; Olanzapine; Pirenzepine; Priapism; Psychotic Disorders; Risperidone

The use of two antipsychotics for the treatment of individuals with psychiatric disorders is not uncommon in clinical practice but is rarely documented in the literature. The present article suggests an alternative method of treating individuals who show a partial but inadequate response to antipsychotic monotherapy. A rational strategy for augmenting one antipsychotic with a second, based on pharmacodynamic and pharmacokinetic principles, is provided. The present approach considers the 5-hydroxytryptamine2 to dopamine2 ratio, other complementary receptor affinities and drug-drug interactions involving the cytochrome P450 isoenzymes. The present article presents a rationale for augmenting haloperidol in patients who are partially responsive to clozapine.

Topics: Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme System; Drug Interactions; Haloperidol; Humans; Isoenzymes; Polypharmacy; Psychotic Disorders

For patients hospitalized with acute episodes of psychosis, rapid stabilization of intense positive symptoms, hostility, and agitation is typically a preeminent therapeutic goal. These goals often differ from those of the nonhospitalized patient with psychosis for whom long-term treatment goals such as improvement of negative symptoms, cognitive function, compliance, and reduction in side effect burden may be paramount. Therefore, when selecting an antipsychotic treatment for hospitalized patients, efficacy against positive symptoms and hostility as well as speed of therapeutic onset should strongly be considered. At the same time, selection of antipsychotic treatment in the inpatient setting should establish a definitive treatment that will address long-term goals effectively after discharge. This article presents the rationale and practical guidelines for selection of treatment regimens for patients hospitalized due to acute psychosis.

Topics: Acute Disease; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Haloperidol; Hospitalization; Hostility; Humans; Olanzapine; Pirenzepine; Practice Guidelines as Topic; Psychomotor Agitation; Psychotic Disorders; Risperidone; Treatment Outcome

Atypical neuroleptic agents are an excellent, safer, and more effective alternative to the widespread practice of maintenance adjunctive treatment with traditional neuroleptic agents in patients with bipolar disorder. Currently, a number of prospective studies are available with clozapine, risperidone, olanzapine, and quetiapine in the treatment of bipolar disorder. Most are short-term studies, although longer-term data are becoming available. Four double-blind studies of acute mania have been conducted with risperidone and olanzapine, leading to recent Food and Drug Administration approval for olanzapine in the indication of acute mania. Given the limited longer-term data, and the evidence for mostly adjunctive benefits with these agents, it seems unlikely that these agents will prove to be primary mood stabilizers in their own right. Nonetheless, they serve an important role as adjunctive treatments along with standard mood stabilizers in the rational polypharmacy of bipolar disorder. To date, differences in efficacy have not been established. However, differences in the side effect of weight gain may be even more relevant in bipolar disorder than in schizophrenia due to the need to use standard mood stabilizers that often potentiate such weight gain.

Topics: Acute Disease; Algorithms; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Humans; Lithium; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Treatment Outcome; Valproic Acid

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

Aggressive behavior of psychotic patients impacts all aspects of their clinical care. Better treatments to address this problem are needed, and atypical antipsychotics, such as clozapine, risperidone, and perhaps quetiapine, have shown promise. However, studying the psychopharmacology of aggression is difficult because of the many methodological problems that arise in the design of appropriate clinical trials. These include imprecise definitions of aggression, the difficulty of measuring outcome because of the relative rarity of aggressive events, bias in the selection of patients for study, inadequate and inappropriate control groups, and inattention to comorbidities and concomitant medications in analyzing results. Since the usual outcome measure is the aggressive event rate, a large sample size and lengthy baseline and trial periods are required when this rate is low. Furthermore, formidable practical and ethical obstacles interfere with the many sound techniques (e.g. randomization) used in typical designs of psychopharmacological clinical trials. Current research methods should be modified and new ones developed in order to progress in assessing the antiaggressive effects of treatments.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Disease Progression; Humans; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Research Design; Risperidone

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

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

Antipsychotic medications are among the most widely prescribed class of medications for elderly patients. Despite their high use, few studies document the efficacy, safety, and tolerability of these agents in this patient population. This is unfortunate because, as a group, the elderly are exceptionally sensitive to the adverse effects associated with antipsychotics, in particular, the extrapyramidal side effects (EPS). The atypical antipsychotics with their lower propensity to cause EPS and lower need for augmenting anticholinergic medication have introduced new options for elderly patients who need antipsychotic therapy for a number of psychiatric and neurologic disorders with psychotic manifestations. This review covers the pharmacologic, clinical, and regulatory issues involving antipsychotic use in elderly patients that warrant consideration by the practicing psychiatrist.

Topics: Accidental Falls; Age Factors; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Drug Costs; Drug Interactions; Dyskinesia, Drug-Induced; Humans; Hyperprolactinemia; Osteoporosis; Psychotic Disorders; Weight Gain

Psychotic symptoms have become increasingly common in patients with idiopathic Parkinson's disease and other parkinsonian syndromes. This increased prevalence of psychoses is in part a reflection of the greater longevity of people with Parkinson's disease and, to a certain extent, is a consequence of our success in treating the motor symptoms of these syndromes. The psychotic symptoms associated with Parkinson's disease can be as varied as the motor symptoms. They stem from interactions between the underlying neuropathologies of the syndromes and the adverse effects associated with chronic antiparkinsonian drug administration. In patients with advanced Parkinson's disease, there is also a high prevalence of affective comorbidity. This increase in affective symptoms and the relatively high incidence of cognitive and affective side effects of the antiparkinsonian medications contribute to the increase in psychoses observed in these older patients. The most significant risk factors for developing psychosis in Parkinson's disease are (1) coexistence of dementia, (2) protracted sleep disturbances, and (3) nighttime use of long-acting dopaminomimetics. This article reviews the phenomenology, pathophysiology, and treatment of psychosis associated with parkinsonism and discusses how atypical antipsychotic medications have revolutionized the management of the symptoms and improved the quality of life of those affected.

Topics: Algorithms; Antiparkinson Agents; Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Comorbidity; Decision Trees; Dibenzothiazepines; Humans; Olanzapine; Parkinson Disease; Pirenzepine; Psychoses, Substance-Induced; Psychotic Disorders; Quetiapine Fumarate

Significant consequences of untreated psychosis in patients with dementia have led clinicians to seek improved therapeutic options. This review presents the scope of the problem, discusses some of the underlying neurobiology, and highlights the evidence for appropriate therapies. A range of potentially effective pharmacologic therapies is available and is discussed.

Topics: Aged; Antipsychotic Agents; Clozapine; Comorbidity; Delusions; Dementia; Hallucinations; Humans; Psychotic Disorders; Risperidone; Treatment Outcome

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

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 estimate and compare the effects of antipsychotics-both the newer ones and the conventional ones-on body weight.. A comprehensive literature search identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information.. Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks.. Both conventional and newer antipsychotics are associated with weight gain. Among the newer agents, clozapine appears to have the greatest potential to induce weight gain, and ziprasidone the least. The differences among newer agents may affect compliance with medication and health risk.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Confidence Intervals; Drug Administration Schedule; Humans; Molindone; Piperazines; Placebos; Psychotic Disorders; Research Design; Thiazoles; Treatment Outcome; Weight Gain

Since the discovery of the neuroleptics in 1952, french psychiatrists have proposed a classification of neuroleptics taking into account the pharmalogical and therapeutic differences between these drugs. They distinguished three different clinical effects of neuroleptics: sedative effects, effects on the positive symptoms of schizophrenia and effects on the negative symptoms. However these agents have many side effects including the extrapyramidal syndrome (EPS), akathisia, dystonia and parkinsonism. These side effects occur in up to 75% of patients receiving typical neuroleptics and are the main cause of non-compliance. Since the eighties, clozapine was introduced for use in refractory patients because it has a better efficacy (than haloperidol) specifically on negative symptoms, a better tolerance and fewer effects. After clozapine, several new antipsychotic agents are now available, such as risperidone, olanzapine, sertindole, quietapine, ziprasidone ... Their therapeutical effects are probably linked with a dual antagonist effect on 5HT2 and D2 receptors. The present article reviews the evolution of the use of these new agents, their real efficacy, their adverse effects and their expanding indications. Future research will more clearly establish appropriate treatment guidelines for their use. These new antipsychotics should add a positive modification in schizophrenia care and in some mood disorders. The approach consisting on individualizing dimensions and clusters analysis might be useful to test the efficiency of each antipsychotic on a syndromic dimension.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Sulpiride; Thiazoles

The authors emphasize the need for careful differential diagnosis when symptoms of psychosis arise in patients over the age of 65 years. Prevalence of psychotic disorders in the elderly ranges from 0.2%-4.7% in community-based samples to 10% in a nursing home population and as high as 63% in a study of Alzheimer's patients. Risk factors associated with the development of psychotic symptoms and common causes of delirium are reviewed. Because age-related changes affect the pharmacokinetics of neuroleptics, the authors' treatment recommendations, which include the use of traditional and novel antipsychotics, take into account the higher risk of side effects in the elderly.

Topics: Age Factors; Aged; Antipsychotic Agents; Clozapine; Decision Trees; Delirium; Diagnosis, Differential; Drug Administration Schedule; Female; Half-Life; Humans; Male; Middle Aged; Nursing Homes; Psychotic Disorders; Risk Factors; Risperidone; United States

Antipsychotic agents have been used commonly in the treatment of bipolar disorder. This article reviews the evolution of the use of antipsychotic agents and their role in the acute and maintenance treatment of bipolar disorder. The focus is on neuroleptic drugs, the atypical antipsychotic drugs (risperidone and clozapine), and two fo the new atypical antipsychotic drugs that were recently approved.

Topics: Acute Disease; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Lithium; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Treatment Outcome

The author reviews the evolution of emergency psychiatric practice over the past 20 years--from the concept of high-dose antipsychotic medication to the more rational treatment approach for acute psychosis made possible by modern pharmacodynamic insight and the availability of new pharmacotherapeutic agents. A decision tree for current practice in the rapid tranquilization of agitated, apparently psychotic patients is described.

Topics: Acute Disease; Antipsychotic Agents; Benzodiazepines; Clozapine; Decision Trees; Drug Administration Schedule; Emergency Services, Psychiatric; Emergency Treatment; Haloperidol; History, 20th Century; Humans; Lorazepam; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.

Topics: Antipsychotic Agents; Binding, Competitive; Cholinergic Antagonists; Clozapine; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Resistance; Dyskinesia, Drug-Induced; Humans; Levodopa; Ligands; Limbic System; Nerve Tissue Proteins; Parkinson Disease, Secondary; Protein Binding; Psychoses, Substance-Induced; Psychotic Disorders; Radioligand Assay; Receptors, Dopamine D2; Receptors, Muscarinic; Receptors, Serotonin; Recurrence; Serotonin Antagonists; Tomography, Emission-Computed

Antipsychotic drugs are effective in psychoses, whatever the aetiology of the disorder. The positive symptoms tend to respond more readily. The need for developing new drugs arises from the refractoriness of the negative symptoms, the 10-25% of the patients that are treatment-resistant and the problems of short-, and long-term extrapyramidal side-effects. Thus far, five drugs differing from the classical antipsychotics have been licensed for use: clozapine, olanzepine, risperidone, sertindole and sulpiride, and in at least some European countries quetiapine is now in the final phase of clinical research. This review starts with a brief introduction to symptomatology, is limited to the registered drugs and addresses differences with the classical drugs in pharmacology, pharmacokinetics, clinical aspects and side-effects. Clozapine, risperidone and sulpiride can be considered for clinical use in refractory patients, and these three together with olanzapine and sertindole are candidates when extrapyramidal side-effects cause a clinical problem.

Topics: Antipsychotic Agents; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Humans; Psychotic Disorders; Risperidone; Serotonin Antagonists; Sulpiride

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

This review examines the evidence supporting the proposition that a threshold clozapine plasma level can predict clinical response. In addition, it provides a brief overview of the pharmacokinetics, side effects, drug interactions and assay methodology of clozapine.. A comprehensive search of relevant literature was made with respect to the above criteria. The findings were collated and analysed to produce an overview of the usefulness of using clozapine levels in clinical practice.. Most researchers find that, although the correlation between dose of clozapine and clinical effect is not high, a threshold plasma level of 350-420 ng mL-1 of clozapine is associated with an increased probability of a good clinical response to the drug. Results vary, however, with the study design.. The data reviewed present a case for increasing the dose of clozapine in non-responsive patients to achieve a plasma level of at least 350-420 ng mL-1. Non-response at these levels, however, should not preclude a further upward titration of dose. This should occur unless (i) clinical response is obtained at a lower dose, (ii) intolerable side effects occur, or (iii) a daily dose of 900 mg is reached.

Topics: Antipsychotic Agents; Clozapine; Decision Making; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Humans; Psychotic Disorders

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

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

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

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

Both the rapid emergence of new antipsychotic medications and the increasing fertility rate among women with psychotic disorders have contributed to the growing clinical importance of the treatment of pregnant women who have psychotic illnesses. The treatment of this patient population must always take into consideration the effect of that treatment on the fetus. With regard to the high risk of decompensation during pregnancy and postpartum, continuous antipsychotic medication is needed using the minimum effective dose. The use of high-potency agents appears to be preferable for first-line management, as there are few data regarding the use of atypical agents such as clozapine in pregnancy. Guidelines for treating pregnant women with psychoses vary little from those for nonpregnant patients. Clinicians must always carefully weigh up the risks and benefits for each patient on an individual basis.

Topics: Antipsychotic Agents; Behavior; Breast Feeding; Clozapine; Female; Fetus; Humans; Postpartum Period; Pregnancy; Pregnancy Complications; Psychotic Disorders; Risk Assessment

Clozapine, the only commercially available atypical neuroleptic, is approved for the treatment of schizophrenic patients who are unresponsive to or intolerant of typical neuroleptics. It has an unusual pharmacologic profile compared with standard neuroleptics, and it follows that clinical response to this drug is also different. It has shattered the notion that a drug must be capable of inducing or worsening parkinsonism to be a potent antipsychotic. Based on these findings, it is being used increasingly by neurologists for psychiatric and nonpsychiatric problems in patients with movement disorders. The most common use for clozapine among neurologists is in the management of drug-induced psychosis in Parkinson's disease (PD). This problem has been a source of increased morbidity and mortality in PD because of a lack of adequate therapeutic intervention. At this time, because of success in numerous open trials, with improvement of > 80% of patients, clozapine therapy for psychosis in PD is becoming the standard of care. It also appears to be of value in the management of some motor features of PD, including tremors and dyskinesia and possibly even sensory symptoms such as akathisia and pain. The literature also suggests that clozapine may be of potential benefit in hyperkinetic movement disorders including essential tremor, Huntington's disease, and tardive dyskinesia. We review the current data concerning the use of clozapine in patients with these movement disorders and others.

Topics: Antiparkinson Agents; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Huntington Disease; Movement Disorders; Parkinson Disease; Psychotic Disorders; Tremor

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

Topics: Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Psychotic Disorders

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

Schizoaffective disorder is a common, chronic, and frequently disabling psychiatric disorder. However, the pharmacologic treatment of this disorder has not been well studied.. The authors reviewed the available literature regarding the acute and prophylactic pharmacologic treatment of schizoaffective disorder. Fourteen controlled studies, and only 10 using modern criteria to define the disorder, reported on the efficacy of typical antipsychotics, thymoleptics, or the combination in the acute treatment of schizoaffective disorder. In acute treatment studies of schizoaffective disorder, bipolar type (manic), typical antipsychotics and lithium were comparable in efficacy except in agitated patients for whom antipsychotics were superior. The combination of lithium and antipsychotics appeared to be superior to antipsychotics alone in this patient subtype. In the only controlled study of the acute treatment of schizoaffective disorder, depressive type, combined treatment with antipsychotics and antidepressants was not superior to treatment with antipsychotics alone.. Although combination treatment with antipsychotics and thymoleptics is common practice in the prophylactic management of schizoaffective disorder, the efficacy of this strategy has not been studied in controlled trials. Recent preliminary data from open trials suggest that the mood stabilizers valproate and carbamazepine and the novel antipsychotics clozapine and risperidone may be promising new treatments for schizoaffective disorder. Evidence implicating 5-HT2 receptor blockade as an important mechanism underlying possible thymoleptic activity for clozapine and risperidone is also reviewed.

Topics: Antidepressive Agents; Antipsychotic Agents; Carbamazepine; Clinical Trials as Topic; Clozapine; Drug Therapy, Combination; Humans; Psychotic Disorders; Receptors, Serotonin; Risperidone; Serotonin Antagonists; Treatment Outcome; Valproic Acid

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

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

Agitation or psychosis or both occur in half or more of patients with dementia at some point during the course of illness. The treatment of these signs and symptoms ideally entails identification and alteration of physical, environmental, social, and psychiatric factors. Environmental modification, education of caregivers, and therapeutic activity programs are nonpharmacologic approaches that can effectively reduce some signs and symptoms of this nature. For those that remain, empirical administration of pharmacologic agents may be appropriate. One approach is to inventory the specific behaviors and develop a "therapeutic metaphor," i.e., subtype the agitated behaviors according to the presence of target symptoms likely to respond to specific classes of medication. Available evidence is reviewed regarding the efficacy and safety of somatic therapies for agitation, including antipsychotics, antidepressants, anticonvulsants, benzodiazepines, and cholinesterase inhibitors.

Topics: Aged; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Clozapine; Dementia; Humans; Psychomotor Agitation; Psychotic Disorders; Risperidone; Selective Serotonin Reuptake Inhibitors; Trazodone

Clozapine [8-chloro- 11-(4-methyl- 1-piperazinyl)-3H-dibenzo (b,e)(1,4) diazepine], or clozaril, is a member of the dibenazepine class of antipsychotic drugs. Initially, studies in animals using a number of neurochemical, biochemical, electrophysiological, and behavioral paradigms indicated that clozapine was markedly different from various typical antipsychotic drugs such as haloperidol and chlorpromazine. Subsequently, clinical studies have shown that clozapine is effective in ameliorating the core symptoms, as well as the negative symptoms, in schizophrenia. However, clozapine has a much lower propensity for inducing neurological side effects after acute or repeated administration compared to various typical neuroleptics. Furthermore, clozapine is therapeutically effective in treating about 30% of schizophrenic patients who are resistant to standard antipsychotic drugs. Based on the above information, clozapine has been designated an atypical antipsychotic drug. However, at this time, it is not entirely clear why clozapine is such a unique antipsychotic drug. To date, there has not been a comprehensive review regarding clozapine's pharmacological profile. Therefore, we will review clozapine's profile in the following areas: 1) affinity for neurotransmitter receptors in the brain; 2) electrophysiology (in vivo, single-cell recording and iontophoresis; in vitro studies); 3) in vivo microdialysis and voltammetry; 4) monoamine turnover or metabolism; 5) intermediate early gene expression; 6) positron emission tomography studies; and 7) molecular biological studies. We will also compare and contrast clozapine's acute and chronic effects, and discuss the merits of various hypotheses that have been put forward to explain clozapine's unique profile.

Topics: Animals; Clozapine; Humans; Psychotic Disorders

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

Atypical neuroleptics can be defined as dopamine receptor blockers which differ from typical neuroleptics in that they have a markedly lower or absent propensity for the induction of parkinsonian side effects or tardive dyskinesias. The authors are studying varied molecules considering their mechanism of action. The differences between atypical and typical neuroleptics may relate to regional specificity in site of actions and receptor binding profile. The authors insist on clozapine, which is a D2 antagonist and in which many other systems might be involved. New neural models may help understand these interactions. The Swerdlow and Koob's model is a unified hypothesis of cortico-striato-pallido-thalamic function which can explain psychoses, depression, dyskinesias and Parkinsonian disorders. The authors make a linkage between this model and Davis's hypothesis. This author hypothesizes that schizophrenia is characterized by abnormally low prefrontal dopamine activity leading to excessive dopamine activity in mesolimbic dopamine neurons, that explains the both negative and positive symptoms coexistence. For the authors, new ways are then opened for an integrative conception of psychosis and affective disorders. This conception might be integrated into the bio-psycho-social model based on chaotics, evocation of which is the author's conclusion.

Topics: Antipsychotic Agents; Clozapine; Humans; Models, Neurological; Models, Psychological; Neuropsychology; Psychotic Disorders

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

1. This article reviews the prevalence, diagnosis, pathophysiology and management of psychosis in Parkinson's disease. 2. Psychosis in Parkinson's disease has been associated with all antiparkinsonian medications. The most common symptoms are vivid disturbing dreams, visual hallucinations and paranoid delusions. 3. The emergence of psychosis reduces the patient's functional capacity and increases caregiver burden. It also poses a therapeutic dilemma because effective treatment of psychotic symptoms may result in worsening of motor symptoms and vice versa. 4. Increased physician awareness is essential for proper diagnosis and management. Withdrawal of anticholinergic medications and amantadine followed by levodopa dose adjustment is effective in many patients. 5. Atypical neuroleptics, in low doses, may be successful when other measures have failed. However, these agents are not approved for treating Parkinsonian psychosis and must be considered as investigational therapies.

Topics: Clozapine; Diagnosis, Differential; Humans; Parkinson Disease; Psychotic Disorders; Risperidone

Until antipsychotics can be subdivided according to differentiated effects on psychic functions (for example on positive/negative symptoms and cognitive functions), the best classification seems to be one based upon receptor-binding profiles and the side effects that follow. Such a combined pharmacological-clinical approach appears fruitful to clinicians as well as pharmacologists. According to this classification the new antipsychotics can be subdivided into three main categories: the relatively pure dopamine antagonists (D2 antagonists, including sulpiride and amisulpiride); the dopamine (D2)-serotonin (5-HT2)-norepinephrine (alpha 1) antagonists (risperidone, ziprazidone and sertindole); and the multireceptor antagonists (clozapine, olanzapine and seroquel). Clozapine is still the most potent antipsychotic and the least potent at inducing extrapyramidal symptoms. New drugs such as olanzapine, seroquel and sertindole represent the further development of clozapine's positive qualities, while risperidone and ziprasidone are dominated to a greater extent by relatively traditional dopamine D2 receptor blockade.

Topics: Antipsychotic Agents; Binding, Competitive; Clozapine; Dopamine Antagonists; Haloperidol; Humans; Psychotic Disorders; Sulpiride

Lithium remains the mainstay of treatment for patients with bipolar affective disorder; however, nearly half of patients with bipolar disorder fail to respond to lithium. Recently, there have been an increasing number of preliminary clinical reports that clozapine, an atypical antipsychotic agent, has potential efficacy in patients with mood disorders. We review the available clinical data supporting the potential use of clozapine in these psychiatric disorders and report our preliminary data from a study that used clozapine in the acute treatment of mania in treatment-refractory patients. Twenty-five patients meeting the DSM-III-R criteria for the manic phase of either bipolar or schizoaffective disorder entered a 13-week open prospective trial of clozapine. These patients either had failed to respond to or had been intolerant to treatment with lithium, an anticonvulsant, and at least two typical neuroleptics. Eighteen of 25 patients demonstrated a greater than 50% decrease in the Young Mania Rating Scale score. These preliminary data as well as the clinical reports reviewed indicate that the efficacy of clozapine in treatment-resistant patients is not limited to patients with schizophrenia.

Topics: Affective Disorders, Psychotic; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Depressive Disorder; Humans; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies

Clozapine, a novel antipsychotic agent, is an alternative to standard neuroleptic therapy for psychotic disorders. Some advantages of clozapine over neuroleptics are that it may be a more effective antipsychotic in treatment resistant patients and has a lower incidence of extrapyramidal side effects. However, seizures associated with clozapine treatment occur at a rate of about three percent. Factors which seem to increase the likelihood of seizures include high doses of clozapine, rapid dose titration, the concurrent use of other epileptogenic agents and a previous history of neurological abnormalities. A strategy that has been proposed to reduce the occurrence of seizures is the addition of an anticonvulsant agent. At present, little rigorous scientific evidence exists to establish the effectiveness of this strategy or the choice of an anticonvulsant. However, based on what evidence there is and the side effect profiles of the various anticonvulsants, the authors propose the use of valproic acid for the prophylaxis and management of clozapine related seizures.

Topics: Anticonvulsants; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Psychotic Disorders; Seizures

Since the development of clozapine the investigation of atypical neuroleptic compounds has become increasingly relevant. Compared with classic neuroleptics they are distinguished by either fewer or absent (clozapine) extrapyramidal side effects, some of them also by lower increases of serum prolactin concentrations. Pharmacologically they are a group of heterogeneous substances. At the level of transmitter systems a high 5HT2/D2-ratio is regarded as the best criterion to distinguish between atypical and classic neuroleptics. Further differences involve: the preferred effects of atypical neuroleptics on mesolimbic D2 receptors compared to striatal dopaminergic neurotransmission; a higher potency of some atypical neuroleptics to antagonize D1-receptors; the increase of serum corticosterone concentrations by some of the atypical neuroleptics.

Topics: Animals; Antipsychotic Agents; Brain; Butyrophenones; Clinical Trials as Topic; Clozapine; Humans; Psychotic Disorders; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Serotonin

Clozapine is an atypical neuroleptic drug characterised by a striking lack of extrapyramidal side effects. Although these features would seem to make clozapin an unlikely agent for the induction of neuroleptic malignant syndrome (NMS), several putative clozapin-related cases of NMS have recently been reported. A reevaluation of these articles raised some doubts on the causal relationship between clozapin therapy and NMS in most cases. We report on the clinical history of nine consecutive NMS patients who required reinstitution of neuroleptic therapy and received clozapine in our clinic. We conclude (1) that the alleged NMS induction by clozapine monotherapy needs further substantiation and (2) that clozapine should be considered a drug of choice if a psychotic relapse necessitates neuroleptic treatment for patients with a history of NMS.

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders; Recurrence

Full neuropharmacological understanding of the atypical antipsychotic agent clozapine remains elusive. Antidopaminergic actions of most neuroleptics probably contribute to their antipsychotic benefits, but also to neurological side-effects. Clinical evidence of abnormalities of dopamine (DA) and serotonin (5-HT) in psychotic disorders is inconsistent, but there is substantial metabolic and post-mortem evidence for hyperactivity of noradrenaline (NA). Clozapine is only weakly antidopaminergic but is a potent antagonist at brain alpha 1-adrenergic, 5-HT2-serotonergic, and muscarinic receptors. Its apparent limbic-over-extrapyramidal neurophysiological selectivity can be mimicked by combining a typical neuroleptic with a central alpha 1 antagonist. Clozapine strongly upregulates alpha 1, but not DA, receptor abundance, and may supersensitise alpha 1 but not DA receptors in rat brain. Clozapine also selectively increases activity of NA neurons and metabolic turnover in NA more than DA areas of rat brain, and also increases NA, but not DA or 5-HT, metabolites in human CSF. Potential psychotropic effects of selective central antiadrenergic agents may deserve reconsideration.

Topics: Clozapine; Female; Humans; Male; Parasympatholytics; Psychotic Disorders

Clozapine's clinical profile is unique among antipsychotic drugs. What makes it different? For almost two decades researchers have been attempting to answer this question. Based on various data, many hypotheses have been proposed. Using electrophysiological techniques we have found that clozapine, like typical antipsychotic drugs, inactivates most midbrain dopamine cells secondary to the induction of depolarisation block. However, unlike classical antipsychotic drugs, clozapine does not inactivate the nigrostriatal dopamine system. Based on these and other findings the hypothesis of 'depolarisation block' is reviewed and presented as an explanation for clozapine's unique clinical profile. Research data both for and against the hypothesis are then discussed.

Topics: Clozapine; Dopamine; Female; Humans; Male; Psychotic Disorders

The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medication's actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.

Topics: Adult; Aged; Agranulocytosis; Blood Chemical Analysis; Central Nervous System Diseases; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders; Seizures

Topics: Clozapine; Humans; Parkinson Disease; Psychotic Disorders; Tremor

Clozapine is the first truly new antipsychotic drug introduced in the last 40 years. Compared to traditional neuroleptic agents, clozapine appears to have a stronger effect on most schizophrenic symptoms. Thus, it seems to be more effective than other agents in severely ill, treatment-resistant patients. Clozapine rarely causes extrapyramidal symptoms such as pseudoparkinsonism or akathisia. To date, no confirmed cases of tardive dyskinesia have been attributed to the drug. Despite these advantages, the usefulness of clozapine is limited by its potentially life-threatening side effects, which include agranulocytosis and respiratory depression.

Topics: Agranulocytosis; Clozapine; Humans; Psychotic Disorders

Topics: Agranulocytosis; Clozapine; Humans; Psychotic Disorders

Topics: Brain; Clozapine; Dibenzazepines; Humans; Psychotic Disorders; Receptors, Neurotransmitter; Risk Factors

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 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

Topics: Antidepressive Agents; Clozapine; Depressive Disorder; Dopamine; Electroconvulsive Therapy; Female; Homovanillic Acid; Humans; Levodopa; Male; Mental Disorders; Nomifensine; Nortriptyline; Parkinson Disease; Personality; Psychotic Disorders; Serotonin; Tryptophan

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Psychotic Disorders

Antipsychotic induced weight gain is a frequent reason for treatment discontinuation in psychosis, subsequently increasing the risk of relapse and negatively affecting patient well-being. The metabolic effect of weight gain and the subsequent risk of obesity constitute a major medical problem on the long term. Despite its consequences, to date few risk factors have been identified (age, gender, body mass index at baseline), with some authors suggesting the implication of early life stressful events, such as perinatal conditions. We aim to describe if a surrogate marker of intrauterine environment (birth weight) might predict weight gain in a cohort of 23 antipsychotic naïve patients at the onset of the psychotic disease evaluated during 16 weeks with olanzapine treatment and in another cohort of 24 psychosis-resistant patients initiating clozapine assessed for 18 weeks. Two independent linear mixed model analyses were performed in each cohort of patients, with prospective weight gain as the dependent variable, age, gender, body mass index, duration of treatment and time as independent variables. Only in naïve patients, weight gain due to antipsychotics was significantly associated with birth weight, while male gender and body mass index at baseline were associated in both cohorts of patients. Treatment-resistant psychotic patients under clozapine were older, had previous antipsychotic treatment and more years of disease, confounders that might have influence a non significant association. Our results suggest that early environmental events might be playing a role in weight evolution in naïve patients treated with antipsychotics.

Topics: Adult; Antipsychotic Agents; Birth Weight; Body Mass Index; Clozapine; Cohort Studies; Female; Humans; Male; Models, Biological; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Psychotic Disorders; Sex Factors; Weight Gain; 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

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

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

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

Mental disorder is associated with criminal reoffending, especially violent acts of offending. Features of mental disorder, psychosocial stresses, substance use disorder, and personality disorder combine to increase the risk of criminal recidivism. Clozapine, an atypical antipsychotic, is indicated in the treatment of patients with psychotic disorders. This article is the report of a community follow-up study of a matched control of those treated with clozapine (n = 41) and those treated with other antipsychotics (n = 21). Rates of reoffending behavior in the general, nonviolent, violent, and sexual categories were calculated after two years of follow-up. Although not statistically significant, the two-year criminal conviction rates of those treated with other antipsychotics in all offense categories except sexual reoffending were two-fold higher than in those treated with clozapine. The time from release to the first offense and crime-free time in the community were significantly longer in the clozapine group. By prolonging the time it takes from release to first offense, clozapine confers additional crime-reduction advantages.

Topics: Antipsychotic Agents; Clozapine; Crime; Criminals; Follow-Up Studies; Humans; Psychotic Disorders

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

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

People with psychosis often experience weight gain, which places them at risk of cardiovascular disease, diabetes, and early death.. To determine the uptake, adherence, and clinical effectiveness of a healthy living intervention designed to reduce weight gain.. An exploratory randomized controlled trial, comparing the intervention with treatment as usual (TAU) in 2 early intervention services for psychosis in England. DSM-IV classification was the diagnostic criteria used to assign the psychiatric diagnoses. The primary outcome was change in body mass index (BMI) from baseline to 12-month follow-up. The study was conducted between February 2009 and October 2012.. 105 service users, with a BMI of ≥ 25 (≥ 24 in South Asians), were randomized to intervention (n = 54) or TAU (n = 51) after stratification by recent commencement of antipsychotic medication. Ninety-three service users (89%) were followed up at 12 months. Between-group difference in change in BMI was not significant (effect size = 0.11). The effect of the intervention was larger (effect size = 0.54, not significant) in 15 intervention (28%) and 10 TAU (20%) participants who were taking olanzapine or clozapine at randomization.. The healthy living intervention did not show a significant difference in BMI reduction compared to the TAU group.. www.isrctn.org identifier: ISRCTN22581937.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Diet; Drug Therapy, Combination; Female; Follow-Up Studies; Health Behavior; Humans; Male; Motor Activity; Olanzapine; Pilot Projects; Psychiatric Status Rating Scales; Psychotherapy; Psychotic Disorders; Single-Blind Method; Treatment Outcome; Young Adult

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

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

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

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

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

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

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

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

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

To investigate the neurocognitive effectiveness of haloperidol, risperidone, and olanzapine in first-episode schizophrenia-spectrum disorders.. This prospective, randomized, open-label study was conducted from February 2001 to February 2005. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention program of first-episode psychosis (DSM-IV criteria) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred four patients randomly assigned to haloperidol (N = 35), olanzapine (N = 30), or risperidone (N = 39) who completed clinical and cognitive evaluations at baseline, 6 months, and 1 year were included in the final analysis. Thirty-seven healthy individuals were also longitudinally assessed. A neuropsychological battery that comprised 9 cognitive domains was used. The contribution of clinical changes, concomitant medications, and the severity of motor side effects to cognitive changes was controlled. The main outcome measure was cognitive changes at 1-year follow-up.. The 3 treatment groups showed a significant improvement in cognitive scores after 1 year. The differential cognitive effectiveness between antipsychotics was insignificant. The magnitude of cognitive changes was similar in the 3 treatment groups and controls, although a greater improvement on the Finger Tapping Test, Trail Making Test B, and Rey Complex Figure Test was found in the treatment groups. Clinical changes, use of concomitant medications, and the emergence of motor side effects did not significantly account for cognitive changes over time.. Haloperidol, olanzapine, and risperidone were equally effective in treating cognitive deficits of psychosis. The effect of practice clearly contributes to cognitive score improvements after treatment with antipsychotics. Our results provide important information regarding the practical utility of antipsychotic treatments to improve cognition and could have implications for developing novel approaches for cognitive pharmacotherapy in schizophrenia.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Brain; Clozapine; Cognition Disorders; Female; Follow-Up Studies; Haloperidol; Humans; Male; Neuropsychological Tests; Olanzapine; Perphenazine; Piperazines; Prospective Studies; Psychotic Disorders; Risperidone; Severity of Illness Index; Sulpiride; Thiazoles

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 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

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

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

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

Undesirable metabolic effects of modern antipsychotics, especially clozapine and olanzapine, merit development of new weight-control strategies, including pharmacologic ones. We investigated the feasibility of treatment with orlistat, a weight-control drug with no central effects, for overweight/obesity in clozapine- or olanzapine-treated male and female patients.. Add-on orlistat was prescribed for 16 weeks in a randomized, double-blind, placebo-controlled clinical trial to patients who were receiving stable clozapine or olanzapine medication and were aged 18 to 65 years, with no compliance with nonpharmacologic programs or hypocaloric diet required. The primary efficacy variable was body weight change. The study was conducted from 2004 through 2005.. Of 71 randomly assigned subjects, 63 were eligible for modified intent-to-treat analysis. While no statistically significant effect was observed in the whole population, male (but not female) patients benefited from treatment with orlistat (-2.36 kg vs. 0.62 kg on placebo, p = .011). There were 5 responders (16.1%) (those with >or= 5% weight loss) that received orlistat versus 2 responders (6.3%) that received placebo (number needed to treat = 11), but the difference was not statistically significant.. Without a hypocaloric diet, the effect of orlistat in overweight/obese clozapine-or olanzapine-treated patients is modest and may only be seen in men. More studies should define the optimal length of treatment and feasibility of combination of orlistat with behavioral programs in this population.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Double-Blind Method; Female; Humans; Lactones; Male; Middle Aged; Obesity; Olanzapine; Orlistat; Overweight; Psychotic Disorders

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

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

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

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

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

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

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

Creatine kinase is an important enzyme in the energy metabolism of many cell types, including muscle cells. Increased serum levels of creatine kinase may serve as a marker of enhanced creatine kinase synthesis in muscle cells or muscle cell membrane damage. The purpose of this study was to compare serum creatine kinase levels in chronic psychosis patients treated with either atypical or conventional antipsychotics. Forty-nine patients, receiving clozapine (n=18), or olanzapine (n=18), or conventional agents (n=13), were studied. Fasting serum samples were analyzed for creatine kinase. A significant difference in median creatine kinase level was found among the treatment groups (p=0.03), in that the creatine kinase level was higher both in the patients receiving clozapine and in the patients receiving olanzapine, compared to that in patients receiving conventional antipsychotics, p=0.001 and p<0.0001, respectively. In addition, elevated creatine kinase levels above the upper limit of normal were found in 6 (17%) of the patients treated with clozapine or olanzapine, but in none of the patients treated with conventional agents. In summary, the present results indicate that therapy with atypical antipsychotics like clozapine and olanzapine, in contrast to conventional agents, may be associated with serum creatine kinase elevation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chromatography, High Pressure Liquid; Clozapine; Creatine Kinase; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders

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

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

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

Topics: Adult; Amisulpride; Antipsychotic Agents; Clozapine; Drug Combinations; Drug Interactions; Female; Half-Life; Humans; Male; Middle Aged; Psychotic Disorders; Spectrophotometry, Ultraviolet; Sulpiride

Topics: Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Lamotrigine; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triazines

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 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

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

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

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

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

Sleep disturbances are strongly associated with mood disorders, although the majority of data have been obtained in patients with major depressive disorder. Studies reporting results in bipolar disorder are few, and results have not been consistent. Clozapine is a prototype of atypical antipsychotics, which is effective in improving symptoms of manic episodes in patients with bipolar disorder, or schizoaffective disorder, bipolar type and has been shown to influence sleep in other psychiatric disorders. The present study evaluated the sleep effects of clozapine in bipolar and schizoaffective disorders.. Participants were 11 women and 4 men (range:28-53 years of age, mean 40.9+/-8.6 years), all with a history of mania by DSM-IV criteria for either bipolar I disorder or schizoaffective disorder, bipolar type. They participated in a sleep study at baseline and again after 6 months initiation of clozapine add-on therapy.. Sleep latency was longer on clozapine and the number of awakenings were increased, whereas time in bed (TIB) and total sleep period (TSP) were increased (range: F=6.2-17.9; df=l,12; p<0.05). Although none of the individual sleep stage showed significant treatment changes, both Stage 2 and slow-wave sleep were increased and Stage 2 decreased on clozapine. Subjective sleep measures improved on clozapine with a small but significant improvement in how rested patients felt upon awakening (t=-2.1; df=26; p<0.05).. Clozapine prolonged sleep latency, improved restedness, and increased total sleep time. Although lack of a control group limits interpretation of these results, they are in general agreement with studies in other psychiatric populations, and support the view that clozapine is primarily a NREM sleep enhancer. The improvement in restedness may be of positive clinical consequence.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Polysomnography; Psychiatric Status Rating Scales; Psychotic Disorders; Sleep Stages; Sleep Wake Disorders

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

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

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

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

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 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

To examine the long-term outcome of PD patients with psychosis requiring antipsychotic therapy; to explore predictors of mortality, nursing home placement, dementia, and persistent psychosis; and to compare outcomes of those with persistent psychosis vs those whose psychosis resolved.. Baseline data available from 59 patients enrolled in the PSYCLOPS (PSychosis and CLOzapine in PD Study) trial included age, age at onset of PD, duration of PD and psychosis, character of psychosis, medications, living setting, and scores for Mini-Mental State Examination (MMSE), Unified Parkinson's Disease Rating Scale, Hoehn and Yahr Scale, and Clinical Global Impression Scale. Longitudinal data were collected 26 months later regarding four outcomes: death, nursing home placement, diagnosis of dementia, and persistence of psychosis. Logistic regression was used to explore whether any baseline characteristics were associated with an increased likelihood of one of these outcomes.. At baseline, 56% of patients had an MMSE score of <25, 12% were in a nursing home, 95% had hallucinations, and 60% had paranoia. On follow-up, 25% were dead, nursing home placement occurred in 42%, psychosis was persistent in 69%, and dementia was diagnosed in 68%. Select baseline characteristics predicted individual outcomes: Nursing home placement was associated with the presence of paranoia and older age; persistent psychosis was associated with younger age at onset of PD and longer disease duration; dementia was associated with older age at PD onset and lower initial MMSE score; no characteristics predicted death. Whether psychosis persisted or not had no significant effect on the development of the other three outcomes. The prevalence of hallucinations at follow-up was not different between groups currently receiving antipsychotics vs those on no treatment.. Psychosis in PD requiring antipsychotic therapy is frequently associated with death, nursing home placement, development and progression of dementia, and persistence of psychosis. Still, it appears the prognosis has improved with atypical antipsychotic therapy based on the finding that 28% of NH patients died within 2 years compared with 100% in a previous study done prior to availability of this treatment.

Topics: Aged; Antipsychotic Agents; Clozapine; Dementia; Double-Blind Method; Female; Hallucinations; Humans; Longitudinal Studies; Male; Nursing Homes; Parkinson Disease; Psychotic Disorders; 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

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

The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder.. In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period).. Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain.. The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Patient Admission; Pirenzepine; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Newer antipsychotic drugs have shown promise in ameliorating neurocognitive deficits in patients with schizophrenia, but few studies have compared newer antipsychotic drugs with both clozapine and conventional agents, particularly in patients who have had suboptimal response to prior treatments.. The authors examined the effects of clozapine, olanzapine, risperidone, and haloperidol on 16 measures of neurocognitive functioning in a double-blind, 14-week trial involving 101 patients. A global score was computed along with scores in four neurocognitive domains: memory, attention, motor function, and general executive and perceptual organization.. Global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were superior to those seen with haloperidol. Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with other treatments. Patients treated with risperidone exhibited improvement in memory that was superior to that of both clozapine and haloperidol. Clozapine yielded improvement in motor function but not more than in other groups. Average effect sizes for change were in the small to medium range. More than half of the patients treated with olanzapine and risperidone experienced "clinically significant" improvement (changes in score of at least one-half standard deviation relative to baseline). These findings did not appear to be mediated by changes in symptoms, side effects, or blood levels of medications.. Patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs, and there may be differences between atypical antipsychotic drugs in their patterns of cognitive effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Double-Blind Method; Female; Haloperidol; Humans; Male; Neuropsychological Tests; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine was discovered in 1959 but withheld from the United States market after several deaths due to agranulocytosis. The medication was approved in the United States in 1989 on a compassionate-use basis and was first marketed in 1990 as Clozaril. In 1999, following approval by the U.S. Food and Drug Administration, Zenith Goldline Pharmaceuticals (ZGP) introduced a generic form of clozapine.. After 5 weeks of data collection (phase I), 24 patients were randomly assigned to group A and 21 patients to group B. Patients had DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, or atypical psychosis with mood disorder. In phase II, group A received a mean daily dose of 630 mg of generic clozapine, and group B continued to receive Clozaril at a mean daily dose of 610 mg, each for 8 weeks. In phase III, group A was reassigned to Clozaril, and group B was switched to generic clozapine, each for 8 weeks. At the end of phase III, group B resumed Clozaril. Efficacy was measured with the Clinical Global Impressions-Improvement (CGI-I) scale, the Brief Psychiatric Rating Scale (BPRS), and the Beck Depression Inventory (BDI).. Five patients experienced relapse when they were switched from Clozaril to generic clozapine. Eleven patients worsened short of full relapse, 9 while receiving ZGP generic clozapine and 2 while receiving Clozaril. CGI-I scores and BPRS scores favored patients receiving Clozaril significantly. Only BDI scores favored patients receiving generic clozapine significantly.. Until more studies have been performed, clinicians and administrators should carefully monitor stable Clozaril-treated patients who are being switched to generic clozapine.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Cost Savings; Drug Administration Schedule; Drug Costs; Drugs, Generic; Female; Humans; Male; Personality Inventory; Psychiatric Status Rating Scales; Psychotic Disorders; Recurrence; Schizophrenia; Schizophrenic Psychology; Therapeutic Equivalency; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychotic Disorders; Risperidone; Substance-Related Disorders; Treatment Outcome

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

Topics: Adult; Aged; Antipsychotic Agents; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Psychotic Disorders; Reference Values; Schizophrenia; Smoking

Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months.. Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled.. Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol.. Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Topics: Adult; Anorexia; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Xerostomia

This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol.. A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE).. Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol.. Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Emotions; Female; Haloperidol; Hostility; Humans; Linear Models; Male; Olanzapine; Pirenzepine; Prospective Studies; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Statistics, Nonparametric; Survival Analysis

There is a paucity of data on the use of clozapine in patients with mental retardation and comorbid psychiatric illness. The authors describe their recent clinical experience using clozapine in treatment-refractory patients with mental retardation and severe psychiatric illness.. A retrospective review was performed on the records of all patients admitted to a university-affiliated, specialized inpatient psychiatry service who were selected for clozapine therapy from March 1994 through December 1997 (N = 33). Patients had DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder, or psychotic disorder NOS and were considered treatment resistant. All had deficits in functioning well beyond those expected for their degree of cognitive deficits and adaptive delays.. Of 33 initial patients, 26 remained on clozapine therapy for a follow-up duration of 5 to 48 months (mean = 24.8 months). Evaluation at follow-up revealed Clinical Global Impressions-Improvement (CGI-I) scores from 1 to 4 with a mean +/- SD improvement of 2.0 +/- 0.8 (much improved). The mean +/- SD rating of the CGI-Efficacy Index was 5 +/- 2.6 (decided improvement and partial remission of symptoms with no interference from side effects). The 6 patients who were not maintained on clozapine therapy over the study period did not significantly differ from the clozapine group in gender, race, age, side effects, or diagnosis. One patient was lost to follow-up. Side effects were mild and transient with constipation being the most common (N = 10). There were no significant cardiovascular side effects and no seizures. No patients discontinued treatment due to agranulocytosis.. The current investigation lends support to the conclusion that clozapine appears to be safe, efficacious, and well tolerated in individuals with mental retardation and comorbid psychiatric illness.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Comorbidity; Female; Follow-Up Studies; Humans; Intellectual Disability; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenia, Paranoid; Treatment Outcome

This study evaluated anticholinergic effects among patients with schizophrenia, schizoaffective disorder, or bipolar I disorder who were receiving either olanzapine (N = 12) or clozapine (N = 12) at standard clinical doses in a naturalistic setting. Serum anticholinergic levels were determined in adult male and female subjects using a radioreceptor binding assay. The Udvalg for Kliniske Undersogelser Scale was used to evaluate anticholinergic side effects clinically, and the Mini-Mental State Examination provided a global cognitive measure. Patients had achieved target doses that were stable at the time at which blood samples were obtained, and no other concomitant medicine with known anticholinergic potential was allowed. Patients receiving olanzapine (average dose, 15 mg/day) had serum anticholinergic levels of 0.96 (+/-0.55) pmol/ atropine equivalents compared with levels of 5.47 (+/-3.33) pmol/atropine equivalents for those receiving clozapine (average dose, 444 mg/day) (p < 0.001). Rates of increased and decreased salivation were significantly more common among the clozapine- and olanzapine-treated patients, respectively, whereas constipation, urinary disturbances, and tachycardia/palpitations were significantly more common among clozapine-treated patients. Neither group showed any global cognitive deficits. Olanzapine-treated patients had serum anticholinergic levels that were less than one fifth those of the clozapine-treated patients. Furthermore, clinical evaluations confirmed that clozapine-treated patients experienced more frequent and severe anticholinergic side effects (except dry mouth). However, none of the patients in either group expressed any desire to discontinue these medications as a result of the anticholinergic side effects.

Topics: Adult; Antipsychotic Agents; Atropine; Autonomic Nervous System Diseases; Benzodiazepines; Cholinergic Antagonists; Clozapine; Female; Humans; Male; Muscarinic Antagonists; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Psychotic Disorders; Radioligand Assay; Receptors, Muscarinic

The goal of this 5-year naturalistic study of patients treated with clozapine was to examine the incidence of treatment-emergent diabetes mellitus in relation to other factors, including weight gain, lipid abnormalities, age, clozapine dose, and treatment with valproate.. Data on age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation were collected from medical records of 82 outpatients with schizophrenia or schizoaffective disorder. Clozapine dose, data on use of valproate, and laboratory test results were recorded at 6-month intervals.. The mean age at the time of clozapine initiation of the 82 patients was 36.4 years; 26.8% of the patients were women, and 91.5% were Caucasian. The mean baseline weight was 175.5 lb, and the mean body mass index was 26.9 kg/m(2). Thirty patients (36.6%) were diagnosed with diabetes during the 5-year follow-up. Weight gain, use of valproate, and total daily dose of clozapine were not significant risk factors for developing diabetes mellitus. Patients experienced significant weight gain that continued until approximately month 46 from initiation of clozapine. There was a nonsignificant increase in total serum cholesterol and a significant increase in serum triglycerides level.. The results support the hypotheses that patients treated with clozapine experience significant weight gain and lipid abnormalities and appear to be at increased risk for developing diabetes.

Topics: Adult; Age Factors; Antipsychotic Agents; Body Mass Index; Body Weight; Cholesterol; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Family; Female; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Hypertriglyceridemia; Incidence; Male; Obesity; Psychotic Disorders; Risk Factors; Schizophrenia; Triglycerides; Valproic Acid

The aim of this study was to evaluate the 24-month response to clozapine in patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder.. Ninety-one psychotic patients with a principal DSM-III-R diagnosis of schizophrenia (N = 31), schizoaffective disorder (N = 26), or bipolar disorder with psychotic features (N = 34) were treated naturalistically with clozapine at flexible dosages over a 24-month period. Improvement was assessed by the 18-item Brief Psychiatric Rating Scale and the Clinical Global Impressions-Severity of Illness scale.. All patients showed significant improvement 24 months from intake (p < .001). Such an improvement was significantly greater among patients with schizoaffective disorder or bipolar disorder than in patients with schizophrenia (p < .05). The presence of suicidal ideation at intake predicted greater improvement at endpoint.. Clozapine appears to be effective and relatively well tolerated in acute and long-term treatment of patients with psychotic bipolar disorder or schizoaffective disorder who have not responded to conventional pharmacotherapies.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Comorbidity; Female; Follow-Up Studies; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Suicide; Treatment Outcome

The authors compared efficacy and safety of risperidone and clozapine for the treatment of psychosis in a double-blind trial with 10 subjects with Parkinson's disease (PD) and psychosis. Mean improvement in the Brief Psychiatric Rating Scale psychosis score was similar in the clozapine and the risperidone groups (P=0.23). Although the mean motor Unified Parkinson's Disease Rating Scale score worsened in the risperidone group and improved in the clozapine group, this difference did not reach statistical significance. One subject on clozapine developed neutropenia. In subjects with PD, risperidone may be considered as an alternative to clozapine because it is as effective for the treatment of psychoses without the hematologic, antimuscarinic, and seizure side effects. However, risperidone may worsen extrapyramidal symptoms more than clozapine and therefore must be used with caution.

Topics: Aged; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Double-Blind Method; Humans; Middle Aged; Parkinson Disease; Psychotic Disorders; Risperidone

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.

Topics: Adult; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Paroxetine; Psychotic Disorders; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Sertraline

Clozapine is an atypical antipsychotic indicated for the management of severely ill patients with schizophrenia who have failed to respond adequately to standard drug treatment. The significant risk of agranulocytosis and seizure associated with clozapine has led to the restrictions in its use. Additionally, drug-induced sedation, sialorrhea, enuresis, and weight gain are often cited as problematic consequences of clozapine treatment. Our primary objective was to determine the effectiveness and safety of a method of slow cross-titration from clozapine to olanzapine among patients responsive to clozapine treatment but experiencing medication-induced adverse events.. Changes in symptomatology, mood, subjective response, and safety were examined in 20 outpatients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder who converted from clozapine to olanzapine. Patients were considered clozapine-responsive as evidenced by improved social function and decreased symptoms with clozapine therapy; however, they were interested in alternative pharmacologic treatment because of clozapine-related side effects.. Equivalent efficacy of olanzapine to clozapine was found in 90% of the patients (18/20) in the study group, without rehospitalization or suicidal behavior in any of the patients. Also notable was a reduction in drug-induced side effects and improved subjective response to pharmacotherapy.. The successful conversion from clozapine to olanzapine has the potential to provide great benefits for the patient, including reducing drug-induced side effects while maintaining symptom control. These preliminary results suggest that further research on converting clozapine responders to olanzapine is warranted.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine, risperidone, and other new "atypical" antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.

Topics: Adult; Amphetamine; Antipsychotic Agents; Clozapine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neostriatum; Psychotic Disorders; Raclopride; Risperidone; Salicylamides; Tomography, Emission-Computed

Fluvoxamine (FLUVOX) is an inhibitor of the cytochrome P450 isoenzyme 1 A2 and thereby inhibits clozapine (CLOZ) metabolism. We performed an open clinical study to gather experience in necessary dosages, plasma levels, side effects and clinical efficiency of the coadministration of the two drugs. Eighteen psychotic patients were studied. 50 mg FLUVOX were given throughout the study period, while the CLOZ dosage was increased individually (week 5: 96.9+/-37.2 mg). After 5 weeks the plasma concentrations were as follows: CLOZ 252+/-174 ng/ml, N-desmethylclozapine (DM-CLOZ) 143+/-74 ng/ml and clozapine N-oxide (CLOZ N-OX) 30+/-14 ng/ml. There were no differences in side effects, especially sedation, after 5 weeks compared to the pretreatment condition. Moreover, we found a significant improvement in measures of cognitive speed which might be regarded as a measure of vigilance. The BPRS scores dropped continuously until week 5 (pretreatment: 53.3+/-13.4; week 5: 33.2+/-12.9) and 5 patients were considered treatment responders (BPRS reduction > 50%). Ten patients continued the combination treatment after the study period and 9 of these patients were in clinical remission when discharged. Given strict therapeutic drug monitoring, coadministration of FLUVOX and CLOZ seems to be a safe and efficient treatment strategy with a low occurrence of the side effects associated with CLOZ treatment. This might be due to additive effects of the two drugs and/or metabolic interaction.

Topics: Adult; Anti-Anxiety Agents; Antipsychotic Agents; Clozapine; Depressive Disorder; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Psychotic Disorders; Schizophrenia; Schizophrenia, Paranoid

Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania.. Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study.. Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder.. The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Regression Analysis; Treatment Outcome

This study explored the relative efficacy of three different doses of clozapine.. Fifty patients who met Kane et al.'s criteria for treatment-refractory schizophrenia or schizoaffective disorder were studied. All subjects were randomly assigned to 100, 300, or 600 mg/day of clozapine for 16 weeks of double-blind treatment. Forty-eight patients completed this first 16 weeks. Of the 50 patients, 36 went on to second and third 16-week trials of double-blind treatment at the remaining doses.. Four subjects (8%) responded to the first 16-week condition, and one subject (2%) responded to the next 16-week crossover condition. A chi-square comparison of the response rates from the three dose groups failed to show a significant effect. An analysis of variance (ANOVA) comparison of Brief Psychiatric Rating Scale-Anchored (BPRS-A) total change scores from baseline to last observation carried forward showed a significant dose effect (600>300>100 mg/day) at 16 weeks of treatment. A crossover ANOVA of the BPRS-A total scores from the 48-week study also showed that the main effect for dose was highly significant; the 100-mg/day dose gave the higher (poorer) values, and the 300- and 600-mg/ day doses gave equal (better) values. Gender played a role in clinical response to treatment at 100 mg/day.. Clozapine treatment at 100 mg/day was less effective than at 300 or 600 mg/day. At 100 mg/day, women responded better than did men. The 600 mg/day group had the best results, but an occasional patient required up to 900 mg/day. Overall response rates were lower than expected.

Topics: Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Male; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Acute extrapyramidal side effects (EPS) are a common phenomenon of treatment with conventional antipsychotics. Previous studies found that clozapine has little propensity to cause EPS, while risperidone produces some EPS, but at levels lower than those of conventional antipsychotics.. We compared the prevalence and severity of EPS in patients treated with clozapine, risperidone, or conventional antipsychotics for at least 3 months. Our main hypothesis was that there would be differences between the three treatment groups with regard to akathisia, measured with the Barnes Akathisia Scale, and extrapyramidal motor side effects (rigidity, rigidity factor, tremor, salivation), measured with the Simpson-Angus scale. Secondarily, we were interested in possible differences between the three groups with respect to the anticholinergic comedication and the subjective impression of the patients, measured with the van Putten scale.. We studied 106 patients (41 patients treated with clozapine, 23 patients with risperidone, and 42 patients treated with conventional antipsychotics). The sample was 57.5% male and had a mean +/- SD age of 36.6 +/- 9.3 years. The mean dose of antipsychotics calculated in chlorpromazine equivalents was 425.6 +/- 197.1 mg/day in the clozapine group, 4.7 +/- 2.1 mg/day in the risperidone group, and 476.5 +/- 476.9 mg/day in the group treated with conventional antipsychotics. The point-prevalence of akathisia was 7.3% in the clozapine group, 13% in the risperidone group, and 23.8% in the group treated with conventional antipsychotics. The point-prevalence of rigidity and cogwheeling respectively was 4.9% and 2.4% in the clozapine group, 17.4% and 17.4% in the risperidone group, and 35.7% and 26.2% in the group treated with conventional antipsychotics.. Our results indicate that risperidone is superior to conventional neuroleptics in that it causes fewer EPS. In comparison to clozapine, risperidone produces EPS levels that are intermediate between clozapine and conventional antipsychotic drugs.

Topics: Acute Disease; Adolescent; Adult; Akathisia, Drug-Induced; Ambulatory Care; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Prevalence; Product Surveillance, Postmarketing; Psychotic Disorders; Risperidone; Schizophrenia; Severity of Illness Index

The cost, side effect profile, and required weekly blood draws associated with clozapine may dissuade some clinicians from prescribing this atypical neuroleptic to mentally retarded patients. All publications on clozapine use in mentally retarded patients are reviewed and the treatment of 10 such patients is described, bringing the total number of published cases to 84. Clozapine is efficacious and well tolerated in this population and should be considered for those patients with psychosis or bipolar illness who are intolerant of or unresponsive to other agents.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Follow-Up Studies; Humans; Intellectual Disability; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders

The aim of this naturalistic study was to compare the outcome of patients who continued on clozapine with that of those who discontinued treatment with this drug. Data from 113 patients who commenced clozapine between January 1990 and June 1995 were available for analysis. The main outcome measures were hospitalization status at each anniversary since starting treatment, and the proportion of time spent in hospital by the survey endpoint. On average, patients had been ill for 11.8 years (SD 7.9) and had spent a total of 3.5 years (SD 5.3) in hospital, before treatment with clozapine. The mean duration of follow-up was 2.5 years (SD 1.25, range: 0.32-5.5), by which time 39 patients (35%) had discontinued clozapine. Patients who remained on clozapine (n = 74) were no more likely to have been discharged from hospital than those who discontinued it (n = 39) by the end of the first, second or third year of treatment (p < 0.05). Recent reports of the cost-effectiveness of clozapine treatment should be interpreted with caution.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Follow-Up Studies; Humans; Long-Term Care; Male; Patient Dropouts; Psychotic Disorders; Treatment Outcome

Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Evoked Potentials; Female; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Seizures

In the present study we tested the hypothesis that individual response to clozapine treatment and/or the occurrence of side-effects may be influenced by genetic variation in the serotonin 5-HT2C receptor. We investigated the frequency of a common Cys23Ser substitution, which is known to alter the pharmacological properties of the protein, in 152 patients treated with clozapine. Presence of the Ser23 variant was previously reported to predict a good response to clozapine. However, our results did not support an association between genetic variation of the 5-HT2C receptor and response to clozapine. This held true whether the patients were subgrouped for sex and length of treatment. Moreover, we found no consistent association with any of the observed side-effects.

Topics: Adult; Alleles; Antipsychotic Agents; Clozapine; Female; Genotype; Humans; Male; Mutation; Polymerase Chain Reaction; Psychotic Disorders; Receptors, Serotonin; Schizophrenia; Seizures; Weight Gain

We conducted a within-subject comparison of the effects of clozapine and haloperidol on plasma levels of neurotransmitters and metabolites, and related changes in specific plasma neurochemicals with clozapine response. The subjects were 14 inpatients with schizophrenia or schzoaffective disorder, who were refractory to haloperidol and at least one other typical antipsychotic medication. Subjects underwent, in the following order: a 6-week "fixed, flexible dose" haloperidol trial, followed by a 2-4 week medication-free phase, and a 6-week clozapine trial. Plasma levels of norepinephrine (NE), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), and objective clinical ratings of total, positive, negative, and depressive symptoms were obtained at the end of each phase. As expected, we found a substantial increase of plasma NE with clozapine but not with haloperidol. However, the increase in NE was not associated with improvement in total or positive symptomatology. There was some evidence for an association between improvement in negative symptoms and increased HVA on clozapine, as well as diminished HVA during the medication-free phase. The implications of these data for understanding the mechanisms of action of clozapine are discussed.

Topics: Aged; Analysis of Variance; Antipsychotic Agents; Clozapine; Haloperidol; Homovanillic Acid; Humans; Hydrocortisone; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Prolactin; Psychotic Disorders; Schizophrenia

We investigated the striatal dopamine-2 (D2) receptor occupancy caused by different antipsychotic substances in 18 psychotic patients (16 with schizophrenic and two with schizoaffective disorder according to DSM-IV) with single photon emission computed tomography (SPECT) using 123I-iodobenzamide (IBZM) as tracer substance. Four patients were treated with the novel antipsychotic compound quetiapine (300-700 mg/day), six with clozapine (300-600 mg/ day) and eight with haloperidol (10-20 mg/day). They were compared with eight healthy controls. Measurement of S/F ratios and consecutive calculation of D2 receptor occupancy revealed a significantly lower striatal D2 occupancy rate with quetiapine and clozapine in comparison to haloperidol. In correspondence with the low striatal D2 receptor occupancy rates and again in contrast to the haloperidol treatment group, there were no extrapyramidal motor side-effects (EPS) in the quetiapine and clozapine treatment groups. Therefore, the reported data support the position that quetiapine can be considered to be an atypical antipsychotic substance due to its relatively weak striatal D2 receptor blocking property and therefore its low propensity to induce EPS.

Topics: Adult; Antipsychotic Agents; Benzamides; Clozapine; Dibenzothiazepines; Dopamine Antagonists; Female; Haloperidol; Humans; Male; Middle Aged; Neostriatum; Psychotic Disorders; Pyrrolidines; Quetiapine Fumarate; Receptors, Dopamine D2; Schizophrenia; Tomography, Emission-Computed, Single-Photon

The purpose of this study was to compare the side effect +profiles of clozapine and risperidone.. The subjects were 20 outpatients with schizophrenia or schizoaffective disorder who were clinically stable on a regimen of clozapine at the time of screening. They underwent a randomized-order crossover comparison of 6 weeks of risperidone treatment and 6 weeks of clozapine treatment. Clinical and neurocognitive variables were assessed by raters blind to medication status, and severity of side effects was determined from patients' self-reports.. Side effect measures, but not clinical ratings, were significantly different after 6 weeks of treatment with the two drugs. Patients required more benztropine for motor effects and complained of more insomnia with risperidone and more sedation with clozapine. Body weight was higher at the end of clozapine treatment than at the end of risperidone treatment.. In this exploratory study, the side effect profiles of clozapine and risperidone were consistent with the different pharmacodynamic profiles of the two drugs.

Topics: Akathisia, Drug-Induced; Ambulatory Care; Clozapine; Cognition Disorders; Cross-Over Studies; Humans; Neuropsychological Tests; Pilot Projects; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome

After noting a striking difference in the dosing practices of two treating psychiatrists, each responsible for the operation of a clozapine unit in a state psychiatric hospital, the authors conducted a retrospective chart review to assess the clinical efficacy of low dose x = 294 mg. per day) versus high dose (x = 525 mg. per day) clozapine treatment for a cohort of 31 inpatients. Levels of psychopathology, behavior, and social functioning were assessed six months pre and during clozapine treatment for 16 patients who received low dose clozapine treatment and 15 patients who received high dose clozapine treatment. Patients on both units demonstrated significant reductions in their levels of psychopathology, improved social functioning and improvement in their behavior following six months clozapine treatment. This naturalistic study suggests that the use of low dose clozapine provides effective treatment for chronic, severely treatment resistant inpatients with schizophrenia or schizo-affective illness, at the same time reducing the potential for significant side effects.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Dose-Response Relationship, Drug; Female; Hospitalization; Hospitals, Psychiatric; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome

The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder.. The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS).. Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score.. These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.

Topics: Adult; Aged; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Lithium; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Treatment Outcome

Patients who develop psychosis or agitated behavior secondary to neurological disorders present a therapeutic dilemma. The authors review clinical efficacy and side effect profiles of clozapine in a cohort of 16 patients with various neurobehavioral disorders. One-third showed a marked decrease in symptoms while on clozapine. However, one-quarter developed an acute confusional state; of these, all had diffuse slowing on their baseline EEG prior to starting the drug.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Nervous System Diseases; Psychotic Disorders; Retrospective Studies

The records of 49 patients with Parkinson's disease and psychosis who were treated with clozapine for up to 18 months were reviewed. Average starting dose of clozapine was 16 mg. Average maximum dose was 39 mg. The psychotic symptoms improved in 76% of the patients at 3 months, and response to clozapine within the first year ranged from 71% to 80%. This response allowed a maximization of levodopa dose. Improvements in scores on the Unified Parkinson's Disease Rating Scale and tremor subscale were seen in some patients but were not statistically significant. This study, the largest of its kind to date, suggests that clozapine is well tolerated and effective in treating psychosis in patients with Parkinson's disease.

Topics: Aged; Antipsychotic Agents; Clozapine; Female; Humans; Male; Parkinson Disease; Psychotic Disorders; Retrospective Studies

Twenty patients with Parkinson's disease (PD), who developed delusions and psychotic behavior, underwent electroencephalogram (EEG) recordings before and during treatment with low-dose clozapine. Resolution of the psychotic features was observed in all cases. The EEG was unaltered in 15, whereas five patients exhibited increased generalized or focal slowing when compared with the pretreatment tracings. These findings contrast with the high incidence of EEG abnormalities, including epileptiform activity, which are observed when larger doses of clozapine are used in schizophrenic patients, but they underscore that even in low doses, clozapine may cause EEG changes.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders

Treatment with the atypical antipsychotic drug clozapine appears to be associated with an increased incidence of urinary incontinence (UI). We posited that the potent anti-alpha-adrenergic effects of clozapine were involved, and hence that an alpha-adrenergic agonist would reduce UI. We tested this hypothesis by using ephedrine, an approved alpha-adrenergic agonist.. Fifty-seven inpatients with schizophrenia or schizoaffective disorder (DSM-IV) who met the Kane criteria for being treatment refractory were treated with clozapine (75-900 mg/day). Patients who developed UI were then openly treated with ephedrine in increasing doses until UI was attenuated or a dose of 150 mg/day was attained.. Seventeen patients developed UI as evidenced by either urine-stained sheets/clothing or direct patient reports. In 2 cases, the UI was sufficiently severe that adult diapers had to be used. Comparison of patients who developed UI and those who did not showed that UI was associated with female gender and with concomitant treatment with typical antipsychotic drugs. One patient was treated with a behavioral program, but the remaining 16 patients were treated with ephedrine. Ephedrine treatment was very effective, with 15/16 patients showing improvement within 24 hours after reaching maximum ephedrine dosage. Twelve of 16 (including the 2 most severe) eventually had a complete remission of their UI. In the remaining 4 patients, 3 had a reduction in the frequency of UI and 1 showed no response. These benefits have been maintained over the course of 12 months of subsequent treatment for several patients. There were no side effects associated with the use of ephedrine nor were there any changes in neuropsychiatric status.. Ephedrine appears to be a safe and effective treatment clozapine-associated UI. By inference, it is likely that clozapine may cause UI via its anti-alpha-adrenergic properties.

Topics: Adrenergic alpha-Agonists; Adult; Aged; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Ephedrine; Female; Humans; Incidence; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Treatment Outcome; Urinary Incontinence

The purpose of this trial was to assess the potential utility of adjunctive treatment with a typical neuroleptic for patients with refractory psychosis insufficiently responsive to clozapine alone. Seven chronic schizophrenic or schizoaffective patients who remained stabilized for at least 9 months on clozapine received open clinical trials with adjunctive loxapine lasting from 18 to 50 weeks. Their symptoms were documented with periodic Brief Psychiatric Rating Scale assessments. All patients improved at least somewhat and two improved remarkably. In the four cases in which the assessment was made, the loxapine had no apparent effect on plasma clozapine levels. We conclude that adjunctive treatment with typical neuroleptics for patients with an incomplete response to clozapine merits further investigation.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Humans; Loxapine; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine has been increasingly shown to be effective in the acute and maintenance treatment of bipolar disorders. For this reason, we studied whether clozapine alone is effective as a mood stabilizer in patients with refractory bipolar disorders.. Subjects were part of a long-term follow-up study cohort of 193 patients with refractory mood disorders who were treated with clozapine at McLean Hospital prior to July 1, 1992. Patients included in this study were those older than 16 years with bipolar disorder (manic or mixed) and schizoaffective disorder, bipolar type, discharged taking clozapine alone (N = 17). Hospital records on all patients were reviewed by trained raters blind to "best-estimate" diagnoses. Response to clozapine was determined by the Clinical Global Impressions-Improvement (CGI-I) scale. Patients were contacted at least 6 months after clozapine initiation for semistructured follow-up interviews by raters blind to diagnosis and baseline information.. Seventeen subjects were contacted 16.1 +/- 5.6 months after clozapine initiation. Most of the 17 patients had previously failed trials of lithium, valproate, carbamazepine, neuroleptics, combinations of these, and electroconvulsive therapy; or had tardive dyskinesia. Of these patients, 65% (11/17) continued to be on clozapine therapy alone at follow-up and had no subsequent rehospitalization or affective episode. At follow-up, there was a significant decrease in the rehospitalization rate (p = .025) than before starting clozapine and a significant improvement in CGI-I scores (p = .02).. Clozapine monotherapy is an effective mood stabilizer, reducing both the number of affective episodes and rehospitalizations in patients with severe refractory bipolar illness.

Topics: Adult; Bipolar Disorder; Clozapine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Readmission; Psychiatric Status Rating Scales; Psychotic Disorders; Recurrence; Retrospective Studies; Schizophrenia; Treatment Outcome

It is well known that psychotropic drugs can induce EEG alterations. Dose dependence seems established; however, there are no data concerning the impact of plasma levels. The authors investigated the influence of clozapine plasma levels on the frequency of EEG alterations. Data from 29 inpatients (18 male, 11 female, 31.7 +/- 10.2 years) receiving clozapine in a dose range between 25 and 600 mg were collected prospectively. There was no psychotropic or anticholinergic comedication. All patients had normal EEGs before taking clozapine. Fifteen patients showed pathological changes (group 2) and 14 no changes (group 1). Discriminant analysis showed that EEG changes are dependent on plasma levels (P = 0.0009, plasma levels in group 1 mean 81.6 ng/ml, +/- SD 64.6, in group 2 235.7 ng/ml, +/- 169.8). A total of 72.4% of the patients were correctly classified as having either pathological EEG changes or none by this analysis. Variables such as dose, age, sex, weight and duration of treatment were not statistically relevant. It can therefore be suggested that clozapine plasma levels are a valid indicator for the appearance of electrophysiological reactions.

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Female; Humans; Male; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

To test the hypothesis that interindividual differences in response to clozapine therapy might be attributable to the D4 dopamine receptor (DRD4) alleles they carry. Different alleles of the D4 dopamine receptor, coded by the DRD4 gene, differ in the affinity with which they bind the atypical antipsychotic drug clozapine in vitro. This may have physiologic implications. Clinical response to clozapine therapy varies among patients. The observation that, in vitro, clozapine binds the protein products of different DRD4 alleles with differing affinity characteristics suggested this hypothesis.. The region of the DRD4 gene that encodes the putative third cytoplasmic loop of the D4 receptor contains a 48-base pair sequence repeated a variable number of times. With use of polymerase chain reaction amplification, we assessed this variable number of tandem repeats polymorphism in a series of schizophrenic and schizoaffective subjects who had been treated with clozapine, and related genotype with treatment response, to test the hypothesis that DRD4 alleles lead to varying response to clozapine.. Allelic variation at the DRD4 locus does not predict clinical response to clozapine relative to either fluphenazine hydrochloride or placebo in subjects with treatment-refractory schizophrenia or schizoaffective disorder.. DRD4 alleles do not predict therapeutic response to clozapine in schizophrenic and schizoaffective patients. There are implications from these data for the pathophysiology of schizophrenia and the mechanism of clozapine's therapeutic effect are discussed.

Topics: Alleles; Base Sequence; Clozapine; Cross-Over Studies; Double-Blind Method; Gene Frequency; Genetic Variation; Genotype; Humans; Molecular Sequence Data; Placebos; Probability; Psychotic Disorders; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Schizophrenia; Treatment Outcome

We treated 17 patients with Parkinson's disease (PD) complicated by psychosis with the atypical antipsychotic drug, clozapine, for 6 to 24 months (mean, 15 months) in a prospective, open-label trial. At 3-month intervals we evaluated patients, using a simplified brief Psychiatric Rating Scale (PRS), the motor examination portion of the Unified Parkinson's Disease Rating Scale, and the Mini-Mental State Examination (MMSE). Mean PRS score was significantly improved when compared with baseline over 1 year (p < 0.01) and nonsignificantly improved for the second year. We maintained the levodopa dose at levels that were 17 to 68% higher than baseline, and the mean motor examination score improved by 11 to 22% in the first 15 months. Clozapine dosage utilized in the trial ranged from 6.25 mg every other day to 150 mg/d. Adverse effects, including sedation and confusion, were common. These results demonstrate that clozapine therapy can be effective in treating psychosis in PD patients over 1 to 2 years. The decline in efficacy in the second year was most likely related to an increase in daily levodopa dose, progression of dementia (illustrated by a decline in MMSE score), and an inability of PD patients to tolerate higher doses of clozapine.

Topics: Aged; Aged, 80 and over; Clozapine; Female; Humans; Male; Middle Aged; Parkinson Disease; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders

Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoxetine; Humans; Male; Psychotic Disorders; Schizophrenia; Stimulation, Chemical; Valproic Acid

The clinical benefit of the atypical antipsychotic drug clozapine may be related to a combined effect on D2 and 5-HT2 receptors. To examine the basis for this hypothesis, positron emission tomography (PET) and the radioligand [11C]N-methylspiperone were used to determine cortical 5-HT2 receptor occupancy in three psychotic patients treated with 125 mg, 175mg and 200mg clozapine daily. The uptake of [11C]N-methylspiperone in the frontal cortex was very low compared to that in neuroleptic naive schizophrenic patients. 5-HT2 receptor occupancy calculated in the clozapine treated patients was 84%, 87% and 90%. The results show that clinical treatment with clozapine induces a high 5-HT2 receptor occupancy in psychotic patients at a low dose level.

Topics: Adult; Antipsychotic Agents; Clozapine; Dopamine Agonists; Female; Humans; Male; Middle Aged; Prefrontal Cortex; Psychotic Disorders; Raclopride; Receptors, Serotonin; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed

To explore serotonin function in patients with schizophrenia during typical and atypical neuroleptic treatment. We hypothesized that clinically relevant doses of the atypical neuroleptic clozapine would attenuate responses to the serotonin agonist m-chlorophenylpiperazine (m-CPP).. m-CPP or placebo was administered intravenously over 90 seconds to patients who had been receiving no medications for at least 3 weeks. m-CPP was also administered during treatment with the typical neuroleptic fluphenazine and the atypical neuroleptic clozapine.. Fifteen inpatients (two women and 13 men) who met DSM-III-R criteria for chronic schizophrenia (n = 13) or schizoaffective disorder (n = 2) participated in the study. Mean age (+/- SD) was 33.8 +/- 8.0 years.. Measures of m-CPP effects included plasma cortisol and prolactin, body temperature, and the Brief Psychiatric Rating Scale (BPRS). The final BPRS total score at approximately 12 weeks of treatment was used to assess response to clozapine.. m-CPP infusion significantly increased plasma cortisol and prolactin levels in drug-free patients. There was a range of behavioral responses while drug-free, but no statistically significant effects on BPRS total or BPRS factor scores. Clozapine treatment significantly blocked neuroendocrine responses to m-CPP, whereas fluphenazine had no effect. Clozapine also appeared to attenuate behavioral responses.. These results demonstrate that clozapine treatment has potent serotonin antagonist effects in patients with schizophrenia. This may be related to clozapine's therapeutic effects since patients with greater cortisol response to m-CPP while drug-free had a better subsequent response to clozapine.

Topics: Adult; Body Temperature; Clozapine; Female; Fluphenazine; Hospitalization; Humans; Hydrocortisone; Infusions, Intravenous; Male; Piperazines; Placebos; Prolactin; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin; Stimulation, Chemical

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Mental Status Schedule; Middle Aged; Parkinson Disease; Psychomotor Performance; Psychotic Disorders

The effect of typical neuroleptic drugs or clozapine on smooth pursuit eye movements was tested in 13 patients with schizophrenia or schizoaffective disorder with a repeated measures design. Nineteen normal control subjects were also studied. Compared with controls, patients in the unmedicated state had low smooth pursuit gain, had a higher rate of corrective catch-up saccades, and tended to spend less time engaged in the tracking task. The patients did not significantly differ from controls on catch-up saccade amplitude, square wave jerk rate, or anticipatory saccade rate. Medication with clozapine, but not typical neuroleptics, was associated with an increase in median catch-up saccade amplitude. Number of days on clozapine and clozapine dose both correlated significantly with a worsening of oculomotor performance. No effect of medication with typical neuroleptics was found, although there was some evidence suggesting that such an affect may occur after more prolonged treatment.

Topics: Adult; Age Factors; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Female; Hospitalization; Humans; Male; Neurologic Examination; Psychiatric Status Rating Scales; Psychotic Disorders; Pursuit, Smooth; Saccades; Schizophrenia; Schizophrenic Psychology

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

Thirty-eight chronically ill psychotic patients were treated with clozapine for indications of tardive dyskinesia, severe extrapyramidal side effects caused by other neuroleptics, or treatment-resistant psychosis. Fifty-five percent of all patients and 40% of schizophrenics improved with clozapine. Abnormal involuntary movements were suppressed during treatment and, with 1 exception, returned to baseline levels after clozapine was discontinued. Our results support the conclusion that clozapine's efficacy in refractory cases and its lack of neurological side effects make it a unique neuroleptic with advantages over conventional antipsychotic agents. The drug appears to be safe when treatment is accompanied by frequent clinical and hematologic monitoring.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Outcome and Process Assessment, Health Care; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Two hundred and sixteen psychiatric patients (183 men and 33 women) hospitalized in Sct. Hans Hospital were treated with clozapine between 1971-1983. All had been treated previously with one or more neuroleptic(s) and had either failed to respond adequately, or their response was limited by side effects. Eighty-five patients were treated exclusively with clozapine, while the remaining 131 received additional medication, mainly other neuroleptic drugs. The mean clozapine dosage was 317 mg/day (range 50-1200), and the mean duration of treatment was 23/4 years (range 1/12-12). The tolerability to clozapine was determined by an evaluation of haematological changes, pronounced side effects and mortality. One patient treated with clozapine (8 months) and nitrofurantoin (8 days) developed a reversible granulocytopenia. One patient (treated with a combination of drugs) had clinically insignificant depression of the leucocytes and three of segmented granulocytes. Seven had a reduction in thrombocytes. Two patients developed cardiac insufficiency, and four epileptic seizures. None of the patients treated exclusively with clozapine developed neurological side effects. A global estimation of therapeutic effect revealed that clozapine alone or in combination with other neuroleptic drugs was significantly better than previous antipsychotic therapy, although 47-63% of the patients showed no change. It is concluded that clozapine is a potent antipsychotic drug offering particular advantages in the treatment of schizophrenic patients with a pronounced symptomatology and tendency towards developing extrapyramidal side effects. Caution is advised in patients with cardiac insufficiency and epilepsy. There appears to be a slight risk of granulocytopenia, and therefore the present monitoring of WBC should continue in order to prevent this reaction and to obtain more complete information regarding risk of granulocytopenia.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Clozapine; Dementia; Denmark; Dibenzazepines; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Leukocyte Count; Male; Middle Aged; Paranoid Disorders; Psychoses, Alcoholic; Psychoses, Substance-Induced; Psychotic Disorders; Retrospective Studies; Schizophrenia

Topics: Aged; Biperiden; Clinical Trials as Topic; Clozapine; Dibenzazepines; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Thioridazine

The chemical structure of a neuroleptic does not relaibly predict the exact profile of its therapeutic action. We considered the question whether the biochemical action of a neuroleptic, and specifically the ratio between DA-receptor block and NA-receptor block, might have a higher predictive value in this respect. In this context we carried out a double-blind study of the therapeutic value of clozapine and perphenazine in acute psychoses of varying symptomatology anc aetiology. There are strong indications that clozapine has only a slight inhibitory effect on transmission in central DA-ergic neurons, but markedly inhibits transmission in central NA-ergic neurons, and that the reverse applies to perphenazine. In view of these data we expected perphenazine to be a stronger antipsychotic and a weaker sedative than clozapine, and vice versa. The plausibility of this hypothesis was demonstrated. Partly also on the basis of earlier research, we concluded that the biochemical action of a neuroleptic is a more faithful predictor of its therapeutic action profile than the chemical structure.

Topics: Adult; Clozapine; Dibenzazepines; Dopamine; Female; Homovanillic Acid; Humans; Hypnotics and Sedatives; Male; Middle Aged; Neurocognitive Disorders; Norepinephrine; Perphenazine; Placebos; Psychotic Disorders; Receptors, Dopamine

Topics: Antipsychotic Agents; Clozapine; Cognition; Haloperidol; Humans; Psychotic Disorders

The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls.. The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model.. GSH levels were significantly reduced and, conversely, GPx activity was higher in PD patients compared to controls. GCLC_GAG-7/9 genotype (OR=4.3, CI95=1.40-14.31, p=0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR=6.09, CI95=1.93-22.59, p=0.003) were found as risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or to metabolic ratio.. GCLC variants were associated with the oxidative stress profile of PD patients raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

Topics: Antioxidants; Case-Control Studies; Clozapine; DNA Copy Number Variations; Genetic Predisposition to Disease; Genotype; Glutathione; Humans; Oxidative Stress; Polymorphism, Genetic; Psychotic Disorders

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders

Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices.. To examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics.. This genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022.. Polygenic risk scores for SCZ.. Multinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics.. Polygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10-46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10-22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10-6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10-6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10-6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ.. In this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Multifactorial Inheritance; Psychotic Disorders; Risk Factors; Schizophrenia

Both the underutilization of clozapine and treatment resistance of patients to clozapine are serious problems worldwide. Identifying clinical markers predicting response to clozapine would help clinicians more effectively utilize clozapine treatment. The present study retrospectively assessed dopamine supersensitivity psychosis (DSP) in addition to other measures such as age at disease onset and delay of clozapine introduction for a total of 47 treatment-resistant schizophrenia (TRS) patients. The response to clozapine was judged with CGI-C at 1 and 2 years from clozapine introduction. Results revealed that the DSP group tended to have a longer delay between designation of TRS and introduction of clozapine and continued to have slightly more severe psychopathology after treatment with clozapine, showing only slight improvement. The logistic regression analysis showed that the age at disease onset was the only significant indicator, predicting responsiveness to clozapine: patients with an onset age <20 years had a significantly better response to clozapine than patients with an onset age ≥20 years. The present study suggests that DSP might be related to a longer delay in clozapine introduction and the persistence of refractory symptoms despite clozapine treatment, whereas early age of disease onset might be related to a better response to clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Dopamine; Humans; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenia, Treatment-Resistant; Young Adult

Pimavanserin is the only approved drug for Parkinson's disease psychosis (PDP) and is an increasingly used therapy where available. Clozapine has proven efficacy for PDP but is much less commonly used secondary to frequent blood tests to monitor for agranulocytopenia. We identified 27 patients with PDP (72 ± 7.3 years, 11 (41%) female), with an inadequate response to pimavanserin, who subsequently started clozapine. The final mean daily dose of clozapine was 49.5 mg [range 25-100] at night, and mean duration of follow-up was 17 months [range: 2-50 months]. Patients reported clozapine to be markedly effective in 11 (41%), moderately effective in 6 (22%), somewhat effective in 5 (18%). No patient reported that it was ineffective, but 5 (19%) had inadequate follow-up. Clozapine should be considered in pimavanserin refractory psychosis.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Parkinson Disease; Psychotic Disorders

There is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy.. We conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement ("agree" and "strongly agree" responses) on a question. Agreement of ≥ 50% but < 75% in a second or third Delphi round was deemed to provide guidance.. Forty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia.. Given the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia.

Topics: Clozapine; Consensus; Delphi Technique; Humans; Psychotic Disorders

Clozapine is the treatment of choice in refractory psychosis. In most countries, clozapine must be stopped indefinitely if white blood cells fall below a defined threshold during routine monitoring. Despite evidence of severe adverse consequences of clozapine discontinuation, published accounts on the lived experiences and perspectives of patients and carers are scarce.. We completed semi-structured interviews with patients (n = 4) and family carers (n = 4) on experiences of clozapine cessation following suspected drug-induced neutropenia. Interviews were audio-recorded, transcribed and analysed thematically.. The two overarching themes comprised:(i) stress of clozapine below threshold neutrophil results and (ii) patient and carer priorities.. There is a suggested need for evidence-based pharmacological and psychological approaches to support patients and carers after clozapine cessation. Such approaches will minimise the potentially negative physical and emotional sequela in the aftermath of a below threshold neutrophil result and reduce the likelihood of experiencing additional health and social inequalities after clozapine discontinuation.

Topics: Antipsychotic Agents; Caregivers; Clozapine; Humans; Neutropenia; Psychotic Disorders; Records

Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown.. To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this.. Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport.. There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone.. There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed.

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

This report highlights a rare single-gene cause of early-onset, treatment-resistant schizophrenia, and its unique responsiveness to clozapine therapy. This case describes a pediatric female who was diagnosed with early-onset schizophrenia and catatonia in her early adolescence, and was later found to have DLG4-related synaptopathy, also known as SHINE syndrome. SHINE syndrome is a rare neurodevelopmental disorder caused by dysfunction of the postsynaptic density protein-95 (PSD-95), encoded by the DLG4 gene. After failing three antipsychotic drug treatments, the patient was started on clozapine, which resulted in significant improvements in positive and negative symptoms. This case illustrates the impact of clozapine in treatment-resistant early-onset psychosis and exemplifies practical implications for genetic testing in early-onset schizophrenia.

Topics: Adolescent; Antipsychotic Agents; Child; Clozapine; Female; Humans; Psychotic Disorders; Schizophrenia; Schizophrenia, Treatment-Resistant; Syndrome

To describe (i) the clinical characteristics of individuals referred to the Tertiary Referral Service for Psychosis (TRSP) and (ii) the recommendations TRSP made for future treatment across psychopharmacological and other intervention domains.. Retrospective audit of clinical data collected during the assessment process of individuals who accessed TRSP between 02/06/2020 and 31/12/2022. Categories of recommendations made following collaborative care planning comprised psychopharmacological, neuropsychological, psychological, psychosocial, physical health, substance misuse and other domains.. Eighty-two individuals were included, with diagnoses most commonly of schizophrenia (54.9%) and schizoaffective disorder (30.5%). The median PANSS score was 88.0 (73-100). Social occupational functioning was very poor (SOFAS M = 37.0, SD = 15.1). Cognitive functioning was poor (RBANS: M = 74.6; SD: 15.0). 67.1% had physical health comorbidities, with high prevalence of smoking (52.4%) and substance misuse (25.6%). Psychopharmacological recommendations (made for 81.7%) included clozapine trial (25.6%), clozapine dose change/augmentation (22.0%) and rationalisation of polypharmacy (12.2%). Neuropsychological (73.2%), psychological (39.0%) and psychosocial (85.4%) recommendations included access to cognitive remediation, psychological therapy and disability support. Physical health and substance misuse interventions were recommended for 91.5% and 20.7%, respectively.. Individuals referred to the TRSP had marked clinical and functional impairments. Holistic collaborative care planning complemented psychopharmacological interventions with psychological, psychosocial and physical healthcare recommendations.

Topics: Clozapine; Humans; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Asian People; Clozapine; Female; Hospitals, Psychiatric; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Tertiary Care Centers; Time-to-Treatment; Young Adult

Previous studies have shown mixed evidence on ethnic disparities in antipsychotic prescribing among patients with psychosis in the UK, partly due to small sample sizes. This study aimed to examine the current state of antipsychotic prescription with respect to patient ethnicity among the entire population known to a large UK mental health trust with non-affective psychosis, adjusting for multiple potential risk factors.. This retrospective cohort study included all patients (N = 19,291) who were aged 18 years or over at their first diagnoses of non-affective psychosis (identified with the ICD-10 codes of F20-F29) recorded in electronic health records (EHRs) at the South London and Maudsley NHS Trust until March 2021. The most recently recorded antipsychotic treatments and patient attributes were extracted from EHRs, including both structured fields and free-text fields processed using natural language processing applications. Multivariable logistic regression models were used to calculate the odds ratios (OR) for antipsychotic prescription according to patient ethnicity, adjusted for multiple potential contributing factors, including demographic (age and gender), clinical (diagnoses, duration of illness, service use and history of cannabis use), socioeconomic factors (level of deprivation and own-group ethnic density in the area of residence) and temporal changes in clinical guidelines (date of prescription).. The cohort consisted of 43.10 % White, 8.31 % Asian, 40.80 % Black, 2.64 % Mixed, and 5.14 % of patients from Other ethnicity. Among them, 92.62 % had recorded antipsychotic receipt, where 24.05 % for depot antipsychotics and 81.72 % for second-generation antipsychotic (SGA) medications. Most ethnic minority groups were not significantly different from White patients in receiving any antipsychotic. Among those receiving antipsychotic prescribing, Black patients were more likely to be prescribed depot (adjusted OR 1.29, 95 % confidence interval (CI) 1.14-1.47), but less likely to receive SGA (adjusted OR 0.85, 95 % CI 0.74-0.97), olanzapine (OR 0.82, 95 % CI 0.73-0.92) and clozapine (adjusted OR 0.71, 95 % CI 0.6-0.85) than White patients. All the ethnic minority groups were less likely to be prescribed olanzapine than the White group.. Black patients with psychosis had a distinct pattern in antipsychotic prescription, with less use of SGA, including olanzapine and clozapine, but more use of depot antipsychotics, even when adjusting for the effects of multiple demographic, clinical and socioeconomic factors. Further research is required to understand the sources of these ethnic disparities and eliminate care inequalities.

Topics: Antipsychotic Agents; Clozapine; Electronics; Ethnicity; Humans; Minority Groups; Olanzapine; Psychotic Disorders; Retrospective Studies

To present a practical, easy-to-implement clinical framework designed to support evidence-based quality prescribing for people with early psychosis.. Identification and explanation of key principles relating to evidence-based pharmacotherapy for people with early psychosis. These were derived from the literature, practice guidelines and clinical experience.. Key principles include (1) medication choice informed by adverse effects; (2) metabolic monitoring at baseline and at regular intervals; (3) comprehensive and regular medication risk-benefit assessment and psychoeducation; (4) early consideration of long-acting injectable formulations (preferably driven by informed patient choice); (5) identification and treatment of comorbid mood disorders and (6) early consideration of clozapine when treatment refractory criteria are met.. Current prescribing practices do not align with the well-established evidence for quality pharmacotherapy in early psychosis. Adopting evidence-based prescribing practices for people with early psychosis will improve outcomes.

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders

Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.

Topics: Animals; Antipsychotic Agents; Clozapine; Haloperidol; Hippocampus; Mice; Phencyclidine; Prefrontal Cortex; Psychotic Disorders; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Risperidone; Serotonin Antagonists

Most evidence about efficacy and safety of antipsychotics in schizophrenia spectrum disorders relies on randomized clinical trials (RCTs). However, owing to their strict eligibility criteria, RCTs represent only a part of the real-world population (ie, unselected patients seen in everyday clinical practice), which may result in an efficacy-effectiveness gap.. To quantify the proportion of real-world individuals with schizophrenia spectrum disorders who would be ineligible for participation in RCTs, and to explore whether clinical outcomes differ between eligible and ineligible individuals.. This study applied eligibility criteria typically used in RCTs for relapse prevention in schizophrenia spectrum disorders to real-world populations. Individuals with diagnoses of schizophrenia spectrum disorders recorded in national patient registries in Finland and Sweden were identified. Individuals who had used antipsychotics continuously for 12 weeks in outpatient care were selected. Individuals were followed up for up to 1 year while they were receiving maintenance treatment with any second-generation antipsychotic (excluding clozapine). Follow-up was censored at treatment discontinuation, initiation of add-on antipsychotics, death, and end of database linkage.. Proportions of RCT-ineligible individuals with schizophrenia spectrum disorders owing to any and specific RCT exclusion criteria. The risk of hospitalization due to psychosis within 1-year follow-up in ineligible vs eligible persons were compared using hazard ratios (HR) and corresponding 95% CIs.. The mean (SD) age in the Finnish cohort (n = 17 801) was 47.5 (13.8) years and 8972 (50.4%) were women; the mean (SD) age in the Swedish cohort (n = 7458) was 44.8 (12.5) years and 3344 (44.8%) were women. A total of 20 060 individuals (79%) with schizophrenia spectrum disorders would be ineligible for RCTs (Finnish cohort: 14 221 of 17 801 [79.9%]; Swedish cohort: 5839 of 7458 [78.3%]). Most frequent reasons for ineligibility were serious somatic comorbidities and concomitant antidepressant/mood stabilizer use. Risks of hospitalization due to psychosis was higher among ineligible than eligible individuals (Finnish cohort: 18.4% vs 17.2%; HR, 1.14 [95% CI, 1.04-1.24]; Swedish cohort: 20.1% vs 14.8%; HR, 1.47 [95% CI, 1.28-1.92]). The largest risks of hospitalization due to psychosis were observed in individuals ineligible owing to treatment resistance, tardive dyskinesia, and history of suicide attempts. Finally, with more ineligibility criteria met, larger risks of hospitalization due to psychosis were observed in both countries.. RCTs may represent only about a fifth of real-world individuals with schizophrenia spectrum disorders. Underrepresented (ineligible) patients with schizophrenia spectrum disorders have moderately higher risks of admission due to psychosis while receiving maintenance treatment than RCT-eligible patients. These findings set the stage for future studies targeting real-world populations currently not represented by RCTs.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia

Clozapine, an antipsychotic, is associated with increased susceptibility to infection with COVID-19, compared to other antipsychotics. Here, we investigate associations between clozapine treatment and increased risk of adverse outcomes of COVID-19, namely COVID-related hospitalisation, intensive care treatment, and death, amongst patients taking antipsychotics with schizophrenia-spectrum disorders. Using the clinical records of South London and Maudsley NHS Foundation Trust, we identified 157 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders, were taking antipsychotics (clozapine or other antipsychotics) at the time of COVID-19 pandemic in the UK and had a laboratory-confirmed COVID-19 infection. The following health outcomes were measured: COVID-related hospitalisation, COVID-related intensive care treatment and death. We tested associations between clozapine treatment and each outcome using logistic regression models, adjusting for gender, age, ethnicity, neighbourhood deprivation, obesity, smoking status, diabetes, asthma, bronchitis and hypertension using propensity scores. Of the 157 individuals who developed COVID-19 while on antipsychotics (clozapine or other antipsychotics), there were 28% COVID-related hospitalisations, 8% COVID-related intensive care treatments and 8% deaths of any cause during the 28 days follow-up period. amongst those taking clozapine, there were 25% COVID-related hospitalisations, 7% COVID-related intensive care treatments and 7% deaths. In both unadjusted and adjusted analyses, we found no significant association between clozapine and any of the outcomes. Thus, we found no evidence that patients with clozapine treatment at time of COVID-19 infection had increased risk of hospitalisation, intensive care treatment or death, compared to non-clozapine antipsychotic-treated patients. However, further research should be considered in larger samples to confirm this.

Topics: Antipsychotic Agents; Clozapine; COVID-19; Critical Care; Hospitalization; Humans; Pandemics; Psychotic Disorders; SARS-CoV-2

A proportion of people with treatment-resistant schizophrenia fail to show improvement on clozapine treatment. Knowledge of the sociodemographic and clinical factors predicting clozapine response may be useful in developing personalised approaches to treatment.. This retrospective cohort study used data from the electronic health records of the South London and Maudsley (SLaM) hospital between 2007 and 2011. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression statistical learning approach, we examined 35 sociodemographic and clinical factors' predictive ability of response to clozapine at 3 months of treatment. Response was assessed by the level of change in the severity of the symptoms using the Clinical Global Impression (CGI) scale.. We identified 242 service-users with a treatment-resistant psychotic disorder who had their first trial of clozapine and continued the treatment for at least 3 months. The LASSO regression identified three predictors of response to clozapine: higher severity of illness at baseline, female gender and having a comorbid mood disorder. These factors are estimated to explain 18% of the variance in clozapine response. The model's optimism-corrected calibration slope was 1.37, suggesting that the model will underfit when applied to new data.. These findings suggest that women, people with a comorbid mood disorder and those who are most ill at baseline respond better to clozapine. However, the accuracy of the internally validated and recalibrated model was low. Therefore, future research should indicate whether a prediction model developed by including routinely collected data, in combination with biological information, presents adequate predictive ability to be applied in clinical settings.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Psychotic Disorders; Retrospective Studies; Schizophrenia

Persistent negative symptoms (PNS) contribute to impairment in psychosis. The characteristics of PNS seen in youth remained under-investigated. We aimed to demonstrate clinical, treatment-related, and psychosocial characteristics of PNS in early-onset schizophrenia-spectrum disorders (EOSD). 132 patients with EOSD were assessed with Positive and Negative Symptom Scale, Brief Negative Symptom Scale, Calgary Depression Scale for Schizophrenia, and Simpson-Angus Scale. Parenting skills and resilience were evaluated using Parental Attitude Research Instrument and Child and Youth Resilience Measure-12. Longer duration of untreated psychosis (DUP) and prodromal phase were found in primary and secondary PNS groups, compared to the non-PNS group. The primary PNS group was characterized by earlier age-onset, lower smoking rates, and more common clozapine use. Resilience and egalitarian/democratic parenting were negatively correlated with symptoms related to motivation/pleasure and blunted expression. More blunted expression-related symptoms and longer DUP in the first episode significantly predicted primary/secondary PNS at follow-up. Using the data from total negative symptom scores and DUP, Receiver Operating Characteristic analyses significantly differentiated primary/secondary PNS groups from the non-PNS counterparts. PNS associated with blunted expression and low motivation/pleasure in the first episode could persist into clinical follow-up. Effective pharmacological treatment and psychosocial interventions are needed in youth.

Topics: Adolescent; Age of Onset; Child; Clozapine; Humans; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Adherence to therapeutic guidelines in psychiatry is anchored and facilitated by rating scales. However, they are rarely used in routine care, particularly for psychotic disorders. Consequently, adherence to treatment guidelines are not ideal and patient outcomes are often sub-optimal. In this study, we used the clinician-rated Clinical Global Impressions Scale (CGI) to implement a measurement-based care (MBC) approach and derive indices of quality of care at a first episode psychosis (FEP) program.. At the individual level, an algorithm was created using CGI scores and their changes over time to define the concept of Patient Requiring Clinical Attention (PRCA) that encompasses several categories (e.g. episode of severity, treatment inertia, or treatment resistance). At the service level, CGI scores were used to derive several indices of quality of care: severity of illness and its change over time, conformity to the use of low doses of antipsychotic medications, and clozapine offer index.. 135 Patients were included in this study of whom 19 patients were identified as PRCA. Of these, 12 (63%) received timely medication, and 7 (37%) were suspected cases of therapeutic inertia. Additionally, 15 patients met criteria for treatment resistance of whom 7 were offered clozapine (47%). At the service level, the average CGI improved by 2 points from baseline to month 1 and average doses of antipsychotic medications prescribed were in line with prescription guidelines for FEP patients.. The proposed CGI-based treatment algorithm and service evaluation strategy can help to optimize quality care and services for patients.

Topics: Algorithms; Antipsychotic Agents; Clozapine; Humans; Psychiatric Status Rating Scales; Psychotic Disorders

Identifying early predictors of response or nonresponse to medications in youth with first-episode psychosis is essential to optimize outcome. Specifically, longer duration of untreated psychosis is associated with less long-term improvement in youth.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders

Clozapine is a highly effective medication used in management of treatment-resistant schizophrenia. Clozapine-associated myocarditis (CAM) is a rare but increasingly recognised complication of clozapine titration. Following an episode of CAM, clinicians can face a challenging dilemma of balancing the risks of recurrent myocarditis against the harms of ongoing psychosis. We describe the case of a woman in her 60s who developed acute myocarditis during clozapine titration and was then cautiously rechallenged with a successful outcome.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Myocarditis; Psychotic Disorders; Schizophrenia

Antipsychotics (APs) can cause weight gain. Little is known about changes in weight when APs are combined with other psychotropics. This study examines the weight change in patients undergoing long-term treatment with APs or with AP combined with other psychotropics.. Patients with non-affective psychotic disorder from the GROUP study were divided into three groups: AP medication group (APm) (n = 100), AP in combination with other psychotropics (APc) (n = 73), and medication-free (Meds-free) (n = 100). Weight change was examined at inclusion and after three years using a paired-sample t-test. An Independent-sample t-test was performed to evaluate weight change among patients taking clozapine, olanzapine, and quetiapine and individuals not taking these medications. Linear regression was performed to evaluate the association between covariates and weight.. Patients in the APm group [mean = 1.800 kg, t(99)=2.849, 95% CI(0.546, 3.054), p = 0.005] and the APc group [mean = 1.877 kg, t(72)=2.688, 95% CI(0.485, 3.268), p = 0.009] showed significant weight gain. Patients taking clozapine, olanzapine or quetiapine showed significant weight gain compared to those not taking these medications [mean difference=1.707 kg, t(271)= 2.061, 95% CI(0.077, 3.337), p = 0.040)].. Patients receiving APs and APs with other psychotropics gain weight during long-term treatment. It is possible that weight gain is mainly driven by APs.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Longitudinal Studies; Olanzapine; Psychotic Disorders; Psychotropic Drugs; Quetiapine Fumarate; Risperidone; Weight Gain

Clozapine is seldom prescribed in treatment-resistant schizophrenia (TRS) patients during early phases of the illness. We aimed to examine the pathway and patterns and the impact of clozapine use in patients with TRS who were followed up for 10 years after the first outbreak of the illness. Data were obtained retrospectively from an epidemiological cohort of first episode schizophrenia patients (n = 218) who had been treated in a specialized intervention program (PAFIP). Out of 218, 35 (16%) individuals were on clozapine at 10-year assessment, while 183 (84%) were taking other antipsychotics. Among those 183 psychosis subjects who were not on clozapine, 13 (7.1%) met criteria for TRS. In the clozapine group, ten (28.6%) met criteria for early-TR and twenty-five (71.4%) met criteria for late-TR. Before clozapine treatment was initiated, the median number of days under other antipsychotic treatment was 1551 days (IQR = 1715) and the median time that subjects remained on clozapine was 6.3 years (IC95%: 5.49-7.20). At 10 years, we found that those individuals taking clozapine had higher CGI total scores (F = 12.0, p = 0.001) and SANS total scores (F = 9.27, p = 0.003) than subjects taking other antipsychotics after correcting for baseline values. Interestingly, when performing these analyses at 10 years between subjects taking clozapine (n = 35) and subjects who despite meeting TRS criteria were not taking clozapine (n = 13), we found that subjects taking clozapine had significantly lower total scores on all clinical scales compared with subjects who met TRS criteria and were not taking clozapine (p values < 0.05). TRS patients who took the longest time to start clozapine (third tertile) showed significantly higher CGI scores at 10-year follow-up compared to those who initiated clozapine earlier (first tertile) (t = 2.60; p = 0.043). Our findings reinforce the need of a timely assessment of treatment-resistant criteria in early schizophrenia patients and highlight the long-term benefits of an early introduction of clozapine on those patients meeting treatment-resistant criteria.

Topics: Antipsychotic Agents; Clozapine; Follow-Up Studies; Humans; Psychotic Disorders; Retrospective Studies

Topics: Clozapine; Humans; Neurodegenerative Diseases; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate; United States

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Health Services; Psychotic Disorders; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Humans; Psychotic Disorders; Recurrence

Schizophrenia is the most common psychotic mental disorder, and those affected have two to four times higher mortality than the general population. Genetic and environmental factors increase the risk of developing schizophrenia, and substance use disorder (particularly cannabis) may have the strongest link. Schizophrenia typically develops in young adulthood and is characterized by the presence of positive and negative symptoms. Positive symptoms include hallucinations, delusions, and disorganized speech. Negative symptoms include blunted affect, alogia, avolition, asociality, and anhedonia. Symptoms must be present for at least six months and be severe for at least one month to make a diagnosis. Because schizophrenia is debilitating, it should be treated with antipsychotics, and early treatment decreases long-term disability. Treatment should be individualized, and monitoring for effectiveness and adverse effects is important. Patients with a first episode of psychosis who receive a formal diagnosis of schizophrenia should be treated in a coordinated specialty care program. Second-generation antipsychotics are the preferred first-line treatment because they cause fewer extrapyramidal symptoms. Patients with schizophrenia who are treated with second-generation antipsychotics are at increased risk of cardiovascular disease and should receive at least annual metabolic screening and counseling with interventions to prevent weight gain and encourage smoking cessation. Treatment-resistant schizophrenia should be treated with clozapine. Adjunctive treatments include electroconvulsive therapy, antidepressants, and cognitive behavior therapy for psychosis. Family and social support are keys to improved outcomes.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognitive Behavioral Therapy; Humans; Psychotic Disorders; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Schizophrenia; Suicide, Attempted; Veterans

Topics: Antipsychotic Agents; Catatonia; Clozapine; Humans; Psychotic Disorders; Quetiapine Fumarate

Topics: Clozapine; Humans; Huntington Disease; Psychotic Disorders

In psychosis, treatment often focuses on symptom reduction whereas social functioning is also essential. In this study, we investigate positive psychotic symptoms and medication use in relation to social functioning over a 3-year time-period in 531 patients diagnosed with psychosis. Furthermore, relations of positive symptoms with needs for care and quality of life were also investigated.. Using repeated measures analysis, changes were measured over time. Hereafter, mixed model analyses were performed to determine the associations of social functioning, needs for care, and quality of life with psychotic symptoms and patient characteristics. Finally, we assessed differences in symptoms and medication dose between those with an increase and those with a decrease in social functioning.. Patients significantly improved in social functioning, while psychotic symptoms increased. Improvement in social functioning was associated with younger age, higher IQ, and lower social functioning at T1, but not with positive symptoms. Also, improvement in social functioning was found to be related to a decrease in the dose of clozapine. Improvement in social functioning occurs despite worsening of positive symptoms.. The findings suggest the need to further explore the relation between symptomatology, social functioning, and medication use. In the treatment of psychotic disorders, one should reconsider the strong focus on reducing psychotic symptoms. The current focus needs to shift much more toward improving functional outcome, especially when the patient expresses a desire for change in this respect.

Topics: Clozapine; Humans; Psychotic Disorders; Quality of Life; Social Interaction

A patient in a medium secure psychiatric unit with a 19-year history of treatment-resistant schizophrenia and violence whose mental illness only responded to clozapine, was noted to have a sustained tachycardia. Echocardiography revealed mild biventricular cardiomyopathy. The patient was not significantly affected by this. Initial recommendation from Cardiology was to consider discontinuation of clozapine. It was decided, however, that the risk of worsening psychosis and resultant violence outweighed the risk of the patient's relatively mild cardiomyopathy. The patient was commenced on ramipril, and later bisoprolol. The patient no longer requires treatment in a medium secure unit and has remained on clozapine with follow-up from cardiology.

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

This study examined the effect of clozapine on time assigned to restrictive housing (RH; i.e., solitary confinement), disciplinary infractions, and assaults on custody staff among patients treated within the North Carolina prison system. Records were reviewed for patients initiated on clozapine (

Topics: Antipsychotic Agents; Clozapine; Housing; Humans; Personality Disorders; Prisons; Psychotic Disorders

Topics: Antipsychotic Agents; Clozapine; Humans; Moyamoya Disease; Psychotic Disorders; Schizophrenia

Clozapine is under-used in the UK, and Casetta et al's recent paper in the BJPsych adds to a growing number of small studies that support the use of intramuscular clozapine to initiate and maintain treatment with oral clozapine. However, intramuscular clozapine remains unlicensed and, because of the risks associated with its administration, it should be used only cautiously before it can be adopted more widely into mainstream clinical practice.

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

Improving access to clozapine is a recognized priority nationally across Early Intervention in Psychosis Services (EIPS) in the UK. Treatment resistance (TR) may be identifiable from early episode psychosis and appears to be characterized by negative symptoms and younger age of onset. This mixed method cross-sectional snapshot analysis of antipsychotic (AP) prescribing in an EIPS, explored clozapine eligibility (CE) and prioritization of AP prescribing based on choice, selectivity and appropriateness.. We screened 150 service users and 79% (n = 119) were retained after inclusion criteria were applied. We explored CE in all service users who were indicated clozapine based on the product licence (n = 78), and whether there was association between CE and number of hospital admissions, AP trials, age at first episode and duration of untreated psychosis.. Following multidisciplinary clinical discussions, we found that 23 service users were CE; 8 were offered and declined clozapine. When compared to non-CE service users, significant factors associated with CE were history of two or more hospital admissions (Mann-Whitney U = 269, P = .008), more than two trials of two different APs (Mann-Whitney U = 517, P ≤ .01), and younger age first episode (independent-samples t-test, P = .047). A total of 47.5% of all service users had been started on olanzapine as their first AP, despite high risk of cardiometabolic syndrome.. We propose that EIP services adopt a proactive approach in screening for TR, taking into account negative symptoms and young age at onset, prioritizing service users with two or more hospital admissions and AP trials.

Topics: Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Humans; Psychotic Disorders; Schizophrenia

Emergency psychiatry has the main role of resolving suicidal behavior and aggression. These severe psychiatric symptoms can be found in many psychiatric disorders such as schizophrenia, bipolar disorder, major depression, personality disorders, cognitive disorders, intellectual disability and substance abuse. Although indications for the use of antipsychotics are limited to a specific group of diseases, they are frequently used as rescue medication in high-risk or nonresponsive cases. Clozapine, the gold standard for TRS (treatment resistant schizophrenia) is effective in controlling aggression. The aim of the research was to identify the use of clozapine for treatment-refractory aggressive behavior in psychiatric emergency. A retrospective study based on the paper files of patients admitted between 2010 and 2019 in the Clinical Hospital of Psychiatry and Neurology of Brasov, Romania. Were included all the patients admitted as a psychiatric emergency and treated with clozapine for aggressive behavior. The hospital is an academic institution with 150 beds for acute patients, serving an area of over 600,000 inhabitants. It is the main public institution where patients with psychiatric emergencies are hospitalized. Off 19,000 patients admitted during the study period, 504 patients (2,4%) with a diagnosis other than schizophrenia or schizoaffective disorder received clozapine for aggressiveness (89.5%). The first four diagnoses identified were bipolar disorder (n = 172), intellectual disability (n = 128), cognitive impairment (n = 112), and personality disorder (n = 92). Other disorders identified but with a smaller number of cases were major depressive disorder (n = 3), adjustment disorders (n = 2), delusional disorder (n = 2), obsessive compulsive disorder (n = 2) and postpartum psychosis (n = 1). Clozapine was used as 3rd or 4th choice. The dose was greater for manic patients (350.29 ± 98.01 mg/day) compared with all the other diagnoses. Clozapine was effective and safe in cases of patients with treatment-refractory aggressive behavior.

Topics: Adult; Aged; Aggression; Bipolar Disorder; Clozapine; Cognition; Cognition Disorders; Female; Humans; Intellectual Disability; Male; Personality Disorders; Psychotic Disorders; Retrospective Studies

Chronic methamphetamine (METH) treatment induces behavioral sensitization in rodents. During this process, hyperactivation of the mesolimbic dopamine system plays a central role, and dopamine D2-like receptor-based antipsychotics are known to alleviate the behavioral hyperactivity. The atypical antipsychotic, clozapine (Clz), acts partially as a dopamine D4 receptor (D4R) antagonist and mitigates hyperdopaminergic drug addiction and/or comorbid psychotic symptoms; however, it remains unclear whether D4R blockade contributes to the therapeutic effects of Clz. Here, we evaluated the potential role of D4R in regulating hyperdopaminergia-induced behavioral hyperactivity in METH behavioral sensitization and dopamine transporter (DAT) knockdown (KD) mice. Clz or a D4R-selective antagonist, L-745,870, were co-administered to mice with daily METH in a METH sensitization model, and Clz or L-745,870 were administered alone in a DAT KD hyperactivity model. Locomotor activity and accumbal D4R expression were analyzed. Clz suppressed both the initiation and expression of METH behavioral sensitization, as well as DAT KD hyperactivity. However, repetitive Clz treatment induced tolerance to the suppression effect on METH sensitization initiation. In contrast, D4R inhibition by L-745,870 had no effect on METH sensitization or DAT KD hyperactivity. Accumbal D4R expression was similar between METH-sensitized mice with and without Clz co-treatment. In sum, our results suggest the mesolimbic D4R does not participate in behavioral sensitization encoded by hyperdopaminergia, a finding which likely extends to the therapeutic effects of Clz. Therefore, molecular targets other than D4R should be prioritized in the development of future therapeutics for treatment of hyperdopaminergia-dependent neuropsychiatric disorders.

Topics: Amphetamine-Related Disorders; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Sensitization; Clozapine; Disease Models, Animal; Dopamine Agents; Locomotion; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Psychotic Disorders; Pyridines; Pyrroles; Receptors, Dopamine D4

Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Early Medical Intervention; Female; Follow-Up Studies; Humans; Male; Outcome Assessment, Health Care; Prognosis; Psychotic Disorders; Schizophrenia; Time Factors; Young Adult

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI

Topics: Adult; Alcohol Drinking; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Cytochrome P-450 CYP1A2; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Variation; Genotype; Humans; Male; Pharmacogenetics; Psychotic Disorders

Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. Clozapine's main metabolite, N-desmethylclozapine (NDMC), has potent 5-HT2C antagonist properties which may explain this metabolic dysfunction, thus the CLZ:NDMC ratio is of particular interest. High insulin resistance states could be associated with CYP1A2 induction and lower CLZ:NDMC ratios. Additionally, lower CLZ:NDMC ratios have been associated with better cognitive, but worse metabolic functioning. This study investigated associations between metabolic and cognitive parameters with the CLZ/NDMC ratio. Primary outcomes included relationships between the CLZ:NDMC ratio to the homeostatic model assessment for insulin resistance (HOMA-IR) and Brief Assessment of Cognition in Schizophrenia (BACS) composite z-scores. Secondary outcomes assessed relationships between CLZ:NDMC ratios to fasting insulin, BMI, weight, fasting glucose, and BACS digit sequencing z-scores. 38 patients who were overweight or obese with schizophrenia or schizoaffective disorder completed fasting bloodwork, anthropometric, psychopathological, and cognitive assessments. Multivariate regressions found a statistically significant inverse association between the CLZ/NDMC ratio and HOMA-IR (B = - 1.028, SE B = .473, β = - 0.348 p = 0.037), which may have been driven by fasting insulin levels (B = - 27.124, SE B = 12.081, β = - 0.351 p = 0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cognition; Female; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Psychotic Disorders; Schizophrenia; Young Adult

Hospital-based restoration of adjudicative competence can be challenging, especially for patients who have treatment-resistant psychosis. Clozapine, which has helped many such individuals in the community, has not been well-studied in individuals who are incapable of proceeding with trial. In their small study, Ghossoub and colleagues have brought attention to the potential for this protocol and advocate for further study. This commentary examines potential barriers to conducting larger studies, including Institutional Review Board requirements for research with individuals who are under court supervision. Also, factors that can result in patients relapsing and being readmitted to the hospital for competency restoration due to poor treatment adherence are described. This adverse outcome burdens the judicial and health care systems and prolongs the time between the patient's arrest and trial. Clozapine may be a promising treatment for competency restoration as long as we are cognizant of barriers to further study and treatment adherence.

Topics: Clozapine; Hospitals; Humans; Mental Competency; Psychotic Disorders; Retrospective Studies

Topics: Aggression; Clozapine; Conduct Disorder; Haloperidol; Humans; Olanzapine; Psychotic Disorders; Schizophrenia; Violence

The widespread prevalence of coronavirus disease 2019 (COVID-19) means that inpatient psychiatric units will necessarily manage patients who have COVID-19 that is comorbid with acute psychiatric symptoms. We report a case of recurrence of respiratory symptoms and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) testing in a patient on an inpatient psychiatric unit occurring 42 days after the initial positive SARS-CoV-2 RT-PCR test, 38 days after initial symptom resolution, and 30 days after the first of 3 negative SARS-CoV-2 RT-PCR tests. Over the course of the admission, the patient was safely initiated on clozapine. Recent literature on COVID-19's potential recurrence and neuropsychiatric effects is reviewed and implications for the management of COVID-19 on inpatient psychiatric units are discussed. In the era of COVID-19 and our still-developing understanding of this illness, psychiatrists' role as advocates and collaborators in our patients' physical health care has become even more critical.

Topics: Adult; Alcoholism; Antidepressive Agents; Antipsychotic Agents; Clozapine; COVID-19; COVID-19 Nucleic Acid Testing; Depressive Disorder, Major; Hospitals, Psychiatric; Humans; Inpatients; Male; Mirtazapine; Psychotic Disorders; Recurrence; SARS-CoV-2; Sertraline; Suicide, Attempted

Clozapine (CZP) is an antipsychotic used in resistant psychosis, but has adverse metabolic effects and is associated with new onset or worsening of epileptic seizures (ES). There is not enough information available regarding its effect on metabolic variables and on ES in patients with epilepsy.. To describe the effect of CZP on the metabolic and hematologic profiles, and on ES in patients with epilepsy and with psychosis and/or aggressive behavior.. A case series of patients with epilepsy and psychosis and/or aggressive behavior that received CZP with an 18-week follow-up. Clinical records were assessed from 2008-2018. 30 patients with epilepsy that received CZP were included. A paired analysis (Student’s t-test or Wilcoxon signed rank test) was performed with metabolic variables (glucose, cholesterol, and triglycerides), hematologic variables, weight, body mass index (BMI), and monthly ES before and after CZP administration.. The median age to CZP initiation was 31.9 ± 16.07 years. Median CZP dosage was 193 mg/day. There were changes on BMI (p = 0.001; 3.2 kg/m2 increase, median = 3.08), triglycerides (p = 0.002) and glucose (p = 0.030). Weight increase was 7 kg (p = 0.292; median = 4 kg). Monthly ES mean was decreased from 4.9 (median = 2) to 2.04 (median = 1; p = 0.001).. This study provide information regarding the security profile of CZP in patients with epilepsy with psychosis and/or aggressive behavior. A decrease on monthly ES was observed, as well as moderate increases in triglycerides, glucose and BMI, which coincide with that described by other authors.. La clozapina (CZP) es un antipsicótico efectivo en la psicosis que no responde a otros antipsicóticos, pero tiene efectos metabólicos adversos y se relaciona con la generación de crisis epilépticas (CE). Existe poca información sobre su efecto en variables metabólicas y sobre las CE en pacientes con epilepsia.. Describir el efecto de la CZP en el perfil metabólico, el perfil hematológico y la frecuencia de CE en pacientes con epilepsia y con psicosis o agresividad.. Serie de casos de pacientes con epilepsia y psicosis o agresividad que recibieron CZP con un seguimiento de 18 semanas. Se revisaron los expedientes clínicos de 2008-2018. Se incluyeron 30 pacientes con epilepsia que recibieron CZP. Se hizo una comparación pareada (prueba t de Student o de signo y rango de Wilcoxon), antes y después del inicio de la CZP, de las variables metabólicas (glucosa, colesterol y triglicéridos) y hematológicas, el peso, el índice de masa corporal (IMC) y las CE mensuales.. La edad media al iniciar la CZP fue de 31.9 ± 16.07 años. La dosis media fue 193 mg/día. Hubo incremento en el IMC (p = 0.001; aumento de 3.2 kg/m2; mediana = 3.08), los triglicéridos (p = 0.002) y la glucosa (p = 0.030). La ganancia de peso fue de 7 ± 10.4 kg (p = 0.292; mediana = 4 kg). El promedio de CE mensuales se redujo de 4.9 (mediana = 2) a 2.04 (p = 0.001; mediana = 1).. Este estudio aporta información del perfil de seguridad del uso de CZP en pacientes con epilepsia y psicosis o agresividad. Se observó una disminución en la frecuencia mensual de CE, así como aumentos moderados de los triglicéridos, la glucosa y el IMC, que coinciden con lo descrito por otros autores.

Topics: Clozapine; Epilepsy; Humans; Metabolome; Psychotic Disorders; Seizures

Topics: Antipsychotic Agents; C-Reactive Protein; Clozapine; COVID-19 Vaccines; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; mRNA Vaccines; Psychotic Disorders; Vaccines, Synthetic

Monitoring of white cell counts during clozapine treatment leads to cessation of therapy if levels fall below predetermined values. Reductions in white cell counts, driven by lower levels of lymphocytes, have been observed with coronavirus disease 2019 (COVID-19). Neutropenia during COVID-19 has not been reported. We present data for 56 patients who were taking clozapine and had COVID-19.. We included patients who were taking clozapine at the time they tested positive for COVID-19. We compared absolute neutrophil counts, lymphocyte counts and white cell counts between baseline and the first week of infection, and baseline and the second week of infection.. We observed reductions in absolute neutrophil counts (p = 0.005), lymphocyte counts (p = 0.003) and white cell counts (p < 0.001) between baseline and the first 7 days of COVID-19. All cell counts had returned to baseline levels by days 8 to 14. Six patients experienced neutropenia (absolute neutrophil counts < 2.0 × 109/L) and of those, 4 underwent mandatory cessation of clozapine. For 3 patients, clozapine treatment had been established for more than 6 months with no previous neutropenia, neutrophil levels returned to baseline within 2 weeks and no further neutropenia was observed on restarting treatment.. This was a retrospective chart review; larger cohorts are required. Clozapine plasma levels were largely not measured by clinicians.. These data strongly suggest that mild neutropenia in the acute phase of COVID-19 in patients who are well established on clozapine is more likely to be a consequence of the virus than of clozapine treatment.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; COVID-19; Female; Humans; Leukocyte Count; Leukopenia; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Neutropenia; Neutrophils; Psychotic Disorders; Retrospective Studies; SARS-CoV-2; Schizophrenia; Young Adult

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject's contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges's g = 2.09, P < .001) and a reduced clustering coefficient (Hedges's g = 1.07, P < .001) with increased length (Hedges's g = -2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.

Topics: Adolescent; Adult; Affective Disorders, Psychotic; Antipsychotic Agents; Cerebral Cortex; Clozapine; Female; Follow-Up Studies; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nerve Net; Psychotic Disorders; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; COVID-19; Humans; Pandemics; Parkinson Disease; Psychotic Disorders; SARS-CoV-2

Little is known about predictors of clinical response to clozapine treatment in treatment-resistant psychosis. Most published cohorts are small, providing inconsistent results. We aimed to identify baseline clinical predictors of future clinical response in patients who initiate clozapine treatment, mainly focusing on the effect of age, duration of illness, baseline clinical symptoms and homelessness.. Retrospective cohort of patients with treatment-resistant schizophrenia, aged between 15 and 60 years, that initiated clozapine between 2014 and 2017. Sociodemographic characteristics, years from illness diagnosis, and clinical presentation before the initiation of clozapine were collected and analyzed. All-cause discontinuation at two years follow-up was used as the primary measure of clozapine response.. 261 patients were included with a median age at illness diagnosis of 23 years old (IQR 19-29) and a median age at clozapine initiation of 25 (IQR: 21-33). 72.33% (183/253) continued clozapine after two years follow-up. Being homeless was associated to higher clozapine non-adherence, with an OR of 2.78 (95%CI 1.051-7.38) (p = 0.039, controlled by gender). Older age at clozapine initiation and longer delay from first schizophrenia diagnosis to clozapine initiation were also associated with higher clozapine non-adherence, with each year increasing the odds of discontinuation by 1.043 (95%CI 1.02-1.07; p = 0.001) and OR 1.092 (95%CI 1.01-1.18;p = 0.032) respectively.. Starting clozapine in younger patients or shortly after schizophrenia diagnosis were associated with better adherence.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Humans; Middle Aged; Psychotic Disorders; Retrospective Studies; Schizophrenia; Young Adult

In many studies, clozapine has been reported to have superior effectiveness compared to other antipsychotics. So far there is little systematic data on the practice of clozapine prescription and characteristics of patients treated.. Retrospective evaluation of all 392 treatment courses of inpatients with schizophrenic psychoses during one year. Detailed analysis of the patients treated with clozapine including the dosages and additional psychotropic medication.. Patients treated with clozapine showed a higher disease severity than patients without clozapine. They received more frequently pharmacological combination therapies, which in some cases significantly contradicted the current guideline recommendations.. The results underline the pronounced disease severity of patients receiving clozapine treatment and substantiate evidence from the literature on the limited implementation of guidelines in prescribing practice. The study carried out serves as a pilot survey of a multicenter research project on the practice of prescribing clozapine in psychiatric hospitals in different German regions.. Clozapin zeigt in vielen Untersuchungen eine überlegene Wirksamkeit gegenüber anderen Antipsychotika. Zur Verschreibungspraxis von Clozapin und den Charakteristika der damit behandelten Patienten gibt es bislang wenig systematisch erhobene Daten.. Retrospektive Auswertung aller 392 Behandlungsverläufe von stationär behandelten Patienten mit schizophrenen Psychosen eines Jahres. Detaillierte Analyse der mit Clozapin behandelten Patienten einschließlich der Dosierungen und der zusätzlichen Medikation.. Patienten mit Clozapinbehandlung weisen eine höhere Krankheitsschwere als Patienten ohne Clozapinbehandlung auf. Sie erhalten häufiger pharmakologische Kombinationsbehandlungen, die den gegenwärtigen Leitlinienempfehlungen teilweise erheblich entgegenstehen.. Die Ergebnisse unterstreichen die ausgeprägte Krankheitsschwere von Patienten mit einer Clozapinbehandlung und belegen Hinweise aus der Literatur auf die begrenzte Umsetzung von Leitlinien in die Verschreibungspraxis. Die durchgeführte Untersuchung dient als Pilotuntersuchung einer multizentrischen Studie zur Verschreibungspraxis von Clozapin in psychiatrischen Kliniken unterschiedlicher Regionen.

Topics: Antipsychotic Agents; Clozapine; Hospitals, Psychiatric; Humans; Psychotic Disorders; Retrospective Studies; Schizophrenia

Although clozapine is the main antipsychotic medication for treatment-resistant schizophrenia, 40-70% of patients on clozapine have persistent psychotic symptoms (i.e. ultra-treatment-resistant schizophrenia, UTRS). We aimed to examine clozapine response/non-response patterns in patients with treatment-resistant schizophrenia, as well as determine patient clinico-demographic factors associated with long-term clozapine non-response. Clinico-demographic characteristics of 241 patients on clozapine were collected through a retrospective chart review. The median (interquartile range, IQR) follow-up from illness onset was 25.0 (IQR = 24.0) years. Clozapine response was assessed at median 10.8 (IQR = 14.0) months (Time 1, T1) and 7.2 (IQR = 13.5) years (Time 2, T2) after its initiation. It was evaluated by chart reviewers based on the information provided in clinical notes. Binomial logistic regression was used to determine clinico-demographic factors associated with clozapine non-response at both T1 and T2 (i.e. stable UTRS, S-UTRS) compared to clozapine response at both times (i.e. stable clozapine responders, S-ClozResp). Among clozapine responders (n = 122) at T1, 83.6% remained clozapine responsive and 16.4% became non-responsive at T2. In the UTRS group (n = 119) at T1, 87.4% remained clozapine non-responsive and 12.6% became responsive at T2. Duration of delay in clozapine initiation (OR = 0.94, Wald χ

Topics: Adult; Age of Onset; Aged; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Ontario; Outcome Assessment, Health Care; Prognosis; Psychotic Disorders; Retrospective Studies; Schizophrenia

Protocol for clozapine rechallenge in patients with a history of clozapine-induced myocarditis.. Clozapine-related cardiovascular adverse effects including myocarditis and cardiomyopathy have limited its widespread use in treatment-resistant schizophrenia. Here, we present a case of clozapine-induced myocarditis and successful cautious rechallenge. Ms. AA, a young female patient with severe psychosis developed myocarditis during her initial clozapine titration phase, which was thus discontinued. Subsequent response to other medications was poor, and she remained significantly disabled. We reviewed blood-based biomarkers identified during the emergence of her index episode of myocarditis and developed a successful clozapine rechallenge protocol, based on careful monitoring of changes in these indices and a very slow clozapine re-titration.. This protocol may have utility in the management of patients with a history of clozapine-induced myocarditis.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Myocarditis; Psychotic Disorders; Schizophrenia

To evaluate the incidence of clozapine induced haematological side effects among patients receiving clozapine.. Data of 333 patients who were on clozapine for a mean duration of 52.96 (45.18) months were reviewed for haematological abnormalities.. Clozapine is associated eosinophilia and thrombocytopenia, which are often benign and in majority of the patients these normalize with time.

Topics: Adolescent; Adult; Aged; Anemia; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Eosinophilia; Female; Hematologic Diseases; Humans; Incidence; India; Male; Middle Aged; Neutropenia; Psychotic Disorders; Retrospective Studies; Schizophrenia; Thrombocytopenia; Young Adult

Ms. D. was a 57-year-old Caucasian female with a past psychiatric history of schizoaffective disorder bipolar type and unspecified anxiety disorder. She presented to the psychiatric unit with cognitive blunting, poverty of thought content, looseness of associations, and inability to respond to questions with meaningful responses. In addition, the patient presented with medical symptoms including rigidity, acute rhabdomyolysis, and elevated liver function tests (LFTs). She was transferred to the inpatient medical unit for stabilization. After acute stabilization, she was transferred back to the psychiatric unit for treatment. A thorough review of the patient's history revealed she had prior episodes of atypical NMS with trials of multiple typical and atypical antipsychotics at therapeutic doses and with clinically appropriate titration schedules. These trials included clozapine, which is known to have decreased likelihood of NMS symptoms. The patient was stabilized during admission, but later decompensated and required re-admission in the months following. At that time, clozapine was reinstituted at very low doses and with a slower titration schedule. This approach was successful in ameliorating the patient's symptoms and without recurrence of NMS. In this case report, we discuss the importance of identifying atypical NMS in patients treated with typical and atypical antipsychotics, and propose that successful treatment of these patients may be possible with slower and gradual titration of clozapine.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Beijing; Clozapine; Female; Humans; Male; Middle Aged; Pneumonia; Psychotic Disorders; Retrospective Studies; Young Adult

One-third of individuals with schizophrenia have treatment-resistant illness. Of these, up to 60% will respond to clozapine treatment.. This study retrospectively examined clozapine prescribing patterns against National Institute for Health and Care Excellence (NICE) guidelines as treatment-resistant illness emerged in a first-episode psychosis cohort.. A total of 339 individuals with a first-episode psychosis were included in the study. Clozapine prescribing patterns were compared against the NICE guidelines and the impact of clozapine use on one index of service utilisation (hospitalisation) was assessed.. A total of 32 individuals (9.4%) from the cohort were prescribed clozapine. The mean time to clozapine trial was 2.1 years (SD 1.95; range 0.17-6.25). The mean number of adequate trials of antipsychotic prior to starting clozapine was 2.74 (SD 1.13; range 1-5). Following clozapine initiation, mean hospital admissions per year reduced from 2.3 to 0.3 (. Patients are being prescribed clozapine earlier than previously demonstrated, though delays are still evident, and many patients discontinue treatment. More work needs to be undertaken to understand and address factors which lead to its discontinuation.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Female; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Psychotic Disorders; Retrospective Studies; Schizophrenia; Time Factors; Young Adult

Topics: Agammaglobulinemia; Antipsychotic Agents; Betacoronavirus; Clozapine; Contraindications, Drug; Coronavirus Infections; COVID-19; Drug Monitoring; Drug Prescriptions; Humans; Pandemics; Parkinson Disease; Pneumonia, Aspiration; Pneumonia, Viral; Psychotic Disorders; SARS-CoV-2; Schizophrenia; Sialorrhea

Topics: Affective Disorders, Psychotic; Aged; Antipsychotic Agents; Bipolar Disorder; Clozapine; Enuresis; Female; Humans; Psychotic Disorders

Acute pancreatitis is a rare but recognised complication of clozapine leading to termination of treatment.. We present the case of a 39-year-old man with treatment-resistant schizoaffective disorder and a history of recurrent acute pancreatitis attributed to clozapine. After 15 years of unremitting symptoms with disruptive and aggressive behaviour, he was admitted for a clozapine rechallenge. Despite experiencing two further episodes of acute pancreatitis during clozapine treatment that led to its temporary withdrawal, clozapine was successfully re-established under gastroenterology consultation with close monitoring which resulted in progressively marked improvement of his mental state.. This case demonstrates that patients who develop pancreatitis during clozapine treatment may be cautiously rechallenged with specialist gastroenterology support.

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Humans; Male; Pancreatitis; Psychotic Disorders

Topics: Anticonvulsants; Antipsychotic Agents; Betacoronavirus; Clozapine; Coronavirus Infections; COVID-19; Delayed-Action Preparations; Drug Resistance; Drug Therapy, Combination; Humans; Immunologic Factors; Lithium Carbonate; Male; Middle Aged; Paliperidone Palmitate; Pandemics; Pneumonia, Viral; Psychotic Disorders; SARS-CoV-2; Sialorrhea; Treatment Outcome; Valproic Acid

N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria.. Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using the Structured Clinical Interview for DSM-IV disorders (SCID). NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including neuro-imaging, EEG and CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited.. 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was 100 patients with TRS were recruited. One case (1%) seropositive for NMDAR-Ab but did not meet criteria for encephalitis.. NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis.

Topics: Adolescent; Adult; Aged; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Clozapine; Humans; Middle Aged; Prevalence; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Retrospective Studies; Schizophrenia; Seroepidemiologic Studies; Young Adult

Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored.. This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period.. Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication.. Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14-1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11-1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling.. Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.

Topics: Aftercare; Antipsychotic Agents; Clozapine; Humans; Patient Discharge; Prescriptions; Psychotic Disorders; Retrospective Studies; Schizophrenia

Stress-induced changes in pharmacokinetics can significantly alter the plasma levels of some drugs such as clozapine. This report describes the case of a middle-aged man with schizoaffective disorder, bipolar type who showed sustained elevation in clozapine levels 3 days after discontinuation. Before the clozapine levels were drawn, he had developed acute bacterial pneumonia and signs of acute bacterial meningitis followed by neuroleptic malignant syndrome after he received multiple doses of intravenous haloperidol for worsening psychosis and aggressive behavior. Existing literature on this topic is also reviewed to investigate potential reasons for sustained clozapine levels during acute inflammatory stress and neuroleptic malignant syndrome.

Topics: Acute Disease; Antipsychotic Agents; Clozapine; Humans; Male; Meningitis, Bacterial; Middle Aged; Neuroleptic Malignant Syndrome; Pneumonia, Bacterial; Psychotic Disorders

A 57-year-old female patient with a diagnosis of schizo-affective disorder since 1986 was commenced on clozapine due to persistent positive and negative psychotic symptoms in September 2014. After commencement of clozapine she was delusion free and demonstrated an improvement in negative symptoms. Three months after commencement of clozapine she developed a hypersensitivity reaction. Her symptoms continued to deteriorate despite being prescribed an anti-histamine. Clozapine was discontinued 6 days after the appearance of a generalised pruritic rash, as it was believed to be the probable cause. There was complete resolution of symptoms 1 week after discontinuation of clozapine. Clozapine was replaced with olanzapine and amisulpride. There has been no similar cutaneous or allergic reactions for the past 30 months.

Topics: Antipsychotic Agents; Clozapine; Drug Hypersensitivity; Female; Humans; Middle Aged; Psychotic Disorders

Around 30% of patients with schizophrenia are considered treatment resistant (TRS). Only around 40% of TRS patients respond to clozapine. Long acting injectable antipsychotics could be a useful augmentation strategy for nonresponders.. We conducted a multicenter, observational, naturalistic, retrospective, 6-month mirror-image study to evaluate the efficacy and tolerability of clozapine and paliperidone palmitate association in 50 patients with TRS and other psychotic disorders. Clinical outcomes and side effects were systematically assessed.. Six months after starting the combined treatment, participants showed a significant relief of symptoms, decreasing the Brief Psychiatric Rating Scale total score from 18.32 ± 7.71 to 7.84 ± 5.16 (p < 0.001). The number of hospitalizations, the length of hospital stays and the number of visits to emergency services also decreased, while an increase of the functionality was observed (Personal and Social Performance total score increased from 46.06 ± 118.7 to 60.86 ± 18.68, p < 0.001). There was also a significant decrease in the number and severity of side effects with the combination therapy, decreasing the Udvalg for Kliniske Undersogelser total score from 10.76 ± 8.04 to 8.82 ± 6.63 (p = 0.004).. This study provides the first evidence that combining clozapine with paliperidone palmitate in patients with TRS and other psychotic disorders could be effective and safe, suggesting further research with randomized controlled trials of augmentation strategies for clozapine nonresponder patients.. Patients with psychotic disorders such as schizophrenia show a variable response to antipsychotic treatments. Around 30% of patients are considered treatment resistant, indicated by insufficient symptom control to at least two different drugs. In these resistant cases, clozapine should be indicated, as it has shown to be superior to other options. However, only 40% of patients respond to clozapine, being necessary to establish which treatments could best potentiate clozapine action. Combining clozapine with long acting injectable antipsychotics, and particularly paliperidone palmitate, could be a useful strategy. We conducted a multicenter study of 50 patients with treatment-resistant schizophrenia and other psychotic disorders comparing the efficacy and tolerability in the 6 month-period prior and after starting the clozapine and paliperidone palmitate association. Our study suggests that this combination could be effective and safer, laying the groundwork for future clinical trials with this combination.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Drug Therapy, Combination; Female; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Paliperidone Palmitate; Psychotic Disorders; Retrospective Studies; Schizophrenia; Time Factors

Topics: Aging; Biomarkers; Clozapine; Epigenesis, Genetic; Humans; Neoplasms; Neuroimaging; Psychotic Disorders; Schizophrenia; Transcriptome

Clozapine is indicated for treatment-resistant schizophrenia (TRS), but only 30%-60% of patients will respond. There have been studies of clozapine augmentation with oral second-generation antipsychotics with mixed results, but no studies considering the combination with long-acting injectable antipsychotics (LAIAs). This study is the first to attempt to establish the benefits of the combination of clozapine and LAIAs in TRS using a variety of outcome measures of symptomatology and quality of life.. A mirror-image study design was employed to review outcome measures 2 years pre and post combination of clozapine with a LAIA in a small sample of patients with chronic schizophrenia or schizoaffective disorders followed by the assertive community treatment service in the community. Outcome measures include demographic data, Brief Psychiatric Rating Scale, Clinical Global Impressions Scale-Improvement and Severity, 24-item Behavior and Symptom Identification Scale, World Health Organization Quality of Life Scale, Health of the Nation Outcome Scales, Threshold Assessment Grid, number of admissions, emergency department (ED) visits, and hospital bed days.. Paired sample t tests showed a statistically significant reduction in average ED visits and hospital admissions in the 2 years post combination, with an average 1.8 fewer ED visits (95% CI, 0.58-3.02, P = .024) and a mean reduction of 0.85 hospital admissions (95% CI , 0.363-1.337, P = .008). The reduction in hospital bed days post combination was not statistically significant. Chart reviews found insufficient data for analysis of the remaining outcome measures.. The combination of clozapine and a long-acting injectable antipsychotic appears to reduce health care utilization in terms of ED visits and number of hospital admissions. Larger prospective studies will be required to confirm the results.

Topics: Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Community Mental Health Services; Delayed-Action Preparations; Drug Synergism; Drug Therapy, Combination; Emergency Service, Hospital; Facilities and Services Utilization; Female; Humans; Injections; Male; Middle Aged; Outcome Assessment, Health Care; Patient Admission; Psychotic Disorders; Research Design; Retrospective Studies; Schizophrenia; Young Adult

As many as 30% of individuals with a schizophrenia spectrum disorder experience obsessive-compulsive symptoms (OCS). Clozapine has demonstrated superior efficacy for the treatment of medication-resistant schizophrenia but it is also associated with an increased risk for OCS. Because pharmacologic management of clozapine-related OCS can be particularly challenging, cognitive behavioral therapy (CBT) should be considered. Nevertheless, there are few detailed accounts of CBT for OCS and schizophrenia.. The authors describe the interdisciplinary outpatient care of a client who had a 25-year history of schizoaffective disorder, bipolar type, and OCS. The case formulation was used to guide interventions to target core schemas of being dangerous and defective. The case study describes the cognitive behavioral formulation, treatment targets, treatment course, and functional and symptom response.. The client received 21 sessions of a formulation-based CBT for psychosis protocol, which included a 6-session course of exposure with response prevention, consisting of imaginal and in vivo exposure to multiple salient harm stimuli. Reduced ratings of distress and a 50% reduction in OCS suggest that habituation and inhibitory learning occurred. The treatment of OCS resulted in the complete resolution of thought broadcasting. Subsequently, the client was more successful in his efforts to adhere to an action schedule.. The use of both the treatment approach described in this clinical case report and contemporaneous medication management preclude comment on the mechanism(s) of the therapeutic change observed in this case.. This report presents a means of conceptualizing the interplay between thought broadcasting and harm obsessions and discusses considerations in identifying and treating individuals with similar comorbid conditions, particularly in the context of clozapine treatment for medication-resistant psychosis.

Topics: Aged, 80 and over; Antipsychotic Agents; Bipolar and Related Disorders; Clozapine; Cognition; Concept Formation; Female; Humans; Male; Middle Aged; Obsessive Behavior; Obsessive-Compulsive Disorder; Psychotic Disorders; Schizophrenia; Young Adult

To compare the rate of hospitalizations for pneumonia in patients with a psychotic or bipolar disorder who were prescribed 1 of 4 second-generation antipsychotics prior to admission.. This retrospective cohort study included patients who were medically admitted for pneumonia to a 2,059-bed academic medical center or its associated health system hospital. Medical records of 872 admissions from November 1, 2016 to December 15, 2018, were included for all adults with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder prescribed clozapine, olanzapine, quetiapine, or risperidone prior to admission.. There was no significantly increased risk of pneumonia for patients taking olanzapine (odds ratio [OR] = 1.08, 95% CI, 0.48-2.41) or quetiapine (OR = 0.97, 95% CI, 0.42-2.25) prior to admission compared to risperidone. When controlling for various factors, treatment with a combination of antipsychotics including clozapine (OR = 2.28, 95% CI, 1.13-4.62, P = .022) and clozapine alone (OR = 2.37, 95% CI, 1.30-4.32, P = .005) was associated with an increased risk of pneumonia-related hospitalization compared to treatment with risperidone, olanzapine, or quetiapine alone.. The findings of this study in combination with other published literature support an association of an increased risk of pneumonia with the use of clozapine, although this cannot be interpreted as causal. These data show that use of clozapine alone or in combination with other antipsychotics significantly increases risk of pneumonia, although this finding cannot be deemed causal due to study design.

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Hospitalization; Humans; Male; Middle Aged; Pneumonia; Psychotic Disorders; Retrospective Studies; Risk; Schizophrenia

Patients with psychotic disorders often have substance use disorders and other addictions. The objective of this study was to know the current treatment situation of these patients focusing on clozapine, which was proposed in most consensus as antipsychotic of first choice in this indication.. A survey with 14 questions on aspects related to the treatment and management of the dual disorders was developed, emphasizing the role of clozapine in this disease.. The survey was answered by 199 experts in mental illnesses (90.5% physicians and 9.5% psychologists). A total of 88.4% of experts were able to prescribe clozapine, but the majority (89.4%) administered the drug to patients with resistant schizophrenia without considering a dual disorder. Only 30.8% considered the use of clozapine in patients with dual psychosis. The underutilization of clozapine in these patients was mainly attributed to controls of the pharmacovigilance plan, including frequent leukocyte count (57.1%), and lack of drug education (35.6%). The main measures proposed to increase its use are fewer blood tests (29.3%), more training (27.8%), and fewer administrative problems (25.1%).. In order to improve the treatment of patients with dual psychosis, it is necessary to simplify the therapy and increase the training of professionals in the use of atypical antipsychotics, especially clozapine, designed to be the drug of choice in the main expert consensus.

Topics: Antipsychotic Agents; Attitude of Health Personnel; Clozapine; Cross-Sectional Studies; Diagnosis, Dual (Psychiatry); Humans; Leukocyte Count; Perception; Practice Patterns, Physicians'; Psychotic Disorders; Schizophrenia; Substance-Related Disorders

We present a case of non-convulsive status epilepticus in a 57-year-old woman with a schizoaffective disorder, without an antecedent seizure history, with two possible aetiologies including SARS-CoV-2 infection and clozapine uptitration. We discuss the presentation, investigations, differential diagnosis and management. In particular, we focus on the electroencephalogram (EEG) findings seen in this case and the electroclinical response to antiepileptic medication. We review the literature and discuss the relevance of this case to the SARS-CoV-2 global pandemic. We emphasise the importance of considering possible neurological manifestations of SARS-CoV-2 infection and highlight seizure disorder as one of the possible presentations. In addition, we discuss the possible effects of clozapine on the electroclinical presentation by way of possible seizure induction as well as discuss the possible EEG changes and we highlight that this needs to be kept in mind especially during rapid titration.

Topics: Antipsychotic Agents; Betacoronavirus; Clozapine; Coronavirus Infections; COVID-19; Diagnosis, Differential; Electroencephalography; Female; Humans; Middle Aged; Pandemics; Pneumonia, Viral; Psychotic Disorders; SARS-CoV-2; Status Epilepticus

Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. We reported previously lower NDEL1 enzyme activity in blood of treated first episode psychosis and chronic schizophrenia (SCZ) compared to healthy control subjects, with even lower activity in treatment resistant chronic SCZ patients, implicating NDEL1 activity in SCZ. Herein, higher NDEL1 activity was observed in the blood and several brain regions of a validated animal model for SCZ at baseline. In addition, long-term treatment with typical or atypical antipsychotics, under conditions in which SCZ-like phenotypes were reported to be reversed in this animal model for SCZ, showed a significant NDEL1 activity reduction in blood and brain regions which is in line with clinical data. Importantly, these results support measuring NDEL1 enzyme activity in the peripheral blood to predict changes in NDEL1 activity in the CNS. Also, acute administration of psychostimulants, at levels reported to induce SCZ-like phenotype in normal rat strains, increased NDEL1 enzyme activity in blood. Therefore, alterations in NDEL1 activity after treatment with antipsychotics or psychostimulants may suggest a possible modulation of NDEL1 activity secondary to neurotransmission homeostasis and provide new insights into the role of NDEL1 in SCZ pathophysiology.

Topics: Animals; Antipsychotic Agents; Brain; Central Nervous System Stimulants; Clozapine; Cysteine Endopeptidases; Haloperidol; Hippocampus; Male; Nucleus Accumbens; Prefrontal Cortex; Psychotic Disorders; Rats; Rats, Inbred SHR; Rats, Wistar; Schizophrenia

Clozapine treatment may have beneficial effects on behavioral outcomes in psychotic disorders, including violent offending. Although clozapine and other antipsychotics have been linked to lower levels of violent behavior, these have been primarily in small selected samples, and population-based estimates have been limited and imprecise. We aimed to assess the effect of clozapine treatment on the rate of violent and nonviolent offending. We carried out a within-person mirror-image study of the Swedish population with linked prescription, hospitalization, and sociodemographic registers. Outcomes were violent, nonviolent, and overall offences occurring before and after clozapine, or olanzapine, initiation. Comparison of effects of clozapine and olanzapine on key variables was modeled with interaction terms. We found periods of mirror-image observation time with clozapine treatment were associated with a much lower rate of violent offending compared to periods before treatment (rate ratio [RR]: 0.13 (95% CI: 0.05, 0.34). Reductions in nonviolent offences were smaller in magnitude (RR: 0.37, 95% CI: 0.17, 0.80). There was a statistically greater rate reduction effect on violent offences for clozapine than olanzapine (RR for interaction: 4.84, 95% CI: 1.56, 14.86, P = .002). In patients with psychotic disorders, clozapine treatment is associated with a lower rate of violent offending compared to olanzapine.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Criminals; Drug Prescriptions; Female; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Registries; Sweden; Violence; Young Adult

Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches.. We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline.. When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10-6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10-9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10-5) with the same risk allele. Our top genes (p < 5 × 10-5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG.. In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

Topics: Adolescent; Adult; Antipsychotic Agents; Black or African American; Chronic Disease; Clozapine; Diacylglycerol Kinase; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Multifactorial Inheritance; Obesity; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Gain; White People; Young Adult

In this commentary we discuss the findings of the recently published OPTiMiSE trial. In terms of design, important advantages of the trial are the naturalistic, open label set-up that allowed the authors to assess the efficacy of the sequential use of amisulpride followed by olanzapine and clozapine. In terms of results, we highlight the efficacy of amisulpride, while we disagree with the authors of OPTiMiSE when they claim clozapine should be tried in the clinic after one unsuccessful trial of amisulpride. We also show how the actual percentages of those complaining of sexual side effects during amisulpride use are higher than computed by the authors. On a general note, we suggest that whenever symptoms of patients allow it - and gradual improvement is observed - clinicians may wish to wait several weeks before considering a switch to amisulpride.

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Substitution; Humans; Olanzapine; Patient Selection; Psychotic Disorders; Schizophrenia

Psychotic disorders are central to mental health service provision and a common theme of academic research programmes in Ireland, which explore the neurobiological and psychosocial risk factors underpinning the development and progression of these illnesses. While we await the discovery of novel pharmacological treatment targets for psychotic disorders, it is important to employ our existing management strategies to optimal effect. In this special issue on psychosis, a selection of clinical research studies and reviews from Irish researchers, and often of Irish populations, are brought together which span the trajectory of psychotic illness from early intervention to treatment resistance. The topics include the characteristics and course of first episode psychosis cohorts, real-world evaluation of early intervention services, management strategies for treatment resistant schizophrenia and neurobiological research into social stress. The current editorial provides an overview of these papers and highlights the initial steps of the Irish Psychosis Research Network towards developing an integrated clinical research network focusing on the treatment and research into psychotic disorders.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Early Intervention, Educational; Humans; Ireland; Mental Health Services; Psychotic Disorders; Risk Factors; Schizophrenia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Gastric Bypass; Humans; Male; Obesity; Psychotic Disorders

Clozapine is a second-generation antipsychotic typically reserved for refractory psychotic disorders due to its high-risk side effect profile to include agranulocytosis, with its attendant need for regular blood draws. While reports of extrapyramidal symptoms (EPS), including acute dystonic reactions, are exceedingly rare, we present the case of a 44-year-old male with a long-standing history of treatment-resistant schizoaffective disorder and no history of EPS who experienced an acute buccal dystonic reaction in the setting of clozapine initiation and discontinuation of depot and oral risperidone. This case report presents one of the few documented episodes of acute dystonic reactions occurring in the setting of clozapine administration. Based upon the patient's history and the dosing time line of the medications, we propose that an interaction between the clozapine and residual risperidone was responsible for the development of the acute buccal dystonia.

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Dystonia; Humans; Male; Psychotic Disorders; Risperidone

Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy.. We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge.. Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge.. The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted.

Topics: Administration, Oral; Adult; Algorithms; Antipsychotic Agents; Clozapine; Commitment of Mentally Ill; Drug Therapy, Combination; Female; Haloperidol; Humans; Injections, Intramuscular; Male; Methotrimeprazine; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Failure; Treatment Outcome

Specialized early interventions improve outcomes in early psychosis (EP). Experts have proposed a number of essential treatment components. However, it is unclear whether these reflect the views of senior clinic staff charged with implementing this model in practice.. Twenty-Five senior EP clinic staff across California completed a survey indicating which features of EP treatment they considered most important.. Components related to the service structure and the need for a prompt, comprehensive assessment and care planning were considered most important, despite the limited evidence base evaluating these aspects of care. Administration of clozapine to treatment-refractory patients and weight gain interventions were considered the least important, despite the relatively strong evidence base supporting these treatment components.. The findings suggest a bi-directional dissemination gap, where components considered most important by senior providers receive limited research attention, while some areas with supporting evidence may be underappreciated in clinical practice.

Topics: Adult; Attitude of Health Personnel; California; Clinical Competence; Clozapine; Early Medical Intervention; Female; Health Care Surveys; Humans; Male; Patient Care Planning; Psychotic Disorders; Specialization; Weight Gain

Topics: Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Frontal Lobe; Histone Deacetylase 2; Mice; Mice, Knockout; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate

Insight into the effect of clozapine is limited by a lack of controlling for confounding variables in current research. Our objective was to investigate the association between clozapine prescribed at discharge, following an inpatient episode, and risk of readmission into secondary mental health services in patients with schizophrenia and schizoaffective disorder, controlling extensively for confounding variables.. Clinical records from 3651 patients were analysed in a retrospective observational cohort study. Cox proportional-hazards regression models were used to assess the risk of hospital readmission. A series of sensitivity analyses were also conducted. Propensity score methods were used to address confounding-by-indication.. Patients on clozapine ( n=202) had a reduced risk of readmission compared with patients on other antipsychotics (adjusted hazard ratio=0.79; 95% confidence interval: 0.64-0.99; p=0.043). Clozapine also had a protective effect on risk of readmission when compared with olanzapine (adjusted hazard ratio 0.76; 95% confidence interval: 0.60-0.96; p=0.021). The effect size remained consistent after adjusting for an array of possible confounders, as well as using propensity scores to address confounding-by-indication. A statistically significant result was also noted in all but two sensitivity analyses.. Our findings suggest that clozapine is associated with a reduced risk of readmission into secondary mental health services.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Patient Readmission; Proportional Hazards Models; Psychotic Disorders; Retrospective Studies; Schizophrenia; Young Adult

Topics: Adolescent; Adult; Anti-Anxiety Agents; Clozapine; Female; Fluvoxamine; Humans; Male; Psychopharmacology; Psychotic Disorders; Serotonin Antagonists

Clozapine was the widely accepted gold standard treatment for treatment resistant psychotic symptoms. Clozapine has efficacy of about 50% and some responding patients have to discontinue it due to serious adverse effects. The search for novel agents to use for clozapine-non-responders continues. One such possible agent is the non-dopaminergic antipsychotic pimavanserin, an inverse agonist of serotonin 5-HT2A receptors which was recently approved for the hallucinations and delusions of Parkinson's Disease Psychosis. We report here the successful results of using pimavanserin in patients with refractory hallucinations and delusions who failed to respond to clozapine. We also report similar results in refractory psychosis patients who did not receive clozapine.. We present ten cases of patients with schizophrenia and schizoaffective disorder with refractory hallucinations and delusions who received a trial of pimavanserin when clozapine or multiple antipsychotics failed. Six of ten patients had not responded to a clozapine trial. The subjects' ages ranged between 21 and 77 years and were followed up for several months.. All 10 patients with refractory hallucinations and delusions showed marked response to pimavanserin 34 mg/day within 4-8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients.. This series of 10 cases of patients with refractory psychosis who responded to pimavanserin is an important new finding that has never been reported before. Controlled studies comparing clozapine and pimavanserin in refractory schizophrenia are warranted to confirm these clinical observations.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Delusions; Drug Resistance; Female; Hallucinations; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Retrospective Studies; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Urea; Young Adult

To provide additional data concerning the safety, effectiveness and local prescribing trends of clozapine in elderly patients.. Retrospective observational case-series analysis.. Data were collected from the medical files of 167 patients prescribed clozapine.. All patients prescribed clozapine in the last 15 years by the psychogeriatric service in Christchurch, New Zealand. The subjects were mostly aged over 65; however, patients under 65 are also accepted into the service on a case by case basis if they have an age-related health condition.. Twenty-five (15.0%) patients had their clozapine stopped due to a significant adverse reaction, including eleven who developed significant neutropenia. Seventy-four (44.3%) of the patients had no recorded side effects at all. Sixty-five (38.9%) of our elderly patients died while taking clozapine, though none of these deaths was felt to be related to clozapine use. Several patients safely initiated clozapine in either their own home or a nursing home without requiring hospital admission. Only two patients ceased clozapine due to ineffectiveness, and one hundred, forty-two (86.1%) of the patients had positive comments in their medical record regarding the benefits of clozapine for their particular case.. We found clozapine could be used safely and effectively in our patient group, for a wider range of indications and at lower doses than younger patients. Data collection regarding cause of death in elderly patients who were ever prescribed clozapine was problematic, and more research into this area is required.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Drug Prescriptions; Drug Resistance; Female; Humans; Male; Middle Aged; Neutropenia; New Zealand; Practice Guidelines as Topic; Practice Patterns, Physicians'; Psychotic Disorders; Retrospective Studies

Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic [PL] area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.

Topics: Animals; Antipsychotic Agents; Cell Count; Clozapine; Corpus Striatum; Female; Gyrus Cinguli; Haloperidol; Humans; Injections, Intraperitoneal; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Models, Animal; Neuroglia; Neurons; Organ Size; Psychotic Disorders; Receptors, Dopamine D3; Schizophrenia

Pharmacogenetic analysis to explain or predict the response of a specific patient to drug therapy is increasingly used in clinical practice. This holds especially true for CYP genotyping in psychiatry. We present a patient with genetic polymorphisms in more than one CYP450 enzyme, resulting in reduced effectiveness of CYP enzymes, explaining the high drug serum trough levels of antipsychotics and antidepressants and difficulty in optimizing therapy and dosing. Mrs X was found to be a CYP1A2, CYP2D6, CYP3A4 intermediate and in addition a CYP2C19 poor metabolizer. For Mrs X, pharmacogenetic analysis has contributed to reconsider choice and use of medication. Prior knowledge of the genetic polymorphisms in this patient might have avoided treatment delay and discomfort.

Topics: Antidepressive Agents; Antipsychotic Agents; Biomarkers, Pharmacological; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Genotype; Humans; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Psychotic Disorders

Treatment-resistant schizophrenia (TRS) is a major cause of disability. Clozapine is currently the only antipsychotic medication licensed for its treatment. However, the rate of treatment resistance among outpatients with schizophrenia or other psychoses, and the rate of use of clozapine among them, is not known.. The aims of this study are (a) to determine the point prevalence of treatment-resistant psychosis in a community sample, and (b) to determine the number of patients with TRS who have never had a clozapine trial.. Clinico-demographic data were extracted from the case notes for 202 patients from two community mental-health teams.. These findings suggest that TRS is common in the community mental-health team, and a large proportion of these patients have not received clozapine. These findings indicate that identifying and treating treatment resistance should be a focus of community services for schizophrenia.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Humans; London; Male; Middle Aged; Prevalence; Psychotic Disorders; Schizophrenia

Systemic infections are known to alter the metabolism of various drugs via inhibition of the cytochrome P450 family. Here, we report the cases of two patients with schizophrenic psychosis and highly elevated clozapine levels during pulmonary systemic infection, however without experiencing side effects. After antibiotic treatment and temporary reduction of clozapine dosage blood levels of clozapine normalized within a few days. These cases show that clozapine levels may be highly elevated without necessarily causing side effects and that intensified pharmacovigilance should be considered by the clinician in patients with systemic infections.. Systemische Entzündungsreaktionen können über eine Hemmung der Cytochrom-P450-Proteine die Metabolisierung verschiedener Arzneimittel beeinflussen. Hier berichten wir über 2 Patienten mit schizophrener Psychose, die während eines pulmonalen Infekts stark erhöhte Clozapinspiegel, jedoch ohne klinisch sichtbare Nebenwirkungen, aufwiesen. Nach antibiotischer Behandlung und Reduktion der Clozapindosis normalisierte sich der Clozapinspiegel nach wenigen Tagen. Bei systemischen Infekten sollte an die Möglichkeit eines erhöhten Clozapinspiegels gedacht werden.

Topics: Antipsychotic Agents; Clozapine; Germany; Humans; Pneumonia; Psychotic Disorders

The aim of this study was to investigate and compare the incidence of suspected or definite cases of clozapine induced myocarditis (SDM) and clinical factors which could influence its onset in two different time periods, defined by pre- and post-cardiac monitoring at an inpatient setting, during the initiation phase of clozapine treatment. Hospital records of patients started on clozapine in the inpatient unit between 2011 and 2018 were investigated. Eight in 38 patients (11.3%) were classified as SDM after the initiation of the monitoring protocol, whereas only 1 in 33 patients (1.4%) was classified as SDM, before. Monitored and non-monitored patient groups were similar with regard to demographic and clinical variables. Diagnosis of schizoaffective disorder and use of concominant lithium, valproic acid and atypical antipsychotics were higher in patients with SDM, while clozapine dose titration was similar compared to the rest of the patients. Cardiac monitoring seems to be the main factor leading to the increase in the detection of clozapine induced myocarditis (CIM). If not monitored, the outcome of CIM can be fatal without any warning signs and symptoms. Concominant use of mood stabilizers including valproic acid and lithium, are important risk factors for the development of CIM.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Incidence; Inpatients; Lithium; Male; Middle Aged; Monitoring, Physiologic; Myocarditis; Psychotic Disorders; Risk Factors; Valproic Acid; Young Adult

Topics: Antipsychotic Agents; Clozapine; Glutamic Acid; Humans; Nerve Growth Factors; Precision Medicine; Psychotic Disorders; Schizophrenia

Although clozapine has demonstrated unique efficacy for the treatment of seriously ill patients with refractory psychosis, its real-world use presents challenges to clinicians in a variety of settings, leading to its underutilization in the United States. The barriers include a lack of prescriber knowledge and confidence, negative prescriber attitudes, special monitoring requirements, administrative burden, unprepared health systems, and inadequate appreciation of clozapine's unique nature by policy makers and payers. In 2016, the National Association of State Mental Health Program Directors (NASMHPD) gathered a national team of expert clinicians and researchers to identify and address barriers to clozapine use. NASMHPD has since expanded the work group, which convenes monthly to continue addressing specific recommendations. This Open Forum describes the deliberations of the work group and urges practitioners, administrators, local and state governments, researchers, families, and patients to join similar efforts to promote better access to clozapine and improve the treatment management for patients receiving clozapine.

Topics: Antipsychotic Agents; Clozapine; Drug Utilization; Health Knowledge, Attitudes, Practice; Humans; Psychotic Disorders; United States

Using national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation.. Through nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted.. Three thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%.. Cardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.

Topics: Adult; Aged; Ambulatory Care; Antipsychotic Agents; Bipolar Disorder; Cardiomyopathies; Clozapine; Denmark; Female; Humans; Male; Middle Aged; Myocarditis; Pericarditis; Psychotic Disorders; Registries; Schizophrenia

The inconsistency in clinician and patient ratings of clozapine-induced side effects underscore the need to supplement clinician-based estimates of side effects with patient-reported ones.. The main aims of the study are validation of the Glasgow antipsychotic side-effects scale for clozapine (GASS-C) in Serbian inpatients/outpatients with schizophrenia or schizo-affective disorder and recommendations for its future use, based on common and rare clozapine-associated side-effects.. The GASS-C was administered to 95 outpatients/inpatients diagnosed with schizophrenia, schizoaffective, or chronic psychotic disorder.. The scale showed good overall reliability, with an internal consistency coefficient of α = 0.84, an average retest coefficient of rho = 0.76, and a Spearman-Brown coefficient of validity of 0.81. Side effects were absent or mild in 64.2% of the patients, moderate in 31.6%, severe in 4.2%; 14% of the subjects considered their symptoms distressing. The most commonly reported side-effects were drowsiness, thirst, frequent urination, and dry mouth. Women reported more side effects than men, and patients not in a relationship reported significantly fewer side effects than patients in a relationship. Results indicate a weak positive correlation (rho = 0.231; p = .025) between severity of side effects and clozapine dose.. The GASS-C showed good psychometric characteristics in clinical population of patients on clozapine. In future studies, clozapine serum concentrations should be measured when using the GASS-C to monitor side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Female; Humans; Inpatients; Male; Middle Aged; Outpatients; Psychotic Disorders; Reproducibility of Results; Schizophrenia; Young Adult

Objective Serious infections or inflammations have been associated with serum clozapine concentration increases and sometimes with clozapine toxicity. Method These two cases describe Chinese patients (Case 1: a 57-year-old female nonsmoker with severe dermatitis and Case 2: a 47-year-old male nonsmoker with influenza and secondary infection). Results In both cases, the Drug Interaction Probability Scale established the presence of a probable drug-drug interaction. In both cases, the clozapine and the total clozapine concentration-to-dose ratios followed a temporal pattern (normal-high-normal), consistent with an inhibition of clozapine metabolism during peak inflammation. In the first case, the total clozapine concentration-to-dose ratio (8 with no/low inflammation: median of 3.10 and 2 at peak inflammation: median of 3.90) provided a significant difference (P = 0.044). In the second patient, because of the smaller sample size and reduced statistical power (4 with no infection: a median of 1.59 and 2 at peak infection: 3.46), the increase did not reach significance (P = 0.13). In the first case, the median baseline clozapine concentration-to-dose ratio increased by a factor of 1.45 from 2.00 to a peak of 2.89. To compensate for the inhibition of clozapine metabolism, the dose correction factor was 0.69 (1/1.45) or a decrease in dose of approximately one-third. In the second case, the median baseline clozapine concentration-to-dose ratio increased by a factor of 2.56 from 1.15 to a peak of 2.94. Conclusion This provided a dose correction factor of 0.40 (1/2.56) or approximately half the dose, similar to published cases in Caucasians with serious respiratory infections.

Topics: Antipsychotic Agents; Asian People; Clozapine; Cytokines; Dermatitis; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Inflammation; Influenza, Human; Male; Middle Aged; Psychotic Disorders; Respiratory Tract Infections

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

Topics: Antipsychotic Agents; Celiac Disease; Clozapine; Colitis, Microscopic; Humans; Male; Middle Aged; Psychotic Disorders

To comprehensively assess cardio-metabolic risk factors and their management in a large sample of outpatients treated with clozapine.. Observational cross-sectional study of all clozapine users attending specialized clozapine monitoring outpatient clinics in three public hospitals in Sydney, Australia were approached to participate over the one-year period 01/10/2015-30/09/2016. Cardio-metabolic risk factors including metabolic syndrome, risk for future development of diabetes, smoking, physical activity, nutrition, and prescribed medications were assessed at face-to-face interview and through medical record review. Among patients who had cardio-metabolic risk factors, the proportion receiving appropriate management was assessed.. Of 451 registered clozapine clinic attenders, 92.2% completed questionnaires and anthropometric measurements. 58.3% met criteria for metabolic syndrome. 79.6% were overweight or obese. 55.9% had blood pressure meeting metabolic syndrome criteria. 46.6% had elevated fasting blood glucose and 55.2% had elevated blood triglycerides. 43.6% were current smokers. Only 10% achieved recommended weekly physical activity levels. Unhealthy food categories were highly consumed. 32.1% were on additional antipsychotics. In the majority of individuals, cardio-metabolic risk factors were untreated or under-treated.. Clozapine use was associated with very high rates of cardiovascular and metabolic risk factors, which were frequently under-treated. Management of both physical and mental health should be prioritized. Polypharmacy should be rationalized. Future research should investigate the effectiveness of smoking cessation and lifestyle interventions in this high-risk population.

Topics: Adult; Aged; Ambulatory Care; Antipsychotic Agents; Clozapine; Cohort Studies; Cross-Sectional Studies; Female; Heart Diseases; Humans; Male; Metabolic Syndrome; Middle Aged; Polypharmacy; Prevalence; Psychotic Disorders; Risk Factors; Schizophrenia

The superior efficacy of clozapine in treatment resistant schizophrenia has been clearly demonstrated, yet there are often delays in the commencement of clozapine. In this study, we aimed to determine; the proportion of young people with a first episode of psychosis (FEP) who would be considered eligible for clozapine treatment, the theoretical delay in commencing clozapine and to compare the outcomes of those treated with clozapine to those who were eligible but not treated with clozapine.. This study was conducted at Orygen Youth Health (OYH), a youth mental health service for young people aged 15-24. All clients who were treated at the Early Psychosis Prevention and Intervention Centre (EPPIC) clinic between 01.01.2011 and 31.12.2013 were included.. 544 young people presented with a FEP in the study period and 9.4% (N = 51) subsequently fulfilled criteria for treatment-resistant schizophrenia. Of these individuals, thirty (58.8%) were commenced on clozapine, in addition to a further eleven. The median delay to the commencement of clozapine was 42 weeks (I.Q.R. = 7.5-64). Of those commenced on clozapine, 76.6% achieved remission of positive psychotic symptoms and 50% were in employment or education by the time of discharge or transfer to the adult mental health services. The rate of discontinuation of clozapine was 24.4% and 60.0% of discontinuations were due to cardiac complications and the remainder were due to non-compliance.. These findings suggest that early intervention for psychosis services have a crucial role in ensuring timely initiation of clozapine in individuals with a diagnosis of treatment-resistant schizophrenia.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Drug Resistance; Drug Substitution; Female; Humans; Male; Patient Acceptance of Health Care; Psychotic Disorders; Retrospective Studies; Schizophrenia; Socioeconomic Factors; Time-to-Treatment; Treatment Outcome; Young Adult

Topics: Adult; Aggression; Clozapine; Fatal Outcome; Female; Heart Failure; Humans; Psychiatric Department, Hospital; Psychomotor Agitation; Psychotic Disorders; Restraint, Physical

Valproic acid and clozapine are drugs commonly used in the treatment of schizophrenic and schizoaffective disorders. Pharmacokinetic interactions of valproic acid with several drugs are well known, yet results concerning the interaction with clozapine are inconsistent.. Steady-state dose-corrected serum concentrations of clozapine and its main metabolite norclozapine were retrospectively analyzed in 45 patients receiving both clozapine and valproic acid. Controls were matched for sex, age, smoking, comedication, and inflammatory response.. The group receiving comedication with valproic acid showed significantly lower median dose-corrected serum concentrations of norclozapine (0.44 [0.27-0.58] (ng/mL)/(mg/d) vs 0.78 [0.60-1.07] (ng/mL)/(mg/d)) as well as metabolite to parent compound ratios (0.40 [0.36-0.47] vs 0.71 [0.58-0.84]) by approximately 44%. Dose-corrected serum concentrations of clozapine were not significantly lower. The effect of valproic acid was independent of sex and smoking.. Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapine. Therapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Monitoring; Female; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Valproic Acid

The use of clozapine, particularly in young people, is often limited by early treatment-emergent adverse effects including drowsiness and lethargy. Concerns about adverse effects, medication adherence, and the need for blood monitoring often impede the use of clozapine in this population, leading to repeated trials of less effective medications. Current clozapine dosing recommendations are based on people further in the course of their illness and thus reflect different responsiveness and sensitivities to antipsychotic medication. As such, there is a need for evidence-based guidelines for titration and dosing of clozapine among people in early psychosis.. We performed a chart review of 14 people treated with clozapine within our early psychosis team. Data regarding dose titration, response, time to discontinuation, symptom severity, weight gain, and other adverse effects were gathered at clozapine initiation, 3 months, and last available visit on clozapine.. People treated with slow titration within their first year of psychosis onset achieved sustained response at very low maintenance doses (mean dose = 81 mg/d, mean duration of treatment = 200 weeks) compared with slow titration with longer duration of illness (mean dose = 350 mg/d, mean duration of treatment = 68 weeks) or standard dose titration in early psychosis (mean dose = 112 mg/d, mean duration of treatment = 38 weeks). The most common adverse effects in all groups were weight gain and sedation, with the groups requiring higher mean doses reporting a broader range of adverse effects. There was no apparent difference in the clinical global impression for severity or improvement between the slow titration and standard titration groups in people with early psychosis. These observations are synthesized into a proposed treatment guideline for use of clozapine among people in early psychosis.. We describe development of a slow titration approach to initiating clozapine among people in early psychosis. This approach resulted in clinical response at remarkably low maintenance doses of clozapine among people within their first year of illness, but not in those with longer duration of symptoms. Slow titration also led to good tolerability and acceptance of clozapine treatment for some patients.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Practice Guidelines as Topic; Psychotic Disorders; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

Topics: Animals; Antipsychotic Agents; Central Nervous System Sensitization; Clozapine; Dopamine Agents; Humans; Psychotic Disorders; Schizophrenia

Retrospective data were collected from 330 individuals who were treated at a tertiary care program for treatment-resistant psychosis between 1994 and 2010. The main objectives were to compare the use of antipsychotic monotherapy to polypharmacy and to characterize within-individual changes in treatment and symptomatology between admission and discharge. At admission, individuals who were prescribed only one antipsychotic were comparable to those who were prescribed at least two antipsychotics with regard to demographics and symptom severity. The use of psychotropic medications other than antipsychotics was also similar between the two groups. However, the magnitude of antipsychotic utilization was greater in individuals who were receiving antipsychotic polypharmacy. In addition, a greater proportion received excessive doses at admission. Similar findings were observed when the two antipsychotic prescribing practices were compared at discharge. Three important patterns were identified when investigating within-individual changes. First, fewer individuals were prescribed more than one antipsychotic at discharge. This was accompanied by a general decrease in the magnitude of antipsychotic utilization. Second, the number of individuals who were prescribed clozapine had increased by discharge. Most who were already prescribed clozapine at admission had their doses increased. Third, improvements in symptomatology were observed across all of the subscales included in the Positive and Negative Symptom Scale (PANSS); 57.9% of individuals experienced a relative reduction in total PANSS scores exceeding 20%. Based on these findings, it is possible to alleviate symptom severity while reducing antipsychotic utilization when patients are treated at a tertiary care program for treatment-resistant psychosis.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Patient Admission; Patient Discharge; Polypharmacy; Practice Patterns, Physicians'; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Time Factors; Treatment Outcome

Topics: Amisulpride; Clozapine; Humans; Olanzapine; Psychotic Disorders; Schizophrenia

Mitochondrial pathology has been implicated in the pathogenesis of psychotic disorders. A few studies have proposed reduced leukocyte mitochondrial DNA (mtDNA) copy number in schizophrenia and bipolar disorder type I, compared to healthy controls. However, it is unknown if mtDNA copy number alteration is driven by psychosis, comorbidity or treatment. Whole blood mtDNA copy number was determined in 594 psychosis patients and corrected for platelet to leukocyte count ratio (mtDNAcn

Topics: Adult; Antipsychotic Agents; Clozapine; DNA Copy Number Variations; DNA, Mitochondrial; Female; Humans; Male; Middle Aged; Models, Genetic; Neurons; Psychotic Disorders; Risperidone; Severity of Illness Index

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Humans; Olanzapine; Psychotic Disorders; Schizophrenia

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Humans; Olanzapine; Psychotic Disorders; Schizophrenia

Serotonin 5-HT. Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated.. The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion.. These findings further support the existence of a functionally relevant crosstalk between 5-HT

Topics: Animals; Antipsychotic Agents; Clozapine; Frontal Lobe; Male; Mice; Mice, Knockout; Phencyclidine; Psychomotor Agitation; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Schizophrenia

Antipsychotics produce electroencephalogram (EEG) modifications and increase the risk of epileptic seizure. These modifications remain sparsely studied specifically for atypical antipsychotics. In this context, our study focuses on EEG modifications associated with atypical strict antipsychotic monotherapies.. Electroencephalogram recordings of 84 psychiatric patients treated with atypical antipsychotics in strict monotherapy (clozapine, n = 22; aripiprazole, n = 22; olanzapine, n = 17; risperidone, n = 9; quetiapine, n = 8; risperidone long-acting injection, n = 4; and paliperidone long-acting injection, n = 2) were analyzed. The modifications were ranked according to both slowing and excitability scores.. Electroencephalogram modifications (in 51 subjects, 60.71%) were graded according to 4 stages combining general slowing and sharp slow waves and/or epileptiform activities. The presence of sharp or epileptiform activities was significantly greater for clozapine (90.9%) compared with other second-generation antipsychotics (aripiprazole, 50%; olanzapine, 58.8%; quetiapine, 37.5%; risperidone, 44.4%). Age, duration of disease progression, and diagnosis were not associated as risk factors. Electroencephalogram modifications were associated with lower doses for treatment with quetiapine but not for specific antipsychotics. Electroencephalogram modifications and severe excitability were associated with higher chlorpromazine equivalent doses.. Atypical antipsychotics (clozapine, aripiprazole, quetiapine, olanzapine, and risperidone) induce EEG modifications, and these are significantly greater for clozapine and appear dependent on chlorpromazine equivalent dose. No encephalopathy was observed in these antipsychotic monotherapies, whatever dose.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Cerebral Cortex; Clozapine; Depressive Disorder, Major; Electroencephalography; Female; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Young Adult

Patients with psychiatric disorders in critical condition are difficult to treat. In this study, we report on a patient with underlying schizoaffective disorder who developed catatonia, cardiac arrest, and pulmonary embolism, as well as a successful treatment strategy.. The inpatient is a 41-year-old morbidly obese male with schizoaffective disorder whose clozapine dosage was titrated from 100 mg to 175 mg due to auditory hallucination and agitation. The patient abruptly developed acute cardiopulmonary symptoms associated with an elevated troponin-I level. He was transferred to a cardiac intensive care unit, where he remained for 3 days. He was also found to have excited catatonic symptoms, and the lorazepam-diazepam protocol was initiated to quickly relieve the catatonia. Once the coronary angiogram was read as normal, the patient was transferred back to the psychiatric ward. However, the patient then suffered from in-hospital cardiac arrest. He was resuscitated and again transferred to the medical intensive care unit. Computed tomography confirmed the diagnosis of a pulmonary embolism. The patient was treated with Rivaroxaban 30 mg/d for the first 21 days, followed by 20 mg daily for 3 months. To control his severe and refractory psychotic symptoms, the patient was re-prescribed clozapine. During the 15-month follow-up period, the patient demonstrated a fair response and tolerability to clozapine 150 mg without symptoms relapse and no thromboembolic event.. This report can serve to remind psychiatrists and physicians to be aware of fatal conditions in patients with psychiatric diseases and physical illnesses.

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Drug Therapy, Combination; Factor Xa Inhibitors; Hallucinations; Humans; Male; Obesity, Morbid; Psychotic Disorders; Pulmonary Embolism; Rivaroxaban; Treatment Outcome

Clozapine is the drug of choice for treatment-resistant schizophrenia. While pediatric clozapine use is not contraindicated, the literature describing its clinical application is limited. The primary objective of this study was to assess the use of clozapine in a child and adolescent population by characterizing the documented safety and clinical benefits of the medication.. A multicenter retrospective study at sites in the United States and Australia included children and adolescents admitted to a psychiatric unit who were administered at least one dose of clozapine. Information related to demographics, patient history, past treatments, clozapine, and adverse events was collected.. Eighty-two patients from eight sites were included in this study. Patients were predominantly clozapine naive (76.8%), and most had a discharge diagnosis of a primary psychotic disorder (61%) or bipolar disorder (25.6%). Four clozapine discontinuations occurred during hospitalization due to severe neutropenia, ileus, need for diagnostic clarification, and significant psychomotor retardation. The remainder (n = 78) were discharged on a mean clozapine dose of 218.1 ± 142.2 mg. Sedation (26.8%) and sialorrhea (17.1%) were the most common documented adverse events. The mean number of previously trialed antipsychotics before clozapine was 3.5 ± 1.4 (range 1-10). Improvement with clozapine was documented as significant (31.7%), moderate (32.9%), minimal (12.2%), no improvement (2.4%), and not described (20.7%).. In this cohort, 95% of pediatric patients admitted with or started on clozapine during an acute psychiatric hospitalization were discharged on the medication. The high incidence of adverse events should reinforce to clinicians the need for vigilant monitoring. Pediatric guidelines recommend clozapine for refractory schizophrenia but stress the critical need to ensure an accurate diagnosis. Limited data exist for the use of clozapine in pediatric patients with other diagnoses.

Topics: Adolescent; Antipsychotic Agents; Australia; Bipolar Disorder; Child; Clozapine; Female; Humans; Male; Neutropenia; Psychiatric Department, Hospital; Psychotic Disorders; Retrospective Studies; Sialorrhea

Cessation of clozapine therapy and insufficient response may result in relapse of psychotic symptoms and in clinical admissions. However, discontinuation rates are high. Identifying patients at risk for unsuccessful clozapine use might enable clinicians to direct specific attention to them.. Routinely collected data from a large insurance company were used to develop a simple prediction model for unsuccessful clozapine treatment in psychiatric patients 1 year after clozapine was first dispensed by a community pharmacy in the Netherlands. Multivariate logistic regression analyses were performed with the Nagelkerke R statistic as a measure of the predictive value of the model.. A total of 937 patients were dispensed clozapine for the first time by their community pharmacy between January 1, 2011, and December 31, 2015 (index date). Of these, 741 patients had started their clozapine treatment in hospital before the index date (inpatient starters); the remaining 196 patients started clozapine as outpatients on the index date (outpatient starters). In 191 patients (20.4%), clozapine treatment was unsuccessful 1 year after the index date. Unsuccessful treatment was more common among outpatient starters than among inpatient starters (32.1% vs 17.3%). Using backward selection of the variables, a model consisting of 61 variables had the best predictive value overall (Nagelkerke R = 0.301), whereas a model consisting of 52 variables had the best predictive value in outpatient starters (Nagelkerke R = 0.676).. The likelihood of unsuccessful clozapine treatment after 1 year was higher among patients who started clozapine as outpatients. Despite the use of a diversity of variables and different statistical approaches, it was not possible to make a simple prediction model for unsuccessful clozapine treatment using relatively easily accessible data.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychotic Disorders; Treatment Failure

Topics: Clozapine; Humans; Psychotic Disorders; Schizophrenia

Schizophrenia treatment needs to cover several psychological interventions and pharmacological treatment for stabilizing the disease course and decreasing relapses. Sexual side effects are a major hindrance to patients and lead to decreased adherence to therapy and reduced quality of life. Recently, several studies outlined that sexual dysfunction is one of the most distressing side effects of antipsychotics and a major cause of a poor quality of life. We hereby report a case of hypersexuality probably associated with clozapine in a middle-aged woman with schizoaffective disorder.. 45-year-old female diagnosed as a case of schizoaffective disorder, was initiated on quetiapine 150 mg, risperidone 4 mg, lithium 900 mg for her psychotic and maniac symptoms, and lorazepam 2 mg for insomnia. Due to non-compliance and relapse of symptoms, she was started on clozapine 450 mg which was further increased to 650 mg along with an injectable antipsychotic zuclopenthixol 400 mg. After 3 months of treatment with an increased dose of clozapine, patient exhibited unprovoked and increased sexual urges towards male relatives, exhibitionism and an increased libido compared to normal days. A complete physical examination ruled out any extrapyramidal signs. Clozapine was tapered to 400 mg and stopped. Upon cessation of clozapine, her symptoms of hypersexuality gradually reduced.. Clozapine's dopaminergic agonistic effects at the mesolimbic circuit may be responsible for this hypersexuality phenomenon. Poor understanding of the condition by the patient could lead to marital discord and suffering. WHO scale indicates clozapine as the probable cause of sexual dysfunction in our patient.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Libido; Middle Aged; Psychotic Disorders; Sexual Behavior; Sexual Dysfunction, Physiological

A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG.. We analysed 40 tagSNPs in HRH1 (n = 34) and HRH3 (n = 6) in schizophrenia/schizoaffective disorder patients (n = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates.. In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine (P. The current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Psychotic Disorders; Receptors, Histamine H1; Receptors, Histamine H3; Schizophrenia; Weight Gain

The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy.. Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients' CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients.. The patients' CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53±56.53 in low expressers vs 78.05±29.57 or 66.52±0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18±0.64 vs 4.98±1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers.. Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Mutation; Prospective Studies; Psychotic Disorders; RNA, Messenger; Schizophrenia; Young Adult

In the recent study by Verhoeven and Egger, 2015 and the recent letter to the editor by Boot et al. 2015 an emphasis is given to the best possible pharmacological treatment of 22q11-2 Deletion-Syndrome related psychoses. We would like to present the case of a 23-year old Cypriot patient with 22q11.2 deletion syndrome who fulfilled criteria for treatment resistant schizophrenia (TRS). He was sequentially treated with aripiprazole, risperidone, olanzapine, haloperidol and a combination treatment with olanzapine and haloperidol. Clozapine was the only antipsychotic medication that has improved his condition.

Topics: Antipsychotic Agents; Clozapine; DiGeorge Syndrome; Drug Resistance; Humans; Male; Psychotic Disorders; Young Adult

Since the middle of the 19th century, both neurologists and psychiatrists have linked psychosis and epilepsy. Clozapine, the most effective antipsychotic drug, alters electroencephalographic activity and carries a significant risk of causing seizures. Unfortunately, this risk limits the drug's potential use in treating pharmacoresistant psychosis in patients with epilepsy. We present a unique case in which we used clozapine successfully as a last resort treatment for chronic interictal psychosis in a 43-year-old woman with severe pharmacoresistant epilepsy and recurrent status epilepticus. Her psychotic symptoms improved markedly without an increase in the frequency of seizures despite gradual titration of the clozapine dose up to 300 mg daily. Her response demonstrates that, properly monitored, clozapine can be an effective treatment for psychosis even in patients with daily seizures.

Topics: Adult; Antipsychotic Agents; Clozapine; Epilepsy; Female; Humans; Psychotic Disorders; Treatment Outcome

Despite its superior efficacy, clozapine is an underutilized agent, primarily owing to the "Clozaphobia"-fear of clozapine's adverse effects. Emergent cautions on metabolic side-effects have contributed to avoidance of clozapine prescription. Here, we describe our clinical experience with nine patients having schizophrenia/schizoaffective disorders with comorbid diabetes mellitus and treated with clozapine. Interestingly, all patients could be maintained on optimal glycemic control even after clozapine. In conclusion, a critique on the potential risks versus benefits of clozapine amidst our observations from this case series adds further supporting evidence to the emerging literature on the clinical utility of clozapine in treating schizophrenia patients with diabetes mellitus.

Topics: Adult; Antipsychotic Agents; Clozapine; Comorbidity; Diabetes Mellitus; Female; Health Knowledge, Attitudes, Practice; Humans; Male; Middle Aged; Phobic Disorders; Psychotic Disorders; Schizophrenia

Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition. The opposite effects of clozapine and n-desmethylclozapine (NDMC) on cholinergic system have been suggested to underlie these inconclusive findings. The aim of this study is to determine whether clozapine/NDMC ratio can predict cognitive performance in patients with treatment-resistant psychosis. Nineteen clinically stable patients with schizophrenia or schizoaffective disorder treated with clozapine monotherapy completed demographic and clinical interviews. For the purpose of the study, patients were assessed with a neuropsychological battery and on the same day a blood sampling was obtained from each patient to measure plasma levels of clozapine and NDMC. Our results showed that clozapine/NDMC ratio, but not clozapine or NDMC plasma levels separately, was a predictive factor of cognitive performance, specifically of executive functioning. Our results showed that lower clozapine/NDMC ratios are associated with better executive functioning in clinically stable patients. These findings could be interpreted by the different pharmacodynamic properties on cholinergic, dopaminergic and serotonergic systems of NDMC compared to clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Choline; Clozapine; Cognition; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Middle Aged; Prognosis; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin

Clozapine has been regarded as the gold standard for patients with treatment-resistant schizophrenia, but a recent network meta-analysis has questioned its relative superiority over other second-generation antipsychotics (SGAs) such as olanzapine and risperidone.. We conducted a retrospective mirror-image study of clozapine vs other SGAs to evaluate real-world effectiveness of clozapine in terms of the duration of hospitalization and seclusion, both of which represent a critical outcome.. We included all patients who initiated clozapine at the Yamanashi Prefectural KITA Hospital and had continued to take any SGA(s) other than clozapine for at least 1 year before the initiation of clozapine. We obtained data on hospitalization and seclusion during 1 year of SGA treatment (SGA phase) and 1 year after the treatment was switched to clozapine (clozapine phase).. The study included 35 patients (21 men, 31 with schizophrenia, 4 with schizoaffective disorder) with the average ± SD age of 37.3 ± 11.1 years. The results indicated that total hospitalization days did not differ significantly between SGA and clozapine treatment. However, total duration of seclusion was significantly shorter in the clozapine phase than in the SGA phase. Furthermore, the number of patients who were secluded at least once was significantly smaller in the clozapine phase than in the SGA phase. The results were essentially unchanged when outlier patients were excluded and only when patients taking olanzapine and/or risperidone during the SGA phase were considered.. Although the findings from this retrospective analysis need to be further tested in prospective trials, they endorse the relative effectiveness of clozapine over other SGAs in the real world.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Hospitalization; Hospitals, Psychiatric; Hospitals, Public; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Patient Isolation; Psychotic Disorders; Retrospective Studies; Schizophrenia

Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables.. Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators.. One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups.. Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.

Topics: Adult; Antipsychotic Agents; Australia; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Medication Adherence; Polypharmacy; Psychotic Disorders; Schizophrenia; Treatment Outcome

Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine.. Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR). Clozapine levels and other potential confounders, including concurrent medications, were also included in the analysis.. This study confirms a high prevalence of metabolic side effects with clozapine and suggests higher clozapine level and pharmacogenetic markers in CYP2C19, LEP, LEPR, and HTR2C receptors as important predictors of BMI and metabolic syndrome.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Obesity; Overweight; Pharmacogenomic Testing; Prevalence; Psychotic Disorders; Schizophrenia; Young Adult

Topics: Administration, Sublingual; Adult; Antipsychotic Agents; Atropine; Clozapine; Humans; Male; Middle Aged; Muscarinic Antagonists; Psychotic Disorders; Schizophrenia; Sialorrhea

Thioredoxin is a serum antioxidant that has been investigated in the etiology of schizophrenia. The aim of this study is investigating the relationship between serum thioredoxin levels and cognitive functions in acute psychotic episode and remission state patients with schizophrenia; and examining whether there were differences between patients using clozapine and other atypical antipsychotics; including risperidone, olanzapine and amisulpride. This research was performed in schizophrenia patients hospitalized with acute psychotic episode (n=57), reevaluated patients after the initiation of treatment (mean 16 weeks) (n=46), and healthy controls (n=41). Positive and Negative Syndrome Scale, Clinic Global Impressions Scale, Neuropsychologic test battery to assess cognitive performance, and serum thioredoxin levels measured by ELISA were used in this research. Serum thioredoxin levels were highest in acute psychotic episode, lower in the remission state and the lowest in healthy controls. Significant correlation has been established between serum thioredoxin levels and Trail Making Test-A performance in remission state patients. In conclusion, serum thioredoxin levels were increased in acute psychotic episode and decreased in remission state, and its relationship with attention is worth to consider in schizophrenia patients.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Sulpiride; Thioredoxins; Young Adult

Topics: Acute Kidney Injury; Antimanic Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Male; Middle Aged; Pancreatitis; Psychotic Disorders; Valproic Acid

We aimed to evaluate the association between sex and hospitalization characteristics in psychotic disorders. We identified all acute hospitalizations, between 2010 and 2013, for psychotic disorders in patients younger than 45 and older than 55 years (n = 5411) in the hospital's database. In addition, we identified patients who were prescribed with intramuscular risperidone (n = 280) or clozapine (n = 192) at discharge. The results showed that women younger than 45 years had lower proportions of hospitalizations (33.52% vs. 66.47%) and involuntary hospitalizations (33.85% vs. 45.55%) than did men in the same age group. Women older than 55 years had higher proportions of hospitalizations (57.22% vs. 42.77%) and similar proportion of involuntary hospitalizations. Women younger than 45 years were prescribed similar doses of intramuscular risperidone and lower doses of clozapine (345.8 vs. 380.2 mg) and women older than 55 years were prescribed higher doses of intramuscular risperidone (44.8 vs. 34.4 mg/2 weeks) and clozapine (164.32 vs. 154.5 mg) than were men in the same age group. Women in the reproductive years have better hospitalization characteristics than do men on these measures.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Commitment of Mentally Ill; Female; Hospitalization; Hospitals, Psychiatric; Humans; Length of Stay; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Risperidone; Sex Factors; Young Adult

To evaluate efficacy and tolerability of the combination of clozapine with an antipsychotic long-acting injectable (LAI) in multi-episode patients with schizophrenia or schizoaffective disorder. Efficacy and tolerability were assessed in seventeen patients admitted to a hospital in Paris between January 2010 and June 2015, using a one-year mirror-image design. Number and length of hospitalizations significantly decreased after introducing the combination (2.1 vs 0.8, p=0.004 and 155.4days vs 26.6days, p<0.001 respectively). No major adverse events occurred in terms of increased weight, agranulocytosis, hyperglycemia and/or dyslipidemia. This combination can be beneficial and safe in multi-episode patients.

Topics: Adult; Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Drug Therapy, Combination; Female; Humans; Injections; International Cooperation; Length of Stay; Male; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome

Psychotic disorders in Parkinson's disease (PDPD) are common and significantly influence the quality of life and disability level. The pathogenesis of PDPD is complex and not yet fully understood. Taking into consideration the features of the Parkinson's disease (usually older patients with a risk of cognitive decline), and the pharmacodynamics of the antiparkinsonian and traditional antipsychotic drugs, the management of PDPD is a challenging issue of clinical neurology and psychiatry. In this systematic review, scientific publications for the period 2014-2016 were analyzed within two bibliographic databases: MEDLINE/PubMed and eLIBRARY.RU. Additionally, the guidelines of the International Parkinson and Movement Disorders Society, American Academy of Neurology and European Academy of Neurology were included in the analysis. Clozapine is recommended to use in the treatment of PDPD, quetiapine is possible to use, pimavanserin will probably become a remedy of choice. Nonpharmacological approaches have positive effects on the general condition of the patients with PDPD, however the efficacy of such approaches to treat psychosis is unclear.. Психотические расстройства при болезни Паркинсона (ПРБП) отмечаются у большого числа пациентов. Они оказывают значительное влияние на качество жизни и уровень инвалидизации. Патогенез ПРБП является сложным и до конца не изученным. Принимая во внимание специфику БП (как правило, пациенты пожилого возраста с риском появления когнитивных нарушений), а также фармакодинамические особенности антипаркинсонических и классических антипсихотических средств, лечение ПРБП требует особого внимания неврологов и психиатров. Представлен систематический обзор, в котором обобщены результаты научных публикаций за период 2014-2016 гг. в двух библиографических базах данных: MEDLINE/PubMed и eLIBRARY.RU, а также клинических рекомендаций Международного общества болезни Паркинсона и нарушений движения, Американской и Европейской академий неврологии. Из антипсихотических средств клозапин является препаратом, рекомендованным к применению, кветиапин - препарат, который признается возможным к применению, пимавансерин, вероятно, станет одним из препаратов выбора в терапии ПРБП. Нефармакологические методы лечения оказывают положительный эффект в плане улучшения общего состояния пациентов с ПРБП, однако их эффективность по лечению собственно ПРБП остается неясной.

Topics: Antiparkinson Agents; Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Quetiapine Fumarate; Urea

In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient.. The aim of this study was to find out whether elevated serum levels (≥5 mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone.. Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5 mg/l) and pathological (>5 mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis.. Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0 % (clozapine), 11.9 % (quetiapine), and 24.2 % (active moiety of risperidone), respectively.. In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Biomarkers; C-Reactive Protein; Clozapine; Female; Humans; Inflammation; Male; Psychotic Disorders; Psychotropic Drugs; Quetiapine Fumarate; Risperidone; ROC Curve

Topics: Antipsychotic Agents; C-Reactive Protein; Clozapine; Dose-Response Relationship, Drug; Female; Fever; Humans; Middle Aged; Psychotic Disorders

The authors compared the effectiveness of initiating treatment with either clozapine or a standard antipsychotic among adults with evidence of treatment-resistant schizophrenia in routine clinical practice.. U.S. national Medicaid data from 2001 to 2009 were used to examine treatment outcomes in a cohort of patients with schizophrenia and evidence of treatment resistance that initiated clozapine (N=3,123) and in a propensity score-matched cohort that initiated a standard antipsychotic (N=3,123). Interventions were new initiation of clozapine or a standard antipsychotic medication, defined as no exposure to the new medication in the prior 365 days. The primary outcome was hospital admission for a mental disorder. Secondary outcomes included discontinuation of the index antipsychotic, use of an additional antipsychotic, incidence of serious medical conditions, and mortality.. Initiation of clozapine was associated with a significantly decreased rate of psychiatric hospital admission (hazard ratio=0.78, 95% CI=0.69-0.88), index antipsychotic discontinuation (hazard ratio=0.60, 95% CI=0.55-0.65), and use of an additional antipsychotic (hazard ratio=0.76, 95% CI=0.70-0.82). Clozapine was associated with significantly increased incidence of diabetes mellitus (2.8% for clozapine vs. 1.4% for standard antipsychotic; hazard ratio=1.63, 95% CI=0.98-2.70), hyperlipidemia (12.9% for clozapine vs. 8.5% for standard antipsychotic; hazard ratio=1.40, 95%CI=1.09-1.78), and intestinal obstruction (0.9% for clozapine vs. 0.3% for standard antipsychotic; hazard ratio=2.50, 95% CI=0.97-6.44).. In adults with schizophrenia and evidence of treatment resistance, initiating clozapine compared with initiating a standard antipsychotic was associated with greater effectiveness on several important outcomes. Increasing the judicious use of clozapine is warranted together with vigilance to prevent and detect serious medical adverse effects.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Databases, Factual; Diabetes Mellitus; Female; Hospitalization; Humans; Hyperlipidemias; Intestinal Obstruction; Logistic Models; Male; Medicaid; Mental Health Services; Middle Aged; Proportional Hazards Models; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome; United States

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Psychotic Disorders; Systemic Inflammatory Response Syndrome

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Female; Humans; Male; Neutropenia; Parkinson Disease; Psychotic Disorders

To analyze antipsychotic prescribing patterns in a UK high security hospital (HSH) that treats seriously violent men with either schizophrenia or personality disorder and examine how different groups consented to treatment and prescribing for metabolic conditions. We hypothesized that there would be high prevalence of antipsychotic polypharmacy, and high-dose antipsychotic and clozapine prescribing.. HSHs treat seriously violent, mentally disordered offenders, and the extant literature on prescribing patterns in forensic settings is sparse.. Prescribing and clinical data on all 189 patients in a UK HSH were collected from the hospital's databases. Data were analyzed using SPSS.. The population was split into the following groups: schizophrenia spectrum disorder (SSD-only), personality disorder (PD-only), and comorbid schizophrenia spectrum disorder and PD. The majority (93.7%) of all patients were prescribed at least one antipsychotic, and (27.5%) were on clozapine. Polypharmacy was prevalent in 22.2% and high-dose antipsychotic in 27.5%. Patients on clozapine were more likely to be prescribed antidiabetic, statins, or antihypertensive medication. Patients in the PD-only group were more likely to be deemed to have the capacity to consent to treatment and be prescribed clozapine in contrast to the SSD-only group.. Rates of clozapine and high-dose antipsychotic prescribing were higher than in other psychiatric settings, while polypharmacy prescribing rates were lower. Higher clozapine prescribing rates may be a function of a treatment-resistant and aggressive population. A higher proportion of PD-only patients consented to treatment and received clozapine compared with in-house SSD-only as well as other psychiatric settings. Implications of the findings are discussed.

Topics: Adult; Antihypertensive Agents; Antipsychotic Agents; Clozapine; Criminals; Diabetes Mellitus; Dyslipidemias; Hospitals, Psychiatric; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypoglycemic Agents; Informed Consent; Male; Middle Aged; Personality Disorders; Polypharmacy; Practice Patterns, Physicians'; Psychotic Disorders; Schizophrenia; United Kingdom; Violence

Topics: Antipsychotic Agents; Clozapine; Cogan Syndrome; Drug Resistance; Humans; Male; Middle Aged; Psychotic Disorders

The aim of this retrospective study is to examine the clinical outcomes and safety of clozapine in children and adolescents with schizophrenia or other psychotic disorders/autism spectrum disorder (ASD) or affective disorders.. The inpatient and outpatient files of all children and adolescents treated with clozapine over a period of 34 months (from October 2011 to July 2014) were reviewed. Demographic and clinical data were examined to describe clinical and metabolic findings, dosing, and tolerability of clozapine treatment in youth with schizophrenia, other psychotic disorders, ASD, or bipolar disorder.. The 37 pediatric patients included 26 patients with schizophrenia or other psychotic disorders, 7 patients with ASD complicated by schizophrenia or other psychotic disorders or affective disorders, and 4 patients with ASD only. In all groups (n = 37) there was a significant reduction (p < 0.001) in Brief Psychiatric Rating Scale (BPRS) points after clozapine treatment during the inpatient period (38.78 ± 27.75 days). In patients with schizophrenia or other psychotic disorders co-occurring with ASD or not (n = 31), there was a significant improvement in psychotic symptoms according to Positive and Negative Syndrome Scale (PANSS) total scores and subscores (p < 0.001). Of the 26 patients with schizophrenia or other psychotic disorders, 8 (30.8%) showed a positive response (>30% symptom reduction on BPRS). In patients with ASD complicated by schizophrenia or other psychotic disorders or bipolar disorders (n = 7), there was a significant reduction (p = 0.017) in BPRS scores after clozapine treatment. The discontinuation rate for clozapine was 10.8%, and the most frequently observed side effect was hypersalivation (54.1%). Neutropenia associated with clozapine was observed in only one patient (2.7%).. Clozapine seems to be effective and safe in children and adolescents with schizophrenia or other psychotic disorders co-occuring with ASD or not. There is a need for further studies for determining the efficacy of clozapine in children and adolescents with bipolar affective disorder or ASD.

Topics: Adolescent; Antipsychotic Agents; Autism Spectrum Disorder; Bipolar Disorder; Child; Clozapine; Female; Humans; Inpatients; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome; Turkey

To explore the socioeconomic and health resource characteristics associated with geographical variations of lithium and clozapine dispensing rates in France.. The study was performed using reimbursement data from the French Insurance Healthcare system over the period 2006-2013 in a community-based sample of persons aged 16 years and over. An ecological design was used to assess whether lithium and clozapine prescribing rates were associated with socioeconomic and health resource characteristics of the zone of residence (n = 95 French administrative subdivisions).. Large geographical disparities were observed in dispensing rates: lithium dispensing rates by zone of residence ranged from 0 to 6.6 per 1000 (mean 2.4 per 1000) and clozapine dispensing rates ranged from 0 to 4.9 per 1000 (mean 0.8 per 1000). Higher density of GPs and regular communication between mental health services and primary care were independently associated with higher rates of lithium and clozapine dispensing and with a higher proportion of lithium users among mood-stabilizer users.. A sufficient density of GPs and an effective communication and collaboration between mental healthcare services and primary care seems to favor greater access to psychotropic drugs with demonstrated efficacy but often viewed as 'risky' to prescribe.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Prescriptions; Female; France; Humans; Insurance, Health; Lithium Compounds; Longitudinal Studies; Male; Middle Aged; Psychotic Disorders; Socioeconomic Factors; Young Adult

Topics: Antipsychotic Agents; Clozapine; Female; Hospitalization; Humans; Male; Mental Health Services; Psychotic Disorders; Schizophrenia

Topics: Affective Symptoms; Clozapine; Electroconvulsive Therapy; Humans; Huntington Disease; Male; Middle Aged; Psychotic Disorders; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Psychomotor Agitation; Psychotic Disorders; Time Factors

Clozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries a poor prognosis.. We investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation.. A total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR=2.12, 95% CI 1.30-3.47).. Living in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; London; Male; Middle Aged; Patient Dropouts; Proportional Hazards Models; Psychotic Disorders; Registries; Retrospective Studies; Risk Factors; Schizophrenia; Time Factors; Withholding Treatment; Young Adult

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Male; Psychotic Disorders; Recurrence; Young Adult

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

Clozapine is an atypical antipsychotic primarily prescribed for treatment-resistant schizophrenia. We tested the specific effect of clozapine versus other drug treatments on whole-blood gene expression in a sample of patients with psychosis from the UK.. A total of 186 baseline whole-blood samples from individuals receiving treatment for established psychosis were analysed for gene expression on Illumina HumanHT-12.v4 BeadChips. After standard quality-control procedures, 152 samples remained, including 55 from individuals receiving clozapine. In a within-case study design, weighted gene correlation network analysis was used to identify modules of coexpressed genes. The influence of mood stabilizers, lithium carbonate/lithium citrate and sodium valproate was studied to identify their possible roles as confounders.. Individuals receiving clozapine as their only antipsychotic (clozapine monotherapy) had a nominal association with one gene-expression module, whereas no significant change in gene expression was found for other drugs.. Overall, this study does not provide evidence that clozapine treatment induces medium to large different gene-expression patterns in human whole blood versus other antipsychotic treatments. This does not rule out the possibility of smaller effects as observed for other common antipsychotic treatments.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Gene Expression; Gene Expression Profiling; Humans; Male; Middle Aged; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Middle Aged; Psychotic Disorders; Urinary Tract Infections

Topics: Antipsychotic Agents; C-Reactive Protein; Catatonia; Clozapine; Creatine Kinase; Dantrolene; Drug Monitoring; Drug Substitution; Echocardiography; Humans; Lorazepam; Male; Myocarditis; Neuromuscular Agents; Psychotic Disorders; Treatment Outcome; Troponin; Withholding Treatment; Young Adult

The atypical antipsychotic agent clozapine, although an effective treatment for schizophrenia, is linked with metabolic adverse effects. We report a case of diabetic ketoacidosis and very severe hypertriglyceridaemia associated with clozapine use, in a patient with type 2 diabetes mellitus, who was successfully treated with continuous insulin infusion and fluids. As clozapine proved to be the most efficacious in controlling the patient's psychotic symptoms, the patient has been continued on clozapine despite its known metabolic side effects. Importantly the patient has achieved satisfactory long-term lipid and glycaemic control. The current recommendations related to the metabolic care for patients treated with atypical antipsychotic agents as well as the mechanisms behind abnormal glucose and lipid regulation with clozapine therapy are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Fluid Therapy; Humans; Hypertriglyceridemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Psychotic Disorders; Treatment Outcome

Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated.. This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not.. Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25-4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44-9.56); and patients of male gender (OR 3.13 95% CI 1.35-7.23).. For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

Topics: Adult; Age Factors; Antipsychotic Agents; Black People; Clozapine; Drug Resistance; Female; Humans; London; Longitudinal Studies; Male; Odds Ratio; Psychotic Disorders; Risk Factors; Schizophrenia; Schizophrenic Psychology; Sex Factors; White People; Young Adult

Dynamic relationships between the symptoms of psychosis can be shown in individual networks of psychopathology. In a single patient, data collected with the Experience Sampling Method (ESM-a method to construct intensive time series of experience and context) can be used to study lagged associations between symptoms in relation to illness severity and pharmacological treatment.. The patient completed, over the course of 1 year, for 4 days per week, 10 daily assessments scheduled randomly between 10 minutes and 3 hours apart. Five a priori selected symptoms were analysed: 'hearing voices', 'down', 'relaxed', 'paranoia' and 'loss of control'. Regression analysis was performed including current level of one symptom as the dependent variable and all symptoms at the previous assessment (lag) as the independent variables. Resulting regression coefficients were printed in graphs representing a network of symptoms. Network graphs were generated for different levels of severity: stable, impending relapse and full relapse.. ESM data showed that symptoms varied intensely from moment to moment. Network representations showed meaningful relations between symptoms, e.g. 'down' and 'paranoia' fuelling each other, and 'paranoia' negatively impacting 'relaxed'. During relapse, symptom levels as well as the level of clustering between symptoms markedly increased, indicating qualitative changes in the network. While 'hearing voices' was the most prominent symptom subjectively, the data suggested that a strategic focus on 'paranoia', as the most central symptom, had the potential to bring about changes affecting the whole network.. Construction of intensive ESM time series in a single patient is feasible and informative, particularly if represented as a network, showing both quantitative and qualitative changes as a function of relapse.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Female; Hallucinations; Humans; Middle Aged; Paranoid Disorders; Psychotic Disorders; Regression Analysis

Early symptomatic response is pertinent in improving outcomes in first-episode psychosis. One of the ways in which this may be achieved is by reducing inappropriate delays in clozapine initiation. This study aimed to examine clozapine prescribing practices among clinicians by establishing the prevalence of clozapine use, identifying baseline clinical and demographic factors that were associated with clozapine use, examining outcomes in clozapine users versus nonusers, and identifying inappropriate antipsychotic prescription patterns prior to clozapine initiation.. A retrospective study including all consecutive patients who had presented to the Singapore Early Psychosis Intervention Programme (EPIP) from April 2001 to June 2012 was conducted. Clinical and demographic data were extracted from the EPIP database. Incident cases of clozapine users were identified, and additional treatment histories were obtained from medical records. In addition to descriptive statistics, multivariate analysis was performed to identify factors associated with clozapine initiation.. Data from 1,603 patients were available for baseline analyses. Of these, 69 patients (4.3%) had been prescribed clozapine. Having a younger age at onset, lack of employment, a lower Global Assessment of Functioning disability score, and a higher Positive and Negative Syndrome Scale total score at baseline were factors associated with clozapine use. After adjustment was made for confounders, clozapine users were found to have attained similar rates of remission and recovery as patients who did not use clozapine. Clozapine initiation was delayed by a mean of 19.3 weeks (SD = 27.1; range, 0-117). Prior to commencing clozapine, 29.4% of patients had received antipsychotic treatments above maximum limits, whereas 75% of patients were prescribed ≥ 3 different antipsychotics (median = 3; range, 2-7).. This study has confirmed that the prescribing of clozapine is low, delayed, and preceded by dosing of antipsychotic drugs above maximum limits. Identification of the factors found to be associated with clozapine use may encourage clinicians to consider clozapine sooner in relevant patients in hopes of achieving early symptomatic response.

Topics: Adolescent; Adult; Clozapine; Early Medical Intervention; Female; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Singapore; Young Adult

To determine if clozapine can be safely utilized in psychiatric patients with benign neutropenia.. A single-center, retrospective chart review study of records from 2001 to 2014 was conducted in an inpatient psychiatric hospital. Patients included had benign neutropenia prior to receiving clozapine and received clozapine using modified monitoring guidelines. All available laboratory values for absolute neutrophil count (ANC) before initiation and during treatment were evaluated. The primary endpoint was difference in ANC after initiation of clozapine from before clozapine.. A total of 26 patients were reviewed. The mean age at clozapine initiation was 34 years. The majority were African-American (73% [n = 19]), with more men than women (73% [n = 19] vs 27% [n = 7]). The mean lowest ANC value was not significantly different after clozapine initiation compared to before (1.5× 10³ cells/mm³ and 1.4 × 10³ cells/mm³, respectively; P = .22). The overall mean ANC was significantly higher after initiation than before (2.63 × 10³ cells/mm³ and 2.13 × 10³ cells/mm³, respectively; P < .001). There were no cases of severe neutropenia (ANC < 0.5 × 10³ cells/mm³), and no patient was discontinued for falling below modified guideline limits. There were fewer occurrences of mild neutropenia (ANC < 2.0 × 10³ cells/mm³) after clozapine initiation than before (16.0% and 31.4%, respectively; P < .001). There were also fewer occurrences of moderate neutropenia (ANC < 1.5 × 10³ cells/mm³), with 2.1% after clozapine and 13.3% before (P < .001).. Twenty-six patients with benign neutropenia were safely treated with clozapine. Pre-clozapine neutropenia did not predict increased risk for severe neutropenia with clozapine. Patients had significantly fewer episodes of mild and moderate neutropenia after receiving clozapine compared to before.

Topics: Adult; Child; Clozapine; Female; Guideline Adherence; Hospitals, Psychiatric; Humans; Infant; Leukocyte Count; Male; Middle Aged; Neutropenia; Psychotic Disorders; Retrospective Studies; Risk; Young Adult

Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007-2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2-0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cohort Studies; Drug Prescriptions; Electronic Health Records; Female; Humans; London; Male; Middle Aged; Psychotic Disorders; Registries; Schizophrenia; Young Adult

Clozapine is associated with subjectively unpleasant or clinically serious side-effects, which may affect treatment adherence. The aims of the study were to explore the association of clozapine+ norclozapine serum concentration and other factors with subjective side-effects in schizophrenia patients.. In this cross-sectional study, 237 patients with a diagnosis of schizophrenia, schizo-affective or other non-organic psychoses completed the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), a self-report scale measuring side-effects of antipsychotics and a clinical questionnaire. Clozapine+ norclozapine serum concentration of 190 patients was measured. Of the patients 80 (33.7%) were on antipsychotic combination therapy.. Higher clozapine+ norclozapine concentrations were associated with the depression-anxiety factor of LUNSERS and antipsychotic combination treatments were associated with sympatichotonia-tension factor. Younger patients reported sedation more often than older patients.. According to the present results, high clozapine concentrations were associated with depression-anxiety symptoms, but the causality remains unknown.

Topics: Adult; Aged; Antipsychotic Agents; Anxiety; Causality; Clozapine; Cross-Sectional Studies; Depression; Female; Humans; Male; Medication Adherence; Middle Aged; Psychotic Disorders; Risk Factors; Schizophrenia; Self Report; Sleep Stages; Surveys and Questionnaires; Young Adult

NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms.

Topics: Animals; Antipsychotic Agents; Brain; Calcium-Binding Proteins; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microfilament Proteins; Neuroglia; Phosphopyruvate Hydratase; Psychotic Disorders; Recognition, Psychology

Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia.. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity.. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains.. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Psychometrics; Psychotic Disorders; Schizophrenia; Treatment Outcome; Young Adult

We report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine-antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice.. A 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542 ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days.. Clozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine-antifungals and clozapine-contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity.

Topics: Adult; Antifungal Agents; Antipsychotic Agents; Clozapine; Contraceptives, Oral; Drug Interactions; Eosinophilia; Female; Humans; Pericardial Effusion; Pericarditis; Psychotic Disorders; Tachycardia, Sinus

Topics: Clozapine; Female; Humans; Male; Memory, Short-Term; Psychotic Disorders; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Drug Therapy, Combination; Female; Humans; Lamotrigine; Male; Obsessive-Compulsive Disorder; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Risk; Schizophrenia; Triazines

Cytochrome P450 subtype 1A2 (CYP1A2) is responsible for the metabolism of several drugs, including the antipsychotic agent clozapine. Smoking cigarettes induces CYP1A2. Due to this induction, a higher dosage of the drug is required by patients who smoke tobacco.. The dosage of clozapine was changed for a 34-year-old male because of suspected active psychosis. However, serum levels of clozapine did not change according to expectations. It appeared that the patient had switched from smoking normal cigarettes to using e-cigarettes and then started smoking cigarettes again during the time of the dosage change. This gave a plausible explanation for the observed clozapine concentrations.. When patients switch from smoking normal cigarettes to using e-cigarettes induction of the CYP1A2 enzyme stops. A switch of this type may result in a major, undesirable increase in drug concentrations. Doctors should be alert to this when prescribing medication metabolised by CYP1A2 with a narrow therapeutic window.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Drug Interactions; Electronic Nicotine Delivery Systems; Humans; Male; Psychotic Disorders; Smoking

Decision making ability can change with time, depending on mental or physical health. Little is known about the factors that determine this change and the relationship of capacity to time. As a pilot for studies using functional mental capacities as an outcome measure, we sought to quantify this relationship measuring change over time using competence assessment tools, and rating scales for symptoms and global function.. We assessed 37 inpatients in a secure psychiatric hospital. All patients met the diagnostic and statistical manual of mental disorders-fourth edition and International classification of diseases, 10th edition criteria for an Axis 1 mental illness, all with psychosis. Patients were interviewed twice a mean of 323 days apart (median 176 days range 17-1221 days). The MacArthur competence assessment tools for consent to treatment (MacCAT-T) and fitness to plead (MacCAT-FP) were used to quantify functional capacity along with the Positive and Negative Syndrome Scale (PANSS) and global assessment of function (GAF) scale. A comparison was also made between those patients prescribed clozapine in comparison to other antipsychotics.. The number judged by treating psychiatrists to lack capacity either to make a treatment choice or to plead in court fell from 35 to 8%. Change was greatest for those admitted within the previous 9 months. The measures of capacity improved between time 1 and time 2 for both consent to treatment and fitness to plead. The measures of capacity improved with positive symptoms within the PANSS and with GAF scores. Those with shorter lengths of stay at baseline had the greatest improvements in the MacCAT-FP scores. Effect sizes were medium or large (0.3-0.7+). As expected, patients prescribed clozapine had larger changes in functional mental capacities and larger effect sizes than those prescribed other psychotropics. The results show a strong relationship between the clinicians' assessment of capacity and structured rating scales.. We have shown that there is an improvement in capacity scores with time. More research is needed to compare the effect of treatment on capacity at fixed time intervals. It would also be helpful to look at a more general patient population.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Forensic Psychiatry; Hospitalization; Hospitals, Psychiatric; Humans; Informed Consent; Inpatients; Male; Mental Competency; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Psychotic Disorders; Time Factors

Topics: Adult; Clozapine; Contraceptives, Oral, Synthetic; Drug Therapy, Combination; Frontotemporal Dementia; Humans; Male; Medroxyprogesterone; Psychotic Disorders; Serotonin Agents; Sertraline; Violence

Aripiprazole can cause irreversible tardive dystonia in some individuals, and additional intervention is sometimes needed. Here, we report the first case of aripiprazole-induced irreversible tardive dystonia in which complete recovery of motor function was achieved using the antipsychotic drug clozapine.. A 24-year-old man with bipolar disorder was treated with aripiprazole and gradually developed tardive dystonia. Thorough medical and neurological examinations were performed to rule out other possible causes of tardive dystonia. Clozapine was administered when the patient did not improve following long-term withdrawal of aripiprazole or adjuvant medications. Before administration of clozapine, the patient was experiencing severe dystonia as assessed by the Extrapyramidal Symptom Rating Scale. Dystonic symptoms began to improve about 1 month after starting administration of clozapine and were completely resolved 3 months after clozapine administration.. Clinicians should note the risk of aripiprazole-induced tardive dystonia and consider clozapine as an alternative and effective treatment modality in cases of irreversible tardive dystonia, particularly when concomitant treatment of psychotic symptoms is required.

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Movement Disorders; Neurologic Examination; Psychotic Disorders; Treatment Outcome; Young Adult

Topics: Clozapine; Female; Humans; Male; Memory, Short-Term; Psychotic Disorders; Schizophrenia

Topics: Clozapine; Female; Humans; Male; Memory, Short-Term; Psychotic Disorders; Schizophrenia

The effect of long-term treatment with the atypical antipsychotic clozapine on the serum amino acid profile in schizophrenia patients has not previously been studied.. The aim of this study was to compare serum amino acid patterns in patients on long-term clozapine treatment with long-term conventional antipsychotic treatment, and their relationships to insulin resistance and antipsychotic serum concentrations.. Thirty-three patients with schizophrenia or schizoaffective disorder on long-term treatment (mean 8.3 years) with clozapine (n=20) or conventional antipsychotics (n=13) were studied. Amino acids were quantified in fasting serum samples by ion exchange chromatography and markers of insulin resistance and antipsychotic drug concentrations were determined by standard methods.. Several amino acids, most notably tyrosine and glutamic acid, were elevated above the reference range in several patients receiving clozapine. Additionally, significantly higher mean values of tyrosine (1.5-fold, p=0.001), glutamic acid (2-fold, p=0.0005) and six other amino acids were observed in the clozapine group than in the conventional antipsychotic group. Several amino acids were related to insulin resistance in both treatment groups.. In this study, we show that serum tyrosine and glutamic acid concentrations are markedly elevated in patients on long-term clozapine treatment, compared to patients on long-term conventional antipsychotic treatment. These findings are of importance since these two amino acids have been implicated in the pathophysiology of schizophrenia.

Topics: Adult; Amino Acids; Antipsychotic Agents; Chromatography, Ion Exchange; Clopenthixol; Clozapine; Cohort Studies; Female; Glutamic Acid; Haloperidol; Humans; Insulin Resistance; Male; Middle Aged; Perphenazine; Prospective Studies; Psychotic Disorders; Schizophrenia; Thioridazine; Tyrosine

Topics: Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Exome; Female; Finland; Gene Frequency; Genetic Variation; Genotype; HLA-DQ beta-Chains; Humans; Male; Psychotic Disorders; Schizophrenia

Clozapine is the drug of choice for patients with an unsatisfactory response to routine antipsychotic treatment. Side effects such as sedation, weight gain, hypotension and hypersialorrhea are frequently reported whereas clozapine-induced parotitis is a less known complication.. We report the case of a 32-year-old woman with a refractory schizoaffective disorder, bipolar type. The failure to respond to at least two well-conducted antipsychotic trials with flupentixol and risperidone, led clinicians to prescribe clozapine, which was started three years earlier. Since its introduction, clozapine induced sialorrhea, which has been managed until now with anticholinergic medication. Recently, Mrs B. was hospitalized for a new relapse. Once treatment compliance checked (good level of plasmatic dosage), we decided to increase the dose of clozapine from 350 mg/d to 500 mg/d. Twenty days later, Mrs B. exhibited improvement of symptoms but complained of acute bilateral auricular pain and odynophagia. The bilateral and comparative clinical exam displayed a bilateral filling of the retromandibular depression, the painful swelling of the parotid gland, along with ptyalism and a slight inflammatory oedema of the Stenon duct orifice. Mrs B. was apyretic, with physiological constants within the limits of normal values. The biological analyses displayed a discrete inflammatory syndrome (mild hyperleucocytosis and anemia), a negative mumps IgM test and positive mumps IgG test, and a 1050 ng/mL clozapine blood level. Once viral parotitis was ruled out, the involvement of clozapine was evoked. Symptomatic medication was prescribed with per os analgesic (paracetamol) and antiseptic mouthwash (Éludril). Clozapine dosage was lowered to 400 mg/d. A week later, clinical examination confirmed improvement of the medical and psychiatric conditions.. We report the case of a patient who developed a parotitis following clozapine dose adjustment. Clozapine induced parotitis was retained once the infectious and other organic etiologies had been ruled out. Previous cases of clozapine-induced parotitis have already been reported and we have some arguments to suspect this etiology in our case. First, Mrs B. experienced more hypersialorrhea with the increase in clozapine dosage. Second, the anticholinergic medication was interrupted 3 days before the episode of parotitis. Two main pathophysiological hypotheses, immune and inflammatory, have already been proposed to explain clozapine-induced parotitis. In the former, the immunomodulating properties of clozapine may sensitize the mononuclear blood cells, leading to the sialadenitis. The latter hypothesis is the more documented and proposes that clozapine-induced hypersialorrhea may be responsible for a chronic inflammatory state that can lead to the formation of a parotid lithiasis and consequently parotitis. This case report illustrates clozapine induced-parotitis, a poorly known complication of this compound. Clinicians should be aware of its hypersialorrhea and inflammatory consequences in order to better prevent the occurrence of this complication.

Topics: Adult; Bipolar Disorder; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Parotitis; Psychotic Disorders; Recurrence; Sialorrhea

The National Audit of Schizophrenia (NAS) examined the quality of care received in England and Wales. Part of the audit set out to determine whether six prescribing standards, set by the national clinical guidelines for schizophrenia, were being implemented and to prompt improvements in care. Mental Health Trusts and Health Boards provided data obtained from case-notes for adult patients living in the community with schizophrenia or schizoaffective disorder. An audit of practice tool was developed for data collection. Most of the 5055 patients reviewed were receiving pharmacological treatment according to national guidelines. However, 15.9% of the total sample (95%CI: 14.9-16.9) were prescribed two or more antipsychotics concurrently and 10.1% of patients (95%CI: 9.3-10.9) were prescribed medication in excess of recommended limits. Overall 23.7% (95%CI: 22.5-24.8) of patients were receiving clozapine. However, there were many with treatment resistance who had no clear reason documented as to why they had not had a trial of clozapine (430/1073, 40.1%). In conclusion, whilst most people were prescribed medication in accordance with nationally agreed standards, there was considerable variation between service providers. Antipsychotic polypharmacy, high dose prescribing and clozapine underutilisation in treatment resistance were all key concerns which need to be further addressed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Drug Resistance; Drug Therapy, Combination; England; Female; Guideline Adherence; Humans; Male; Medical Audit; Middle Aged; Practice Guidelines as Topic; Practice Patterns, Physicians'; Psychotic Disorders; Schizophrenia; Wales; Young Adult

Topics: Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Paliperidone Palmitate; Psychotic Disorders; Pyrimidines; Social Behavior Disorders

Cytochrome P450 1A2 gene (CYP1A2) polymorphisms have been suggested to be associated with increased side effects to antipsychotics. However, studies on this are scarce and have been conducted with either various antipsychotics or only in small samples of patients receiving clozapine. The aim of the present study was to test for an association between the CYP1A2 -1545C > T (rs2470890) polymorphism and side effects in a larger sample of patients during long-term clozapine treatment.. A total of 237 patients receiving clozapine treatment completed the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) assessing clozapine-induced side effects. Of these patients, 180 completed the questionnaire satisfactorily, agreed to provide a blood sample, and were successfully genotyped for the polymorphism.. The TT genotype of CYP1A2 polymorphism -1545C > T (rs2470890) was associated with significantly more severe side effects during clozapine treatment (p = 0.011). In a subanalysis, all seven types of side effects (sympathicotonia-tension; depression-anxiety; sedation; orthostatic hypotension; dermal side effects; urinary side effects; and sexual side effects) appeared numerically (but insignificantly) more severely among TT carriers. In addition, use of mood stabilizers was more common among patients with the TT genotype (OR = 2.63, p = 0.004).. This study has identified an association between the CYP1A2 polymorphism -1545C > T (rs2470890) and the occurrence of more severe clozapine side effects. However, these results should be regarded as tentative and more studies of larger sample sizes will be required to confirm the result.

Topics: Adult; Aged; Alleles; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Female; Genetic Association Studies; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Psychotic Disorders; Young Adult

Topics: Adult; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Hypotension; Inpatients; Male; Psychotic Disorders; Takotsubo Cardiomyopathy

Neuroleptic malignant syndrome (NMS) is a potentially fatal manifestation of antipsychotic use associated with symptoms that include mental status changes, muscle rigidity, fever and autonomic dysfunction. An occurrence of NMS with clozapine has been reported in the past but there are very few reports of successfully rechallenging the drug in individuals who have developed the syndrome. This case report discusses one of the few instances in literature where clozapine has been re-administered successfully to a patient without a reoccurrence of NMS. In conclusion, a rechallenge of clozapine after neuroleptic malignant syndrome can be done if care is taken to avoid concurrent use of lithium and other psychotropics, monitoring for NMS symptoms and titrating the dose upward slowly after a reasonable period of time.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Neuroleptic Malignant Syndrome; Psychotic Disorders; Young Adult

To examine our eight year clinic-based experience in a Parkinson's disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinson's disease (PD).. The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy.. There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45-87 years (mean 68.3±10.15), disease duration of 17-240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = -0.36, p<0.01) and H&Y score (r = -0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05).. This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.

Topics: Age Factors; Aged; Aged, 80 and over; Antiparkinson Agents; Antipsychotic Agents; Clozapine; Female; Hematologic Tests; Humans; Levodopa; Male; Medication Adherence; Middle Aged; Nursing Homes; Parkinson Disease; Psychotic Disorders; Retrospective Studies

Tardive syndromes are among the most debilitating side effects associated with use of antipsychotics. In this case series we present 5 cases of drug induced tardive syndromes, who had not responded to many of the other therapeutic measures but responded to clozapine. The response rate with clozapine varied from 50% to 100% and the response was seen by week 3 in most cases. Over the long term follow-up of as long as 6 years the response to clozapine was sustained. In two cases clozapine could be stopped.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychotic Disorders; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Contraceptives, Oral; Drug Interactions; Female; Humans; Psychotic Disorders

Antipsychotics are effective in treating schizophrenia symptoms. However, the use of clozapine and olanzapine in particular are associated with significant weight gain. Mouse and human studies suggest that the protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene may be involved in energy metabolism, and there is evidence that it is associated with clozapine's effects on triglyceride levels. We aimed at assessing PRKAR2B's role in antipsychotic-induced weight gain in schizophrenia patients.. DNA samples from adult schizophrenia or schizoaffective disorder patients of mixed ancestry were genotyped, and weight gain was assessed. We analyzed 16 tag single-nucleotide polymorphisms across the PRKAR2B gene in a Caucasian subset treated either with clozapine or olanzapine (N = 99). Linear regression based on an additive model was performed with the inclusion of relevant covariates.. Normalized per cent weight change was analyzed, revealing that patients with the minor allele at rs9656135 had a mean weight increase of 4.1%, whereas patients without this allele had an increase of 3.4%. This association is not significant after correcting for multiple testing.. Because of limited power, PRKAR2B's role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved. Further research in larger sample sizes is warranted.

Topics: Adolescent; Adult; Aged; Alleles; Antipsychotic Agents; Benzodiazepines; Clozapine; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Female; Genetic Predisposition to Disease; Genotyping Techniques; Humans; Linkage Disequilibrium; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia; Weight Gain; White People; Young Adult

Both obesity and smoking are common in schizophrenia patients taking clozapine, causing cardiovascular disease and premature deaths.. Two hundred and thirty-seven patients with schizophrenia or related psychoses treated with clozapine completed the Liverpool University Neuroleptic Assessment Scale (LUNSERS) and a questionnaire including current height, weight, changes therein and smoking status.. The aim of this study was to analyze weight and weight change in smoking and non-smoking patients taking clozapine. A possible interaction between obesity and smoking was explored.. No association was found between weight change and smoking status during clozapine treatment. There was no significant difference in body mass index (BMI) between non-smokers and smokers. In the analysis of covariance (ANCOVA) with BMI as the dependent variable, the best fitting model comprised age, sex, intensity of sedation, and reported amount of smoking as explanatory variables (ηp(2)= 0.116; P = 0.029; power = 0.750). None of the explanatory proportions of any single factor was significant.. Estimated according to reported weight gain and BMI, no difference was found between smoking and non-smoking clozapine-treated patients. Number of cigarettes smoked explained BMI if age and sex were taken into account. This result is in line with the findings of some general population studies, where heavy smoking has been associated with a greater risk of obesity.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Comorbidity; Female; Humans; Male; Middle Aged; Obesity; Psychotic Disorders; Schizophrenia; Smoking; Weight Gain

This study investigated the MPV of patients with major psychoses before and after 1year of clozapine exposure. Data were obtained from chart reviews of patients who were initiated on clozapine at the Centre of Addiction and Mental Health (CAMH) in Toronto. 100 patients were eligible for this study; 65 remained on clozapine after 1year. Prior to clozapine initiation, MPV was 10.79±0.91fL and there was no difference in MPV after 1year of clozapine exposure (p=0.777). We found high MPV in patients with schizophrenia and related psychoses, which was unaltered after 1year of clozapine treatment.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Humans; Male; Mean Platelet Volume; Ontario; Psychotic Disorders; Registries; Schizophrenia; Schizophrenia, Paranoid

Clozapine, an evidence-based treatment of refractory schizophrenia, is associated with increased weight gain and metabolic dysregulation compared with most antipsychotics in short-term clinical trials. However, there are limited data describing comparative long-term metabolic risks. In this report, we examined whether short-term differences persist with long-term exposure to clozapine.. The data of all patients in a university-based clinic with a psychotic illness or a mood disorder with psychotic features, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis, and treated with an antipsychotic in calendar year 2012 were examined. A total of 307 patients met the criteria; 96 patients were treated with clozapine and the remaining 211 patients were treated with 1 or more non-clozapine antipsychotics. Body mass index, type 2 diabetes, hypertension, dyslipidemia, and obesity were compared.. The mean duration of the clozapine treatment was 7.6 years (range, 2 months to 21 y). On all metabolic measures, there were no statistically significant differences between the clozapine and non-clozapine groups (mean body mass index, 31 vs 32; type 2 diabetes, 17% vs 18%; dyslipidemia, 35% vs 38%; hypertension, 32% vs 39%; and obesity, 48% vs 54%). Removing the olanzapine-treated patients (n = 51) from the non-clozapine group did not change the findings.. In this university-based clinic sample with a large number of clozapine-treated patients, we found no evidence of increased risk in any individual measure for those receiving clozapine. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time because multiple other variables likely also impact metabolic risk during the life span. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time due to the accumulated impact of other variables that also impact metabolic risk across the life span.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Electronic Health Records; Female; Humans; Male; Metabolic Diseases; Middle Aged; Obesity; Psychotic Disorders; Schizophrenia; Weight Gain; Young Adult

Antipsychotics frequently cause changes in glucose metabolism followed by development of weight gain and/or diabetes. Recent findings from our group indicated an influence of glucose-related genes on this serious side effect. With this study, we aimed to extend previous research and performed a comprehensive study on the peroxisome proliferator-activated receptor gamma (PPARG) and the adiponectin (ADIPOQ) genes. In 216 schizophrenic patients receiving antipsychotics for up to 14 weeks, we investigated single-nucleotide polymorphisms in or near PPARG (N=24) and ADIPOQ (N=18). Statistical analysis was done using ANCOVA in SPSS. Haplotype analysis was performed in UNPHASED 3.1.4 and Haploview 4.2. None of the PPARG or ADIPOQ variants showed significant association with antipsychotic-induced weight gain in our combined sample or in a refined subsample of patients of European ancestry treated with clozapine or olanzapine after correction for multiple testing. Similarly, no haplotype association could withstand multiple test correction. Although we could not find a significant influence of ADIPOQ and PPARG on antipsychotic-induced weight gain, our comprehensive examination of these two genes contributes to understanding the biology of this serious side effect. More research on glucose metabolism genes is warranted to elucidate their role in metabolic changes during antipsychotic treatment.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Haplotypes; Humans; Male; Middle Aged; Olanzapine; Overweight; Polymorphism, Single Nucleotide; PPAR gamma; Psychotic Disorders; Weight Gain; White People; Young Adult

Psychiatric hospital readmissions correlate with illness severity, drug selection, and compliance with treatment in the outpatient setting. The risk factors for psychiatric rehospitalization have been mainly assessed in databases lacking information regarding somatic comorbidity and anthropometric variables, such as body mass index (BMI), which are known to predict readmissions in nonpsychiatric settings.. To determine independent predictors of 1-year readmission occurring among unselected adults consecutively admitted for treatment of severe mental illness to an academic, freestanding psychiatric hospital in New York City from August 2010 through January 2011.. After identifying univariate correlates of readmission, we used logistic regression with backward elimination to identify independent predictors of readmissions within 1 year after the index psychiatric hospitalization.. Among 224 (23.7%) of 945 readmitted patients, psychiatric readmission was significantly associated with age (P = .0029), length of stay (P = .036), schizophrenia/schizoaffective disorder (P < . 0001), dementia (P = .027), major depressive disorder (P = .0006), treatment with atypical antipsychotic drugs (P = .0054), electroconvulsive therapy (P < .0001), and BMI (P = .0079), but not with physical comorbidities and routine laboratory data.The independent predictors of readmission were higher BMI (median = 28.5 kg/ m2; odds ratio [OR] = 3.6; Cl, 1.2-10.6), a diagnosis of schizophrenia/schizoaffective disorder (OR = 2.2; Cl, 1.5-3.4), clozapine treatment (OR = 2.8; CI, 1.1-6.9), no electroconvulsive therapy (OR = 0.13; Cl, 0.02-0.45), and shorter length of stay (median = 18 days; OR = 0.08; Cl, 0.01-0.42).. Body mass index was identified, for the first time, as an independent predictor of psychiatric rehospitalization. Enhanced outpatient treatment programs for overweight and obese psychiatric patients might influence readmission rates and should be explored in prospective studies.

Topics: Adult; Age Factors; Antipsychotic Agents; Body Mass Index; Clozapine; Combined Modality Therapy; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Length of Stay; Male; Mental Disorders; Middle Aged; Patient Readmission; Prognosis; Psychotherapy; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

Four cases in which glycopyrrolate was used to treat clozapine-induced sialorrhea (CIS) are reported.. Glycopyrrolate is an antimuscarinic agent that can be used preoperatively to inhibit drooling and excessive secretions of the respiratory tract. The outcomes of four patients who received glycopyrrolate for the treatment of CIS are described. The Thomas-Stonell and Greenberg Drooling Severity and Frequency Scale (DSFS) was used retrospectively to rate patients' drooling. Glycopyrrolate was effective in alleviating CIS in cases 1-3. Two patients (cases 1 and 4) exhibited severe drooling, which caused their clothing, hands, and objects to consistently become wet. One patient (case 1) responded well to glycopyrrolate and was restarted on the medication when CIS returned after discontinuation of the drug. While another patient (case 3) displayed a similar response to therapy for CIS as the patient described in case 1, this patient did not experience the psychosocial complications as did the patient in case 1, possibly due to the use of glycopyrrolate as the initial treatment of choice. The patient in case 2 experienced moderate but frequent drooling. Thioridazine's high anticholinergic potential may have contributed to this patient's lower baseline DSFS score compared with the scores of the other three patients, or it could have augmented initial symptom improvement. CIS continued in the patient described in case 4 despite treatment with glycopyrrolate, with only mild improvement in the severity and frequency of drooling.. Glycopyrrolate was effective in alleviating symptoms in three of four patients with CIS. In a fourth patient, the degree of improvement was unknown due to documentation discrepancies; however, mild improvement was noted initially.

Topics: Adult; Antipsychotic Agents; Clozapine; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Psychotic Disorders; Schizophrenia; Sialorrhea; Young Adult

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

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Topics: Agranulocytosis; Alleles; Amino Acid Substitution; Antipsychotic Agents; Case-Control Studies; Clozapine; Exome; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; HLA-B Antigens; HLA-DQ beta-Chains; Humans; Odds Ratio; Psychotic Disorders; Severity of Illness Index

To describe a practical approach to the community management of treatment-resistant schizophrenia (TRS).. A descriptive review of an approach to the assessment and management of patients with TRS, including the community titration of clozapine treatment, and a report of the management recommendations for the first one hundred patients assessed by the Treatment REview and Assessment Team (TREAT).. The standardized model for the community assessment, management and titration of clozapine is described. To date, 137 patients have been referred to this service and 100 patients (72%) attended for assessment. Of these, 33 have been initiated on clozapine while fifteen have had clozapine recommended but have not wished to undertake clozapine treatment. Other management options recommended have included augmentation strategies and long-acting injectable antipsychotics.. The service had increased the number of patients receiving community assessment and initiation of clozapine by five-fold relative to the rate prior to the establishment of the service. The large number of referrals and high attendance rate indicates that there is clinical demand for the model. Systematic evaluation is required to determine the clinical and cost-effectiveness of this model and its potential application to other clinical settings.

Topics: Adult; Antipsychotic Agents; Clozapine; Community Mental Health Services; Disease Management; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Treatment Failure

To explore the pattern of clozapine use in persons with severe mental illness and in persons with Parkinson's disease and the characteristics associated with early discontinuation in naturalistic conditions.. A historical fixed cohort study of persons newly treated with clozapine was performed on a representative community-based sample of persons affiliated to the French health insurance system (n = 611,393). Treatment for Parkinson's disease was used as a proxy for this condition and lack of such treatment as a proxy for severe mental illness (SMI).. The prevalences of antipsychotic and clozapine use were 4.4% and <0.1% respectively. Of the 237 persons with a new outpatient prescription of clozapine, 25% were prescribed an antiparkinsonian treatment. In persons with SMI, the median duration of the index episode of clozapine treatment was 4.9 months (Interquartile range 1.0-20.5). Longer duration was independently associated with coprescription of anxiolytics or antidepressant. Few new additions of antipsychotics were observed during the clozapine episode.. Efforts have to be made to optimize clozapine treatment in real-world conditions. Considering the high frequency of persons with Parkinson's disease among clozapine users, further studies have to be performed in this population.

Topics: Adult; Affective Disorders, Psychotic; Aged; Anti-Anxiety Agents; Antidepressive Agents; Antiparkinson Agents; Antipsychotic Agents; Bipolar Disorder; Case-Control Studies; Clozapine; Cohort Studies; Female; France; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders; Schizophrenia

Psychotic symptoms in Parkinson's disease (PD) caused by dopamimetic treatment are a relevant clinical problem. As clozapine does not cause extrapyramidal side effects, it is suitable for treatment of dopamimetic psychosis. The main aim of the present study was (1) to establish an indication-specific recommendation for therapeutic reference range of clozapine among patients with dopamimetic psychosis in PD and related disorders. Secondary goals were (2) to test whether clozapine therapy is safe and calculable despite pharmacokinetic changes expected in the study population and (3) to assess influencing variables on clozapine serum levels.. We carried out a retrospective chart review of patients suffering from dopamimetic psychosis as well as Lewy body dementia treated with clozapine. We extracted demographic and clinical data as well as results from therapeutic drug monitoring that was carried out via high-performance liquid chromatography in order to analyse clozapine and norclozapine serum concentrations.. n = 35 patients could be identified and were included in the study. Mean age was 72.4 years. Clozapine treatment for patients with dopamimetic psychosis in PD and related disorders seems to be safe and calculable. Mean clozapine serum concentration was 77.9 ng/ml (SD 63.4 ng/ml). Clozapine dose is significantly correlated with serum clozapine concentration (r = 0.35; R (2) = 0.122). Women showed lower clozapine serum concentrations although they received higher weight-corrected clozapine doses.. We suggest an orienting indication-specific therapeutic reference range of 15-141 ng/ml among PD patients with dopamimetic psychosis. Therapeutic drug monitoring is recommended and might help to minimize the risk of adverse events by screening for unexpectedly high serum concentrations of clozapine.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders

The first of the atypical antipsychotics introduced in the 1970s, clozapine remains the most efficacious neuroleptic to this day. However, serious and potentially fatal side effects have necessitated careful regular monitoring among prescribing clinicians. Some adverse effects (e.g. ischaemic bowel) remain under recognized, while newly identified adverse effects continue to be described in the literature.. In this report, we describe a healthy 43-year old Caucasian male who experienced onset of a full body deep burning pain several months after the onset of treatment with clozapine. The pain worsened over time, ceased with cessation of treatment, and returned soon after the patient was rechallenged.. We describe an unusual adverse effect from clozapine treatment that has not been described elsewhere to our knowledge. We present the time course of the pain symptom, relationship to dose, associated laboratory results, and ultimately how it was dealt with and how it improved for the benefit of clinicians who may encounter it in the future.

Topics: Adult; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Humans; Male; Pain; Psychotic Disorders

To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities.. Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher's exact test.. Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%-2%).. Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Prescriptions; Female; Humans; Male; Middle Aged; Polypharmacy; Psychotic Disorders; Retrospective Studies; Schizophrenia; United States; United States Department of Veterans Affairs

The association between the use of antipsychotics and diabetes mellitus (DM) is still unclear, as depicted by several conflicting reports. Our study aims to assess the risk of DM in new users of antipsychotics.. Our nested case-control study used the Quebec Health Insurance Board databases. People in the source cohort were DM-free and had initiated an antipsychotic treatment. Subjects were cohort members who initiated an antidiabetic or had a diagnosis of DM during their follow-up period. Three variables were used to assess antipsychotic exposure: the antipsychotic used (any typical, clozapine, olanzapine, quetiapine, risperidone, or more than 1 drug); the number of 30-day periods of use; and antipsychotic use at index date (current or past). A paired multivariate logistic regression model was used to calculate adjusted odds ratios.. Among the 88 467 people included in the cohort, 6109 subjects with DM were identified and were matched to 61 090 control subjects. New users of quetiapine were less likely to develop DM than new users of typical antipsychotics (OR, 0.89; 95% CI 0.81 to 0.99). The risk of DM was not statistically different across the atypical antipsychotics. A longer exposure to any antipsychotic (for each 30-day period, OR 1.009; 95% CI 1.006 to 1.011) and current use of antipsychotics (OR 1.26; 95% CI 1.17 to 1.36) were associated with DM.. These results suggest that metabolic parameters of people exposed to antipsychotics should be monitored, irrespective of the drug taken, among the drugs available at the time of analysis.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Clozapine; Cohort Studies; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Humans; Logistic Models; Male; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risperidone; Time Factors; Young Adult

We report on the successful use of a combined psychopharmacological treatment in a patient with Huntington's disease, at age 39, suffering from severe psychotic and behavioral symptoms. He presented with a schizophreniform psychosis accompanied by aggressive behavior leading to admission to the locked ward of our hospital. After unsatisfactory control of the psychiatric symptoms with olanzapine, risperidone, and amisulpride, we introduced aripiprazole. This did not affect the psychotic symptoms; however, led to an improvement in aggressive behavior, motivation, and even chorea. Accordingly, we choose not to switch medication but to add clozapine. Nevertheless, his delusions improved slightly, and further add-on treatment with reboxetine brought a further beneficial effect on motivation and activities of daily living. As chorea was not disabling in our patient, tetrabenazine has not yet been tried. Treatment was safe without any relevant side effects.

Topics: Adult; Aggression; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Humans; Huntington Disease; Male; Morpholines; Piperazines; Psychotic Disorders; Quinolones; Reboxetine; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Psychotic Disorders; Schizophrenia; Vitamin B Deficiency

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Polypharmacy; Psychotic Disorders; Schizophrenia

Neuroleptic malignant syndrome (NMS) is a rare life-threatening condition associated with the use of antipsychotics and other drugs that influence dopaminergic transmission. Although NMS is typically associated with classical antipsychotics, it can also be induced by atypical antipsychotics. In this paper, we report a case of NMS associated with clozapine use.. A 27-year-old male was diagnosed as schizophrenia in 2006 and zuclopenthixol depot was administered parenterally. Following the second injection, NMS was diagnosed and he was switched to clozapine. After 4 years of clozapine use, one day, he suddenly stopped eating, stayed in bed all day, and had incontinence. Upon examination at our hospital the patient had muscle rigidity, high fever, leukocytosis, and a high creatine phosphokinase level, and NMS was diagnosed. He was put on bromocriptine. NMS resolved, but psychotic relapse and catatonia developed. 10 sessions of electro convulsive treatment (ECT) were administered. Quetiapine 25 mg/day was introduced and titrated up to 600 mg/day afterwards. He has been using quetiapine 600 mg/day for 18 months and at the time this manuscript was written has not had any signs of psychosis or NMS.. NMS is usually induced by the use of agents with high dopaminergic affinity. Incomplete or extraordinary NMS cases have been reported due to clozapine and atypical antipsychotics. The presented case is noteworthy due to the complete and typical presentation of NMS. It should always be kept in mind that all atypical antipsychotics including clozapine have the probability to induce NMS although not common.

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Creatine Kinase; Diagnosis, Differential; Humans; Male; Neuroleptic Malignant Syndrome; Psychotic Disorders; Quetiapine Fumarate; Schizophrenia; Serotonin Antagonists

Genetic variation in the cytochrome P450 2D6 (CYP2D6) enzyme is responsible for interindividual differences in the metabolism of many antipsychotic drugs, but the clinical relevance of polymorphisms in CYP2D6 for response to antipsychotic treatment is relatively unknown. In the Netherlands, clozapine is prescribed only when patients are non-responsive to or intolerant of at least two different antipsychotics. The aim of our study was to determine the association of the CYP2D6 genotype with switching to clozapine, which served as a surrogate outcome marker for treatment response to antipsychotics.. CYP2D6 genotype was assessed in patients who had been switched to clozapine and compared with antipsychotic users whose treatment regimen included no more than two different antipsychotic drugs and no clozapine. We also performed the analysis in patients who only used CYP2D6-dependent antipsychotics.. A total of 528 patients were included in the study (222 cases, 306 controls). No statistically significant differences were found in the distribution of the polymorphisms among the case and control groups, both in all patients and in only those patients using CYP2D6-dependent antipsychotics. However, a trend was observed, suggesting an inverse association between CYP2D6 genotype and the switch to clozapine. (9.5 vs. 5.1 % poor metabolisers and 1.3 vs. 2.6 % ultrarapid metabolisers in cases vs. controls, respectively).. Although the results of our study suggest that the CYP2D6 phenotype is not a major determining factor for patients to be switched to clozapine treatment, larger studies are warranted with a focus on the clinical consequences of the CYP2D6 ultrarapid metaboliser and poor metaboliser phenotypes.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP2D6; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Psychotic Disorders; Young Adult

No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the effective doses of quetiapine, clozapine, and the nondopaminergic, selective 5-HT2A inverse agonist/antagonist, pimavanserin, in an animal model of PDP and compared them with the doses that caused dopamine blockade and sedation. Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra lesions was used to assess antipsychotic efficacy, whereas blockade of apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine lesions was used to assess antidopaminergic action and reduction in spontaneous locomotion was used to assess sedation. The estimated therapeutic ratios for clozapine and quetiapine varied between 0.81 and 3.3. In contrast, the estimated therapeutic ratios for pimavanserin were at or above 170. These results suggest that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP.

Topics: Amphetamine; Animals; Antiparkinson Agents; Antipsychotic Agents; Apomorphine; Clozapine; Dopamine; Dose-Response Relationship, Drug; Male; Parkinsonian Disorders; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Urea

Treatment guidelines suggest antipsychotic monotherapy in the treatment of psychosis. 20-40% of patients take combination therapy in clinical practice due to inadequate treatment response to monotherapy. First-generation antipsychotic monotherapy was ineffective in case of our patient who had severe psychotic symptoms. Switching to a second generation antipsychotic had partial therapeutic effect, the severe psychotic condition was persistent. For this reason the therapy was changed to olanzapine-clozapine combination. Due to this combination the patient's psychotic symptoms disappeared. He was able to maintain the relationship with psychiatrist. During this therapy we observed good compliance, no more drug abuse and no relapse.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Humans; Male; Marijuana Abuse; Medication Adherence; Olanzapine; Psychotic Disorders; Treatment Outcome

In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity.. This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis.. Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed.. Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day).. Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Disease Models, Animal; Down-Regulation; Hallucinogens; Haloperidol; Lysergic Acid Diethylamide; Male; Mice; Mice, 129 Strain; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Time Factors

A case is presented of a 23-year-old lady with treatment-resistant schizoaffective disorder who had responded well to treatment with clozapine. Fifteen months after satisfactory use of clozapine she had 'red alerts' from routine haematological monitoring indicating neutropenia. Clozapine was discontinued and she was admitted to the psychiatric hospital to manage the aftermath of discontinuing clozapine and start alternative treatment with other antipsychotics. Her mental health rapidly deteriorated. Adequate trials with amisulpride, haloperidol, olanzapine and flupenthixol decanoate yielded little improvement in her clinical state. After 9 months of non-response to other antipsychotic medications, she was rechallenged with clozapine, followed by improvement in her mental state. She was eventually discharged home after 14 months of hospitalisation in a stable mental state. She remained mentally stable in the community on clozapine for 18 months after rechallenge, with no further red alerts.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Psychotic Disorders; Young Adult

Clozapine remains the antipsychotic of choice for people who, having met the criteria for a diagnosis of schizophrenia or a related psychotic disorder, do not respond adequately to other antipsychotic medications. Utilization rates appear highly variable across jurisdictions, with an overall tendency toward underuse. This paper describes patterns of clozapine use in the province of Québec, Canada.. Individuals with a diagnosis of schizophrenia were identified using linked government medical claims and hospitalization records for 2003 and 2004. Linked data on their filled prescriptions in 2004 were then used to determine clozapine-use rates at the level of the province, the region, and the hospital at which individuals received most of their services. Individual predictors of clozapine use were identified using logistic regression.. Only 6.7% of the 29,155 individuals identified with schizophrenia received clozapine for six months or longer in 2004. Utilization rates ranged from 3.9 to 9.0% among regions with 1,000 or more people with schizophrenia. Over 8% of 61 hospitals did not prescribe clozapine at all. People with schizophrenia taking clozapine experienced 3.4 fewer days of hospitalization per year than those not taking clozapine-representing a cost offset of about $1,800 per year. Medication costs were higher, however, by about $3,000 per year.. Given the increasingly clear benefits of clozapine for people who do not respond to other antipsychotics, measures to increase access to clozapine for people who can benefit from it are likely to be cost effective and are urgently needed.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Drug Costs; Drug Prescriptions; Female; Hospitals; Humans; Male; Middle Aged; National Health Programs; Practice Patterns, Physicians'; Psychotic Disorders; Quebec; Schizophrenia; Young Adult

Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory schizophrenia is clozapine. However, a significant number of patients cease clozapine therapy; therefore this study explores patient's motives for cessation.. The motives for cessation and duration of clozapine treatment from a retrospective database of 151 patients with schizophrenia or schizo-affective disorder who had ceased clozapine once or more were reviewed, with the motives for cessation coded. The general motives for cessation were non-compliance, own decision, medical, poor response and other. In addition, the medical reasons for cessation were further codified: cardiac complications, neutropenia, fevers, other side effects and pregnancy.. The majority of patients ceased clozapine owing to non-compliance with medical protocols or citing their own decision. Approximately half ceased after a period of 6 months or less. Seventeen per cent of patients ceased owing to medical reasons, with the largest proportions discontinuing treatment because of other side effects or neutropenia.. Future research should seek to further investigate why patients decide to be non-compliant and formulate their own decision to cease treatment, as this will facilitate strategies to promote adherence amongst these two groups that are potentially the most amenable to change.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Medication Adherence; Motivation; Neutropenia; Physician-Patient Relations; Pregnancy; Pregnancy Complications, Hematologic; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

Tardive dyskinesia (TD) is a complex involuntary movement disorder affecting about 23% of neuroleptic-treated patients. Our objective was to retrospectively analyze a combination of tetrabenazine (TBZ), clonazepam (CLONAZ) and clozapine (CLOZ) used simultaneously for TD in psychotic patients. Six patients with severe, unsuccessfully controlled TD were referred for treatment (mean age 51.5 years; three male; four schizophrenics; one bipolar disease; one borderline personality disorder). They were being treated with neuroleptics (classic, three; risperidone, two; olanzapine, one) and developed severe neck and buccolingual dyskinesias. At our clinic, all of them were treated simultaneously with TBZ (mean dose 141.6 mg); CLONAZ (mean dose 4.3 mg); and CLOZ (mean dose 125 mg). In parallel, we stopped the offending medication. With 1 week, we observed a very impressive improvement in symptoms and within 1 month all the patients were free of symptoms. The mean observation period was 4 years. The combination of TBZ, CLONAZ and CLOZ is a rapid and beneficial option for the management of TD. An augmentation effect probably played a role in the rapid alleviation of symptomatology.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Clonazepam; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; GABA Modulators; Humans; Male; Middle Aged; Movement Disorders; Psychotic Disorders; Retrospective Studies; Tetrabenazine; Young Adult

To investigate the influence of a single episode of psychiatric inpatient treatment on metabolic parameters.. A total of 294 consecutive patients of an Upper Austrian psychiatric department were assessed at admission and discharge regarding bodyweight, body mass index (BMI), high density cholesterol (HDL), low density cholesterol (LDL), triglycerides (TG) and fasting glucose (FG), and the TG/HDL ratio.. Patients showed an increase of BMI of 0.35 kg/m² (+ 1.3%) during a mean duration of inpatient stay of 25.8 days. LDL rose by 10.7 mg/dl (+ 8.1%), triglycerides by 23.0 mg/dl (+ 17%), HDL decreased by 4.4 mg/dl (-7.4%). Fasting glucose decreased by 3.6 mg/dl (-3.8%), yet the TG/HDL ratio, as a marker for insulin resistance, increased significantly from 2.86 to 3.58 (+ 25.2%) on average. Patients with psychotic disorders gained about three times more weight than patients with other diagnoses. Negative alterations of serum lipids were to be found in all diagnostic groups but were especially pronounced in patients with psychotic disorders who were treated with second-generation antipsychotics clozapine, olanzapine and quetiapine.. Psychiatric inpatient treatment leads to clinically relevant deterioration of metabolic parameters within a short time, most pronouncedly in patients with psychotic disorders.

Topics: Antipsychotic Agents; Austria; Benzodiazepines; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Dibenzothiazepines; Female; Glucose; Hospitalization; Humans; Insulin Resistance; Length of Stay; Lipid Metabolism; Male; Mental Disorders; Middle Aged; Multivariate Analysis; Olanzapine; Polypharmacy; Prospective Studies; Psychiatric Department, Hospital; Psychotic Disorders; Quetiapine Fumarate; Regression Analysis; Triglycerides; Weight Gain

Topics: Aggression; Antipsychotic Agents; Clozapine; Forensic Psychiatry; Homicide; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia, Paranoid; Violence

A 25-year-old male developed sinus tachycardia after given clozapine for treatment-resistant psychosis in schizophrenia. The tachycardia was treated successfully with propranolol for several weeks. The patient developed skin eruptions, later diagnosed as psoriasis. Propranolol is known to be capable of causing, evoking or aggravating psoriasis. Several other drugs commonly used in psychiatric practice are also known to cause psoriasis. Doctors need to be aware to the possible side effects of such drugs because they can jeopardise the patient's wellbeing and reduce the efficacy of psychiatric treatment.

Topics: Adrenergic beta-Antagonists; Adult; Antipsychotic Agents; Clozapine; Humans; Male; Propranolol; Psoriasis; Psychotic Disorders; Schizophrenia; Tachycardia

The aggregation of psychiatric disorders within families is well-known. The relative role of biological, psychogenic and socialization-related factors varies with the individual case. Another well-known fact is that parents play a very important role in influencing whether their child gets the right treatment when it is necessary. In this paper we highlight the complex links between childhood and adulthood through the presentation of three psychiatric cases. The first story starts with a lactation psychosis of a mother and ends when the daughter who became psychotic at the age of 15 enters adulthood. During these 18 years several psychiatrically relevant episodes happened in the family. During our care, step by step, in relation to emerging psychological problems, the family revealed more and more secrets, explaining past events, and offering a possibility for psychoeducation and psychotherapy. Knowledge concerning the life and psychiatric history of parents, in spite of the fears of the family, largely contributed to evaluating the symptoms of the daughter, reaching a diagnosis, initiating and maintaining therapy and achieving the present balanced state. The next two cases present the stories of two boys with Attention-Deficit/Hyperactivity Disorder (ADHD). One of the children was 6 years old when the family sought professional help, and now he is 11, the other child was 8 years old when the parents sought help and he is 15 now. The two families reacted differently to the offered treatment, but in both cases the family stayed continuously in touch with their child psychiatrists. With these two different stories on ADHD we would like to present several issues and successes which may surface during the long-term treatment of ADHD.

Topics: Adolescent; Adolescent Behavior; Adult; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Child; Clozapine; Epilepsy, Generalized; Family; Fathers; Female; Humans; Hungary; Low Back Pain; Male; Mothers; Pregnancy; Pregnancy Complications; Psychotic Disorders

Recognizing and incorporating the patient's own perspective into treatment recommendations are essential to optimizing clozapine use. The study describes how the patient's perspective influences clinicians' decision strategies and affects their clozapine recommendations.. Psychiatric trainees examined six case vignettes of varying complexity that included clinical and patient perspective information. They made treatment recommendations guided by a well-known switching guideline and rated the factors that influenced their recommendations.. The decision to follow the guideline's switch recommendation was influenced principally by the importance of the patient's positive symptom profile. The decision to recommend clozapine in lieu of another treatment was influenced principally by the importance of patient's perspective and patient-specific clinical information. These factors had a significant combined influence on the clozapine recommendation rate: When clinical factors were moderately important, the rate was 8%. When clinical factors were extremely important, the rate was 22% when the patient's perspective was moderately important, but 80% when the patient's perspective was very or extremely important.. A clozapine optimization strategy requires skill in advanced decision making, and specifically in prioritizing the patient's perspective without diminishing the importance of clinical information. This skill can be developed through practice-based learning.

Topics: Adult; Antipsychotic Agents; Clozapine; Decision Making; Female; Guideline Adherence; Humans; Male; Psychiatric Status Rating Scales; Psychiatry; Psychotic Disorders; Treatment Outcome

Topics: Adolescent; Antipsychotic Agents; Clozapine; Humans; Male; Neuroleptic Malignant Syndrome; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Myocarditis; Psychotic Disorders

As a keratinized material, nail recently has attracting researchers' attention in the pharmaceuticals analysis. There are comparatively limited studies concerning nail's xenobiotic determination and its mechanism. This article reported the development of a sensitive, specific and reproducible LC-MS/MS method, which could be as a foundation of other studies on drug determination in nail. It can also be regarded as the first report on organic drug in mainland China. Sixteen nail samples from volunteers, who were ingested clozapine for more than nine months, are confirmed positive after being analyzed by the method. It is found that contents of clozapine in the patients' nails are above the nanogram level. Besides, a comparative study of clozapine concentration in nails and hair was made, with a result that there exists a correlation between the two materials in terms of clozapine concentration.

Topics: Adult; Antipsychotic Agents; China; Chromatography, Liquid; Clozapine; Female; Hair; Humans; Male; Middle Aged; Nails; Psychotic Disorders; Tandem Mass Spectrometry

Lack of appropriate animal models simulating core behavioural aspects of human psychosis is a major limitation in schizophrenia research. The use of drugs, that is believed to act through N-methyl d-aspartate receptor, has been demonstrated to mimic relatively broader range of behavioural symptoms in putative animal models. Our goal in this study has been to further evaluate one such drug, ketamine in mice and characterize some selective behavioural phenotypes associated with the drug dosage, treatment period and withdrawal effects to extend the understanding of this model. Our results indicate that acute treatment of ketamine (100 mg/kg, i.p.) induced hyperlocomotory response and reduced the 'transfer-latency time' in passive avoidance test but did not have any effect in the forced swim test (negative symptoms). In contrast, chronic administration of ketamine not only produced significant 'hyperactivity' response but also enhanced the immobility period in animals during the forced swim test and reduced the latency period in the passive avoidance test. Further, these behavioural alterations persisted at least for 10 days after the withdrawal of ketamine treatment. These observations were substantiated by using standard typical and atypical antipsychotic drugs, haloperidol (0.25 mg/kg, i.p.), clozapine (10 mg/kg, i.p.) and risperidone (0.025 mg/kg, i.p.). Therefore, the present study suggests that the chronic treatment with ketamine has the potential of exhibiting changes in broader range of behavioural domains than the acute treatment. Hence, animals chronically treated with ketamine might serve as a useful tool to study the underlying pathogenic mechanisms associated with some symptoms in schizophrenia and other psychiatric disorders.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Haloperidol; Ketamine; Male; Mice; Motor Activity; Psychotic Disorders; Random Allocation; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Swimming

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Synergism; Humans; Male; Piperazines; Psychotic Disorders; Quinolones

In the healthy population, several pathways are known to exert an effect on basal metabolic factors. Previous studies have found associations between single nucleotide polymorphisms in clock genes or downstream hormone receptors such as the leptin receptor (LEPR) or glucocorticoid receptor (NR3C1) and obesity in the healthy population, but this association remains to be examined in patients with schizophrenia treated with antipsychotics.. To assess anthropomorphic parameters in patients taking second-generation antipsychotics (SGA) as a function of nine polymorphisms in three core genes of the clock pathway, and two genes of downstream hormone receptors.. Clinical parameters were evaluated in 261 patients with schizophrenia spectrum disorder. Polymorphisms in LEPR, MC3R, NR3C1, PER2 and SDC3 were genotyped. In order to control for multiple testing, permutation tests were used to generate corrected empirical p-values using the Max(T) procedure in PLINK.. A significant effect of the rs6196 polymorphism in the NR3C1 on weight (β=-4.18; SE=2.02; p=0.018), BMI (β=-1.88; SE=0.64; p=0.004), waist (β=-5.77; SE=1.75; p=0.001) and waist/hip ratio (β=-0.03; SE=0.012; p=0.009) was found. Permutation tests confirmed the findings for BMI (p=0.037) and waist (p=0.024). Carriers of the G allele consistently displayed better parameters than patients with the wild type allele. A weak effect of rs4949184 in SDC3 on BMI was found, but this did not sustain permutation testing (β=-1.27; SE=0.58; p=0.030, p=0.270 after permutations).. Variations in genes implicated in circadian regulation or its related downstream pathways may be important in the regulation of antropomorphic parameters in patients with schizophrenia during long-term treatment with SGA.

Topics: Adult; Age Factors; Alleles; Amisulpride; Anthropometry; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Composition; Body Mass Index; CLOCK Proteins; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Female; Genetic Association Studies; Genetic Carrier Screening; Genotype; Humans; Long-Term Care; Male; Middle Aged; Mutation, Missense; Olanzapine; Period Circadian Proteins; Piperazines; Polymorphism, Single Nucleotide; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Receptor, Melanocortin, Type 3; Receptors, Glucocorticoid; Receptors, Leptin; Risperidone; Schizophrenia; Sex Factors; Sulpiride; Syndecan-3

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Female; Gastrointestinal Diseases; Humans; Middle Aged; Omeprazole; Proton Pump Inhibitors; Psychotic Disorders

To examine disease and treatment characteristics of patients with schizophrenia treated with electroconvulsive therapy (ECT). We examined charts from 79 patients diagnosed with schizophrenia (n = 55), persistent delusional disorders (n = 7), and schizoaffective disorders (n = 17) between 2003 and 2008. We recorded age, sex, indication for ECT, number of ECT sessions, ECT series, outcome, maintenance ECT, use of antipsychotics, duration of illness, and duration of the current exacerbation. All patients were taking antipsychotics at the time of enrolment in the study. Acute ECT included 2-26 sessions; maintenance ECT (M-ECT) was given to 18 patients for up to 12 years. Initial indications for ECT included psychosis (n = 28), pronounced affective symptoms (n = 28), delirious states (n = 20), and M-ECT (n = 3). Most patients experienced excellent/good outcomes (n = 66), but others experienced moderate (n = 8) or poor (n = 5) outcomes. No factors were identified that predicted treatment responses in individual patients. ECT proved to be effective in a population of patients that were severely ill with treatment-refractory schizophrenia. This does not imply that the patients were cured from schizophrenia. Rather, it reflects the degree of relief from psychosis and disruptive behaviour, as described in the patient charts. The treatment was often offered to patients after considerable disease durations.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Catchment Area, Health; Clozapine; Coercion; Combined Modality Therapy; Delusions; Denmark; Diagnosis, Differential; Electroconvulsive Therapy; Female; Humans; International Classification of Diseases; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Failure; Treatment Outcome; Young Adult

The aim of this study was to review the use of clozapine in a Sydney area old age psychiatry service. Data were extracted from case files of all people who were treated in a health area's old age psychiatry units with clozapine during a 15-year period. Additional details were obtained from clinicians who provided ongoing care after discharge from the hospital. Note was made of psychiatric diagnoses, length of time taking clozapine, dosage, side effects and outcome. Sixteen patients aged over 65 years commenced or continued taking clozapine while inpatients of the service. Of the 13 patients who had a history of schizophrenia or schizoaffective disorder, four patients (all female) developed neutropenia and therefore clozapine was stopped. In one case, neutropenia was first diagnosed 6 years after commencing the medication. Two women died; the nine other women, and one of the deceased, stopped taking clozapine, usually because of side effects. The mean daily dose at cessation was 236 mg. All five men were still taking clozapine (mean 260 mg daily) when followed at a mean age of 72 years, having taken it for an average of 10 years. This case review adds to evidence of the risk of neutropenia when older people are prescribed clozapine.

Topics: Age of Onset; Aged; Clozapine; Dementia; Drug Utilization; Female; Humans; Inpatients; Male; Mental Disorders; Middle Aged; Neutropenia; New South Wales; Psychiatry; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Biopsy; Bronchoalveolar Lavage Fluid; Clozapine; Female; Humans; Lung; Lymphocytosis; Psychotic Disorders; Pulmonary Fibrosis

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Myocarditis; Psychotic Disorders

Treatment of shared delusional disorder (folie à deux) often involves separation and use of antipsychotic medication, with uncertain outcomes and potential risks.. We report on two highly interdependent and chronically psychotic sisters with shared systematic delusion, followed by psychiatrists over several years.. The dominant patient was diagnosed with schizoaffective disorder and her non-dominant sister with paranoid schizophrenia. Both received antipsychotics and supportive therapy as outpatients and allowed to continue conjoint therapy with individual psychiatrists-therapists. They returned for follow-up visits for 20 months, when the dominant decided to continue treatment alone, as her sister gradually improved symptomatically and functionally. After separation, the dominant became increasingly anxious. She impulsively ingested an overdose of the non-dominant sister's medicines and died of cardiac arrest, despite her sister's efforts to seek medical assistance. The surviving non-dominant sister developed anxiety and increasing agitation requiring psychiatric hospitalization and increased pharmacotherapy. She improved gradually, but continued to be dysfunctional and required placement in a psychiatric inpatient unit for several months, eventually doing better in a community-based rehabilitative program with regular psychiatric follow-up.. Combined treatment of patients with folie à deux may encourage continuous pathological interactions, but separation may increase risk of adverse outcomes.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Clozapine; Combined Modality Therapy; Epilepsy; Fatal Outcome; Female; Haloperidol; Humans; Nordazepam; Olanzapine; Patient Compliance; Psychotherapy; Psychotic Disorders; Schizophrenia, Paranoid; Shared Paranoid Disorder; Sibling Relations; Suicide; Valproic Acid

Authors studied the level of cytotoxic activity of natural killer lymphocytes (NKCA) and the effect of monocytes, serotonin, rate of serotonin reuptake by lymphocytes and psychotropic therapy on NKCA levels in 59 male patients, aged 18-30 years, with the first episode of attack-like progressive schizophrenia (33 patients) and schizoaffective psychosis (26 patients). All patients were examined at baseline, 4 and 8 weeks after the beginning of treatment with haloperidol and clozapine. Before the treatment, the decrease of NKCA was found in a half of patients compared to controls. In other patients, the NKCA levels were high and did not differ from those in controls. The treatment resistance was estimated as 70,6% in patients with schizophrenia with initially low NKCA levels and 30,8% in patients with schizoaffective psychosis with initially low NKCA levels. During the treatment, the initially high NKCA level decreased while the initially low level increased but remained lower compared to controls. These changes suggest the active reaction from the immune system of the patient to treatment with neuroleptics. The changes of NKCA values during the treatment were reciprocally related to the maximal rate of serotonin reuptake by lymphocytes. Serotonin added to the cell culture in vitro normalized the NKCA level in cultures with- and without monocytes. This effect was revealed in both pathologies only in responders, regardless of the presence or absence monocytes, that may be explained by the presence of active serotonin receptors on the NK cell surface in these patients.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cytotoxicity, Immunologic; Haloperidol; Humans; Killer Cells, Natural; Male; Psychotic Disorders; Schizophrenia; Serotonin; Young Adult

Clozapine is considered as a strong psychopharmaceutic agent in symptom control of psychotic disturbances. However, possible side effects to hematologic, metabolic and cardiologic systems are still entailing a defensive application in psychiatric praxis.. A patient suffering from schizoaffective disorder clinically developed symptoms of cardial disturbances under the psychopharmacotherapy of Clozapine. Specific laboratory analysis and technical procedures were applied, clarifying the background of this serious event.. ECG and specific myocardial enzymes (CK, Troponine-I) requesting an acute myocardial infarction were negative. Specific laboratory analysis revealed positive inflammation markers with elevated C-reactive protein and interleukin-6. Additionally, there was increasing of TNF-alpha and C3 as well as an eosinophilia at differential blood cell count. Echocardiography found an unspecific dyskinesia of the left ventricle, but contrast-enhanced cardial MRI showed structural intramyocardial inhomogeneities suggesting a myocarditis.. In spite of the striking psycho-pharmacotherapeutic benefit, Clozapine may be associated with serious cardial events. We discuss these cardiological problems in association to a Clozapine therapy in regard to its clinical relevance in treatment of psychotic disturbances.

Topics: Adult; Antipsychotic Agents; Clozapine; Crisis Intervention; Dangerous Behavior; Delusions; Dose-Response Relationship, Drug; Humans; Male; Myocarditis; Patient Admission; Psychotic Disorders; Ventricular Dysfunction, Left

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Neutropenia; Psychotic Disorders

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Smoking Cessation

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Humans; Psychotic Disorders; Smoking Cessation

Obsessive-compulsive disorder (OCD) is a heterogenous disorder with different clinical presentations. The most common symptoms are those that involve contamination, possible harm, ordering/symmetry, aggressive/sexual/religious concerns and hoarding. A variety of less common symptoms have been described. Unusual OCD symptoms may lead to misdiagnosis, inappropriate treatment with possible serious side effects. In this report we present a case of an adolescent girl in which unusual OCD presentation and symptoms were misinterpreted to represent psychosis and exacerbation of OCD symptoms with risperidone and clozapine treatment. We discuss the possible pathophysiological mechanisms of OCD symptom exacerbation, clinical implications, and successful management of this case, with fluvoxamine therapy. This case may represent the first report of musical obsessions successfully managed with fluvoxamine therapy.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Diagnostic Errors; Female; Fluvoxamine; Humans; Obsessive-Compulsive Disorder; Psychotic Disorders; Risperidone

To describe a case of clozapine-induced sialorrhea alleviated by immediate-release oxybutynin.. A 53-year-old female with schizoaffective disorder-bipolar type was admitted to a psychiatric unit and initiated on clozapine. During titration to a dose of 300 mg daily and despite taking concomitant oral benztropine 1 mg twice daily, the patient began to experience mild sialorrhea. The sialorrhea became profuse when the clozapine dose reached 400 mg daily, and the patient was routinely seen with a saliva-soaked shirt. Additionally, she had become self-conscious and wanted to stop clozapine therapy. Immediate-release oxybutynin 5 mg daily was started, resulting in significant reduction of the sialorrhea within 24 hours. The patient was discharged on clozapine 300 mg daily, risperidone 6 mg at bedtime, immediate-release oxybutynin 5 mg twice daily, and oral benztropine 1.5 mg daily, with only mild sialorrhea.. It is unknown why clozapine induces sialorrhea. One speculation is that clozapine interrupts muscarinic receptor homeostasis. Immediate-release oxybutynin is an anticholinergic agent with high affinity for salivary gland M₃ receptors that may have restored muscarinic receptor imbalance in our patient. N-Desethyl-oxybutynin, an active metabolite of oxybutynin, is largely responsible for oxybutynin's anticholinergic activity. The activity of oxybutynin and its metabolite may result in dry mouth in over 80% of patients taking the immediate-release formulation, while producing dry mouth in only 40% and 7.5% of patients taking the extended-release and topical formulations, respectively.. To our knowledge, this is the first report of immediate-release oxybutynin successfully reducing clozapine-induced sialorrhea. If oxybutynin is considered for this indication, use of the immediate-release formulation seems prudent. Additional data, including randomized controlled trials, are needed to confirm whether immediate-release oxybutynin has a significant role in the management of this stigmatizing adverse effect.

Topics: Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Humans; Mandelic Acids; Middle Aged; Muscarinic Antagonists; Psychotic Disorders; Sialorrhea

This study consisting of two subprojects was undertaken to evaluate the effects of hyperprolactinemia on cardiovascular disease (CVD) risk parameters such as anthropometric measures, insulin sensitivity and blood lipids in patients with schizophrenia or related psychoses on long term treatment with antipsychotics.. In subproject Ι, 45 patients receiving the 2nd generation antipsychotics risperidone, clozapine or olanzapine were compared regarding prolactin (PRL), body mass index (BMI), insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and blood lipids. In subproject Π, 24 patients receiving 1st or 2nd generation antipsychotics were investigated with diurnal profile of PRL and oral glucose tolerance test (OGTT).. Elevated PRL levels were found in about 45% of the patients and occurred more often in patients receiving risperidone or haloperidol, compared to patients receiving clozapine or olanzapine. In contrast, in subproject Ι, insulin and HOMA-IR were higher and high density lipoprotein cholesterol was lower in patients receiving clozapine or olanzapine, compared with patients receiving risperidone. However, PRL levels did not correlate to BMI, insulin, HOMA-IR or lipids in any of these three treatment groups. In subproject Π, OGTT showed impaired glucose tolerance in 25% and new-onset diabetes in 4% of the 24 patients investigated. Additionally, the PRL (median 24 h) levels correlated positively to the 2 h glucose level at OGTT (rs=0.42, p=0.04).. Our findings point to that hyperprolactinemia due to 1st and 2nd generation antipsychotics may decrease insulin sensitivity, whereas other mechanisms probably underlie insulin resistance induced by PRL-sparing antipsychotics such as clozapine and olanzapine.

Topics: Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Female; Glucose Intolerance; Humans; Hyperprolactinemia; Insulin Resistance; Lipids; Male; Middle Aged; Olanzapine; Prolactin; Psychotic Disorders; Risperidone; Schizophrenia; Young Adult

The present study aims to evaluate effectiveness of antipsychotics in a cohort of chronic outpatients affected by schizophrenia and related disorders.. Three hundred chronic patients affected by schizophrenia (n=173), schizoaffective (n=117) and delusional (n=60) disorder who were in treament with antipsychotics on 1.3.2008 were considered in the study; effectiveness of antipsychotic treatment was evaluated by means of rates of all cause discontinuation in a 12 months period (31.3.2008-31.3.2009) and of "overall duration of treatment" (DT) (duration of treatment retrospectively evaluated on the basis of clinical records+duration of treatment prospectively evaluated during the 12-months follow up).. Discontinuation of treatment was registered in 25% of patients (29% due to side effects, 14% due to scarce adherence, 11% due to lack of efficacy, 22% due to more causes). Clozapine (7%), Risperidon Long-acting (10%), Typical Antipsychotics depot (11%) and Olanzapine were associated to lower rates of all causes discontinuation. Overall mean duration of antipsychotic treatment was 18± 32 months, with statistically significant differences between drugs (F=4.65, p=0.000). Clozapine (65 mo), Olanzapine (50 mo), butyrophenones (49 mo), typical antipsychotics depot (48 mo), and risperidone (47.5 mo) were the antipsychotics with a longer duration of treatment. Only Clozapine showed a significantly longer DT than any other antipsychotic medication excluding buthyrrohenones.. Rates of all cause discontinuation of antipsychotics appear to be somewhat lower than expected on the basis of pragmatic studied published in the last years; similarly overall duration of treatment seems to be longer. Clozapine is associated to a higher overall effectiveness respect to any other atypical antipsychotic.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Butyrophenones; Clozapine; Delayed-Action Preparations; Delusions; Dibenzothiazepines; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Olanzapine; Patient Dropouts; Prospective Studies; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risperidone; Schizophrenia; Young Adult

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Genotype; HLA-DQ beta-Chains; Humans; Polymorphism, Single Nucleotide; Psychotic Disorders

Three case vignettes are presented documenting the rise in serum clozapine that occurred at a time of acute infection in these patients. The literature on this phenomenon is scant. The physiological processes that occur in the acute phase of the inflammatory response are summarized and provide an explanation of how clozapine levels may rise in response to infection. The risk of clozapine toxicity occurring in association with infections is highlighted.

Topics: Adult; Antipsychotic Agents; C-Reactive Protein; Clozapine; Drug Therapy, Combination; Escherichia coli Infections; Female; Humans; Leukocyte Count; Male; Middle Aged; Pneumonia, Bacterial; Psychoses, Substance-Induced; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Urinary Tract Infections

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Neutropenia; Psychotic Disorders; Time Factors

To investigate the prevalence of and risk factors for overweight and diabetes mellitus in long-stay psychiatric inpatients.. Statistical analysis of data collected from medical, laboratory, and pharmacy files.. 80% of the 256 patients were suffering from schizophrenia or other psychotic disorders. The prevalence of diabetes mellitus was 15%. The prevalence of a disturbed glucose tolerance was 14%. Severe overweight (BMI > 30) was positively associated with the use of clozapine (odds ratio (OR) = 2.7; 95% confidence interval (CI): 1.31-5.75), but negatively with the diagnosis schizophrenia (OR = 0.4; 95% CI: 0.22-0.88). Diabetes mellitus was associated with severe overweight (OR = 3.5; 95% CI: 1.57-7.69). Caucasian patients were at a lower risk for diabetes mellitus (OR = 0.2; 95% CI: 0.08-0.54).. In residential psychiatric patients, diabetes mellitus is especially associated with overweight and non-Caucasian origin. In this survey, the use of clozapine was associated with overweight, but not directly with diabetes mellitus. Diabetes mellitus is highly prevalent, which calls for screening for diabetes mellitus at regular intervals.

Topics: Adult; Clozapine; Diabetes Mellitus; Ethnicity; Female; Glucose Intolerance; Humans; Inpatients; Male; Middle Aged; Obesity; Odds Ratio; Prevalence; Psychotic Disorders; Risk Factors; Schizophrenia

The aim of our study was to assess the time to 'first improvement' associated with specific atypical (AAP) and typical (TAP) antipsychotic drugs in patients with early-onset schizophrenia and other related psychotic disorders.. This study involved a systematic chart review of all patients receiving routine clinical care in our department, with selected AAPs and TAPs, for schizophrenic psychoses, between 1997 and 2007. During this period, our review identified 296 teenage patients (141 males, 155 females; mean age 16.0 ± 1.5 years). The time to first improvement could be estimated in 258 patients; of these, 195 patients (76%) had been treated with AAPs and 63 patients (24%) with TAPs. We found that most patients were taking risperidone (N = 96), followed by olanzapine (64 patients). Other patient numbers were as follows: ziprasidone (16 patients), quetiapine (12 patients), clozapine (7 patients), haloperidol (15 patients), perphenazine (28 patients), and sulpiride (20 patients).. The mean time to first improvement was 6.9 (± 4.2) days in the AAP group and 5.8 (± 3.5) days in the TAP group; the difference was significant at the trend level (p=0.063). With respect to individual drugs, the mean time to first improvement was 7.1 (± 4.1) days for risperidone, 6.7 (± 4.2) days for olanzapine, 6.5 (± 5.2) days for ziprasidone, 6.1 (± 4.4) days for quetiapine, 7.4 (± 3.0) days for clozapine, 5.2 (± 2.4) days for haloperidol, 5.9 (± 3.8) days for perphenazine, and 6.0 (± 3.9) days for sulpiride. Differences among drugs were not significant (p=0.680).. Analysis revealed a significant group level trend indicating that typical antipsychotic drugs have faster onsets of action than atypical antipsychotic drugs.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Female; Haloperidol; Humans; Male; Medical Records; Olanzapine; Perphenazine; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Sulpiride; Thiazoles; Time Factors; Treatment Outcome

To investigate the effect of a complete smoking ban on a group of psychiatric inpatients maintained on the antipsychotic medication clozapine.. Retrospective data on clozapine dose and plasma levels were collected from a three month period before and a six month period after the introduction of the smoking ban.. Before the ban only 4.2% of patients who smoked had a plasma clozapine level > or =1000 microg/l but after the ban this increased to 41.7% of the sample within the six month period following the ban despite dose reductions.. Abrupt cessation of smoking is associated with a potentially serious risk of toxicity in patients taking clozapine. Plasma clozapine levels must be monitored closely and adjustments made in dosage, if necessary, for at least six months after cessation.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; England; Follow-Up Studies; Hospitals, Psychiatric; Humans; Metabolic Clearance Rate; Myoclonus; Psychotic Disorders; Retrospective Studies; Risk Factors; Seizures; Smoking Cessation

To compare employment pay, count of infractions, and clinical symptoms in psychiatric inmates treated with clozapine or other antipsychotics after 6 months of treatment.. Clinical charts and institutional offence records of psychiatric inmates (n = 98), comprised of those on clozapine (n = 65) and on other antipsychotics (n = 33), were reviewed at baseline and after 6 months of treatment. The outcome measures used were Brief Psychiatric Rating Scale (BPRS) scores, employment pay, medication compliance, and the frequency of institutional offences. A binary logistic regression model was used to analyze a categorical change in pay variable, while a negative binomial model was used to analyze the frequency of infractions.. Treatment with clozapine was associated with greater odds of a pay increase (OR = 3.13; 95% CI 1.3 to 7.53, P = 0.01). However, patients on other antipsychotics had a more favourable improvement in BPRS (F = 5.44, df = 1,57, P = 0.02). Patients on other antipsychotics also had a higher count of posttreatment offences (Incidence Rate Ratio = 2.22; 95% CI 1.11 to 4.41, P = 0.02).. Clozapine probably has a favourable effect on inmate behaviour and institutional adjustment. This effect can last up to 36 months after the initial dose.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Criminals; Employment, Supported; Female; Forensic Psychiatry; Humans; Male; Middle Aged; Patient Compliance; Prisoners; Psychotic Disorders; Violence

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Hypersensitivity; Humans; Male; Myocarditis; Olanzapine; Psychotic Disorders; Retreatment

Women with schizophrenia have later onset and better response to antipsychotic drugs (APDs) than men during reproductive years, but the menopausal period is associated with increased symptom severity and reduced treatment response. Estrogen replacement therapy has been suggested as beneficial but clinical data are inconsistent. Latent inhibition (LI), the capacity to ignore irrelevant stimuli, is a measure of selective attention that is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosis-inducing drug amphetamine and can be reversed by typical and atypical APDs. Here we used amphetamine (1 mg/kg)-induced disrupted LI in ovariectomized rats to model low levels of estrogen along with hyperfunction of the dopaminergic system that may be occurring in menopausal psychosis, and tested the efficacy of APDs and estrogen in reversing disrupted LI. 17beta-Estradiol (50, 150 microg/kg), clozapine (atypical APD; 5, 10 mg/kg), and haloperidol (typical APD; 0.1, 0.3 mg/kg) effectively reversed amphetamine-induced LI disruption in sham rats, but were much less effective in ovariectomized rats; 17beta-estradiol and clozapine were effective only at high doses (150 microg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17beta-estradiol (50 microg/kg, an ineffective dose). Reduced sensitivity to dopamine (DA) blockade coupled with spared/potentiated sensitivity to DA stimulation after ovariectomy may provide a novel model recapitulating the combination of increased vulnerability to psychosis with reduced response to APD treatment in female patients during menopause. In addition, our data show that 17beta-estradiol exerts antipsychotic activity.

Topics: Amphetamine; Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Estradiol; Estrogens; Female; Haloperidol; Inhibition, Psychological; Ovariectomy; Psychotic Disorders; Rats; Rats, Wistar; Statistics, Nonparametric; Water Deprivation

Malignant neuroleptic syndrome (MNS) is a serious and potentially fatal side-effect of neuroleptic treatment. Beside antipsychotic drugs, other psychotropic drugs such as antidepressants and lithium carbonate can cause this life threatening side-effect. Underlying mechanism of this side-effect is still unknown and debated. So far some risk factors have been identified, with clinical observations and recent pharmacogenetic research suggesting (with inconsistent findings) correlation between genetic mechanisms and predisposition to MNS. Polymorphisms of CYP2D6 enzyme through which most psychotropic drugs are metabolized and TaqIA DRD2 which is target for antipsychotic drugs could be the link between pharmacogenetic factors and potential for development of MNS. In this paper we present two case reports with clinical presentation of three consecutive MNS. One patient developed MNS while he was taking combination of drugs: first time haloperidol, promazine and fluphenazine, second time fluphenazine and perazine and third time clozapine, promazine and valproic acid consecutively. The other patient developed MNS while taking following combination of drugs: first time haloperidol and lithium carbonate, second time risperidone and third time clozapine consecutively. Pharmacogenetic analysis for CYP2D6 and TaqI A DRD2 polymorphisms for both patients was done. Genotypisation of CYP2D6*1*3*4*5*6 in both patients showed no evidence of poor metabolizer phenotype. On the other hand, first patient was heterozygous for CYP2D6*4 (genotype *1/*4). CYP2D6 polymorphisms could have clinical significance because may lead to toxicity and unwanted side-effects in standard usual antipsychotic dose ranges. Analysis Taql A DRD2 polymorphism for first patient showed that he is heterozygous for A1 allele (genotype A1A2) which is commonly associated with predisposition to MNS. According to our literature three consecutive MNS are rarely described, and incidence of MNS generally is too low to perform clinical research. Many patophysiological mechanisms may probably underlie this complex and potentially fatal syndrome, still unknown etiology. But, genetic mechanisms could be significant. Further pharmacogenetic research, findings and analysis in patients who develop single or repeated MNS are strongly recommended. In long term, pharmacogenetic analysis, implemented in daily clinical practice, could help in prevention of this extremely serious side-effect.

Topics: Adult; Alleles; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cytochrome P-450 CYP2D6; Dibenzothiazepines; Drug Therapy, Combination; Fluphenazine; Genetic Carrier Screening; Genotype; Haloperidol; Humans; Lithium Carbonate; Male; Neuroleptic Malignant Syndrome; Perazine; Polymorphism, Genetic; Psychotic Disorders; Quetiapine Fumarate; Receptors, Dopamine D2; Recurrence; Risperidone

Topics: Adolescent; Antipsychotic Agents; Clozapine; Female; Humans; Hypoglycemic Agents; Metformin; Psychotic Disorders; Weight Gain

There is considerable evidence that cognitive impairment is a better predictor of work and social function in schizophrenia than are positive and negative symptoms. Atypical antipsychotic drugs have been shown to improve cognitive function in schizophrenia patients, but it is unclear whether this improves patients' ability to gain employment. Data from a prospective longitudinal study was used to test the hypotheses that (1) clozapine treatment would improve employment outcome in treatment-resistant schizophrenia or schizoaffective disorder patients, and (2) specific cognitive functioning at baseline and after treatment would predict work status at baseline and change in work status. Employment status and cognitive assessment data were collected in 59 treatment-resistant schizophrenia or schizoaffective disorder patients. Forty-seven of 59 (79.7%) patients were unemployed at baseline. Over a 12-month period, 23 (48.9%) additional patients were able to gain paid or volunteer jobs, or attend school. As predicted, neurocognitive performance was a better predictor of employment status and ability to gain of employment than clinical symptoms. Improvement in verbal working memory was found to be a better predictor of employment outcome than other cognitive functions. Treatment that enhances cognitive function, especially verbal working memory, may lead to better employment outcomes in treatment-resistant schizophrenia or schizoaffective disorder patients.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Cognition Disorders; Employment; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adolescent; Clozapine; Humans; Male; Neutropenia; Psychotic Disorders

Seizures can be a serious adverse effect of clozapine, often a last-resort antipsychotic with unique efficacy for some patients. Several anticonvulsants have been reported to be useful in preventing further clozapine-induced seizures and permitting continued treatment with this medication. The authors describe the first reported successful use of lamotrigine for this purpose.

Topics: Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy, Tonic-Clonic; Humans; Lamotrigine; Lithium Carbonate; Male; Psychotic Disorders; Triazines; Young Adult

To determine the prevalence rates of hepatitis C in patients with schizophrenia and schizoaffective disorder being treated with clozapine.. Clozapine-treated outpatients and inpatients were recruited from the Centre for Addiction and Mental Health Schizophrenia Program in Toronto, Canada. All subjects had liver function tests, and positive HCV status was defined as a positive qualitative HCV RNA assay. Subjects completed a self-report questionnaire assessing HCV risk factors, past history of liver disease, previous diagnosis of human immunodeficiency virus (HIV), past hepatitis B virus (HBV) infection and current alcohol use.. 110 subjects participated in the study and the HCV prevalence rate (antibody and viremia-positive) was 2.7%, compared to a 0.8% prevalence rate in Canada. All study subjects had established housing, none reported a history of HIV, and only one patient had a history of HBV infection. A total of 9% drank two or more drinks on a typical day drinking and 7% endorsed having six or more drinks on one occasion at least monthly. Two of 3HCV-viremia positive subjects had HCV risk factors, specifically intravenous drug use and intranasal cocaine use. There was no difference between HCV infected and HCV negative subjects on liver function tests.. Our study demonstrates elevated rates of HCV in clozapine-treated patients compared to the general population in Canada and are congruent with reports from United States centres. Our study highlights the importance of homelessness and patterns of high-risk behaviour when interpreting HCV prevalence rates in this sub-population of patients and should be explored in future studies.

Topics: Administration, Intranasal; Adult; Alcoholism; Antipsychotic Agents; Canada; Clozapine; Cocaine-Related Disorders; Cohort Studies; Female; Hepacivirus; Hepatitis C; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Risk Factors; Risk-Taking; Schizophrenia; Substance Abuse, Intravenous; Surveys and Questionnaires

Clozapine, a poorly tolerated antipsychotic drug, is widely recognized as the only efficacious option in treatment-resistant psychosis. The United Kingdom (U.K.) National Institute of Clinical Excellence (NICE) guidance for its consideration defined a threshold for treatment resistance substantially more liberal than that utilized in seminal studies of efficacy. This study documented adherence to NICE guidance in a patient group likely to be enriched for treatment resistance: 150 consecutive assertive outreach and former rehabilitation inpatients. Evidence of a NICE-compliant treatment trial was adduced from case notes: treatment resistance was determined through discussion with key workers about ongoing clinical problems, including treatment-resistant patients already on clozapine. Reasons for treatment-resistant patients not receiving clozapine were documented. Levels of ongoing clinical problems were compared between treatment-resistant patients on clozapine, treatment-resistant patients not on clozapine, and non-treatment-resistant patients.. Patients' mean age was 41, with illness duration of 16 years. Twelve percent (18 patients) had not had a NICE-compliant trial of treatment, but all 3 treatment-resistant patients in this subgroup were on clozapine already. Forty-five percent of the whole group was treatment resistant: 54% of the treatment-resistant group was treated with clozapine. Of the remaining 46% (i.e., 31 treatment-resistant patients not taking clozapine), 16 refused and 15 could not be treated for medical reasons including the failure of previous trials and neutropenia. Levels of ongoing clinical problems were generally similar between clozapine-treated patients and nontreatment-resistant patients, with significantly greater problems in treatment-resistant patients not taking clozapine. However, positive symptoms remained relatively high in the clozapine group, while substance abuse was actually lower than in the other two groups, and there were no differences between any of the groups in depression and suicide risk.. Tertiary referral assertive outreach and rehabilitation services include a higher proportion of treatment-resistant patients than secondary services, as appropriate. Most patients receive a NICE-compliant trial for the determination of pharmacological treatment resistance, but only just over half of the patients who need clozapine on clinical grounds are taking it. While half of these refuse, the rest encounter insuperable obstacles to treatment. In general, clozapine reduces levels of ongoing clinical problems to those of nontreatment-resistant patients. In view of the difficulties of delivering clozapine to treatment-resistant patients, the development of treatment resistance should be avoided if possible.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Comorbidity; Drug Resistance; England; Evidence-Based Medicine; Female; Health Services Accessibility; Humans; Male; Medication Adherence; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Quality Assurance, Health Care; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; State Medicine; Substance-Related Disorders; Young Adult

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Leukocyte Count; Leukocytosis; Lithium Carbonate; Male; Neutrophils; Psychotic Disorders; Reference Values

The case of a schizoaffective patient suffering from a malignant catatonic syndrome following combined lithium-risperidone therapy is explored.. A case report and relevant deliberations regarding pathophysiology of the catatonic dilemma are discussed.. There are two critical transitions in the development of a malignant catatonic syndrome. Dopaminergic system and psychopharmacological factors are supposed to play a key role. However, other neurotransmitter systems and the individual predisposition must be considered.

Topics: Antimanic Agents; Antipsychotic Agents; Brain; Catatonia; Clozapine; Diagnosis, Differential; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroencephalography; Humans; Hypnotics and Sedatives; Lithium Carbonate; Long-Term Care; Lorazepam; Male; Middle Aged; Psychotic Disorders; Risperidone; Serotonin

Topics: Adult; Benzodiazepines; Clozapine; Drug Interactions; Drug Therapy, Combination; Duloxetine Hydrochloride; Female; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Risperidone; Thiophenes; Young Adult

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Psychotic Disorders

Previous naturalistic observational studies have produced mixed results concerning the effectiveness of clozapine on hospitalization, partly because the decision to place a patient on clozapine versus another antipsychotic has been confounded with the known efficacy of clozapine over other antipsychotics.. To examine the effectiveness of clozapine compared to other antipsychotic drugs in delaying hospitalization in routine clinical practice.. Consecutive patients with schizophrenia or schizoaffective disorders registered to start on clozapine in one English mental health service over a six-year period were followed up for 2 years from the time of discharge (index admission). Time to hospitalization was used to compare patients started and discharged on clozapine (CG = 126) and those registered to start on clozapine but subsequently discharged on other antipsychotics (OAG = 34) using Kaplan-Meier survival analysis.. There were more hospitalizations with OAG 13 [38%] than CG = 27 [21%]. Time to hospitalization (25th centile) was 299 days in CG and 136 days in OAG among patients who were successfully discharged from hospital (x2 = 4.80, df = 1, p = 0.043). The time to hospitalization was delayed in CG versus other OAG when baseline differences in age, gender, marital status, previous forensic mental health service, case management and site of initiation were controlled [odds ratio (95% confidence intervals) = 1.87 (1.01, 4.33), p = 0.048].. Clozapine delays hospitalization in patients with treatment resistant schizophrenia if they are started on clozapine in the community or successfully discharged from hospital following their index admission.

Topics: Adult; Antipsychotic Agents; Chi-Square Distribution; Clozapine; Cohort Studies; Drug Resistance; England; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Odds Ratio; Patient Discharge; Proportional Hazards Models; Psychiatric Status Rating Scales; Psychotic Disorders; Registries; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome; Young Adult

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition; Dopamine D2 Receptor Antagonists; Drug Evaluation, Preclinical; Drug Industry; Humans; Perphenazine; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Topics: Antipsychotic Agents; Clozapine; Histamine Agonists; Histamine H1 Antagonists; Humans; Leptin; Psychotic Disorders; Receptors, Histamine H1; Seizures; Treatment Outcome

Topics: Catatonia; Clozapine; Family Health; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders; Substance Withdrawal Syndrome

The association between schizophrenia and obsessive-compulsive disorder (OCD) is complex. This study systematically examined a UK cohort of clozapine-treated individuals with schizophrenia/schizoaffective disorder. Fourteen of 59 cases (24%) scored positively on item H of the Mini-International Neuropsychiatric Interview (MINI) for OCD. The mean Yale- Brown Obsessive-Compulsive Scale (Y-BOCS) score in MINI-positive cases was 17.6 (SD+/-6.3). Sixty-four percent scored 16 or more on the Y-BOCS, representing clinically meaningful illness severity. Seven (50%) patients with OCD had previously received the diagnosis by their treating clinicians and were already receiving with selective serotonin re-uptake inhibitors (SSRIs) treatment. OCD cases scored significantly worse than their non-OCD counterparts on the Abnormal Involuntary Movement Scale (P=0.01) and the Simpson Angus Scale (SAS; P=0.01). There was also a non-significant trend toward higher ratings for OCD cases on the Clinical Global Impression-Schizophrenia scale (P=0.06). Comparing the OCD cases taking SSRI (n=7) with those not on SSRI (n=7), significant differences emerged on the SAS (P=0.03). Our results suggest that OCD is common among patients receiving clozapine for schizophrenic disorders and that the comorbidity is associated with greater motoric impairment. The role of medication in this condition remains unclear.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Cross-Sectional Studies; Diazepam; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Obsessive-Compulsive Disorder; Psychotic Disorders; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; United Kingdom

Cortical inhibition (CI) deficits assessed by transcranial magnetic stimulation paradigms, short-interval cortical inhibition (SICI), and cortical silent period (CSP) have been demonstrated in schizophrenia (SCZ) patients. Antipsychotic treatments can modify CI and improve clinical symptoms, suggesting a neurophysiological link between the two. Previous studies have demonstrated that clozapine is associated with prolongation in CSP, a gamma-hydroxybutyric acid (GABA)(B)-mediated phenomenon. Furthermore, SICI deficits were associated with psychotic symptom severity, suggesting alternation in GABA(A)-mediated neurotransmission. Such differential association patterns between clinical symptoms and CI deficits and their relationship to antipsychotic treatment thus might provide insights to the pathophysiology of schizophrenia.. CI was assessed in 78 SCZ patients and 38 healthy subjects. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Subjects were grouped according to antipsychotic medication status: unmedicated (n = 7), clozapine (n = 19), olanzapine/quetiapine (n = 32), and risperidone/typical antipsychotics (n = 20).. Relative to control subjects, patients receiving clozapine had longer CSP and reduced SICI, whereas patients receiving other antipsychotics and unmedicated patients had shorter CSP. Across all subjects with SCZ, CSP was inversely associated with negative symptoms, and SICI was inversely associated with positive symptoms.. These results confirm that unmedicated SCZ patients have CI deficits and that clozapine treatment is associated with potentiation of GABA(B)-inhibitory neurotransmission and reduced GABA(A) inhibitory neurotransmission. Also, the differential associations among SICI, CSP, and clinical symptom dimensions suggest that GABA(A)- and GABA(B)-mediated CI might have different roles in the pathophysiology of symptoms of schizophrenia.

Topics: Adult; Antipsychotic Agents; Case-Control Studies; Cerebral Cortex; Clozapine; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; Humans; Neural Inhibition; Psychotic Disorders; Schizophrenia; Synaptic Transmission; Transcranial Magnetic Stimulation

We report on two cases of drug-drug interactions between ciprofloxacin and clozapine. The first case was a 46-year-old male patient receiving a daily dose of clozapine 900 mg. He was admitted to hospital with urosepsis and was treated with a 5-day course of ciprofloxacin and amoxicillin. Two days after completion of antibacterial therapy, the patient developed symptoms of rhabdomyolysis. Clozapine therapy was discontinued and measurement of the patient's clozapine plasma concentration 1 day after cessation of clozapine therapy and 3 days after cessation of ciprofloxacin treatment showed that it was in excess of recommended therapeutic levels. The second patient was a 58-year-old male patient treated with a daily dose of clozapine 300 mg. He was admitted to hospital because of delirium and suspected urinary tract infection or pneumonia. Treatment with ciprofloxacin was initiated. Measurement of clozapine plasma concentrations prior to and 3 days after commencement of ciprofloxacin showed that clozapine concentrations doubled over that time period. We suggest that inhibition of cytochrome P450 (CYP) enzymes 1A2 and 3A4 by ciprofloxacin resulted in delayed clozapine metabolism and elevated clozapine plasma concentrations. This might cause severe adverse effects. We advise using another antibacterial agent or reducing the clozapine dose and monitoring clozapine levels when this antipsychotic agent is used in combination with ciprofloxacin.

Topics: Anti-Infective Agents, Urinary; Antipsychotic Agents; Ciprofloxacin; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia

Oculogyric crisis is a distressing acute/chronic side effect of neuroleptic medications. Chronic oculogyric crisis can be considered as a tardive hyperkinetic movement disorder and it may be associated with worsening of psychotic symptoms. Treatment strategies for chronic oculogyric crisis include; high potency antipsychotics and anticholinergics drugs for immediate relief and clozapine as a long-term treatment strategy. Here we are presenting case histories of four patients with oculogyric crisis and associated worsening of psychosis, its possible etiology and various treatment strategies.

Topics: Adult; Antipsychotic Agents; Brain; Cholinergic Antagonists; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Eye Movements; GABA Antagonists; Humans; Male; Ocular Motility Disorders; Psychoses, Substance-Induced; Psychotic Disorders; Treatment Outcome; Young Adult

Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally acquired entity characterized by predominantly neurologic symptoms, such as seizures, facial asymmetry, contralateral hemiplegia, and mental retardation. Psychiatric symptoms are rarely reported. We report the first case of left cerebral hemiatrophy and a late onset of treatment-resistant schizoaffective disorder after a stressful life event. The patient finally responded well to clozapine. The clinical history and results from structural neuroimaging are highlighted to discuss the possible developmental bias for psychotic disorders.

Topics: Adult; Antipsychotic Agents; Atrophy; Brain; Brain Diseases; Clozapine; Facial Asymmetry; Hemiplegia; Humans; Magnetic Resonance Imaging; Male; Psychotic Disorders; Syndrome; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Diabetes Mellitus; Drug Monitoring; Humans; Metabolic Syndrome; Obesity; Psychotic Disorders; Risk Factors

Topics: Antipsychotic Agents; Catatonia; Clozapine; Electroconvulsive Therapy; Female; Humans; Long-Term Care; Medication Adherence; Middle Aged; Psychotic Disorders; Substance Withdrawal Syndrome

Usher syndrome, the most common case of deaf - blindness, may be associated with various psychiatric disorders. Inability of communication through spoken language in association with progressive visual impairment affects diagnostics and management in case of co-morbidity with mental disorder. A patient with Usher syndrome and psychiatric symptoms is described and the difficulties in psychiatric assessment in her case are discussed. A 28 years old woman with hearing impairment diagnosed at the age of 3 months and progressive pigmentary retinopathy diagnosed at the age of 19 years, has been treated for ADHD in childhood, eating disorder in adolescence and psychosis-like disorder in adult life. Direct observation of patient behavior and the effects of pharmacotherapy were the main diagnostic procedures, since the use of sign language and handwriting was very limited. The limitations of management are discussed.

Topics: Adult; Anorexia Nervosa; Anti-Anxiety Agents; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Differential; Drug Therapy, Combination; Female; gamma-Aminobutyric Acid; Humans; Mental Disorders; Obsessive-Compulsive Disorder; Pregabalin; Psychotic Disorders; Recurrence; Social Isolation; Usher Syndromes; Violence

Myocarditis is a rare but life threatening adverse effect of clozapine. Some symptoms of myocarditis--elevated temperature, tachycardia and fatigue--appear commonly during the onset of treatment with clozapine and during the dose titration. We present a case of a patient with concurrent schizoaffective disorder and Parkinson's disease, who twice developed clozapine-induced myocarditis. All symptoms disappeared after the discontinuation of the drug. Early diagnosis, discontinuation of clozapine and supportive therapy of myocarditis lower the risk of a fatal outcome.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Myocarditis; Parkinson Disease; Periodicity; Psychotic Disorders; Recurrence

Topics: Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic; Serotonin Antagonists

This paper presents five cases of suicide in women attending a schizophrenia clinic and demonstrates that, in the presence of psychosis, women can act impulsively and aggressively and can use lethal means to end their lives. If generalizations can be made from the stories of these five women, then multiple prior admissions, comorbid psychiatric and substance abuse diagnoses, lack of negative symptoms, full awareness of illness, and current crisis appear to constitute important risk variables. Female-specific factors associated with suicide in this sample were childhood sexual abuse, intimate partner abuse, and child loss. The author, who knew these five women very well over a long period of time, concludes that the deaths might have been prevented by critical interventions such as timely hospital admission, suicide screening prior to hospital discharge, safety check of the immediate environment, in-depth explanation of therapeutic decisions, and complete assessment of the personal meaning attached to recent events.

Topics: Adult; Antipsychotic Agents; Awareness; Bereavement; Cause of Death; Child Abuse, Sexual; Child, Preschool; Clozapine; Comorbidity; Female; Humans; Impulsive Behavior; Life Change Events; Mass Screening; Middle Aged; Patient Discharge; Patient Readmission; Psychotherapy; Psychotic Disorders; Risk Factors; Schizophrenia; Schizophrenic Psychology; Spouse Abuse; Suicide; Suicide Prevention; Suicide, Attempted

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Fluid Therapy; Humans; Lithium Compounds; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Rhabdomyolysis; Time Factors

Catatonia is characterized by the predominance of psychomotor abnormalities and shares many clinical, biological and treatment response features with the neuroleptic malignant syndrome (NMS), a rare adverse reaction to psychoactive medications. It has been advocated that the two conditions should be placed along the same spectrum of disorders. A case of a 49-year-old woman, who developed NMS while on low dose clozapine soon after recovering from catatonia, is presented. The potential relationship between catatonia and NMS is discussed in the light of the existing literature, and attention is drawn to the risk for clozapine-induced NMS in catatonic patients.

Topics: Antipsychotic Agents; Catatonia; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders; Risk Factors; Schizophrenia, Catatonic

This report concerns the case of a 29-year-old male patient suffering from severe psychotic illness who had been satisfactorily treated with clozapine for 4 months. Clozapine had also been successfully administered during a psychotic episode 5 years previously. Though symptoms of psychosis were successfully controlled following the most recent psychotic episode, a medical consultation assessed that exacerbation of pancreatitis warranted discontinuation of the current antipsychotic treatment regime. Following a series of unsuccessful courses of neuroleptic medication, a magnetic resonance cholangiopancreaticography (MRCP) revealed marked cholecystolithiasis suggesting a biliary pancreatitis. Clozapine treatment was readministered following cholecystectomy. After 4 weeks of antipsychotic treatment the patient was discharged from hospital on clozapine monotherapy.

Topics: Adult; Antipsychotic Agents; Cholangiopancreatography, Magnetic Resonance; Cholecystectomy; Cholecystolithiasis; Clozapine; Humans; Male; Pancreatitis; Psychotic Disorders; Withholding Treatment

This naturalistic study aims to compare discontinuation rates for low-dose first-generation versus second-generation antipsychotics in first-episode psychotic patients.. The prescription of antipsychotic medication in 301 consecutively admitted patients with first-episode psychosis from four catchment areas is described. For the first year of inclusion a first-generation antipsychotic in low dose was recommended as the first medication. From the second year a second-generation antipsychotic was recommended as first choice. Switching was allowed when any drug was judged to be ineffective or to have serious side-effects. Switching during the first 2 years after inclusion is described.. Switching from a low-dose first-generation antipsychotic was more frequent than from a second-generation antipsychotic (90.7 vs. 58.4%). Lack of therapeutic effect and side-effects were the more frequently recorded reasons for changing in the first-generation group. Akathisia, parkinsonism, dyskinesias, dystonia and dysphoria were more often reported in patients on first-generation drugs. Weight gain and sedation were more often reported in patients on second-generation drugs.. The findings suggest a better adherence to and tolerability for second-generation antipsychotics than for low-dose first-generation antipsychotics in first-episode psychosis.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Chi-Square Distribution; Clopenthixol; Clozapine; Female; Humans; Imidazoles; Indoles; Kaplan-Meier Estimate; Male; Middle Aged; Olanzapine; Perphenazine; Psychotic Disorders; Risperidone; Statistics, Nonparametric; Time Factors; Young Adult

Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term implantable medication delivery system.. The current study assesses attitudes towards implantable medication in psychiatric patients and their family members. Patients included in the study had diagnoses of Schizophrenia, Schizoaffective Disorder, Mood or Anxiety related disorders.. 49.62% of patients and 74.47% of family members endorse support for implantable medication.. This study demonstrates that implants may be an acceptable alternative to oral and injectable medication for a subset of psychiatric patients and their families.

Topics: Adult; Attitude to Health; Clozapine; Cross-Cultural Comparison; Data Collection; Drug Implants; Family; Female; Haloperidol; Humans; Male; Mental Disorders; Middle Aged; Mood Disorders; Patient Compliance; Psychotic Disorders; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States

In recent years, several studies showed increased rates of hyperglycaemia, diabetes, dyslipidemia, metabolic syndrome as well as cardiovascular disease in schizophrenic patients. The underlying mechanism, however, is poorly understood. Adiponectin is a recently identified adipocyte-derived protein, with low adiponectin levels being associated with metabolic abnormalities such as obesity, insulin resistance and type 2 diabetes.. Fasting adiponectin levels were assessed in a cross-sectional sample of 386 patients with schizophrenia or schizoaffective disorder. All patients were on monotherapy of second-generation antipsychotics (SGA) and underwent an extensive metabolic screening including an oral glucose tolerance test (OGTT).. Adiponectin plasma levels were inversely correlated with BMI, and differed significantly between patients with normal weight, overweight or obesity (p<0.05). Patients who met criteria for the metabolic syndrome, according to adapted National Cholesterol Educational Program - Adult Treatment Panel criteria (NCEP-ATP III) (29.3%), had significantly lower adiponectin levels than patients not meeting metabolic syndrome criteria (p<0.0001). Patients without glucose abnormalities (78%) had significantly higher adiponectin levels than patients with diabetes (5.7%) (p<0.05). After controlling for components of metabolic syndrome and sex, antipsychotic medication independently influenced adiponectin levels (p<0.0001), with the lowest mean levels in patients on clozapine and olanzapine.. Adiponectin levels in schizophrenic patients mirror what is observed in the general population, with the lowest levels in the most metabolically comprised subjects. However, antipsychotic medication may also influence adiponectin regulation independently, a finding that should be confirmed in longitudinal studies.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Male; Metabolic Syndrome; Olanzapine; Psychotic Disorders; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Chemotherapy, Adjuvant; Clozapine; Drug Administration Schedule; Humans; Neutropenia; Psychotic Disorders; Risk Factors; Valproic Acid

To determine the incidence, characteristics, and predictors of clozapine-induced fever in a sample of patients in a local psychiatric unit.. A retrospective review of case notes of 227 inpatients newly started on clozapine from March 2003 to December 2006 was conducted. Demographic characteristics, presence of fever, investigations carried out, fever characteristics, and complications of fever were recorded and analyzed. Patients with clozapine-induced fever were compared with their fever-free counterparts on demographic and clinical factors. Multivariate logistic regression was performed to identify predictors of clozapine-induced fever.. Thirty-one out of 227 patients (13.7%) developed clozapine-induced fever. The means for day of onset of clozapine-induced fever after clozapine initiation and duration of fever were 13.7 and 4.7 days, respectively. The mean highest body temperature was 38.8 degrees C. Fever resolved within 48 hours after clozapine discontinuation in 79% of the patients with clozapine-induced fever. One out of 7 patients (14.3%) had fever on re-challenge. Clozapine-induced fever was associated with rate of titration more than 50 mg/wk (OR 18.9; 95% CI 5.3 to 66.7; P < 0.01), concomitant use of valproate (OR 3.6; 95% CI 1.5 to 8.9; P = 0.01), and presence of physical illnesses (OR 3.2; 95% CI 1.2 to 8.3; P = 0.02).. Clozapine-induced fever is common. Temporary withdrawal of clozapine may result in resolution of fever, and clozapine re-challenge may be considered after fever subsides. Slower rate of clozapine titration may be helpful in patients with underlying physical illness and concomitant valproate treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Hong Kong; Humans; Incidence; Male; Middle Aged; Psychiatric Department, Hospital; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Valproic Acid; Young Adult

The study of depressions in 183 schizophrenic patients after the management of acute psychosis included evaluation of depressive symptoms, their relation to other psychopathologic syndromes, and the efficiency of drug therapy. The Calgary scale (CDSS) was used to assess severity of depression in schizophrenia along with other standardized psychometric scales to characterize general psychopathologic, positive, and negative symptoms, locomotor disturbances, other concomitant disorders, and general clinical picture. The predominance of depressive conditions with adynamic symptoms was documented. The majority of depressions occurred after the first attack. Those developing in the early post-attack period differed from depressions within a few months after the reduction of psychosis. Syndromic nature of depressions was evident from the number of psychotic episodes experienced by the patients. Depressive symptoms that developed after the management of the acute psychotic state could be efficiently and safely relieved by additional differential treatment with antidepressants. Depressive symptoms in schizophrenia are not predictors of poor prognosis provided the patient receives adequate therapy. More attention is needed to identification and adequate treatment of depression in schizophrenia. Optimized therapy of affective disorders in schizophrenic patients permits to improve prognosis of the disease.

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Drug Administration Schedule; Female; Humans; International Classification of Diseases; Male; Patient Compliance; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Time Factors

The present report describes a case of a 33-year old male patient with homozygous sickle cell disease (SCD) with comorbid psychotic symptoms. The systematical evaluation revealed an intimate association between acute SCD complications, associated with hematological abnormalities, and psychotic symptoms worsening. Clozapine was effective in controlling psychotic symptoms refractory to previous antipsychotic trials.

Topics: Adult; Anemia, Sickle Cell; Antipsychotic Agents; Black or African American; Clozapine; Follow-Up Studies; Homozygote; Humans; Magnetic Resonance Imaging; Male; Psychotic Disorders; Tomography, Emission-Computed, Single-Photon

The long-term evolution of neuroleptic-induced extrapyramidal syndromes (EPS) of Parkinsonism, akathisia and tardive dyskinesia (TD) is still a controversial issue worth exploring.. A total of 200 inpatients on regular typical neuroleptics (NL) and/or clozapine were assessed in 1995 with regard to the prevalence of EPS. Altogether, 83 patients could be reassessed in 2003/04 (63 had died) using the same methods. Strict definitions of EPS were used. The complete account of NL therapy the patients were prescribed between 1995 and 2003/04 (including atypical NL other than clozapine) was considered.. The prevalences found in 1995 and 2003/04 were 17% and 29% for Parkinsonism, 14% and 14% for akathisia, and 24% and 13% for TD. There were considerable intra-individual fluctuations in EPS occurrence even when the overall prevalence rate remained the same. In intra-individual comparisons of EPS ratings on both assessments, there was a tendency for worsening of Parkinsonism to be associated with a current (2003/04) therapy with typical NL; worsening of akathisia was associated with a current therapy with atypical NL other than clozapine, amelioration of akathisia with a current therapy with clozapine; and, basically, there were no significant associations found between the changes in TD ratings and the long-term therapy with typical NL, clozapine, and other atypical NL, considering cumulative doses of all these drugs. In a multivariate analysis, there was a tendency for the long-term evolution of TD to depend on illness duration as the only variable.. There are intra-individual fluctuations in all EPS over longer time periods. The choice of current NL therapy has an impact on Parkinsonism and akathisia. The long-term evolution of TD appears independent of NL prescriptions.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Dyskinesias; Female; Follow-Up Studies; Hospitalization; Humans; Longitudinal Studies; Male; Middle Aged; Neurologic Examination; Parkinsonian Disorders; Patient Dropouts; Prevalence; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

To document and measure various parameters and outcomes in patients prescribed clozapine in a forensic psychiatric setting.. A retrospective file review was conducted on patients prescribed clozapine. Parameters and outcomes were recorded and compared against a group prescribed other antipsychotics, matched for sex and diagnosis.. Patients prescribed clozapine had higher rates of substance misuse syndromes and comorbidity when compared to patients prescribed other antipsychotics. Clozapine was found to be effective in treatment of psychosis. High rates of adverse effects were noted. Discontinuation of clozapine for a variety of reasons was common.. Patients identified as treatment resistant who are prescribed clozapine are often more complex in the pattern of illness and subsequent needs. Clozapine is effective in the treatment of psychosis in this forensic service. Its benefits need to be balanced against the potential for adverse effects and problems ensuring adherence. Regular, objective monitoring of clinical and adverse effects would aid patient safety, clinical decision-making and future research.

Topics: Adult; Antipsychotic Agents; Clozapine; Crime; Diagnosis, Dual (Psychiatry); Drug Monitoring; Drug Resistance; Forensic Psychiatry; Health Status; Hospitals; Humans; Incidence; Male; Middle Aged; Neutropenia; New South Wales; Patient Dropouts; Prisoners; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Schizophrenic Psychology; Seizures; Substance-Related Disorders

This study sought to clarify the prevalence of various side-effects experienced by consumers taking clozapine (n = 27) and to elucidate the impact of clozapine on their quality of life. Responses of consumers were contrasted with those of clinicians to highlight any discrepancies between the two groups, thus providing a focus for the improvement of clinical practice. Consumers completed a demographic questionnaire, the Liverpool University Neuroleptic Side-Effect Rating Scale. They next took part in a semistructured interview, which explored their attitudes to clozapine treatment. File searches provided historical data for antipsychotic use before the prescription of clozapine. Clinicians completed the same instruments and submitted them by mail. Most clinicians overestimated the prevalence and severity of clozapine side-effects. Consumers reported drooling mouth as the most prevalent and severe side-effect, whereas clinicians estimated that difficulty staying awake was the most prevalent side-effect, and the most severe side-effect was sleeping too much. Clinicians and consumers agreed that clozapine lifts mood. Only 19% of consumers were unhappy about blood tests, whereas 52% of clinicians estimated that consumers were unhappy about blood tests. This study suggests that despite significant side-effects and regular blood tests, most stable consumers taking clozapine were happier and more satisfied with their treatment than many of their clinicians believed they were. The study also highlights the need for clinicians to ask consumers about the different side-effects they may be experiencing, so they can provide clinical support to improve their quality of life.

Topics: Adult; Antipsychotic Agents; Attitude of Health Personnel; Attitude to Health; Clozapine; Drug Monitoring; Female; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Quality of Life; Schizophrenia; Victoria

This study compares patient characteristics and treatment response between inpatients treated with clozapine in a research setting as compared to those initiated on clozapine during routine inpatient treatment.. Subjects on clozapine, in clinical trials, were compared with clozapine inpatients receiving routine clinical care.. At baseline, patients in routine clinical practice had more negative symptoms (P < 0.001), activation (P < 0.001) and greater total Brief Psychiatric Rating Scale (BPRS) scores (P = 0.022) than those in the research setting. Routine clinical practice subjects had larger decreases in BPRS total scores (P = 0.042) and positive item scores (P = 0.0005) compared to research subjects. Response to clozapine was observed in 15/85 (18%) research subjects as compared to 60/223 (27%) patients in routine care (P = 0.09).. Patients treated in routine clinical practice have more severe baseline symptoms, but experience significantly greater improvements in psychiatric symptoms.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Female; Hospitalization; Humans; Male; Practice Patterns, Physicians'; Psychotic Disorders; Research Subjects; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Two patients with a psychotic depression showed insufficient response to pharmacotherapy and electroconvulsive therapy. The problem therefore was which alternative treatment options should be considered at this stage. On the bases of the available literature the most suitable options seemed to be clozapine, a monoamine oxidase inhibitor and lithium addition. Patient A responded well to clozapine and the condition of patient B improved during treatment with tranylcypromine, lithium and quetiapine.

Topics: Antipsychotic Agents; Clozapine; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Lithium Compounds; Middle Aged; Psychotic Disorders; Therapeutics; Tranylcypromine

Topics: Adult; Aluminum Hydroxide; Antacids; Antipsychotic Agents; Clozapine; Humans; Male; Metabolic Diseases; Psychotic Disorders

The aim of the present paper was to examine the concept of benign ethnic neutropenia and to consider the implications of ethnicity in the current clozapine regulatory system.. The case of a young Palestinian man who lost access to clozapine due to a fall in his neutrophil count, is presented herein, and a brief review of ethnic variations in neutrophil levels is given.. This patient's clozapine was ceased, with unfortunate consequences, despite his having normal immune function.. By using normative haematological data established in white populations, the Australian clozapine regulatory system places some non-white patients at a considerable disadvantage.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Arabs; Australia; Clozapine; Genetic Predisposition to Disease; Humans; Leukocyte Count; Lithium Compounds; Male; Neutropenia; Neutrophils; Psychotic Disorders; Withholding Treatment

Antipsychotic (AP) treatment, in particular with some second-generation drugs, is associated with weight gain and other metabolic side effects. However, the relationship between drug-induced weight gain and dyslipidemia is not well understood. We investigated how cardiometabolic risk factors were related to body mass during treatment with different APs under real-life conditions.. This cross-sectional naturalistic study included 242 subjects with severe mental disorders who were on monotherapy with olanzapine (OLZ) or clozapine (CLZ) (n = 80), monotherapy with other APs (n = 80), or unmedicated (n = 82). Groups were adjusted for age and compared for prevalence of the metabolic syndrome and its components. Groups were further adjusted for body mass and compared for mean values of blood pressure, lipids, and fasting glucose.. There was no significant intergroup difference in the prevalence of metabolic syndrome, obesity, hypertension, or hyperglycemia. Despite similar body mass index, OLZ/CLZ-treated subjects had significantly higher prevalence of dyslipidemia (high triglyceride and low HDL cholesterol levels) than unmedicated subjects. They also had higher mean values of triglycerides (P = 0.003) and lower mean values of HDL cholesterol (P < 0.001). Patients treated with other APs had intermediate values.. Intergroup differences in body mass index were minimal in this naturalistic setting, probably because of awareness of this treatment hazard among clinicians. However, independently of body mass, dyslipidemia was significantly associated with AP treatment, in particular with OLZ and CLZ. These findings indicate a primary effect of APs on lipid regulation, important in understanding their mechanism of action, and with clinical implications.

Topics: Adolescent; Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Cholesterol, HDL; Clozapine; Cross-Sectional Studies; Drug Therapy, Combination; Dyslipidemias; Female; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged; Obesity; Olanzapine; Prevalence; Psychotic Disorders; Schizophrenia; Sex Factors; Triglycerides; Weight Gain

To investigate 3-month changes in glucose metabolism in a naturalistic sample of patients with schizophrenia newly started on or switched to specific atypical antipsychotic medication therapy.. One hundred eighty-three patients were evaluated before initiation and 3 months after with a 75-g glucose load oral glucose tolerance test (OGTT). Data were collected between November 2003 and January 2007.. Eight patients (4.4%) developed new-onset diabetes within 3 months. Initiation of clozapine resulted in a significantly higher risk for new-onset glucose abnormalities than initiation of aripiprazole (odds ratio = 67.29, 95% CI = 5.23 to 866.49). Significant drug x time interactions were found for all OGTT glucose assessments (fasting: F = 6.79, df = 5,177; p < .0001; 30 minutes: F = 3.89, df = 5,177; p = .0023; 60 minutes: F = 5.03, df = 5,177; p = .0002; 120 minutes: F = 3.78, df = 5,177; p = .0028), with the evolution of plasma glucose levels being significantly worse in patients initiated on clozapine therapy (fasting, 30 minutes, and 60 minutes), olanzapine therapy (fasting, 60 minutes, and 120 minutes), and quetiapine therapy (fasting and 60 minutes) than in patients initiated on aripiprazole therapy (p < .05). Clozapine was also significantly more deleterious than risperidone and amisulpride for fasting plasma glucose level changes (p < .05). Type of initiation (start or switch) did not affect any of the metabolic parameters.. The incidence of new-onset glucose abnormalities, including diabetes, in the first 3 months after newly starting or switching atypical antipsychotic medication is high and may be markedly influenced by type of prescribed antipsychotic. The importance of accurately screening for new-onset glucose abnormalities after initiation of an atypical antipsychotic is emphasized.

Topics: Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Body Mass Index; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Fasting; Feeding Behavior; Female; Glucose; Glucose Tolerance Test; Humans; Incidence; Insulin; Male; Middle Aged; Olanzapine; Piperazines; Prevalence; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk Factors; Schizophrenia; Time Factors

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Epilepsy; Epilepsy, Complex Partial; Epilepsy, Tonic-Clonic; Humans; Male; Psychotic Disorders

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Therapy; Haloperidol; Humans; Olanzapine; Perphenazine; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles

There is increasing concern that the use of second-generation antipsychotic medications in schizophrenia is associated with the development of metabolic syndrome.. This study assessed the prevalence and clinical associations of metabolic syndrome among patients receiving clozapine within the catchment area of a mental health service in the west of Ireland.. A total of 84 patients (96% response rate) taking clozapine were interviewed and thoroughly investigated using physical assessments, comprehensive laboratory testing and review of medical records.. Of the patients, 46.4% taking clozapine fulfilled the criteria for metabolic syndrome. Male gender, high body mass index, high insulin level and receiving a concomitant antipsychotic medication were significantly associated with the presence of metabolic syndrome.. Almost half of the patients receiving clozapine have metabolic syndrome and are consequently at risk of cardiovascular morbidity and mortality. Such patients should be closely monitored in order to facilitate interventions, which could alleviate the adverse health consequences of this syndrome.

Topics: Adult; Antipsychotic Agents; Chi-Square Distribution; Clozapine; Female; Humans; Ireland; Logistic Models; Male; Metabolic Syndrome; Prevalence; Psychotic Disorders; Risk Factors

Topics: Adult; Antipsychotic Agents; Atorvastatin; Cholesterol; Clozapine; Female; Fenofibrate; Gemfibrozil; Heptanoic Acids; Humans; Hyperlipidemias; Hypolipidemic Agents; Lovastatin; Male; Middle Aged; Pravastatin; Psychotic Disorders; Pyrroles; Retrospective Studies; Schizophrenia; Treatment Outcome; Triglycerides

The purpose of this study was to estimate the effect sizes of drug interactions on plasma clozapine concentrations, adjusting for potentially confounding factors such as smoking.. The estimation was performed by using a mixed model, and a combination of unpublished (N=83) and published (N=172) data that included patients taking phenobarbital, valproic acid, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram and reboxetine, and patients not taking co-medications.. The 255 patients provided a total of 415 steady-state trough plasma clozapine concentrations. Each patient provided 1 to 15 measures of plasma clozapine concentrations. Total plasma clozapine concentration, defined as the sum of plasma clozapine and norclozapine concentrations, was also investigated. A random intercept linear model of the natural log of plasma clozapine concentration with the natural log of dose and other variables as independent variables was built. The model confirmed that phenobarbital induces clozapine metabolism (effect size, E=-28%), and that fluoxetine (E=+42%), fluvoxamine (E=+263%) and paroxetine (E=+30%) inhibit it. Valproic acid appeared to inhibit clozapine metabolism in non-smokers (effect size, E=+16%), whereas it appeared to induce clozapine metabolism in smokers (E=-22%). The effect sizes of smoking on plasma clozapine concentration were -20% in patients not taking valproic acid, and -46% in patients taking valproic acid. Thus, smoking induces clozapine metabolism, and this induction may be stronger when the patient is taking valproic acid. The effect sizes allowed the computation of clozapine dose-correction factors for phenobarbital, 1.4 [95% confidence interval, CI, (1.1, 1.7)]; paroxetine, 0.77 (0.67, 0.89); fluoxetine, 0.70 (0.64, 0.78); fluvoxamine, 0.28 (0.22, 0.35); and valproic acid [0.86 (0.75, 1.0) in non-smokers, and 1.3 (0.96, 1.73) in smokers]. Sertraline, reboxetine and citalopram had no obvious effects.. The results for total plasma clozapine concentrations are similar to those for plasma clozapine concentrations. The main limitations of this study were that the computed effect sizes reflect only the doses and treatment-durations of the co-medications studied, and that the substantial "noise" of the clinical environment may make it difficult to detect the effects of some variables, particularly those with small effect sizes. Gender was not significant probably due to its relatively small effect size in the studied population, and age was not significant probably due to the limited age variability.. This article contributes to the clozapine literature by describing a possible interaction between taking valproic acid and smoking, which modifies plasma clozapine concentrations, by estimating the effect sizes of other compounds on plasma clozapine concentrations after correcting for confounders, and by providing dose-correction factors for clinicians.

Topics: Antipsychotic Agents; Clozapine; Confounding Factors, Epidemiologic; Female; Humans; Linear Models; Male; Psychotic Disorders; Reference Values; Weights and Measures

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Middle Aged; Psychotic Disorders; Serositis; Time Factors

The authors report an improvement in delusions and hallucinations after antidepressant treatment (Clomipramine) in a parkinsonian patient with psychosis and comorbid depression. Their findings, which support a previous case treated with Citalopram, highlight the possible effectiveness of antidepressant therapy on psychotic symptoms in parkinsonian patients.

Topics: Affect; Antidepressive Agents; Antidepressive Agents, Tricyclic; Antiparkinson Agents; Antipsychotic Agents; Clomipramine; Clozapine; Delusions; Depressive Disorder; Hallucinations; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Psychiatric Status Rating Scales; Psychotic Disorders

There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT(2) antagonist and as a partial agonist to dopamine D(2) and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D(2) and 5-HT(2) receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT(2) (64-79%), but minimal D(2) occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Avoidance Learning; Biomarkers; Brain; Brain Chemistry; Catalepsy; Clozapine; Dopamine Agonists; Drug Evaluation, Preclinical; Haloperidol; Male; Piperazines; Prolactin; Proto-Oncogene Proteins c-fos; Psychotic Disorders; Quinolones; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Serotonin Antagonists; Treatment Outcome

Significant weight gain is a serious side effect of many antipsychotic medications, yet successful strategies for significant weight loss are lacking. The transtheoretical model for weight management can be used to identify people who are ready to change (contemplation-preparation group) their eating habits and physical activity. This study compared characteristics of patients in Canada who had a psychotic disorder and were ready to make lifestyle changes with characteristics of patients who were not considering lifestyle changes.. Participants were surveyed to determine their stages of change for eating habits and physical activity, and various characteristics were measured, including body mass index, body image, nutritional intake, and level of physical activity.. A total of 101 participants (64 men) (mean+/-SD age 35+/-11 years) were taking antipsychotic medications. Seventy-one percent had schizophrenia spectrum disorders, and 15% had affective psychosis. The prevalence of patients identified as being ready for change was higher than expected: 68% for eating habits and 54% for physical activity. Participants who were ready to change eating habits were also ready to change physical activity habits (p<.04). Stages of change for eating habits were associated with body mass index (p<.004), whereas stages of change for physical activity were associated with self-reported vigorous (p<.001) and moderate (p<.005) physical activity but not mild physical activity.. Clinicians may help patients develop healthier eating and physical activity habits by using the transtheoretical model, because it identifies patients who are ready to change to healthier lifestyle strategies and may help patients with antipsychotic-induced weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise; Feeding Behavior; Female; Health Knowledge, Attitudes, Practice; Humans; Life Style; Male; Middle Aged; Nutrition Surveys; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Weight Gain

Topics: Anticonvulsants; Antipsychotic Agents; Blepharospasm; Blinking; Clonazepam; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Cataplexy; Clozapine; Electroencephalography; Eye Movements; Female; Humans; Psychotic Disorders

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

Topics: Acute Disease; Adult; Antipsychotic Agents; Ascites; Chemical and Drug Induced Liver Injury; Clozapine; Female; Humans; Pleurisy; Psychotic Disorders; Serositis

There is a paucity of empirical support for polypharmacy with second generation (atypical) antipsychotics (SGAs), especially in understudied populations.. To investigate the frequency, effectiveness, and safety of this practice in patients with severe and persistent mental illness who are chronically hospitalized.. A chart review was conducted at a state psychiatric hospital in Syracuse, NY. The study subjects (N=26) were chronically hospitalized individuals with DSM-IV diagnoses of schizophrenia or schizoaffective disorder who were initially prescribed at least one SGA and then received at least one other SGA during the study period. Demographic and clinical data were collected. Baseline and 6-month assessments were compared for statistical significance (p<0.05).. Of the 117 chronically hospitalized inpatients at the study center, 22.2% (N=26) received treatment regimens involving polypharmacy with SGAs. These patients as a group achieved statistically significant reductions on their scores on the Brief Psychiatric Rating Scale (34.2 +/- 11.0 compared with 25.3 +/- 11.8; p=0.016) and the Clinical Global Impressions-Improvement Scale (5.5 +/- 0.6 compared with. 5.0 +/- 0.8; p=0.016) at 6 months. There was a significant decrease in the use of prn medications (7.6 +/- 19.6 compared with 1.6 +/- 2.6; p<0.04). However, the number of patients receiving anticholinergic medications increased from 5 to 8 (p<0.04).. Polypharmacy with SGAs is quite frequent among chronic inpatients with severe and persistent mental illness despite a limited empirical database supporting its use. The results of our pilot study do not demonstrate the effectiveness and safety of this practice. However, methodological shortcomings may have contributed to our failure to detect a true, positive effect. Controlled studies are needed to accurately determine the risks and benefits of SGA polypharmacy.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Cholinergic Antagonists; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Neurologic Examination; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Up to now direct toxic effects or immunological processes have been said to explain clozapine-induced agranulocytosis. However, more recent studies may suggest that not yet metabolized clozapine is taken up by leukocytes and transformed by oxidative processes to apoptosis-inducing metabolites. To verify this hypothesis the concentrations of clozapine were measured in the plasma and the leukocytes of a patient receiving clozapine who developed clozapine-induced leukocytopenia and in 10 patients receiving clozapine who did not show any serious adverse side effects. The patient who developed leukocytopenia showed clozapine concentrations in the leukocytes that were about 8 times higher than the mean clozapine concentrations in the leukocytes in the group of 10 patients receiving clozapine with no changes in the leukocyte count in the history. However, no major difference was found in the clozapine plasma concentrations. The results may suggest that patients at risk of developing clozapine-induced leukocytopenia show increased clozapine concentrations in the leukocytes although the clozapine plasma concentration is in the therapeutic range. It is assumed that changes or abnormalities of clozapine uptake at the cell membrane might play a role in the development of clozapine-induced leukocytopenia and/or agranulocytosis.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Leukocyte Count; Leukocytes; Leukopenia; Male; Middle Aged; Psychotic Disorders

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Piperazines; Psychotic Disorders; Quinolones; Treatment Outcome

Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, chi=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Schizophrenia; Sexual Dysfunction, Physiological; Sialorrhea

A case of acute myocarditis associated with the commencement of clozapine is described, highlighting the onset, course and possible contributing factors. There is an urgent need to raise awareness about this potentially fatal complication of clozapine use.. A 20-year-old male with schizophrenia developed a sudden onset of myocarditis after commencement of clozapine. The patient recovered with intensive medical support. The symptoms occurred around 2 weeks after starting clozapine in an inpatient setting. Possible contributing factors may have been concomitant antidepressant use and unaccustomed physical activity.. Myocarditis is an increasingly recognized complication associated with the use of clozapine. It can be fatal if not recognized and treated early. Considering that clozapine remains the gold standard in treatment of resistant psychosis, there is an urgent need to raise awareness among medical and paramedical staff involved in the care of these patients. There are also implications for recommendations and regulations regarding the use of clozapine.

Topics: Acute Disease; Adult; Antidepressive Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Fluoxetine; Humans; Lithium Compounds; Male; Myocarditis; Psychotic Disorders; Risk Factors

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Fluphenazine; Glycopyrrolate; Humans; Male; Muscarinic Antagonists; Psychotic Disorders; Sialorrhea; Valproic Acid

Although most patients treated for first-episode schizophrenia will experience considerable improvement with initial antipsychotic therapy, a subgroup experiences significant ongoing positive symptoms. Clozapine has unique efficacy in improving treatment-resistant patients with chronic schizophrenia, but its role in the treatment of first-episode patients remains unclear. A standardized treatment algorithm was implemented in our First Episode Psychosis Program, with patients receiving 2 trials with 2 second-generation antipsychotics (olanzapine, quetiapine, or risperidone at low, medium, and high doses), followed by a trial of clozapine as early as 25 weeks into the start of their treatment. Patients progress along the algorithm according to their response as defined by clinical rating scales. To date, 123 patients with first-episode schizophrenia have been treated according to the algorithm. Of these, 93 (76%) responded to the first trial of an antipsychotic. Only 7 (23%) of the remaining 30 patients responded to a second antipsychotic trial; 13 of the remaining 23 individuals agreed to a trial of clozapine. We compared the clozapine-treated group with a group of 9 patients who refused clozapine and chose to continue the same antipsychotic treatment as before. Subjects who received clozapine experienced a mean Brief Psychiatric Rating Scale change of 19 points (from 53.5 to 34.5) and a change in the Clinical Global Inventory severity rating from 5.4 to 3.5 (from severely ill to mildly ill); those who refused clozapine had a 2-point increase in mean Brief Psychiatric Rating Scale (from 53 to 55) and a 0.6-point increase in the mean Clinical Global Inventory severity rating from 5.4 to 6 (remaining markedly to severely ill). In clinical practice, there is a hesitancy to switch individuals to clozapine given its side effect profile and position as treatment of "last resort." The present findings suggest that clozapine may have an important role in the early treatment of first-episode patients whose psychosis does not remit with other second-generation antipsychotics during the first months of treatment.

Topics: Adolescent; Adult; Algorithms; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Resistance; Female; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

To study the prescribing practices of atypical antipsychotic drugs in French psychiatric hospitals.. A 1-day cross-sectional observational survey was performed in seven psychiatric hospitals to study prescribing practices of the four atypical antipsychotics (AAP) marketed in France. These hospitals are members of the PIC network, a pharmacists' working group based in southwestern France.. Type and dosages of prescribed atypical antipsychotics, indication and concomitant prescriptions.. The study included 1475 adult inpatients' prescriptions with an antipsychotic drug; 647 prescriptions included an AAP with risperidone and olanzapine accounting for about 70% cases. AAP prescriptions concerned psychotic patients in 65% of cases. Patients receiving an AAP in this indication were more likely to be male, were younger, and received higher daily doses than patients treated for other troubles. They were also more likely to receive associated neuroleptic and anticholinergic antiparkinsonian agents. There were 59 prescriptions (9.1%) for bipolar disorders. Clozapine wasn't used in this indication. In 76.3% of cases, mood stabilizers were associated to the AAP prescribed in this indication.. This observational survey underlines the significant place taken by AAP for the treatment of psychiatric diseases in hospital prescribing practices. They show usage patterns of these drugs: dose, indications and concomitant medications, in line or not with current recommendations and reference guidelines. In bipolar disorders, AAPs seem more likely to be associated to an ongoing therapy using mood stabilizer than to replace it.

Topics: Adult; Age Factors; Amisulpride; Antimanic Agents; Antiparkinson Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; France; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Practice Patterns, Physicians'; Psychotic Disorders; Risperidone; Sex Factors; Sulpiride

The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10-12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20-40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D(2) receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed "the Youdim factor", directing a DA-NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Brain Chemistry; Catecholamines; Clozapine; Denervation; Dopamine; Dopamine Agents; Female; Haloperidol; Iron; Iron Overload; Levodopa; Male; Mice; Mice, Inbred C57BL; Motor Activity; Movement Disorders; MPTP Poisoning; Norepinephrine; Pregnancy; Psychotic Disorders; Signal Transduction; Weight Gain

A 25-year-old woman, known to have schizoaffective disorder, presented with symptoms that had arisen a few weeks earlier. The symptoms indicated that she had a toxic clozapine blood level. The probable cause of the toxicity was a pharmacokinetic interaction between citalopram and clozapine at the level of the cytochrome P450 system. A literature search reveals the importance of monitoring the interactions between selective serotonin reuptake inhibitors and clozapine, a procedure which should, if possible, be accompanied by blood level measurements. Caution is called for, particularly when non-smokers are involved.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Enzyme Inhibitors; Female; Humans; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors

Topics: Adult; Aged; Canada; Clozapine; Drug Monitoring; Drugs, Generic; Female; Humans; Male; Middle Aged; Psychotic Disorders; Research Design

Recently, there has been an increased recognition of the association of clozapine with myocarditis and myocardiopathy. Commonly used diagnostic tests have very limited sensitivity in diagnosing this potentially life-threatening complication. We present 3 case reports of clozapine-induced myocarditis/cardiomyopathy that illustrate the development of a combined approach involving a clinical questionnaire and diagnostic testing at our hospital. This combination approach helped in the early recognition and successful treatment of clozapine myocarditis in one of our patients. Given the increasing recognition of this adverse reaction, we felt it timely to report our experience in diagnosing and treating this clinical syndrome.

Topics: Adult; Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug Monitoring; Female; Hospitals, University; Humans; Male; Middle Aged; Myocarditis; Psychotic Disorders; Surveys and Questionnaires

Fifty-six patients (mean age 21,5+/-0,4 years) with first episode of endogenous psychosis (ICD-10 diagnosis F20.0, F20.2, F25) were studied before and after 4 and 8 weeks of the treatment with haloperidol and clozapine. The level of interleukin-1beta (IL-1beta) production increased significantly (p<0,05) in responders in the total group compared to the control one before and after the treatment. In patients with the prevalence of catatonic and catatonic-hallucinatory-delusion disorders, the increase of IL-1beta production was significant only to the 4-8 week of treatment. The increased level of cytokine production in patients with the prevalence of delusion and hallucinatory-delusion disorders reached a significance level (p<0,01) only in responders at all stages of the study. In non-responders, this index was similar to normal but significantly differed as compared to the subgroup of responders (p<0,05). In patients with affective and delusion disorders, the level of IL-1beta production did not differ from the controls during the treatment. In conclusion, the therapy proved more effective in patients with higher levels of IL-1beta production that suggests this index as a marker of immune system activation and a predictor of therapeutic efficacy.

Topics: Adolescent; Adult; Antipsychotic Agents; Biomarkers; Clozapine; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Haloperidol; Humans; Interleukin-1beta; Male; Psychotic Disorders; Retrospective Studies; Severity of Illness Index; Treatment Outcome

We studied a sample of schizophrenia out-patients to test the hypotheses that serum homocysteine concentrations would correlate positively with measures of glucose metabolism.. Subjects underwent a nutritional assessment and fasting plasma, serum insulin and homocysteine tests.. Males had a significantly higher homocysteine levels than females (7.69 +/- 1.42 microM vs. 6.63 +/- 1.40 microM; P = 0.02). Comparing subjects with normal fasting glucose (NFG) (glucose < 100 mg/dl) and impaired fasting glucose (IFG) (> or = 100 mg/dl) subjects with IFG (mean 8.2 +/- 1.5 microM) had significantly higher homocysteine levels than those with NFG (mean 7.2 +/- 1.4 microM, P = 0.03). IFG was also associated with greater mean values for a Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) (P = 0.002) and diastolic blood pressure (P = 0.045).. The group with IFG had higher fasting serum homocysteine concentrations than those with NFG which supports a connection to an important cardiovascular risk factor.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Chronic Disease; Clozapine; Community Mental Health Centers; Female; Folic Acid; Homeostasis; Homocysteine; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Nutrition Assessment; Olanzapine; Prediabetic State; Psychotic Disorders; Reference Values; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Statistics as Topic; Waist-Hip Ratio

To determine whether atypical antipsychotic polytherapy is a risk factor for drug treatment for extrapyramidal side-effects (anti-EPS drugs) and whether the risk is attributable to antipsychotic dose.. We studied Iowa Medicaid beneficiaries aged 18-64 years with an active atypical and no conventional antipsychotic on January 1, 2001. The association of atypical antipsychotic polytherapy with anti-EPS drug treatment was determined. Multiple logistic regression was utilized to adjust for covariates in two models, the first adjusting for age, sex and the specific antipsychotic(s) prescribed, and the second also adjusting for doses.. Among 4400 patients, the unadjusted odds of anti-EPS treatment were increased two-fold with polytherapy. Polytherapy remained a risk factor in the first model (OR 1.5, 95% CI 1.1-2.0), but not after adjusting for doses (OR 1.0, 95% CI 0.7-1.4).. Atypical antipsychotic polytherapy is a risk factor for anti-EPS drug treatment, apparently because of higher cumulative doses.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Cross-Sectional Studies; Delayed-Action Preparations; Dibenzothiazepines; Drug Therapy, Combination; Female; Humans; Iowa; Male; Mathematical Computing; Medicaid; Middle Aged; Models, Statistical; Olanzapine; Product Surveillance, Postmarketing; Psychotic Disorders; Quetiapine Fumarate; Regression Analysis; Risk Factors; Risperidone; Statistics as Topic

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Myocarditis; Psychotic Disorders

Massive elevations of serum creatine kinase (CK) can occur in a significant number of patients treated with neuroleptics in the absence of neuroleptic malignant syndrome (NMS). We report two cases of CK-elevations associated with quetiapine treatment, which disappeared after drug discontinuation. To our knowledge, case number one is the first case of quetiapine-induced CK elevation in a neuroleptic-naïve patient. We thus suggest CK assessment when myalgia occurs with neuroleptic treatment.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Creatine Kinase; Depressive Disorder, Major; Dibenzothiazepines; Humans; Male; Mianserin; Mirtazapine; Olanzapine; Pain; Psychotic Disorders; Quetiapine Fumarate

Topics: Atomoxetine Hydrochloride; Clozapine; Depressive Disorder, Major; Drug Therapy, Combination; Female; Humans; Middle Aged; Nortriptyline; Propylamines; Psychotic Disorders; Recurrence; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index

A substantial number of patients treated with clozapine shows insufficient response. The author presents the results of adding aripiprazole in patients resistant to clozapine.. Three cases of individuals with psychotic symptoms despite clozapine use and with significant side effects that were treated via this combination are presented. Response was evaluated by clinical assessment.. Good clinical results were obtained in all three patients, with improvement of psychotic symptoms and of some of the side effects of clozapine.. The findings from this case series suggest that adjunctive therapy with aripiprazole can be of benefit for treating clozapine resistant schizophrenic patients.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Male; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Quinolones; Schizophrenia, Disorganized; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Quinolones; Schizophrenia; Schizophrenia, Paranoid; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Health Knowledge, Attitudes, Practice; Humans; Leukocyte Count; Male; Mental Recall; Middle Aged; Patient Education as Topic; Psychotic Disorders; Risk; Schizophrenia; Schizophrenic Psychology

Previous correlational research with schizophrenic patients has suggested that the second-generation antipsychotic medication clozapine helps to induce remissions of substance use disorder in patients with co-occurring psychosis and substance abuse. This research, however, could be biased by selection factors. Studying patients who are currently in substance abuse remission could control for level of motivation to stop using substances and other methodological confounds.. To test whether clozapine was associated with prevention of substance abuse relapses, we examined patients with schizophrenia or schizoaffective disorder who were in their first 6-month remission of substance use disorder during a prospective 10-year follow-up study. All patients received yearly multimodal assessments of substance use. Antipsychotic medications were prescribed by community doctors as part of usual clinical care.. Patients using clozapine at the first 6-month period of substance abuse remission (n = 25) were much less likely to relapse over the next year compared with those on other antipsychotic medications (n = 70): 8.0% vs 40.0%, chi(2) = 8.73 (df = 1), P = .003. Although medication assignment was not randomized, several potential confounders were similar between the groups.. Clozapine should be considered for the treatment of patients with schizophrenia and co-occurring substance use disorder to prevent relapses to substance abuse.

Topics: Adult; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Dual (Psychiatry); Female; Follow-Up Studies; Humans; Male; New Hampshire; Prospective Studies; Psychotic Disorders; Recurrence; Remission Induction; Schizophrenia; Substance-Related Disorders

This study compared the prevalence of the metabolic syndrome among outpatients with schizophrenia and schizoaffective disorder receiving clozapine with a matched comparison group from the National Health and Nutrition Examination Survey.. Ninety-three outpatients and a matched group of 2,701 comparison subjects were compared according to National Cholesterol Education Program criteria. Outpatient data were obtained through physical assessments, laboratory testing, and reviews of medical records.. The prevalence of the metabolic syndrome was significantly higher among clozapine patients (53.8%) than among the comparison group (20.7%). For clozapine patients, logistic regression analysis revealed significant associations with age, body mass index, and duration of clozapine treatment. Only age and body mass index were associated with the prevalence of metabolic syndrome in both groups.. Patients receiving clozapine are at significantly increased risk for developing the metabolic syndrome. Psychiatrists and other providers should consider performing regular physical health monitoring to prevent long-term adverse health consequences.

Topics: Adolescent; Adult; Age Factors; Ambulatory Care; Antipsychotic Agents; Body Mass Index; Clozapine; Female; Humans; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Nutrition Surveys; Prevalence; Psychotic Disorders; Risk Factors; Schizophrenia

To report the findings of a switch from brand-name to generic clozapine in a Canadian outpatient population.. The medical records of 58 outpatients diagnosed with schizophrenia and other psychotic disorders and stabilized on brand-name clozapine therapy were reviewed retrospectively. Patients were switched from brand-name to generic clozapine on their next dispensing supply after September 29, 2003. Data regarding clozapine dose regimens, physicians' visits, hospitalizations, and adverse events were collected from the patients' charts for the 6 months preceding and the 6 months after the switch from brand-name to generic clozapine. Relevant measurement changes in those data associated with the switch are evaluated.. No significant changes in dose, number of physician's visits, or hospitalization rates were observed as a consequence of the switch from brand-name to generic clozapine. In addition, there were no reported increases in the frequency of the most common adverse events, including decreases in white blood cell counts. None of the patients received a "nonrechallengeable" status, and no discontinuation of clozapine therapy occurred for any reason (toxicity or treatment failure) in the 6 months after the formulation switch.. In the current outpatient population, retrospective evaluation of the conversion from brand-name clozapine to the first generic alternative available on the Canadian market did not reveal any significant treatment changes.

Topics: Adult; Aged; Agranulocytosis; Ambulatory Care; Canada; Clozapine; Drug Administration Schedule; Drugs, Generic; Evaluation Studies as Topic; Female; Follow-Up Studies; Hospitalization; Humans; Legislation, Drug; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

A man affected by schizoaffective disorder and alcohol abuse presented priapism after eleven years of clozapine treatment. After surgical intervention and resolution of priapism, he continued clozapine treatment at the same dose without problems. Clozapine withdrawal is not mandatory in patients who develop priapism in the course of treatment.

Topics: Adult; Alcoholism; Antipsychotic Agents; Clozapine; Humans; Male; Priapism; Psychotic Disorders; Treatment Outcome

The aims of our study were (1) to compare the dose of clozapine needed to achieve remission in patients who stopped their treatment (study group) versus patients who continued taking this medication (control group) and (2) to compare the clinical characteristics of remission between these 2 groups.. We retrospectively reviewed the medical records of all treatment-resistant schizophrenic and schizoaffective patients (according to DSM-IV criteria) who were treated with clozapine over a period of 9 years, from January 1995 through December 2003. The study group consisted of 43 patients and the control group of 12 patients. All patients' files from both groups were examined, and each patient's remission was scored twice--initially on discharge from the hospital and subsequently after final discharge for the study group, or at the end of the study for the control group.. The change of clozapine dose from the first to the last remission expressed by percentage shows a significant difference between the 43% increase in clozapine dose in the study group and the 12.5% decrease in clozapine dose in the control group (p < .001). Quality of remission assessment showed deterioration in the global remission score in the study group, while the quality of remission assessment in the control group did not show any change.. Our findings suggest that the discontinuation of clozapine treatment leads to a deterioration in the quality of remission, with a need for an increased dose of clozapine. Further prospective studies on larger samples are needed to confirm these findings.

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Dropouts; Prognosis; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Neutropenia; Psychotic Disorders; Time Factors

This study aimed to assess racial differences in clozapine prescribing, dosing, symptom presentation and response, and hospitalization status. This study extends previous studies of clozapine by examining patient- and treatment-related factors that may help explain or eliminate reasons for differential prescribing.. Clozapine records for 373 white and African American patients with schizophrenia or schizoaffective disorder treated between March 1, 1994, and December 31, 2000, in inpatient mental health facilities in the state of Maryland were examined. Records for this study were derived from 3 state of Maryland databases: the Clozapine Authorization and Monitoring Program, the State of Maryland Antipsychotic Database, and the Health Maintenance Information System Database.. A total of 10.3% of African Americans (150/1458) with schizophrenia received clozapine treatment compared with 15.3% of whites (223/1453) (chi2 = 16.74, df = 1, p < .001) during inpatient treatment in the public mental health system in Maryland. Clozapine doses were lower in African Americans relative to whites (385.3 +/- 200.6 vs. 447.3 +/- 230.3 mg/day) (t = -2.66, df = 366, p = .008). At the time of clozapine initiation, whites had more activating symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) (t = -3.98, df = 301, p < .0001); however, African Americans had significantly greater improvements in BPRS total symptoms (F = 4.80, df = 301, p = .03) and in anxiety/ depressive symptoms during 1 year of treatment with clozapine (F = 10.04, df = 303, p = .002). The estimated rate of hospital discharge was not significantly different for African Americans compared to whites prescribed clozapine (log-rank chi2 = 0.523, df = 1, p = .470); however, African Americans were more likely than whites to discontinue clozapine during hospitalization (log-rank chi2 = 4.19, df = 1, p = .041).. Our data suggest underutilization of clozapine in African American populations. This racial disparity in clozapine treatment is of special concern because of the favorable outcomes associated with clozapine in treatment-resistant schizophrenia and in the specific benefits observed in African American patients. More research is needed to determine why disparities with clozapine treatment occur and why African Americans may be discontinued from clozapine at a higher rate, despite potential indicators of equal or greater effectiveness among African Americans compared with whites.

Topics: Antipsychotic Agents; Black or African American; Clozapine; Community Mental Health Centers; Drug Administration Schedule; Drug Utilization; Humans; Maryland; Psychotic Disorders; Public Health Practice; Schizophrenia; White People

The assessment, in terms of safety and efficacy, of augmenting clozapine monotherapy, as well as combined psychopharmacotherapy involving clozapine, with electroconvulsive therapy (ECT).. Reviewed were the charts of patients who received clozapine-ECT treatment in the Department of Psychiatry and Psychotherapy of Semmelweis University between November 1999 and December 2003.. During the studied period there were altogether 43 patients treated with the combination of clozapine and electroconvulsive therapy. In the schizoaffective group, the values for post-electroconvulsive therapy CGI were significantly lower than either in the catatonic (Z=-3.72, p<0.01) or in the hebephrenic (Z=-3.17, p<0.01) group. Among the groups created on the basis of the number of augmentation strategies utilized, the clozapine+3 group consisted of patients significantly older than the clozapine+ 1 group (Z=2.45, p=0.01). In the clozapine monotherapy group, the values for post-electroconvulsive therapy CGI were significantly lower than in any of the groups that had received a combination of augmentations (monotherapy-1 augmentation: Z=-3.01, p<0.01; monotherapy-2 augmentation: Z=-2.89, p<0.01; monotherapy-3 augmentation: Z=-2.41, p=0.01).. According to our examinations, the augmentation of clozapine treatment with electroconvulsive therapy should be tried primarily on schizoaffective patients, in case the clozapine monotherapy is ineffective. The simultaneous use of different augmentation strategies is expected to increase only the side effects not the efficacy of the treatment.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Drug Therapy, Combination; Electroconvulsive Therapy; Female; Humans; Male; Medical Records; Middle Aged; Psychotic Disorders; Research Design; Retrospective Studies; Schizophrenia; Treatment Outcome

To determine whether psychiatrically stable patients with a history of drug-induced psychosis could be successfully weaned off their antipsychotic drug, we offered consecutive Parkinson disease (PD) patients on quetiapine or clozapine, who were free of any on-going psychosis, to be slowly weaned off their antipsychotic drug. Before the study was aborted 6 PD patients (mean age, 78 years) with an average antipsychotic exposure of 20 months (5 on quetiapine, 1 on clozapine) were enrolled. After the antipsychotic agent was discontinued, psychosis recurred in 5 of 6 patients. In 3 patients the "rebound psychosis" was worse than the original psychotic episode and required subsequent higher antipsychotic medication doses.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Female; Humans; Male; Parkinson Disease; Prospective Studies; Psychotic Disorders; Quetiapine Fumarate; Recurrence; Time Factors

The atypical antipsychotic clozapine has been reported to be associated with metabolic adverse effects, including type-2 diabetes mellitus. We present two cases of diabetes mellitus associated with clozapine treatment. One case resolved entirely upon withdrawal of the drug, whereas the other did not. We discuss the molecular basis of the diabetogenic action of clozapine and recommendations for monitoring.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Monitoring, Physiologic; Psychotic Disorders; Schizophrenia, Paranoid

Clozapine is an atypical antipsychotic known to cause considerable weight gain. The extent to which genetic factors determine weight gain is unknown. Here we report on a pair of female monozygotic twins concordant for schizophrenia and mild mental retardation who were treated with clozapine over 5.5 years. One twin gained a total of 53.1 kg and had a weight of 107.5 kg (BMI=38.1 kg/m2) at the end of the observation period. The other twin gained a total of 48.2 kg and finally had a weight of 100.4 kg (BMI=33.8 kg/m2). Because both patients experienced considerable weight gain during treatment, our observation suggests that the antipsychotic-induced weight gain is under strong genetic control.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Intellectual Disability; Psychotic Disorders; Schizophrenia; Twins, Monozygotic; Weight Gain

Topics: Antipsychotic Agents; Clozapine; Dibenzothiazepines; Humans; Parkinson Disease; Psychoses, Substance-Induced; Psychotic Disorders; Quetiapine Fumarate

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Humans; Piperazines; Psychotic Disorders; Quinolones; Treatment Outcome

To report a case of severe and sustained tachycardia that developed asymptomatically on a low dose of clozapine (150 mg daily).. Case report.. Serially monitored 24 h heart rate after the introduction of clozapine showed an increase in the 24 h mean from 87 to 126 bpm, a reduction of pulse variability and anomalies in sleep-wake regulation. Cessation of clozapine was followed by a rapid return to preclozapine activity. Application of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship between clozapine and the sustained tachycardia.. Severe and sustained tachycardia can develop asymptomatically with a relatively low dose of clozapine and a slow titration rate. The severity of the tachycardia may not be revealed in isolated pulse measurements and may escape clinical detection without closer monitoring of heart rate.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Electrocardiography; Humans; Psychotic Disorders; Severity of Illness Index; Sleep Disorders, Circadian Rhythm; Tachycardia

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Galactorrhea; Haloperidol; Humans; Psychotic Disorders

The danger of severe haematological abnormalities limits the use of clozapine in the treatment of psychoses. The development of modern second generation antipsychotics such as olanzapine, risperidone, quetiapine, amisulpride, ziprasidone or aripiprazol, however, makes it possible to use the positive effects of this class of drugs without the risks of a clozapine treatment. Nevertheless, there are several case reports about severe haematological abnormalities even during treatment with these second generation antipsychotics. This review summarises recently published cases and discusses the consequences for the daily clinical work.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Leukocyte Count; Leukopenia; Male; Psychotic Disorders; Risk Factors

Clozapine is licensed for the treatment of psychotic illnesses resistant to other antipsychotic medications. Velo-cardio-facial syndrome (VCFS) is associated with a vulnerability to psychotic illness that may be resistant to treatment with conventional typical and atypical antipsychotics.. A 32-year-old man with intellectual disability (ID) and a long history of treatment-resistant psychosis was found to have VCFS. Treatment with typical antipsychotic drugs and with one atypical olanzapine produced no improvement.. Treatment with clozapine produced an improvement in psychotic symptoms and associated behavioural abnormalities, but caused hypersalivation, constipation and a seizure disorder. The latter led to two fractures, one requiring surgery. The addition of sodium valproate stopped seizures.. Clozapine may improve psychotic symptoms for people with ID associated with VCFS, but clinicians should be alert for potential adverse effects.

Topics: Abnormalities, Multiple; Adult; Antipsychotic Agents; Cleft Palate; Clozapine; Face; Genetics, Behavioral; Heart Defects, Congenital; Humans; Intellectual Disability; Male; Psychotic Disorders; Syndrome

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.

Topics: Adult; Aged; Amantadine; Antiparkinson Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesias; Endpoint Determination; Female; Germany; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease; Pergolide; Psychotic Disorders; Retrospective Studies

Treatment with antipsychotic drugs has been associated with increased risk for developing diabetes mellitus. Recent consensus statements suggest that clozapine may pose an especially high risk. The purpose of this study is to examine the prevalence and clinical-demographic correlates of diabetes among outpatients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder receiving clozapine.. One hundred one outpatients receiving clozapine at the University of Rochester Department of Psychiatry, Rochester, N.Y., were evaluated between September 2002 and September 2003. Demographic data were collected from medical records, and body mass index (BMI) and body fat measurements were conducted. Diagnosis of diabetes was established through review of medical records and fasting blood glucose testing. Associations between clinical and demographic variables and diabetes were examined using t tests, Fisher exact tests, and logistic regression.. Mean (SD) age of patients was 40.4 (9.5) years, and 79% were white. Mean (SD) dose and duration of clozapine treatment were 426 (164) mg/day and 5.7 (3.6) years, respectively. Point prevalence of diabetes was 25.7%. Mean (SD) BMI was 32.6 (8.0) kg/m(2), and mean (SD) body fat was 34.0% (11.0%). Logistic regression revealed significant associations between diabetes and nonwhite race/ethnicity and family history of diabetes (p = .02 and .002, respectively). No significant associations were found between diabetes prevalence and BMI or body fat.. Patients receiving clozapine are at substantial risk for developing diabetes, although the level of risk relative to other antipsychotic medications has not been fully determined. Clinicians should monitor all severely mentally ill patients receiving antipsychotic drugs for diabetes, with closer monitoring of patients with established demographic risk factors.

Topics: Adipose Tissue; Adolescent; Adult; Ambulatory Care; Antipsychotic Agents; Blood Glucose; Body Mass Index; Clozapine; Diabetes Mellitus; Diagnostic and Statistical Manual of Mental Disorders; Drug Administration Schedule; Female; Humans; Male; Middle Aged; New York; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Risk Factors; Schizophrenia; Sex Factors

Clozapine, an atypical antipsychotic, depends mainly on cytochrome P4501A2 (CYP1A2) for its metabolic clearance. CYP1A2 is inducible by smoking, and lower plasma concentrations of clozapine are measured in smokers than in nonsmokers. Case reports have been published on the effects of discontinuing smoking in patients receiving clozapine, which might lead to elevated plasma concentrations and severe side effects. We present 2 cases on the consequences of smoking cessation in patients receiving this drug. In the first patient, smoking cessation resulted, within 2 weeks, in severe sedation and fatigue, with an approximately 3-fold increase of plasma clozapine concentrations. In the second patient, a very high plasma concentration of clozapine (3004 ng/mL) was measured 6 days following a 16-day stay in a general hospital, during which smoking was prohibited. In the latter patient, the replacement of omeprazole, a strong CYP1A2 inducer, by pantoprazole, a weaker CYP1A2 inducer, could have contributed, in addition to smoking cessation, to the observed strong increase of plasma clozapine concentrations. Genotyping of the 2 patients revealed that they were carriers of the AA genotype for the -164C>A polymorphism (CYP1A2*1F) in intron 1 of CYP1A2 gene, which has previously been shown to confer a high inducibility of CYP1A2 by smoking. Thus, at the initiation of clozapine treatment, smoking patients should be informed that, if they decide to stop smoking, they are encouraged to do so but must inform their prescriber beforehand. Also, because of the increased use of no-smoking policies in many hospitals, studies examining the consequences of such policies on the pharmacokinetics/pharmacodynamics of drugs metabolized by CYP1A2, taking into account different CYP1A2 genotypes, are needed.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Fatigue; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia, Paranoid; Smoking Cessation; Treatment Outcome

To report a case of severe clozapine-induced hypercholesterolemia and hypertriglyceridemia that resolved after therapy was switched to aripiprazole.. A 42-year-old white man with schizoaffective disorder experienced new-onset hyperlipidemia with the addition of clozapine therapy. Despite treatment with various antihyperlipidemic agents, his total cholesterol level reached 477 mg/dL and his triglyceride level reached 4758 mg/dL. After a decrease in adherence with clozapine and subsequent deterioration, the patient was hospitalized and his antipsychotic therapy was switched to aripiprazole. The patient's lipid levels improved dramatically to the point that antihyperlipidemic treatment was discontinued. Due to lack of adequate symptomatic relief of psychiatric symptoms, the patient was ultimately switched back to clozapine therapy, at which time his lipid levels started to worsen again.. There is a critical scarcity of data that relate to aripiprazole-induced lipid changes. Some studies have suggested that aripiprazole is not associated with the development of hyperlipidemia. Our case indicates that aripiprazole therapy may not have an adverse effect on lipid levels, even in patients who have a history of hyperlipidemia induced by another atypical antipsychotic.. Should aripiprazole be found to have a definitive lipid-neutral effect, then clinicians would be wise to factor this finding into overall benefit-versus-risk considerations in the antipsychotic treatment selection process, especially in a society in which cardiovascular disease continues to be a principal cause of morbidity and mortality.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Cholesterol; Clozapine; Humans; Hypercholesterolemia; Hyperlipidemias; Male; Piperazines; Psychotic Disorders; Quinolones

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Drug Therapy, Combination; Female; Humans; Lamotrigine; Lithium Carbonate; Magnetic Resonance Imaging; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Triazines; Valproic Acid

There are few real life independent comparative studies of atypical antipsychotics. We prospectively examined five commonly used atypical antipychotics in the UK, without support from the pharmaceutical industry.. Prospective naturalistic systematic clinical evaluation. Patients being newly prescribed atypical anti-psychotics over a one year period were assessed by psychiatrists at initiation and after six months treatment using five outcome measures: clinical global impression; positive and negative psychotic symptoms; drug related side effects; and quality of life.. 373 patients participated in total. Olanzapine and risperidone produced statistically significant reductions in all ratings at six months. Amisulpride, clozapine, and quetiapine were also studied. There was limited variance between the different drugs, although some sample sizes were small.. Atypical anti-psychotics were found to be clinically effective, and produced similar outcomes. Routine monitoring of outcomes in psychiatry is feasible.

Topics: Adolescent; Adult; Aged; Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Patient Compliance; Probability; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Quality of Life; Quetiapine Fumarate; Risk Assessment; Risperidone; Severity of Illness Index; Statistics, Nonparametric; Sulpiride; Treatment Outcome

Topics: Adult; Anti-Anxiety Agents; Antiparkinson Agents; Antipsychotic Agents; Bromocriptine; Clozapine; Creatine Kinase; Dose-Response Relationship, Drug; Electroconvulsive Therapy; Haloperidol; Humans; Lorazepam; Male; Neuroleptic Malignant Syndrome; Psychotic Disorders; Schizophrenia; Substance Withdrawal Syndrome

To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine.. Clozapine treatment was administered in an open-label fashion using a flexible titration schedule, and data from weekly complete blood counts was obtained. The rate of neutropenia and agranulocytosis (HAEs) development was determined for 172 eligible patients (mean age at clozapine initiation, 15.03 +/- 2.13 years) with a median observation period of 8 months.. Neutropenia (absolute neutrophil count <1,500/mm) developed in 23 (13%) patients and agranulocytosis (absolute neutrophil count <500/mm) in one (0.6%) patient. The cumulative probability of developing an initial HAE at 1 year of clozapine treatment was 16.1% (95% confidence interval 9.7%-22.5%). Eleven (48%) of 24 patients who developed an HAE were successfully rechallenged on clozapine. Eight (5%) of 172 patients from this sample eventually discontinued clozapine because of an HAE (one agranulocytosis, seven neutropenia).. The occurrence of HAEs is a significant risk associated with the administration of clozapine. However, in this sample, few children actually discontinued therapy because of an HAE and the incidence of agranulocytosis does not appear higher than what has been reported in the adult literature.

Topics: Adolescent; Agranulocytosis; Antipsychotic Agents; Child; Clozapine; Cohort Studies; Female; Humans; Male; Neutropenia; Psychotic Disorders; Retrospective Studies

The goal of this 10-year naturalistic study was to examine, in clozapine-treated patients, the change in cardiovascular risk factors following clozapine initiation and the mortality estimates from cardiovascular disease.. Data were collected from medical records from January 1992 to December 2003 and included age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation for clozapine-treated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Clozapine dosage and laboratory results were recorded at 12-month intervals.. At the time of clozapine initiation, the mean +/-?SD age of the 96 patients studied was 36.5 +/- 7.9 years; 28% (N = 27) were women. The Kaplan-Meier estimate for 10-year mortality from cardiovascular disease was 9%. African American and Hispanic American patients exhibited elevated risk of cardiovascular disease-related mortality (odds ratio [OR] = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to white patients. Body mass index (BMI) significantly increased the odds ratio of mortality (OR = 1.2, p < .01). The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43%, and Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) patients showed elevated risks of developing diabetes mellitus compared to white patients. Additionally, BMI (OR = 1.11, p = .0006), total cholesterol level (OR = 1.006, p = .04), and serum triglyceride level (OR = 1.002, p = .04) modestly increased the odds ratio for the development of diabetes mellitus.. These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia.

Topics: Adult; Antipsychotic Agents; Black or African American; Cardiovascular Diseases; Cause of Death; Clozapine; Comorbidity; Diabetes Mellitus; Female; Hispanic or Latino; Humans; Hyperlipidemias; Longitudinal Studies; Male; Metabolic Syndrome; Psychotic Disorders; Risk Factors; Risperidone; Schizophrenia; Survival Analysis

Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric/behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an approximately 200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an approximately 200-kb region of human 22q11.2, containing CDCrel, GP1Bbeta, TBX1, and WDR14, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although Tbx1 has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency, Tbx1 heterozygous mice did not display these behavioral abnormalities. Our results show that the approximately 200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnormalities and suggest that distinct genetic components within 22q11.2 mediate physical and behavioral abnormalities.

Topics: Abnormalities, Multiple; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Chromosome Deletion; Chromosomes, Human, Pair 22; Clozapine; Disease Models, Animal; Female; Heterozygote; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Psychotic Disorders; Schizophrenia; Time Factors

Topics: Adult; Antipsychotic Agents; Case-Control Studies; Clozapine; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Psychotic Disorders; Risk Factors

Topics: Antipsychotic Agents; Clozapine; Hematoma, Subdural; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychiatric Status Rating Scales; Psychotic Disorders

The introduction of new antipsychotics has resulted in the availability of drugs with improved safety and tolerability as well as proven efficacy compared to the older antipsychotics. New compounds might show new or different adverse effects that arise in the post-marketing phase when a greater number of patients are treated. One goal of the drug safety program in psychiatry AMSP ( Arzneimittelsicherheit in der Psychiatrie) is the detection and description of severe, new, or rare adverse drug reactions (ADRs). Between 1993 and 2000, 122,562 patients were monitored in 35 psychiatric institutions, 86,349 patients of which received antipsychotics. Hyperglycemia related to antipsychotics was observed in association with only two compounds so far: clozapine and olanzapine (clozapine 2 cases, olanzapine 7 cases). In 6 of 9 patients, weight gain preceded hyperglycemia. The relative frequency of these adverse drug related events was 0.013 % for clozapine and 0.075 % for olanzapine. The symptomatology included reversible hyperglycemia, worsening of existing diabetes, and new-onset diabetes. Control for glycemic dysregulation should be maintained in clinical practice with these drugs.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Product Surveillance, Postmarketing; Prospective Studies; Psychotic Disorders; Retrospective Studies; Risk Factors

As a follow-up to our previous study of clozapine, medical records of a state psychiatric hospital were reviewed for patients who were prescribed an atypical antipsychotic. From that sample, demographic and clinical data were obtained for individuals with an initial score of 35 or greater on the Brief Psychiatric Rating Scale (BPRS), and at least two additional successive monthly BPRS ratings. A total of 100 patients met the criteria. Most received either olanzapine (46%) or risperidone (36%), with few administered quetiapine (11%) or clozapine (7%). Most also received adjunctive medications, including conventional antipsychotics, anticonvulsants/mood stabilizers, antidepressants, and antiparkinsonian agents. The number of patients whose BPRS total scores decreased by 20% or more from baseline was significantly greater for those who received olanzapine than those who received risperidone. However, there was no difference between the two antipsychotics in the number of patients who maintained that degree of improvement, in the average latency to achieve that decrease (1.67 and 1.47 months, respectively), or the average length of stay (LOS; 332 and 376 days, respectively). These results indicate a modest therapeutic advantage of olanzapine compared to risperidone, and a substantial degree of polypharmacy in the use of atypical antipsychotics. This uncontrolled "real-world" evaluation supports data from controlled clinical trials, showing that either risperidone or olanzapine would be a reasonable first choice in patients with treatment-resistant schizophrenia, with the decision based on the least adverse side effect profile and economic constraints. When compared to our previous clozapine study, we confirm a slight advantage for the effectiveness of clozapine in the treatment of this refractory population.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Female; Hospitals, Psychiatric; Hospitals, State; Humans; Length of Stay; Male; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Treatment Outcome

Clozapine has been linked to significant weight gain and increase in serum lipids and appears to negatively impact glucose metabolism. In this retrospective chart review study, we examine changes in systolic and diastolic blood pressure and treatment for hypertension in clozapine-treated patients.. Data on demographics and systolic and diastolic blood pressure were examined for up to 5 years (September 1987 to September 1992) in 82 patients treated with clozapine. Rates of hypertension treatment in clozapine-treated patients were compared with patients receiving conventional antipsychotics (N = 56) and other atypical antipsychotic agents (N = 102).. The mean age of the 82 patients at the time of clozapine initiation was 36.4 +/- 7.8 years, with 22 (27%) female, 75 (91%) white, 3 (4%) black, 3 (4%) Hispanic, and 1 (1%) Asian. The baseline weight was 175.5 +/- 34.0 lb (79.0 +/- 15.3 kg) and baseline body mass index was 26.9 +/- 5.0 kg/m(2). There was a significant increase in systolic blood pressure (p =.0004) and diastolic blood pressure (p =.0001). Overall, 22 patients (27%) received treatment for hypertension following clozapine initiation. Only 2 (4%) of 56 patients in the conventional antipsychotic group and 9 (9%) of 102 patients in the other atypical antipsychotic group (olanzapine, N = 6; risperidone, N = 3) received treatment for hypertension.. Our findings suggest that long-term clozapine treatment is associated with increased rates of hypertension, which may have a significant impact on medical morbidity and mortality.

Topics: Adult; Antihypertensive Agents; Antipsychotic Agents; Blood Pressure; Body Mass Index; Body Weight; Clozapine; Diastole; Female; Humans; Hypertension; Male; Medical Records; Psychotic Disorders; Retrospective Studies; Schizophrenia; Systole

This study investigates the efficacy of clozapine in treatment-resistant abused adolescents detained in a secure environment who present with chronic posttraumatic stress disorder and psychotic symptoms. All participants had received at least 2 trials of conventional neuroleptic medication prior to starting clozapine. Efficacy was assessed by using single case methodology across 6 participants employing predependent and postdependent measures of psychiatric symptoms and behavioral observations. Subjective self-reports were also sought after treatment had been established. Evaluation of the data suggests that 4 of the participants demonstrated substantial improvements in psychiatric symptoms and behavioral presentation once a therapeutic dose of clozapine had been achieved. Questionnaire responses from 5 participants indicated that clozapine treatment was associated with a reduction in hallucinatory experiences. The most troubling side effects were those of excessive salivation, dizziness, and weight gain. These findings indicate that clozapine may be effective in decreasing psychiatric symptoms and risk behaviors in traumatized adolescents presenting with psychotic symptoms.

Topics: Adolescent; Aggression; Antipsychotic Agents; Clozapine; Depressive Disorder; Female; Humans; Inpatients; Male; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Risk-Taking; Self-Injurious Behavior; Stress Disorders, Post-Traumatic

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.

Topics: Adult; Antipsychotic Agents; Caffeine; Chromatography, Gas; Clozapine; Cytochrome P-450 CYP1A2; DNA; Drug Resistance; Female; Genotype; Humans; Male; Mutation; Phenotype; Psychotic Disorders; Smoking; Treatment Outcome

To study the effect of the replacement of omeprazole by pantoprazole on clozapine metabolism in 13 psychiatric patients, who used both clozapine and omeprazole.. Retrospective study of the medical files.. In comparison to smokers, a significant rise of the serum clozapine levels was observed in all non-smoking patients, whilst the daily dose of clozapine remained unchanged. This effect was probably caused by the discontinuation of enzyme induction of the cytochrome P450 enzyme 1A2 by omeprazole in non-smokers, whereas CYP1A2 remained induced in patients who smoked.. Omeprazole only influenced clozapine metabolism in non-smokers. In none of the patients an adjustment of the clozapine dose was required.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Antipsychotic Agents; Benzimidazoles; Clozapine; Drug Interactions; Female; Humans; Long-Term Care; Male; Middle Aged; Omeprazole; Pantoprazole; Psychiatric Department, Hospital; Psychotic Disorders; Retrospective Studies; Smoking; Sulfoxides

A retrospective analysis was carried out on 39 parkinsonian patients on clozapine treatment >/=24 months for psychosis. The cohort had a mean age of 76 years and an average clozapine dose of 47 mg/day over 60 months of clozapine use. Of 39 patients, 13 (33%) patients were eventually admitted to nursing homes, 6 (46%) of whom died over a period of 5 years. The overall 5-year mortality rate in this cohort was 44% (17/39). Of 39 patients, 33 (85%) had continued partial/good response and 5 (13%) had complete resolution of psychosis. None discontinued clozapine due to motor worsening. Among patients who responded early on, the long-term efficacy of clozapine for psychosis was sustained. The risk of nursing home placement and mortality among parkinsonian patients treated with clozapine for psychosis in this geriatric cohort was better than that reported previously. Our data are more consistent with recently published long-term outcome data suggesting an improvement in the prognosis of parkinsonian patients with psychosis with the use of atypical antipsychotic agents such as clozapine.

Topics: Aged; Antipsychotic Agents; Clozapine; Cohort Studies; Female; Humans; Male; Parkinson Disease; Psychotic Disorders; Retrospective Studies; Time

Topics: Antipsychotic Agents; Clozapine; Drinking Behavior; Humans; Male; Middle Aged; Psychotic Disorders; Remission Induction; Water

This study examined the difference in the functional capacity of patients receiving clozapine, compared with those prescribed other antipsychotic medication, who attend the forensic psychiatry day hospital at Murray Royal Hospital, Perth. (This facility caters for 34 patients. It provides a number of advantages such as access to therapies and supervision of mental state and medication at this critical time in the care pathway.) This study was cross-sectional in nature and examined the patients' demographic details, diagnosis and medication. A functional assessment was carried out using the social behaviour schedule (SBS) for each patient. We discovered that there was a marked difference in the hostility scores between clozapine patients and non-clozapine patients. Only 10.5% of clozapine patients had a severe score (more than two) on the SBS whereas 61.5% of those not receiving clozapine had a severe score. The non-clozapine group had more socially unacceptable habits and were more destructive than patients receiving clozapine, as scored by the SBS. The slowness and under-activity items were more severe in the clozapine patients. The non-clozapine group scored higher in the category of other behaviours that might impede progress, particularly drug-taking.

Topics: Affective Disorders, Psychotic; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Forensic Psychiatry; Hospitals, Psychiatric; Hostility; Humans; Outpatient Clinics, Hospital; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Social Behavior

There are not many studies on the use of clozapine in patients with intellectual disability (ID). The authors describe a case series of patients treated with clozapine, drawn from a medium secure unit, a low secure assessment and treatment service and a community team in the London region.. A retrospective file-review of patients treated in these three settings during the time period March-June 2002 was performed (n = 24). Information was collected using a semistructured proforma.. Of the 24 patients, 67% had schizophrenia, 17% had schizoaffective disorder and 8% had bipolar disorder. Patients had been unwell for a mean of 6 years and had been tried on a mean of four antipsychotics. The mean maximum dose of clozapine was 488 mg. The outcomes on the clinical global impression (CGI) scale showed 29% very much improved, 42% much improved, 21% minimally improved and 8% no change. 54% of the whole sample and 53% of those from the medium secure unit were discharged to homes in the community. The drug had to be stopped in four patients, of which three were because of neutropaenia.. Clozapine appears to be safe and efficacious in many people with ID. Careful monitoring of side-effects is needed during therapy.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Child; Child Development Disorders, Pervasive; Clozapine; Cognition Disorders; Drug Resistance; Drug Utilization; Epilepsy; Female; Humans; Male; Middle Aged; Personality Disorders; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics.. Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone.. Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31).. Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzazepines; Benzodiazepines; Carbon Radioisotopes; Clozapine; Corpus Striatum; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Prolactin; Psychotic Disorders; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Drug Synergism; Drug Therapy, Combination; Humans; Psychotic Disorders; Sulpiride

Topics: Adult; Aged; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Piperazines; Psychotic Disorders; Quinolones; Schizophrenia, Paranoid; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Liver; Middle Aged; Psychotic Disorders; Steatorrhea

Recently, atypical antipsychotic agents have largely replaced traditional agents as first-line drugs for the treatment of schizophrenia and psychotic mood disorders. Considering the increase in atypical antipsychotics prescriptions and the increased risk of suicide in this patient population, the number of reported cases of antipsychotic drugs may be expected to increase. This paper describes the clinical course of atypical antipsychotic agents intoxication, chiefly clozapine, risperidone and olanzapine. Clozapine was the ingestant in 11 cases of atypical antipsychotics overdose in our material. The major observed effects in this group included deep coma, tachycardia, hypersalivation, delirium and shock. Clozapine has a small therapeutic index; in our patients the mortality rate was 27%. Ten patients with risperidone overdose were identified. Our data show that risperidone toxicity manifests mainly as mild central nervous system effects: somnolence, vertigo and tardive dyskinesia. Olanzapine has been considered to be similar to clozapine, but olanzapine intoxication appeared to have a relatively benign clinical course as compared with clozapine intoxication. In olanzapine intoxications deep coma, myosis and mild cardiovascular effects (hypotonia) were observed.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Middle Aged; Olanzapine; Poland; Psychotic Disorders; Risperidone

We studied whether movements associated with tardive dyskinesia (TD) served operant functions in 2 men with developmental disabilities. We found that TD-related movements occurred more frequently in the alone and attention conditions and less frequently in control and demand conditions. Our findings suggest that TD-related movements may not be maintained by social reinforcers and that decreases in TD movements are possibly a result of engagement in activities that are incompatible with TD movements.

Topics: Antipsychotic Agents; Benztropine; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Observer Variation; Psychotic Disorders; Severity of Illness Index; Videotape Recording

Three patients with Parkinson's disease developed psychosis. None of the three showed any other somatic cause for the psychosis except the Parkinson's disease. The first patient, a 73-year-old male, was initially treated with olanzapine and rivastigmine, without any effect. While treating the second patient, a 75-year-old male who had been suffering from Parkinson's disease for years, the Parkinson medication was first reduced and later on olanzapine and rivastigmine were prescribed, without a lasting effect on the psychotic symptoms. In the third patient, an 85-year-old male, medication reduction was unsuccessful. Finally, all three were treated effectively with clozapine. Psychosis in Parkinson's disease is a serious disorder that is often difficult to treat. In most cases, antipsychotic medication is needed. The atypical antipsychotic clozapine is effective without aggravation of the motor symptoms. Despite the side effects, such as the risk of agranulocytosis, drowsiness and weight gain, clozapine should be considered as a possible treatment.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Neuroprotective Agents; Olanzapine; Parkinson Disease; Phenylcarbamates; Psychotic Disorders; Rivastigmine; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Postmortem Changes; Psychotic Disorders; Tissue Distribution

Clozapine is indicated for the treatment of resistant schizophrenia, which is usually defined as failure to respond to adequate trials of 2 antipsychotics. It is thought that only clozapine is likely to be effective in such cases and that other drugs are ineffective. We sought to discover prior patterns of antipsychotic prescribing in schizophrenic patients eventually prescribed clozapine.. Prescribing histories were obtained from prescription charts and case notes for all inpatients prescribed clozapine in 4 hospitals in southeast London during April 2001.. 120 patients were identified, of whom 112 had been diagnosed with schizophrenia or schizoaffective disorder and whose data were analyzed. The mean duration of illness was 15.1 years. Subjects had experienced a mean of 9.2 (range, 2-35) episodes of antipsychotic prescription before clozapine was first used, with 5.7 (range, 0-25) episodes constituting adequate trials (drug used at therapeutic dose for 6 weeks). The mean number of different antipsychotics used was 5.5 (range, 1-13), with a mean of 4.0 (range, 0-12) given an adequate trial. Ninety percent of patients (N = 101) had received an atypical antipsychotic before first use of clozapine, and 65% (N = 73) had previously received antipsychotic polypharmacy. The mean maximum theoretical delay in using clozapine was 5.0 years (range, 0-11.1 years). Longer delay was significantly (p <.05) associated with being aged over 30 years at the time of the study, being diagnosed with psychotic illness before the introduction of clozapine, and completing adequate trials of 2 different antipsychotics before the introduction of clozapine or risperidone.. Clozapine treatment was quite likely delayed for longer than is clinically desirable. This delay may have important effects on quality of life, clinical outcome, and health resource utilization.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Prescriptions; Drug Therapy, Combination; Drug Utilization; Hospitalization; Humans; Outcome Assessment, Health Care; Practice Patterns, Physicians'; Psychotic Disorders; Retrospective Studies; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Costs; Drug Therapy, Combination; Humans; Polypharmacy; Practice Patterns, Physicians'; Psychiatry; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Haloperidol; Humans; Olanzapine; Pirenzepine; Psychotic Disorders; Research Design; Risperidone; Schizophrenia; Treatment Outcome

The effectiveness of cognitive rehabilitation in ameliorating the symptomatic, cognitive, and functional deficits associated with schizophrenia and schizoaffective disorders was assessed in this prospective study. Thirty-eight participants who met DSM-IV criteria were assigned to cognitive rehabilitation treatment or treatment as usual (TAU) groups, using the method of minimization to equalize groups on prognostic variables believed to affect outcome (i.e., duration and severity of illness, Clozapine). Participants were assessed at baseline, treatment end, and 3-month follow-up. Improvement across time was found for both groups in delayed visuospatial memory and visual information processing speed, and the participant's status on the prognostic variables was found to be related to level of performance on measures of delayed visuospatial memory, negative symptoms, and speech disturbance. However, the findings did not provide evidence that cognitive rehabilitation is associated with greater improvement than TAU. Nor did the findings indicate that prognosis interacted with treatment to produce differential treatment outcomes.

Topics: Antipsychotic Agents; Clozapine; Cognition Disorders; Cognitive Behavioral Therapy; Diagnostic and Statistical Manual of Mental Disorders; Humans; Neuropsychological Tests; Prospective Studies; Psychotic Disorders; Schizophrenia; Severity of Illness Index

This study investigates the subjective experiences of staff from many interdisciplinary teams working with clients in the recovery process from psychosis. The clinical staff interviewed in this study included: staff nurses, clinical nurse specialists, occupational therapists, psychologists, social workers, rehabilitation workers, recreation therapists, music therapists, psychiatrists, and lodging home operators. The purpose of this study was to examine the clinical staff's changing roles and relationships with clients recovering from psychosis. The investigation used a naturalistic qualitative design with an ethnographic method of data analysis. The participants were clinical staff working with clients about to commence treatment with clozapine or risperidone. The settings used were a tertiary-care psychiatric hospital and a general hospital. The clinical staff members who participated in the study were interviewed every 3 months. In the initial interview, members of the clinical staff were asked about their knowledge regarding the new medication and their role in the decision to try the new medication. In all the interviews, clinical staff members were asked about how the recovery process was progressing with the client. Data regarding clinical staff fears related to the client's situation, changes in their relationships with the client and the client's family, and what they perceived to be current rehabilitation implications, were collected. Some of the clinical staff roles that evolved during the recovery process were: health teacher; advocate; counsellor; and support person.

Topics: Adult; Anecdotes as Topic; Antipsychotic Agents; Attitude of Health Personnel; Clozapine; Female; Humans; Male; Middle Aged; Nurse-Patient Relations; Nurse's Role; Nursing Methodology Research; Physician-Patient Relations; Physician's Role; Psychiatric Nursing; Psychotic Disorders; Risperidone; Time Factors; United States

A number of interactions of the atypical antipsychotic clozapine with other drugs are well known, some of which can be attributed in part to the pharmacokinetic interactions associated with cytochrome P450 enzymes during drug metabolism. Clozapine is mainly metabolized by the cytochrome P450 isoenzyme 1A2. The proton pump inhibitor omeprazole can induce CYP1A2. We report on two patients with schizoaffective disorder who received omeprazole in addition to clozapine because of gastrointestinal complaints. Before the co-medication with omeprazole was started, the patients had been receiving clozapine for 78 and 41 days and for 40 and 8 days at a stable daily dose of 325 mg (patients 1 and 2, respectively). The co-medication with omeprazole was associated with a reduction in the plasma levels of clozapine of 41.9 % and 44.7 %, respectively, in these patients. The decrease in the plasma concentrations of clozapine in the presence of omeprazole might be due to the induction of the cytochrome P450 isoenzyme CYP1A2. If patients are receiving omeprazole as co-medication, close monitoring of plasma clozapine levels is recommended. If clozapine levels drop, the drug should be adjusted accordingly. If necessary, an alternative to omeprazole should be chosen.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Drug Antagonism; Esophagitis; Female; Gastritis; Humans; Male; Omeprazole; Proton Pump Inhibitors; Psychotic Disorders

Topics: Anemia, Aplastic; Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders

The authors' goal was to explore whether clozapine given as the first antipsychotic treatment favorably affects the course of schizophrenia.. Thirty-four inpatients experiencing their first episode of schizophrenia or schizoaffective disorder were treated first with clozapine and then followed for up to 4 years. In a previous study, the authors followed patients experiencing their first episode of schizophrenia or schizoaffective disorder who were given fluphenazine as the first treatment. In the current study and the previous study, response criteria required sustained remission of positive symptoms.. Nineteen of the 34 subjects met response criteria while taking clozapine. The median time to treatment response was 11 weeks (range=2-13). Using survival analysis, the authors determined that the cumulative response rate for the 34 patients was 66.4% at the end of 13 weeks, which is comparable to the response rate to fluphenazine in the previous study. All responses to clozapine occurred by 13 weeks. Eight (42%) of the clozapine responders discontinued clozapine before 6 months, and only six (32%) remained on clozapine for all of their time in the study.. The authors found no benefit for clozapine over conventional antipsychotics for acute treatment of the first episode of schizophrenia or schizoaffective disorder. Long-term benefits could not be studied because of the high rate of early discontinuation of clozapine treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Female; Fluphenazine; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Patient Dropouts; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Survival Analysis; Treatment Outcome

Incidence and risk factors for delirium during clozapine treatment require further clarification.. We used computerized pharmacy records to identify all adult psychiatric inpatients treated with clozapine (1995-96), reviewed their medical records to score incidence and severity of delirium, and tested associations with potential risk factors.. Subjects (n = 139) were 72 women and 67 men, aged 40.8 +/- 12.1 years, hospitalized for 24.9 +/- 23.3 days, and given clozapine, gradually increased to an average daily dose of 282 +/- 203 mg (3.45 +/- 2.45 mg/kg) for 18.9 +/- 16.4 days. Delirium was diagnosed in 14 (10.1 % incidence, or 1.48 cases/person-years of exposure); 71.4 % of cases were moderate or severe. Associated factors were co-treatment with other centrally antimuscarinic agents, poor clinical outcome, older age, and longer hospitalization (by 17.5 days, increasing cost); sex, diagnosis or medical co-morbidity, and daily clozapine dose, which fell with age, were unrelated.. Delirium was found in 10 % of clozapine-treated inpatients, particularly in older patients exposed to other central anticholinergics. Delirium was inconsistently recognized clinically in milder cases and was associated with increased length-of-stay and higher costs, and inferior clinical outcome.

Topics: Adult; Antipsychotic Agents; Clozapine; Delirium; Female; Hospitals, Psychiatric; Humans; Male; Multivariate Analysis; Psychotic Disorders; Retrospective Studies

To identify the molecular basis for a low CYP1A2 metabolic status, as determined by a caffeine phenotyping test, in a 71-year-old, nonsmoking, Caucasian woman who presented with very high clozapine concentrations despite being administered a standard dose of the drug.. The nucleotide sequence of the 7 exons, exon-intron boundaries and 5'-flanking region of the CYP1A2 gene was analysed by direct sequencing.. Only one heterozygous point mutation was identified in the donor splice site of intron 6 (3534G > A) of CYP1A2. This mutation could cause abnormal RNA splicing and therefore lead to a truncated nonfunctional enzyme. No other carrier of this mutation was identified in a population of 100 unrelated healthy Caucasians.. This is the first report of a splice-site mutation affecting the CYP1A2 gene. This polymorphism is a likely explanation for the low CYP1A2 activity associated with high clozapine concentrations in this patient.

Topics: Aged; Base Sequence; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Exons; Female; Humans; Introns; Mutation; Phenotype; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Psychotic Disorders; RNA Splice Sites

Topics: Acute Disease; Aged; Antipsychotic Agents; Clozapine; Humans; Male; Pericardial Effusion; Pleural Effusion; Psychotic Disorders; Serositis

To assess whether recovery-focused multimodal psychotherapy can facilitate symptom and function improvement in people with treatment-resistant psychotic illness.. Nine people with treatment-resistant schizophrenia or schizoaffective disorder whose symptoms and level of functioning necessitated inpatient care were engaged in individual multimodal psychotherapy for up to 21 months. In addition to the multimodal therapy they also received standard inpatient care. Twelve people retrospectively matched for diagnosis, age, sex, and chronicity of illness, formed a comparison group. They also received standard inpatient care. The standard inpatient care for both experimental and comparative groups consisted of custodial care, predominantly atypical antipsychotic drug therapy, and ongoing care from a key worker.. The treatment group showed clinically significant improvements in the overall Positive and Negative Symptom Scale (PANSS) scores which was significantly better than the changes found in the comparison group (p = 0.037). There was a 43% reduction in positive symptoms, a 30% reduction in negative symptoms, a 27.5% reduction in general psychopathology symptoms and a 30% reduction in overall scores on the PANSS. General behaviour scores on the Rehabilitation Evaluation of Hall and Baker were clinically improved, with a 32% reduction, as were deviant scores, with a 93.3% reduction. The change in the deviant scores was significantly better in the treatment group (p = 0.025).. Recovery-focused multimodal psychotherapy may facilitate symptom and function improvement in people with treatment-resistant psychotic illness.

Topics: Adolescent; Adult; Clozapine; Cognitive Behavioral Therapy; Combined Modality Therapy; Demography; Female; Hospitalization; Hospitals, Psychiatric; Humans; Interpersonal Relations; Male; Psychotherapy; Psychotic Disorders; Recovery of Function; Social Facilitation

Topics: Aged; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Electrocardiography; Female; Humans; Long QT Syndrome; Psychotic Disorders; Quetiapine Fumarate; Ventricular Premature Complexes

Topics: Adult; Antidiarrheals; Antipsychotic Agents; Bacillaceae Infections; Bacillus cereus; Clozapine; Drug Interactions; Drug Therapy, Combination; Fatal Outcome; Finland; Foodborne Diseases; Gastroenteritis; Hospitals, Psychiatric; Hospitals, State; Humans; Loperamide; Male; Megacolon, Toxic; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Priapism; Psychotic Disorders; Recurrence

Topics: Antipsychotic Agents; Choice Behavior; Clozapine; Humans; Neuroleptic Malignant Syndrome; Psychotic Disorders; Weight Gain

Topics: Antipsychotic Agents; Clozapine; Electroencephalography; Humans; Psychotic Disorders; Terminology as Topic

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Child; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Prolactin; Psychotic Disorders; Schizophrenia

Recently, apolipoprotein D (apoD), a protein that is involved in the essential polyunsaturated fatty acid (EPUFA) transport and metabolism, and neuronal growth and regeneration was reported to have increased in the postmortem brain and decreased in the serum of schizophrenia patients. We studied the plasma apoD levels in never-medicated schizophrenic patients at the onset of psychosis and in chronic patients with clozapine treatment. Plasma apoD levels were elevated in never-medicated patients at the first-episode of psychosis compared to normals (P = 0.047). Interestingly, the increase in apoD level was even more significant in chronic patients treated with clozapine compared to normals and first-episode patients (P = 0.008 and P = 0.03, respectively). The increased apoD level in never-medicated first-episode patients indicate that this increase probably predates the illness, since the duration of illness was < 5 days. Similarly, an even larger increase in apoD after clozapine treatment may be associated with its prophylactic effects, since the psychopathological scores were significantly reduced and the clozapine treatment has been found to increase the EPUFA membrane levels. These altered levels of apoD may help to understand the nature and possible mechanism of phospholipid membrane pathology in schizophrenia.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Apolipoproteins; Apolipoproteins D; Clozapine; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia

Six patients with epilepsy and severe psychosis were treated with the atypical antipsychotic clozapine. The use of clozapine might be complicated in epileptic patients because of an increased risk of seizures. However, none of the reported patients had an increase of their seizure frequency, in contrast, three patients had a substantial reduction of seizures. One patient had a reduction of non-epileptic seizures as well. In the second part of this paper, combinations of clozapine with newer and older anticonvulsants as well as their interactions and associated risks are discussed.

Topics: Adult; Aged; Anticonvulsants; Antipsychotic Agents; Clozapine; Epilepsy; Female; Humans; Male; Psychotic Disorders; Seizures; Treatment Outcome

The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels.. The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses.. Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations.. It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Haloperidol; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Triglycerides; Weight Gain

Clozapine-induced fever is a known side effect that can occur during clozapine initiation. This study aims to characterize patients who experience clozapine-induced fever, the nature of the fevers, and rates of clozapine continuation at 1 year in patients who develop fever versus those who do not.. A retrospective chart review of 93 consecutive clozapine initiations (1991-1999) was conducted. Fever was defined as any 1 temperature at or above 38.0 degrees C (100.4 degrees F). Demographic information, presence or absence of clozapine-induced fevers, and continuation of clozapine treatment at 1 year were extracted from the charts. These variables were analyzed for significance, and subsample analysis was conducted for those with more severe fevers (at or above 38.5 degrees C [101.3 degrees F]).. Of the 93 patients, 20.4% (N = 19) developed clozapine-induced fevers. At 1 year, there was no significant difference in clozapine discontinuation rate between those patients who experienced fever and those who did not. Patients who experienced higher fevers (> or = 38.5 degrees C [101.3 degrees F]) tended to be significantly older than those who did not (p < .027). The mean fever duration was 3.8 days (range, 1-9 days), with a mean temperature of 39.1 degrees C (102.4 degrees F) (range, 38.0-41.0 degrees C [100.4-105.8 degrees F]). At 1 year, the patients who experienced fever showed no increased risk of severe reactions such as agranulocytosis. All patients with fevers continued clozapine treatment with good 1-year continuation rate on treatment with this medication.. Clozapine-induced fever is not an indication for discontinuing this effective medication. It is a benign, self-limited phenomenon not predictive of drug discontinuation at 1 year. Older age at time of treatment may be a risk factor for developing clozapine-induced fever.

Topics: Adolescent; Adult; Age Factors; Body Temperature; Clozapine; Drug Administration Schedule; Female; Fever; Follow-Up Studies; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Severity of Illness Index; Treatment Outcome

Case series suggest that some antipsychotics may induce or exacerbate type 2 diabetes. This study measured the association of antipsychotic treatments with diabetes at a population level.. Claims data for psychosis patients (ICD-CM-9 290.xx-299.xx) within health plans encompassing 2.5 million individuals were analyzed. Patients reporting preexisting type 2 diabetes up to 8 months prior to observation were excluded. The frequency of newly reported type 2 diabetes in untreated patients and among patients treated with antipsychotics from 5 categories (risperidone, olanzapine, clozapine, and high-potency and low-potency conventionals) was compared. Logistic regression models compared the odds of diabetes based on exposure to each of the antipsychotic categories.. Based on 12 months of exposure, the odds of type 2 diabetes for risperidone-treated patients (odds ratio = 0.88, 95% CI = 0.372 to 2.070) was not significantly different from that for untreated patients, whereas patients receiving other antipsychotics had a significantly greater risk of diabetes than untreated patients (p < .05): olanzapine, 3.10 (95% CI = 1.620 to 5.934); clozapine, 7.44 (95% CI = 0.603 to 34.751); high-potency conventionals, 2.13 (95% CI = 1.097 to 4.134); and low-potency conventionals, 3.46 (95% CI = 1.522 to 7.785). Older age and greater use of non-antipsychotic psychotropic medications also contributed to risk of type 2 diabetes. Olanzapine also showed significantly higher (p < .01) odds of diabetes associated with increasing dose.. Consistent with previously published literature, these data suggest that olanzapine, clozapine, and some conventional antipsychotics appear to increase the risk of acquiring or exacerbating type 2 diabetes and that the effect may vary by drug. In contrast to these agents, risperidone was not associated with an increased risk of type 2 diabetes.

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Comorbidity; Confidence Intervals; Databases as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Insurance Claim Review; Logistic Models; Male; Middle Aged; Odds Ratio; Olanzapine; Pirenzepine; Psychotic Disorders; Risk Factors; Risperidone; United States

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Drug Therapy, Combination; Female; Humans; Maprotiline; Middle Aged; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Heart Arrest; Humans; Male; Psychotic Disorders; Schizophrenia, Paranoid; Syncope

We investigated the course of adherence to medication recommendations in 162 patients with psychotic disorders in ambulatory treatment. Data were collected using the clinic's outcome assessment program, maximizing the generalizability of the study. Patients initially adherent to their medication regimens maintained their adherence for an average of 13.3 months. Patients initially nonadherent developed adherence after an average of 5.6 months of treatment. Demographic factors and illness history were unrelated to adherence. This study replicated previous findings of the concurrent association between adherence and global functioning level, substance use, and working alliance with therapist. Cox regression analyses revealed that working alliance, global functioning, and being prescribed clozapine predicted longer maintenance of adherence. Working alliance was the most significant and consistent predictor of adherence to medication recommendations.

Topics: Adolescent; Adult; Ambulatory Care; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Patient Compliance; Prospective Studies; Psychotic Disorders; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Psychotic Disorders

Atypical neuroleptics are increasingly used in the treatment of bipolar and schizoaffective disorders. Currently, numerous controlled short-term studies are available for clozapine, olanzapine, risperidone or quetiapine, but long-term data are still missing. Three patients (2 with bipolar disorder, 1 with schizoaffective disorder) are described who showed a marked reduction of affective symptomatology after clozapine had been added to mood stabilizer pretreatment. The patients were seen once a month before and after the introduction of clozapine for at least 6 months. Treatment response was evaluated using different rating scales (IDS, YMRS; GAF; CGI-BP) and the NIMH Life Chart Methodology. All patients showed a marked improvement after the add-on treatment with clozapine had been initiated. Clozapine was tolerated well with only transient and moderate weight gain and fatigue as only side effects. This case series underlines the safety and efficacy of clozapine as add-on medication in the treatment of bipolar and schizoaffective disorders.

Topics: Adult; Affect; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Psychotic Disorders

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Eosinophilia; Humans; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors

Steady-state plasma concentrations of clozapine and norclozapine, its major metabolite, as well as their sum and ratio (norclozapine/clozapine), were evaluated in 50 in- and outpatients taking clozapine and naturalistically recruited. Drug plasma concentrations were measured by means of a reversed-phase high-performance liquid chromatography (RPLC) method with an ultraviolet detection. Daily doses (milligrams per kilogram of body weight) of clozapine correlated positively with clozapine plasma parameters, except with the norclozapine/clozapine ratio, in all patients. When the patients were divided in subgroups with respect to gender, the corresponding plasma concentrations were no longer dose-related in men. A lack of significant correlation was observed also in patients (n=23) co-treated with typical neuroleptics. Conversely, dose-concentration correlations were significant in either smoker or nonsmoker patients. No significant relationship between body weight and clozapine plasma parameters was reported. Further, we observed (1) a trend towards higher medians of clozapine or total analytes in women than those reported in men (P=.09 and .07); (2) no significant difference in plasma levels obtained in subjects younger than 34 years and subjects 34 years old or older; (3) a trend towards higher norclozapine and clozapine plus norclozapine levels (P=.05 and .08) in nonsmoker than smoker patients; (4) no significant difference between clozapine plasma parameters measured in patients co-medicated with typical neuroleptics and in patients receiving clozapine alone.

Topics: Adolescent; Adult; Aged; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Patients; Psychotic Disorders; Sex Factors; Smoking; Statistics, Nonparametric

Topics: Adult; Antipsychotic Agents; Clozapine; Ego; Female; Humans; Life Change Events; Mental Disorders; Psychotic Disorders

Controversy persists about links between psychotropic drug use, obesity, and consequent menstrual irregularities. Although these interrelationships have been suggested to possibly explain polycystic ovarian syndrome among women taking valproate, less is known about menstrual irregularities associated with weight gain caused by other psychotropics. Clozapine, sparing of prolactin-related menstrual effects yet often associated with weight gain, offers a model psychotropic from which to test such hypotheses. We studied outpatient premenopausal women from a clozapine clinic to preliminarily assess the association between menstrual cycle patterns and body mass index (BMI). Records were reviewed for 13 female premenopausal schizophrenic, bipolar, or schizoaffective outpatients who took clozapine with no conventional antipsychotics for >6 months. Mean 6-month menstrual cycle lengths were compared with BMIs and relative weight changes since starting clozapine. Subjects took clozapine (mean +/- SD dose 392.2 +/- 195.7 mg/day) for a mean +/- SD of 4.4 +/- 3.2 years, with a mean preclozapine weight increase of 27%. Twenty-three percent had menstrual irregularities in the preceding 6 months (mean +/- SD cycle length = 36.4 +/- 18.1 days), although no significant associations were observed between cycle length and (a) mean +/- SD BMI (32.0 +/- 8.4) (r = -0.09, p = 0.78) or (b) weight change since starting clozapine (r = -0.10, p = 0.75). The observed lack of association between clozapine-induced weight gain and menstrual disturbances would provisionally suggest that iatrogenic weight gain does not robustly explain the emergence of irregular menses among premenopausal women taking clozapine.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Data Collection; Female; Humans; Medical Records; Menstruation Disturbances; Middle Aged; Pilot Projects; Psychotic Disorders; Schizophrenia; Weight Gain

A new diaryl-methylene piperidine derivative, 2, displayed an atypical antipsychotic profile both in vitro and in vivo. The main pharmacological characteristics of this compound appears to reside in a more potent antagonism of the 5-HT2 serotonergic receptor than of the D2 dopaminergic receptor. This confirms that molecules displaying a D2/5-HT2 binding ratio < 1 possess clozapine-like antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Mice; Piperidines; Protein Binding; Psychomotor Agitation; Psychotic Disorders; Receptors, Dopamine D2; Receptors, Serotonin; Serotonin Antagonists

The authors examined the relationship between treatment with clozapine and rates of arrest of psychotic outpatients with criminal histories.. Patients who had been given a DSM-IV psychotic diagnosis were selected from an urban outpatient clinic database. Background checks performed on 360 patients identified 165 (45.8%) with positive criminal histories in Massachusetts. The authors reviewed the charts of these patients to determine several variables, including whether and when they had received clozapine. A Poisson regression model was used to regress arrest rates against the variables of age, sex, onset of illness, birth cohort, and clozapine treatment. Risk ratios (i.e., percent change in arrest rates) were then calculated by computing the exponential of the Poisson regression coefficients.. The 165 patients included in the analysis had a total of 1,126 arrests. The mean number of arrests was 6.8. Differences were found between the 65 patients who received clozapine and the 100 patients who did not in number of arrests, sex, and onset of illness. The regression revealed significantly higher arrest rate estimates associated with more recent birth cohort (4.8%) and with onset of illness (64.6%) and lower arrest rate estimates associated with higher levels of education (11.6%), receiving clozapine (32.6%), and receiving clozapine during specific periods of time (68.9%).. Clozapine's effect on arrest rates in this group of patients is large enough to warrant further investigation. The data indicate that clozapine may reduce recidivism in subjects with criminal histories who are in need of antipsychotic medication.

Topics: Adult; Ambulatory Care Facilities; Antipsychotic Agents; Clozapine; Crime; Criminal Psychology; Female; Humans; Male; Poisson Distribution; Psychotic Disorders; Regression Analysis; Social Control, Formal; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Psychotic Disorders; Pulmonary Embolism; Risk Factors

Many practitioners use plasma levels to determine the optimum dosage of clozapine. The aim of this study was to determine the intra- and interlaboratory accuracy in assaying samples of clozapine dissolved in human plasma.. Three samples were sent to one laboratory to obtain an initial determination of accuracy (phase I). Then samples of clozapine dissolved in human plasma were prepared at concentrations of 140, 310 and 580 ng/mL and dispatched on dry ice to 10 assaying centres in Australia and New Zealand. The results of the survey were analysed and posted to each centre (phase II). The programme was repeated using concentrations of 160, 380 and 640 ng/mL (phase III). Samples prepared in purified water and freeze-dried samples were also dispatched.. In phase II there were two centres with results significantly different from the mean. In phase III all the centres returned concordant results. There was a high level of consistency in the measurement of samples with a maximum coefficient of variation of 0.16. The concentrations determined by the centres, however, were significantly lower than the nominal concentrations of the prepared solutions.. Clinicians in Australia and New Zealand who wish to know their patients' plasma-clozapine levels can be confident that the result of the assay is unlikely to vary with the choice of centre or the operator who performs the assay.

Topics: Analysis of Variance; Antipsychotic Agents; Clinical Laboratory Techniques; Clozapine; Drug Monitoring; Humans; Psychotic Disorders; Reproducibility of Results

Several years ago, we reported that the addition of risperidone to clozapine improved response in some patients with schizophrenia. Risperidone, in general, is well tolerated when administered as monotherapy, but has been linked to a persistent elevation of serum prolactin and associated symptoms. The goal of this study was to determine whether the addition of risperidone to clozapine results in an elevation of serum prolactin levels in patients with chronic schizophrenia or schizoaffective disorder.. Twenty patients on clozapine-risperidone combination therapy were matched for age and gender with 20 patients treated with clozapine monotherapy. Demographic information was gathered along with clozapine and risperidone dose and the length of time on risperidone. Serum prolactin levels were measured from a single blood sample.. The 2 groups did not differ in age, race, gender, diagnosis, age at clozapine initiation, age at onset, Abnormal Involuntary Movement Scale scores, or clozapine dose. The mean +/- SD serum prolactin level was 8.42+/-4.17 ng/mL for clozapine monotherapy patients and 35.76+/-17.43 ng/mL for combination therapy patients. The 2 medication categories showed a significant difference in log prolactin values (t = -7.97, df = 38, p < or = .0001). Sixteen combination therapy patients (80%) exhibited elevated prolactin levels (range for entire group, 9.7-69.8 ng/mL) while only 2 clozapine monotherapy patients (10%) exhibited prolactin elevation levels (range for entire group, 2.4-20.2 ng/mL; df = 1, p < .0001).. The combination of risperidone and clozapine appears to result in a moderate elevation of serum prolactin levels. Additionally, controlled prospective studies are needed to clarify the risks of long-term elevations of serum prolactin level.

Topics: Adult; Age of Onset; Ambulatory Care; Antipsychotic Agents; Chronic Disease; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hyperprolactinemia; Male; Middle Aged; Prolactin; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

We performed a retrospective analysis of data involving 121 inpatients to examine the rate of weight gain during antipsychotic-free periods and during treatment with various antipsychotic drugs.. Data were analyzed to determine differences in weekly weight change during antipsychotic-free (N = 65), typical antipsychotic (N = 51), or atypical antipsychotic (N = 130) treatment periods. Atypical antipsychotic treatment periods were further subdivided into olanzapine (N = 45), clozapine (N = 47), or risperidone (N = 36) treatment periods. A paired comparison was conducted on 65 patients who had an antipsychotic-free treatment period preceding or following a neuroleptic drug treatment period. In addition, patients were classified as either non-obese (with a body mass index [BMI] < or = 29.9 kg/ml) or obese (BMI > or = 30.0 kg/m2) to test whether the rate of weight gain during treatment periods was related to initial BMI.. Across all treatment periods, weekly weight gain was as follows: 0.89 lb/wk (0.40 kg/wk) on atypical antipsychotic medication, 0.61 lb/wk (0.27 kg/wk) on typical antipsychotic medication, and 0.21 lb/wk (0.09 kg/wk) on no antipsychotic medications. The atypical antipsychotic versus antipsychotic-free comparison was significant (F = 3.51; df = 2,231; p = .031), while the typical antipsychotic versus antipsychotic-free comparison was not. Among the individual atypical antipsychotic medications, significantly more weight gain occurred during olanzapine treatment (1.70 lb/wk) (0.76 kg/wk) than with either clozapine (0.50 lb/wk) (0.22 kg/wk) or risperidone (0.34 lb/wk) (0.15 kg/wk) treatments (F = 7.77; df = 2,117; p = .001). In the paired analysis with patients serving as their own controls, the difference between weekly weight gain during atypical antipsychotic treatment and antipsychotic-free treatment was significant (t = -3.91; df = 44; p = .001), while the difference between weight gain during typical antipsychotic treatment and antipsychotic-free treatment was not significant. With the individual drugs. treatment with both olanzapine and clozapine caused significantly higher weekly weight gain than antipsychotic-free treatment (p = .001 and p = .036, respectively). while treatment with risperidone did not. Non-obese patients (BMI < 29.9 kg/m2) and obese patients (BMI > 30.0 kg/m2) did not differ significantly in their weight gain during typical or atypical antipsychotic treatment.. Treatment with atypical antipsychotics was associated with more weight gain than treatment with typical antipsychotics. Among the atypical drugs, olanzapine was associated with more weight gain than either clozapine or risperidone. The patient's admission BMI was not associated with the amount of weight gained during subsequent antipsychotic treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Drug Administration Schedule; Female; Hospitalization; Humans; Male; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Regression Analysis; Research Design; Retrospective Studies; Risperidone; Schizophrenia; Weight Gain

The use of generic drugs has resulted in considerable cost savings; however, whether all generics are truly bioequivalent to their brand-name counterparts is questionable. Although the efficacy of clozapine in the management of treatment-resistant schizophrenia has been well established, reports of relapse after conversion to a generic formulation are becoming more common.. This article presents 7 case studies of patients in a long-term residential care facility who experienced a relapse of psychotic symptoms when the pharmacy inadvertently switched their therapy from brand-name clozapine to a generic formulation. Neither patients, physicians, nor staff of the facility were aware of this switch. Possible reasons for the apparent increased risk of relapse in some patients switched to the generic formulation of clozapine are explored, with reference to US Food and Drug Administration bioequivalence standards and reports.. All 7 patients, whose condition had been well stabilized with brand-name clozapine, experienced a rapid and profound deterioration after the switch to the generic formulation. Five patients required hospitalization. All patients responded well when brand-name clozapine was reinstated.. The findings suggest that brand-name clozapine and the generic formulation may display important clinical differences, and a comparable therapeutic response may not be achievable despite adequate monitoring. Large, controlled, prospective trials are needed to clarify the potential for treatment failure with the use of generic clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Depression; Drugs, Generic; Female; Hallucinations; Humans; Male; Middle Aged; Psychotic Disorders; Recurrence; Schizophrenia

Overweight is a considerable clinical problem in patients treated with antipsychotic agents. Recent results suggest that insulin resistance with increased insulin levels is also associated with treatment with the atypical antipsychotic agent clozapine. Leptin is important for the control of body weight and has been proposed to be a link between obesity and the insulin resistance syndrome. This study examined if clozapine-treated subjects and subjects treated with conventional antipsychotics had increased leptin levels compared with the general population and whether there was a gender difference in this respect.. Clozapine-treated patients (N = 41), patients treated with conventional antipsychotic drugs (N = 62), and healthy subjects from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project (N = 189) were investigated with a cross-sectional study design. Weight, body mass index (BMI), and plasma leptin concentrations were measured, and all study subjects were investigated for the presence of diabetes mellitus. Drug treatment, health status, and smoking habits were registered.. After adjustment for gender, BMI, smoking habits, age, and diabetes, hyperleptinemia was independently (p < .001) associated with clozapine treatment and with treatment with conventional antipsychotics (p < .005) within a multiple regression analysis. In separate multiple regression analyses, leptin levels were significantly associated with clozapine treatment in men (p = .002) and women (p =.023) and with conventional antipsychotic treatment in men (p = .027) but not in women.. Treatment with clozapine as well as with conventional antipsychotics is associated with increased levels of circulating leptin. Hyperleptinemia can be an important link in the development of overweight and the insulin resistance syndrome in subjects receiving antipsychotic drugs, especially atypical agents like clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Clozapine; Cross-Sectional Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Hyperinsulinism; Leptin; Male; Middle Aged; Obesity; Psychotic Disorders; Radioimmunoassay

Diagnostic considerations and treatment strategies in adolescents with partial complex epilepsy and emerging psychosis are discussed. We will argue for considering clozapine early in treatment if other antipsychotics have failed based on two cases; these patients both developed epilepsy in early childhood and schizophrenia in mid adolescence. Their partial complex epilepsy were unsuccessfully treated with different antiepileptic drugs. Clozapine was tried with a distinct improvement in psychotic symptoms and functional level. In both cases there was an early unexpected improvement in seizure control on clozapine. It appears that a reduction of psychotic activity improved seizure control. Later on, there appeared to be a trade off between clozapines effect on psychotic symptoms and recurrence of seizure activity.. A schizophrenic development must be taken into consideration if psychiatric symptoms emerge in adolescents with a partial complex epileptic disorder. Clozapine treatment can be considered if other antipsychotic drugs are ineffective or cause motor side effects.

Topics: Adolescent; Anticonvulsants; Antipsychotic Agents; Child; Clozapine; Diagnosis, Differential; Epilepsy, Complex Partial; Female; Humans; Male; Psychotic Disorders

The goal of this study was to identify adverse effects of the atypical neuroleptic clozapine on liver function and lipid metabolism.. Data which included serum levels of clozapine and its hepatic metabolite N-desmethyl clozapine were collected from medical records of patients treated with clozapine and controls.. We identified a clozapine-associated marked elevation of plasma cholinesterase (ChE) with unchanged levels of AST, ALT or g-GT. ChE was correlated to the serum level of clozapine and even closer to N-desmethyl clozapine. For the total patient group we observed significant correlations of ChE with the body-mass index and body weight. However, clozapine-treated patients and controls did not differ with regard to body-mass index, triglycerides, and cholesterol.. We report for the first time a clozapine-associated and dose-dependent elevation of plasma ChE, which may be related to clozapine-associated effects on hepatic lipid metabolism or ChE enzyme induction.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Cholesterol; Cholinesterases; Clozapine; Female; Humans; Lipid Metabolism; Liver Function Tests; Male; Middle Aged; Outpatients; Psychotic Disorders; Retrospective Studies; Triglycerides

Substance use disorders, particularly those involving alcohol, marijuana, and cocaine, are highly prevalent among patients with schizophrenia and contribute markedly to its overall morbidity. Unfortunately, standard (typical) antipsychotic medications do not seem to reduce substance use in patients with schizophrenia and may even increase it. Recently, however, a few anecdotal case reports and two previous small "N" surveys have found that clozapine, an atypical antipsychotic medication, seems to decrease substance use in patients treated with this drug for their psychoses. The authors report data from a retrospective survey of substance use in 58 patients treated with clozapine who had a history of comorbid schizophrenia (or schizoaffective disorder) and substance use disorder. Of these 58 patients, 43 were being treated with clozapine at the time of the survey; the remaining 15 patients had discontinued clozapine before the survey. The survey involved chart review and clinician interview to assess change in substance use and global clinical symptoms while receiving treatment with clozapine. More than 85% of the patients who were active substance users at the time of initiation of treatment with clozapine decreased their substance use over the course of clozapine administration. For patients who continued treatment with clozapine up to the present, the decrease in substance use was strongly correlated with a decrease in global clinical symptoms. Data from this retrospective survey further support the previous observations that clozapine reduces substance use among patients with schizophrenic disorders. Moreover, the data suggest the need for prospective controlled studies of the effects of clozapine on substance use in this population.

Topics: Adult; Antipsychotic Agents; Clozapine; Diagnosis, Dual (Psychiatry); Female; Humans; Male; Medical Records; Middle Aged; Pilot Projects; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

A 72-year-old depressed woman was admitted by court order after a long history of ¿successful' resistance to any treatment, both at home and in a psychiatric hospital. The nature of her disorder had not been recognised and she was diagnosed elsewhere as suffering from factitious disorder, probably based on intense countertransference. The diagnosis of depression with mood-congruent psychotic features was made. After several unsuccessful combination treatments and refusal of electroshock therapy, she finally responded to combination therapy with tranylcypromine, lithium carbonate and clozapine. Dutch medicolegal regulations need not be an impediment in such cases, intercollegiate consultation is most useful and strict adherence to therapy guidelines is beneficial.

Topics: Aged; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Diagnosis, Differential; Drug Therapy, Combination; Factitious Disorders; Female; Humans; Lithium Carbonate; Patient Compliance; Psychotic Disorders; Tranylcypromine; Treatment Refusal

Blepharospasm, the forcible closure of eyelids, is an infrequent consequence of neuroleptic treatment that, when severe, can interfere with the ability to walk, drive, or work. Like tardive dyskinesia, blepharospasm can be disfiguring and aesthetically distressing, contributing to the increased stigmatization of patients.. We report 4 patients with DSM-IV schizoaffective disorder, paranoid schizophrenia, or chronic undifferentiated schizophrenia who developed neuroleptic-induced blepharospasm. In all patients, blepharospasm remitted without the reemergence of psychosis within 3 to 5 months of treatment with clozapine, 100-200 mg/day.. The results suggest that clozapine may successfully treat neuroleptic-induced blepharospasm without the reemergence of psychosis in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder.

Topics: Adult; Antipsychotic Agents; Blepharospasm; Clozapine; Drug Administration Schedule; Female; Humans; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Three patients with psychoses and concomitant prolactin-secreting pituitary tumours are described. Patients A and B had bipolar and schizoaffective disorders, respectively. They had both been treated with neuroleptics for 20 years before the prolactinomas were revealed. Patient C developed a paranoid psychosis after two years of continuous bromocriptine treatment for a pituitary tumour. In patient A the prolactin level was successfully normalized and a good antipsychotic effect was maintained by combined therapy with haloperidol and quinagolide but not bromocriptine. In patient B the prolactinoma was removed by surgery, in view of the serious nature of the psychotic disorder, to avoid psychotic relapse by treatment with a dopamine agonist. In patient C a good result was obtained with the combination of clozapine and bromocriptine. These case reports support the view that neuroleptics being dopamine antagonists and dopamine agonistic agents which are the primary treatment of prolactinomas can cancel out each other's effects. The combination of clozapine and quinagolide is recommended as the treatment of choice for most patients.

Topics: Adult; Aminoquinolines; Antipsychotic Agents; Bipolar Disorder; Bromocriptine; Clozapine; Comorbidity; Dopamine Agonists; Dopamine Antagonists; Drug Interactions; Drug Therapy, Combination; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Psychoses, Substance-Induced; Psychotic Disorders

Neuroleptic-induced tardive dyskinesia, which often appears in middle-aged and older adults early in the course of treatment with low doses of conventional antipsychotics, is 5 to 6 times more prevalent in elderly than in younger patients. In addition to age, other risk factors for tardive dyskinesia include early extrapyramidal symptoms (EPS), cumulative amounts of neuroleptics, duration of neuroleptic treatment, and history of alcohol abuse and/or dependence. The atypical antipsychotics, which have a low liability for EPS, are likely to also have low potential for tardive dyskinesia, despite the paucity of controlled studies. Starting and maintenance doses of the atypical antipsychotics should generally be lower in older than in younger adults.

Topics: Adult; Age Factors; Aged; Alzheimer Disease; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Incidence; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risk Factors; Risperidone

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Interactions; Humans; Male; Olanzapine; Pirenzepine; Priapism; Psychotic Disorders

Side effects of antipsychotic medications are particularly problematic in elderly patients, who experience many age-related changes that may exacerbate medication side effects. Side effects of particular concern in the elderly include anticholinergic reactions, parkinsonian events, tardive dyskinesia, orthostatic hypotension, cardiac conduction disturbances, reduced bone mineral density, sedation, and cognitive slowing. In addition, elderly patients with schizophrenia often have comorbid medical illnesses-such as cardiovascular disease and dementia of the Alzheimer's type-and are thus likely to be taking multiple medications. The effects of polypharmacy must be carefully considered. Patients, caregivers, and family often have different perspectives on side effects. This article addresses the side effects of the currently available antipsychotic medications in light of these concerns.

Topics: Age Factors; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Comorbidity; Dementia; Dibenzothiazepines; Humans; Movement Disorders; Neuroleptic Malignant Syndrome; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Neuroleptic Malignant Syndrome; Psychotic Disorders

Topics: Adult; Citalopram; Clozapine; Confusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Fatigue; Humans; Male; Psychotic Disorders; Sialorrhea; Sleep Wake Disorders

The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine.

Topics: Alleles; Antipsychotic Agents; Bipolar Disorder; Clozapine; Depression; Humans; Polymorphism, Genetic; Psychotic Disorders; Receptors, Serotonin; Reference Values; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Homicide; Humans; Patient Compliance; Psychotic Disorders; Risperidone

Clozapine is effective in up to 60% of patients with refractory schizophrenia, whereas the efficacy of risperidone remains unknown. This retrospective study examined the relative efficacy of these drugs in chronically institutionalized patients refractory to conventional antipsychotic agents.. A total of 24 patients who at different time periods had received adequate trials of both clozapine and risperidone and met our inclusion criteria for minimum dose and duration of each trial were included; for clozapine, a minimum dose of 300 mg/day had to be maintained for at least 12 weeks, and for risperidone, a minimum dose of 6 mg/day for at least 6 weeks. Information obtained from systematic retrospective chart review was blindly rated by 2 psychiatrists using the 7-point Clinical Global Impressions-Improvement (CGI-I) scale on overall clinical state and along specific symptom domains of positive symptoms, negative symptoms, and aggressive behavior.. The mean +/- SD dose was 520+/-94 mg/day for clozapine and 7.5+/-2.2 mg/day for risperidone. Fourteen patients (58%) were classified as responders to clozapine, while 6 (25%) responded to risperidone (CGI-I score of 1 or 2); on specific symptom domains, response rates to clozapine were 38% (9/24) on positive symptoms, 29% (7/24) on negative symptoms, and 71% (12/17) on aggressive behavior. For risperidone, response rates were 17% (4/24) on positive symptoms, 8% (2/24) on negative symptoms, and 41% (7/17) on aggressive behavior.. The results of this study support the utility of first giving a risperidone trial in a treatment algorithm for refractory patients because of its better risk/benefit profile compared with clozapine. Clozapine, however, remains our gold standard in the management of these patients.

Topics: Adult; Aggression; Clozapine; Drug Administration Schedule; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Homicide; Humans; Patient Compliance; Psychotic Disorders; Risperidone

Atypical anti-psychotic drugs (APDs) are widely used in psychotic disorders refractory to conventional neuroleptic agents.. Three cases of new-onset diabetes are reported in Caucasian men who were on clozapine (one) or olanzapine (two) for 3-6 months. They had a distinct presentation: weight loss, ketosis (one ketoacidosis), severe hyperglycaemia requiring insulin therapy, and relative insulin deficiency as reflected by glucagon stimulatory tests. In all cases, insulin was stopped within 1 month after the APD was discontinued.. Novel APDs not only induce diabetes as a result of weight gain in predisposed patients, but can also lead to a reversible state of insulin deficiency, and sometimes ketoacidosis.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Depressive Disorder; Diabetes Mellitus; Glyburide; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Middle Aged; Olanzapine; Pirenzepine; Polypharmacy; Psychotic Disorders; Treatment Outcome

Clinical reports emphasize the therapeutic usefulness of granulocyte colony-stimulating factor (G-CSF) in clozapine-induced granulocytopenia. Only sparse information exists, however, on the natural course of endogenous G-CSF plasma levels in this condition.. We monitored G-CSF and white blood cell (WBC) counts in a 73-year-old patient who developed granulocytopenia while being treated with clozapine for schizoaffective disorder. Clozapine treatment was discontinued immediately, and G-CSF serum levels were determined repeatedly during the clinical course.. Whereas WBC counts increased again within 6 days after discontinuation of clozapine, G-CSF level decreased significantly within the same period. The rapid decrease of endogenous G-CSF levels paralleled by a normalization of neutrophil count was interpreted as the result of an intact regulatory mechanism of granulocytopoesis. Therefore G-CSF therapy was not initiated. Owing to lack of therapeutic alternatives, it was decided to reintroduce clozapine. G-CSF levels decreased further, accompanied by an increase of WBCs, indicating stable bone marrow functioning.. Based on this observation, we assume that the course of G-CSF and WBC counts indicated an abortive form of toxic bone marrow damage with subsequent recovery. We conclude that monitoring of G-CSF levels may serve as a useful tool in the follow-up of patients in whom clozapine-induced bone marrow damage is suspected.

Topics: Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Neutropenia; Psychotic Disorders; Remission Induction; Time Factors; Treatment Outcome

With the advent of atypical antipsychotics, quality of life for patients with schizophrenia has improved significantly. The positive effects are based not only on the compliance-enhancing reduction of extrapyramidal side effects but also due to improved cognitive function and social integration, shorter duration, and overall reduction of hospital treatment. Numerous controlled studies have addressed the issue of switching patients from typical to atypical antipsychotics. However, published data on substituting one atypical antipsychotic for another are preliminary and very limited. This case report describes acute side effects which occurred when switching from clozapine to amisulpride and discusses mechanisms on the receptor level. Regarding these two agents, the clinical relevance of the knowledge of receptor profiles is outlined.

Topics: Acute Disease; Adult; Amisulpride; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Pharyngeal Diseases; Psychotic Disorders; Receptors, Dopamine; Spasm; Sulpiride; Tongue Diseases

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Leukocyte Count; Male; Middle Aged; Neutropenia; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Time Factors

Four patients affected by severe Parkinson's disease developed leucopenia (900-1200 WBC) during treatment of psychosis (3) or untreatable insomnia (1) with clozapine (37.5-75 mg/day). Clozapine withdrawal was followed by recovery of leucopenia (4000-6000 WBC) in two weeks with no need for the administration of leucokines. After 1-6 months olanzapine was administered (increasing the dose from 2.5 to 10 mg/day) to treat persisting disturbances, but the drug induced severe worsening of parkinsonism and also this drug had to be withdrawn.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Female; Hallucinations; Humans; Leukopenia; Male; Olanzapine; Parkinson Disease; Pirenzepine; Psychotic Disorders; Sexual Dysfunctions, Psychological; Sleep Initiation and Maintenance Disorders

The dopamine D4 receptor may be a site through which the clinical effects of antipsychotic drugs are mediated. Polymorphisms of a 48 base pair repeat in the third exon of the DRD4 gene code for different length segments in the third intracytoplasmic loop of the D4 receptor. The most common long (seven repeat) form of the D4 receptor has been shown in both physiologic and pharmacologic experiments to respond differently to dopamine agonists and antagonists than do shorter forms of D4. Thus, variants of D4 may partly determine patient response to antipsychotic drugs and, in particular, response to typical neuroleptics, which have a relatively low affinity for the D4 receptor, as compared to clozapine, which has a relatively high affinity for D4. DRD4 polymorphisms in the third intron were characterized in 28 patients with chronic psychosis who responded well to typical neuroleptics, 32 patients who responded well to clozapine, and 57 healthy comparison subjects. Patients responding to typical neuroleptics carried the allele for the long (seven repeat) form of the D4 receptor (allele frequency 8.9%) less frequently than patients responding to clozapine (allele frequency 23.4%, P = 0.046) or healthy comparison subjects (allele frequency 26.3%, P = 0.004). The results of this study suggest that inherited variants of D4 may explain some of the interindividual variation seen in patient response to different classes of antipsychotic medication.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Polymorphism, Genetic; Psychotic Disorders; Receptors, Dopamine D2; Receptors, Dopamine D4; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Psychotic Disorders; Quetiapine Fumarate; Schizophrenia

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Diabetic Ketoacidosis; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin; Male; Psychotic Disorders

The purpose of this study was to examine rehospitalization rates of people receiving risperidone or clozapine who had been discharged from state psychiatric hospitals in Maryland.. Rehospitalization status was monitored for all patients discharged from state psychiatric facilities on a regimen of either risperidone or clozapine between March 14, 1994, and Dec. 31, 1995. Patients were followed up with respect to readmission until Dec. 31, 1996. Time to readmission was measured by the product-limit (Kaplan-Meier) formula. Risk factors associated with rehospitalization were examined.. One hundred sixty patients were discharged on risperidone, 75 having the diagnosis of schizophrenia. The patients with schizophrenia were more likely to be readmitted than the 85 patients with other mental disorders. Recidivism rates for schizophrenic patients discharged on risperidone versus those discharged on clozapine were not significantly different over the 24-month study period. However, no patient who received clozapine and remained discharged for more than 10 months (N = 49) was readmitted, while the readmission rate for risperidone-treated patients appeared to be steady up to 24 months. At 24 months 87% of the clozapine-treated patients and 66% of the risperidone-treated patients remained in the community. No clinical or demographic variables were found to predict rehospitalization.. This study demonstrates that the rehospitalization rates of patients taking the second-generation antipsychotics risperidone and clozapine are lower than those in previously published reports of conventional antipsychotic treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Hospitals, Psychiatric; Hospitals, State; Humans; Male; Patient Discharge; Patient Readmission; Psychotic Disorders; Recurrence; Risk Factors; Risperidone; Schizophrenia; Treatment Outcome

Clozapine is an effective atypical antipsychotic that has high affinity for serotonin type 6 receptors (5HT6). We tested the hypothesis that clinical response to clozapine in patients refractory to typical antipsychotic treatment is related to the genetic variant (C267T) of the 5HT6 receptors. Ninety-nine schizophrenic patients with a history of non-response to typical antipsychotics were included in the study. The results demonstrated a modest but significant relationship between presence of the variant of the 5HT6 receptors and the response to clozapine in these patients. Patients with homogenous 267T/T genotype had a better response than other patients. Although replication is required, these results suggest that the 5HT6 receptor C267T polymorphism may be involved in clozapine response, especially in patients with anxious or depressed symptoms.

Topics: Antipsychotic Agents; Clozapine; DNA; DNA Primers; Genetic Variation; Genotype; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Psychotic Disorders; Receptors, Serotonin; Schizophrenia

Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.

Topics: Amino Acid Sequence; Aminopyridines; Animals; Benzazepines; Binding Sites; Carbon Radioisotopes; CHO Cells; Clozapine; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Formates; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Methionine; Mutagenesis, Site-Directed; Neuroblastoma; Phospholipids; Phosphorylation; Piperidines; Psychotic Disorders; Pyridines; Pyrroles; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; S-Adenosylmethionine; Salicylamides; Schizophrenia; Transfection; Tumor Cells, Cultured

The increase or emergence of obsessions was compared in young patients with recent-onset schizophrenia or other psychotic disorders taking clozapine and other antipsychotic drugs.. We conducted a retrospective cohort study. Subjects were 121 consecutively admitted patients diagnosed with DSM-III-R schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychotic disorder not otherwise specified. Obsessions were diagnosed according to DSM-IV criteria.. More clozapine-treated subjects (20.6%) than subjects treated with other antipsychotic drugs (1.3%) experienced an emergence or increase of obsessions (p<.01).. Use of clozapine is associated with the emergence or increase of obsessions in early-phase schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Female; Humans; Male; Obsessive-Compulsive Disorder; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In spite of some inherent limitations, naturalistic data can provide information on populations that have greater heterogeneity than can controlled clinical trials and on functional outcomes that may be especially important in clinical practice. In the present retrospective naturalistic study, we evaluated key clinical outcomes among the first wave of risperidone-treated patients at a state psychiatric hospital.. Outcome data were extracted from the charts of 142 patients 2 years after initiation of treatment with risperidone. Their diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%), dementia and other organic conditions (7%), bipolar disorder (5%), and other psychiatric disorders (9%).. During the 2-year period, 92 of 142 patients were discharged from the hospital: 61 (43%) were discharged on risperidone treatment and 31 (22%) were discharged on treatment with other drugs. At the time of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%) were still receiving risperidone. The modal maximum daily dose of risperidone was 4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients still in the hospital. All groups were granted more ward privileges after starting risperidone, the most being granted to patients discharged from the hospital on risperidone treatment (p<.05 versus patients discharged on treatment with other drugs) and those still receiving risperidone in the hospital. Significantly fewer patients discharged on risperidone treatment than on treatment with other drugs were readmitted to the hospital within 2 years after discharge (p<.01).. Improved privilege levels and a reduced readmission rate indicate that risperidone was an effective antipsychotic agent among a heterogeneous patient population in a state hospital. These factors may be especially important to justify use of this agent in the current fiscal climate.

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dementia; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Hospitals, Psychiatric; Hospitals, State; Humans; Length of Stay; Male; Mental Disorders; Patient Readmission; Psychotic Disorders; Retrospective Studies; Risperidone; Schizophrenia

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal side-effect of antipsychotic drug therapy, especially of dopamine receptor antagonists. As a dose relationship has been postulated, low dose neuroleptization would be expected to help to avoid this side-effect. In contrast, we report on a 21-year-old female following low dose fluphenazine treatment with 2.5 mg/day. The patient recovered from NMS after 3 days of dantrolene administration. Eventually, remission from psychotic symptoms was achieved with clozapine. At 8-month follow-up, psychopathology remained stable and there were no more signs of NMS.

Topics: Adult; Antipsychotic Agents; Clozapine; Dantrolene; Female; Fluphenazine; Humans; Muscle Relaxants, Central; Neuroleptic Malignant Syndrome; Psychotic Disorders

During clinical experience with the "atypical" neuroleptic drugs clozapine, risperidone, and zotepine, some patients have shown a marked weight gain. To prove whether weight gain is a relevant side effect of atypical neuroleptics, the charts of all patients admitted with DSM-III-R diagnoses of schizophrenia, schizoaffective disorder, or delusional disorder in the years 1991 to 1995 were evaluated. A retrospective chart review was performed, which included all patients who were treated longer than 2 weeks with a single neuroleptic. The data analysis showed that weight gain must be considered as a common side effect of atypical neuroleptics (clozapine, risperidone, sulpiride, or zotepine). The mean weight gain (3.1, 1.5, 1.9, or 4.3 kg, respectively) was significantly higher than that of patients treated with "classic" neuroleptics (mean, 0.0-0.5 kg) (Kruskal-Wallis, p = 0.01). Young and not obese patients show the highest weight increase. Because weight gain occurs in the first weeks of treatment, particularly in previously untreated subjects, this side effect has to be considered in view of compliance with long-term neuroleptic medication.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Body Mass Index; Clozapine; Delusions; Dibenzothiepins; Female; Humans; Long-Term Care; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Risperidone; Schizophrenia; Sulpiride; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome

This study was conducted to determine serum lipid level changes in patients who received clozapine or haloperidol.. Medical records of 222 inpatients treated with clozapine or haloperidol were reviewed. Age, weight, gender, daily antipsychotic dose, total cholesterol level, serum triglyceride level, and concurrent medications were recorded.. Clozapine-treated men had significantly higher follow-up serum triglyceride concentrations over baseline than did haloperidol-treated men. Female patients experienced serum triglyceride level elevations regardless of antipsychotic treatment. Changes in total cholesterol levels were not significantly different between treatment groups.. An increase in serum triglyceride levels occurred in clozapine-treated patients; screening for serum triglyceride elevations may be warranted before treatment with clozapine.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Female; Haloperidol; Hospital Records; Hospitalization; Humans; Hypertriglyceridemia; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Sex Factors; Triglycerides

Antipsychotic polypharmacy is a surprisingly frequent occurrence that can be both justified and unjustifed, depending on how it is used. To the extent that this phenomenon has been unrecognized and is not being studied, it is a "dirty little secret." To the extent that careful clinicians have uncovered a useful strategy for boosting the effectiveness of available antipsychotic monotherapies, it represents an opportunity to improve the outcomes of patients with psychotic illnesses.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Humans; Olanzapine; Pirenzepine; Polypharmacy; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

Clozapine has been reported to be effective in diminishing violence toward others in psychotic patients. This article describes the impact of clozapine on severe self-mutilation among patients with the dual diagnoses of borderline personality disorder and persistent psychoses.. Seven subjects known to the authors were selected for careful chart audits. These subjects had been admitted to 2 state psychiatric hospitals owing to severe self-mutilation and/or violence and subsequently treated with clozapine. A mirror-image design anchored to the start date of clozapine treatment and extending in either direction to a maximum of 1 year was used to extract data. Data extracted included incidents of self-mutilation (restraint), seclusion, the as and when needed (p.r.n.) use of medications, injuries to staff and peers, hospital privileges, and Global Assessment of Functioning (GAF) scores.. The subjects were all white women with a mean age of 37 years. All subjects carried DSM-III-R or DSM-IV borderline personality disorder diagnoses and an Axis I disorder diagnosis. They had received trials of several psychotropic agents, often in combination and mostly without benefit. After clozapine treatment, there were statistically significant reductions in incidents of self-mutilation (restraint), seclusion, the use of p.r.n. antianxiety medications, and injuries to staff and peers. These subjects received higher levels of hospital privileges, and their GAF scores nearly doubled following clozapine treatment. Four subjects were subsequently discharged from hospital.. These preliminary but nonetheless favorable results suggest that clozapine deserves careful consideration for a controlled study in patients with borderline personality disorder and psychoses, especially if the clinical issues include severe self-mutilation, aggression, and violence. Until such studies are done, the risk-to-benefit ratio of clozapine treatment needs to be carefully evaluated on an individualized basis in such subjects.

Topics: Adult; Aggression; Antipsychotic Agents; Borderline Personality Disorder; Clozapine; Comorbidity; Drug Administration Schedule; Female; Hospitalization; Humans; Medical Records; Middle Aged; Psychotic Disorders; Restraint, Physical; Risk Assessment; Self Mutilation; Severity of Illness Index; Social Isolation; Treatment Outcome

There are many difficulties associated with the late stages of Parkinson's disease (PD), but psychosis and agitation may be the most disturbing for both patients and care givers, and often precipitate the pivotal decision for long-term nursing home placement. While the addition of antipsychotic drugs or the withdrawal of antiparkinsonian drugs may improve the behavioral problem, these strategies usually worsen the motor difficulties. Clozapine has been studied in PD for over a decade, and while it appears to be effective, there are safety and tolerability concerns associated with it. In addition, in New Jersey, Medicaid no longer pays for the home blood draws that are required for home-bound patients. This led to a situation in which we had patients who needed to stop clozapine and begin an alternative therapy. Because quetiapine seems particularly well suited to patients with PD based on in vitro and in vivo studies we have begun to try this medication in PD patients who need to stop clozapine. This article reports three case histories of patients with PD, confusion and dopamimetic psychosis who had been previously managed with clozapine and who were successfully switched to quetiapine. At doses from 12.5 to 150 mg/day quetiapine was well tolerated, resulting in behavioral improvement and no real increase in parkinsonism. These case histories raise the possibility that quetiapine may represent a viable alternative to clozapine in PD patients with dopamimetic psychosis and behavioral disturbances.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Confusion; Dibenzothiazepines; Dose-Response Relationship, Drug; Female; Humans; Male; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate; Treatment Outcome

Weight gain has been reported with nearly every antipsychotic drug on the market (molindone is an exception). Weight gain occurs no matter what the patient's age, sex, or race and is seen with both oral and depot drug formulations. Numerous studies have found that patients gain weight when treated with a conventional antipsychotic, such as chlorpromazine, fluphenazine, and haloperidol. The newer, novel antipsychotics offer advantages over conventional antipsychotics, especially a relative lack of extrapyramidal symptoms, but some still have the disadvantage of causing weight gain. Clozapine and olanzapine in particular appear to cause substantial weight gain, much more so than do most conventional neuroleptics and novel agents such as risperidone. Given the risks to health and treatment compliance associated with weight gain and obesity, clinicians should monitor weight during the course of antipsychotic therapy and consider switching agents if excessive weight gain occurs.

Topics: Administration, Oral; Antipsychotic Agents; Benzodiazepines; Clozapine; Delayed-Action Preparations; Humans; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Weight Gain

Topics: Acute Disease; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Humans; Male; Middle Aged; Perphenazine; Psychoses, Substance-Induced; Psychotic Disorders

Serum triglyceride levels of four patients with psychotic disorders were decreased after switching therapy from clozapine to risperidone. In two patients clozapine was reinstated after risperidone was discontinued; serum triglyceride levels increased. This increase when clozapine was switched to risperidone and vice versa is consistent with our previous report of elevated serum triglyceride levels in clozapine-treated patients. Other reports show increases with the atypical antipsychotics, olanzapine and quetiapine. We believe serum triglyceride levels should be monitored in patients who have other cardiac risk factors and are receiving clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Psychotic Disorders; Risk Factors; Risperidone; Triglycerides

The aim of this paper is to survey patterns of use of new generation and conventional antipsychosis and adjunctive drugs by an inner urban community psychiatric service.. All prescriptions for antipsychosis medications and all patients receiving these drugs in May 1998 were identified. Case record review yielded demographic and diagnostic data. Information was also obtained directly from prescribers.. Of 859 patients, 77% received antipsychosis medication; 53% of prescriptions for antipsychotics were for new generation drugs: risperidone (42%), olanzapine (37%) and clozapine (21%). Mean doses were 4.1+/-2.5 mg (risperidone), 14.7+/-8.2 mg (olanzapine) and 377.4+/-178.9 mg (clozapine). Doses for men tended to be higher than those for women, but the differences were not significant. DSM-IV diagnosis was schizophrenia for 74% of patients on atypicals, but patients with other diagnoses were also being treated with these drugs. Risperidone was more commonly used in combination with benzodiazepines and anticholinergics than olanzapine and clozapine, while clozapine was less likely to be combined with antidepressants and mood stabilisers. Of the conventionals, 66% were in depot form, mostly because of non-compliance. Combinations of antipsychotics were prescribed to 13% of patients.. New generation antipsychosis medications were prescribed more commonly than conventional drugs in this service for a wide range of diagnoses. Adjunctive medications were commonly utilised. These findings underline the clinical complexity of antipsychotic treatment in a changing environment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Community Mental Health Services; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Utilization; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Urban Population

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Psychotic Disorders; Tourette Syndrome

Topics: Adult; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukopenia; Middle Aged; Paroxetine; Psychotic Disorders

This article discusses the controversial use of restraints with a persistently violent adolescent on a child and adolescent psychiatry unit. The authors present an individualized program that used a series of ambulatory restraints on a long-term basis and prophylactically to contain the aggression of a psychotic girl. Clozapine was used concomitantly to control her psychosis. The prophylactic use of mechanical restraints allowed this teenager to be integrated into the milieu and to receive multiple treatments that the standard protocol precluded. This case underscores the difficulties in managing aggression when youths do not respond to standard protocols and do not conform to our assumptions about the least restrictive alternative. It is concluded that prophylactic mechanical restraint provided the least restrictive alternative to personal freedom for this teenager and had therapeutic benefit.

Topics: Adolescent; Aggression; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Female; Humans; Patient Admission; Patient Isolation; Psychiatric Department, Hospital; Psychotic Disorders; Restraint, Physical; Suicide, Attempted; Violence

We wished to study long-term psychiatric hospital utilization in a large sample of patients with schizophrenia and/or schizoaffective disorders who were treated with clozapine for up to 4.5 years, and to determine whether or not the reduction in hospital utilization we previously observed in smaller groups for up to 2.5 years was sustained with larger groups and in the longer term.. Patients in Texas state hospitals who had schizophrenia and/or schizoaffective disorder took either clozapine or traditional antipsychotics for 1.5 to 4.5 years. The number of patients in the clozapine group ranged from 383 (1.5 years of treatment) to 29 (4.5 years). The group of patients who took traditional antipsychotics was made up of all patients (N = 233) with similar diagnoses, symptom severity, and duration of illness present in Texas state hospitals on an index day.. The clozapine group showed a rapid and continuing decrease in hospital bed-days compared with controls who took traditional antipsychotics. The number of clozapine-treated patients who required little or no hospitalization during successive 6-month periods became significant (p < .0001) within 1.5 years, and continued to increase. Conversely, the number of patients taking clozapine who required virtually continuous state hospitalization decreased markedly compared with those taking traditional antipsychotics.. Potential hospital cost savings are substantial, even though overall group results are diluted by clozapine nonresponders. Most treatment costs for clozapine nonresponders were related to hospital care; most or all of such costs would have been present in any event had these patients remained on traditional antipsychotic therapy. We believe a trial of clozapine therapy provides a low-cost opportunity for a highly effective and highly cost-saving outcome in those patients who will favorably respond to this therapy. We discuss clinical, social, and economic advantages of modern pharmaceutical treatments over traditional drugs.

Topics: Antipsychotic Agents; Clozapine; Cohort Studies; Community Mental Health Services; Cost-Benefit Analysis; Economics, Hospital; Follow-Up Studies; Health Care Costs; Hospitalization; Hospitals, Psychiatric; Hospitals, State; Humans; Length of Stay; Psychotic Disorders; Schizophrenia; Texas; Utilization Review

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Psychotic Disorders; Schizophrenia; Treatment Outcome

The cost-effectiveness of using the atypical antipsychotic medication clozapine for severe psychosis was examined in a rural public-sector community mental health setting in Virginia. Based on a sample of 20 patients, use of clozapine resulted in estimated cost savings of between $3,000 and $9,000 per patient per year, including the costs of dropouts from treatment. Savings were mainly due to a decline in hospitalization from 47.7+/-59.8 days per patient in the year before clozapine treatment to 4.6+/-11.3 days in the year after. Although this study had methodological limitations, the results suggest that clozapine may be cost-effective in this setting.

Topics: Adult; Antipsychotic Agents; Clozapine; Community Mental Health Services; Cost Savings; Cost-Benefit Analysis; Female; Humans; Male; Middle Aged; Patient Readmission; Psychotic Disorders; Public Sector; Virginia

1. Tardive Dyskinesia (TD) can be a serious consequence of the use of antipsychotic medications to treat psychotic illness. There is evidence to suggest that the atypical antipsychotic, clozapine, is less likely to cause, and may even ameliorate TD. 2. The authors reviewed their experience regarding clozapine and TD among patients in their Clozapine Clinic, and summarize some of the recent clinical literature in this area. 3. Retrospective review of chart records for 13 patients was carried out. Comparisons of TD and symptom rating scales were made: 1) between groups (with and without TD) at baseline; 2) between individuals (self as own control) in the TD group at baseline and at the end of the follow-up period. 4. Subjects with and without TD at baseline had a significant decrease in psychiatric symptoms over the course of treatment. 5. In those with TD at baseline, mean Abnormal Involuntary Movement Scale (AIMS) score decreased by 85% over 10.3 +/- 5.5 (mean +/- S.D.) months at a dose of 358 +/- 196 mg/day of clozapine. 6. The data, and the recently published clinical literature on clozapine and TD, continue to support the striking utility of clozapine for chronically psychotic patients, and particularly those with TD.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Treatment Outcome

Suicide is a significant cause of death among patients with schizophrenia and schizoaffective disorder, affecting some 10 to 15 percent of these patients. This study examined annual suicide rates over a two-year period (1993-1995) among more than 30,000 patients with schizophrenia and schizoaffective disorder who received services from the Texas Department of Mental Health and Mental Retardation and suicide rates over a six-year period (1991-1996) among a subgroup of patients treated with clozapine.. The annual suicide rate for all patients with schizophrenia and schizoaffective disorder was 63.1 per 100,000 patients, approximately five times higher than in the general population. In contrast, only one suicide occurred in six years among patients treated with clozapine who were of similar diagnosis, age, and sex, for a suicide rate of about 12.7 per 100,000 patients per year. This rate is similar to the 15.7 per 100,000 patients per year for all U.S. patients treated with clozapine, calculated from data reported as of June 1996 to the clozapine national registry system maintained by Novartis Pharmaceuticals Corporation, the U.S. manufacturer of clozapine.. The study results suggest that clozapine therapy is associated with a reduced risk of suicide among patients with schizophrenia and schizoaffective disorder.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Suicide; Suicide Prevention; Texas

Clozapine has been shown to be a cost-effective treatment for refractory psychosis among patients started on the medication in a hospital setting. The study examined service utilization and costs associated with clozapine treatment initiated in an outpatient clinic.. Subjects (N=28) included adult patients with a diagnosis of schizophrenia or schizoaffective disorder who began their clozapine treatment at an urban community mental health center. Subjects' charts were reviewed for information on service utilization in the year before and after starting clozapine, using an intent-to-treat approach. Hospitalization information was cross-checked against the Illinois Department of Human Services database. Costs were computed for hospitalization, medication, community outpatient services, and housing.. Subjects' mean rate of hospitalization was reduced by more than half during the clozapine treatment year, and the mean number of days in the hospital decreased by more than two-thirds, from 23.5 days to 7.6 days. Mean hospitalization costs were reduced by more than half. Mean annual costs of medication rose from $648 in the year before clozapine treatment to $6,760 during the clozapine treatment year. Cost increases for medication, community services, and housing led to a marginal increase in the total cost of treatment.. Patients initiating clozapine treatment on an outpatient basis showed a pattern of decreased hospitalization during the first year on clozapine. The cost savings associated with decreased hospitalization substantially, though not fully, offset the increased expense of clozapine during the first year of community-based treatment.

Topics: Adult; Ambulatory Care Facilities; Antipsychotic Agents; Chicago; Clozapine; Community Mental Health Services; Costs and Cost Analysis; Humans; Psychotic Disorders; Schizophrenia

Topics: Adult; Anti-HIV Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Male; Neutropenia; Psychotic Disorders; Zidovudine

The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non-insulin-dependent diabetes mellitus.. We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases.. Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics.. Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychotic-associated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic beta-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Syndrome

To examine the seizure characteristics and electroencephalogram (EEG) abnormalities in psychiatric patients taking clozapine, given the estimate of a 10% cumulative risk of generalized seizures in this population.. We reviewed all consecutive EEGs of ambulatory psychiatric patients taking clozapine performed at our laboratory during 1996 and 1997.. A university-affiliated urban teaching hospital.. Twelve patients (4 F/8 M; mean age 40.1 y, range 20-63) had either presented with de novo ictal events within the first month of clozapine therapy (n = 8) or had EEGs recorded to assess seizure risk (n = 4).. According to clinical history and interictal EEG findings, the patients were subdivided as follows: three patients with generalized tonic-clonic seizures, two with generalized myoclonic jerks (1 associated with simple partial seizures), two with complex partial seizures, and one with simple partial seizures. The EEGs revealed interictal epileptiform abnormalities (IEDs) in eight patients, two of whom had not had seizures. IEDs were focal or multifocal, with a predominance of left temporal foci. One patient showed a paroxysmal response to photic stimulation.. Patients taking clozapine may be prone to partial seizures and focal EEG abnormalities as well as to generalized seizures and EEG abnormalities, as previously reported.

Topics: Adult; Antipsychotic Agents; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Outpatients; Psychotic Disorders; Seizures; Temporal Lobe

Previous studies of clozapine pharmacokinetics have shown a wide intra- and inter-individual variability of plasma levels in patients on stable clozapine doses. We investigated dose-plasma level relationships and intra-individual variability of plasma levels during maintenance treatment with clozapine.. Forty-one patients on clozapine were followed for 26 weeks with repeated plasma level measurements and assessments of co-medication and clinical symptoms. In a second step, 15 patients on stable clozapine doses between treatment Weeks 12 and 52 were followed in the same way. Coefficient of variation was used as a parameter of plasma level deviation.. Dose-plasma level correlations stayed significant from Week 6 to Week 26 (n = 41). The group of patients followed up to Week 52 showed a mean intra-individual coefficient of variation of 52.8% (s.d. = 20.6), and remained stable psychopathologically.. Even though clozapine plasma levels may show a significant degree of variation, this is not necessarily reflected in a change in psychopathology.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Psychotic Disorders; Schizophrenia

Topics: Adult; Antipsychotic Agents; Circadian Rhythm; Clozapine; Humans; Male; Psychotic Disorders; Recurrence; Travel

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Antipsychotic Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; gamma-Glutamyltransferase; Humans; L-Lactate Dehydrogenase; Liver Function Tests; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Clozapine; Dopamine; Drug Therapy, Combination; Haloperidol; Humans; Norepinephrine; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Lupus Coagulation Inhibitor; Male; Partial Thromboplastin Time; Psychotic Disorders

Clozapine often causes low-grade fever and less frequently spiking fever. We describe three cases of spiking fever that occurred in the first 3 weeks of clozapine therapy. A new set of side effects of clozapine is identified, which includes spiking fever, respiratory and gastrointestinal symptoms, and neutrophilia. Possible mechanisms are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Fever; Gastrointestinal Diseases; Humans; Leukocyte Count; Lung Diseases; Male; Neutrophils; Psychotic Disorders; Schizophrenia, Paranoid

Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis.. We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus.. The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms.. Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.

Topics: Adult; Blood Glucose; Clozapine; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Hyperglycemia; Male; Middle Aged; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Delirium; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Middle Aged; Neurologic Examination; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychotic Disorders; Risk Factors; Risperidone; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Cellulitis; Clozapine; Eosinophilia; Humans; Male; Pleural Effusion; Psychotic Disorders

Recently, American authors pronounced the hypothesis that Clozapine-response may be considered as a predictor of response to atypical neuroleptic. We report the history of a schizoaffektive patient unresponsive to butyrophenone and phenothiazine neuroleptic who was first treated with Clozapine and then with Risperidone and who reacted very differently to these atypical neuroleptic.

Topics: Adult; Amitriptyline; Antipsychotic Agents; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Prognosis; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Treatment Outcome

Hyperprolactinemia is a well-known consequence of conventional antipsychotic therapy. The atypical antipsychotic clozapine is reported to lack this effect. We describe a case of attenuated serum prolactin levels after conversion to clozapine therapy in an adolescent. A 13-year-old female patient developed hyperprolactinemia with galactorrhea and amenorrhea while receiving thioridazine 300 mg daily. These symptoms continued throughout 3 years of treatment with haloperidol 10 mg daily and then fluphenazine 10 mg daily. Subsequently, after an incomplete improvement in her psychiatric symptoms and hyperprolactinemia on thioridazine 150 mg and bromocriptine 15 mg daily, the patient was changed to clozapine at age 16. Clozapine 150 mg twice daily improved her psychiatric status and corrected her serum prolactin concentrations after 2 weeks; bromocriptine was able to be discontinued. We recommend systematic evaluation of atypical neuroleptics as alternative treatments for refractory hyperprolactinemia induced by conventional antipsychotics.

Topics: Adolescent; Amenorrhea; Antipsychotic Agents; Bromocriptine; Clozapine; Female; Fluphenazine; Galactorrhea; Haloperidol; Humans; Hyperprolactinemia; Prolactin; Psychotic Disorders; Thioridazine

The objective was to analyze outcome of clozapine therapy in elderly patients with treatment refractory primary psychosis.. This was an open-label clozapine trial in elderly patients. Patient psychopathology was assessed before and after clozapine therapy.. A psychiatry service at a large urban/suburban Veterans Administration Medical Center.. Inpatients and outpatients age 65 years or older with primary psychotic disorders established to be resistant to conventional antipsychotic therapy (Kane et al., 1988). Ten patients met study inclusion criteria out of a total of 134 patients receiving clozapine at the Cleveland VAMC (7.5%). Mean age of the group was 70.6 years.. Patients were rated with the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962). Additional data on patient demographics, comorbid non-psychiatric diagnoses and concurrent psychotropic medication were collected via chart review.. Mean clozapine dosage was 204 mg/day for a mean duration of 430 days. 7/10 patients had some degree of clinical improvement and 3/10 patients had significant improvement documented by BPRS change of 20% or greater. Patients had a mean of 1.4 comorbid physical illnesses, which were not worsened by clozapine therapy. 4/10 patients discontinued clozapine therapy due to adverse effects or inability to comply with bloodwork; however; only 2/10 were truly treatment intolerant.. Clozapine is a useful alternative treatment option for elderly individuals with refractory primary psychosis. As in younger patients, inability to tolerate drug-related adverse effects or weekly bloodwork may lead to drug discontinuation.

Topics: Aged; Antipsychotic Agents; Clozapine; Female; Humans; Male; Psychotic Disorders; Recurrence; Retrospective Studies; Treatment Outcome

To test the efficacy of clozapine in treatment-resistant manic episodes.. Three cases, two with bipolar disorder (manic) and one of schizoaffective disorder (manic), were treated with clozapine.. Clozapine was used after the failure of standard antipsychotics and mood stabilizers.. All three cases were successfully treated.. A controlled trial of clozapine in treatment-resistant bipolar and schizoaffective manic episodes is indicated.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Combined Modality Therapy; Drug Resistance; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Male; Paranoid Disorders; Psychotic Disorders; Reserpine; Treatment Outcome

Topics: Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; History, 20th Century; Humans; Olanzapine; Pirenzepine; Psychotic Disorders

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Psychotic Disorders; Stuttering

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Haloperidol; Humans; Imidazoles; Indoles; Male; Psychotic Disorders; Risperidone; Schizophrenia; Treatment Failure

Topics: Adult; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Microsomes, Liver; Psychotic Disorders

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Disease Management; Drug Costs; Humans; Mental Health Services; New York City; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Treatment Outcome

Topics: Adult; Clozapine; Deamino Arginine Vasopressin; Enuresis; Female; Humans; Male; Mandelic Acids; Parasympatholytics; Prevalence; Psychotic Disorders; Urination Disorders

Topics: Adult; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Female; Humans; Mixed Function Oxygenases; Oxidoreductases; Psychotic Disorders

Topics: Adult; Agranulocytosis; Clozapine; Drug Therapy, Combination; Female; Humans; Psychotic Disorders; Risperidone

Recent case reports indicate that clozapine treatment diminishes excessive diurnal weight gain and alleviates hyponatremia observed in some chronically psychotic patients. We examined the influence of clozapine on sodium metabolism and water regulation across a group of patients with the syndrome of polydipsia and intermittent hyponatremia.. Eleven patients with treatment-resistant DSM-III-R schizophrenia or schizoaffective disorder were studied. Each had a history of repeated diurnal weight gains of greater than 10% with at least one documented bout of hyponatremia in the 6 months before clozapine treatment. We utilized a target weight protocol and serial laboratory measures to compare changes in sodium metabolism and water regulation during 26 weeks of standard antipsychotic medication and 26 weeks of clozapine treatment.. Across patients, we found significant improvement in routinely monitored 6 a.m. and 4 p.m. serum sodium, reflecting normalization of sodium metabolism. We also found that the frequency (as reflected by diurnal weight gain), severity (lowest serum sodium), and estimated quantity (calculated urine volume) of polydipsia improved across patients. Improvement in polydipsia and hyponatremia was associated with decreased necessity for monitoring and restrictive interventions, and tended to be associated with psychiatric improvement.. We found a corrective and stabilizing effect of clozapine on polydipsia and intermittent hyponatremia. Future studies need to examine the relationship of psychiatric improvement and alterations in the regulation of sodium and water physiology to our findings.

Topics: Adult; Circadian Rhythm; Clozapine; Drinking; Female; Humans; Hyponatremia; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Sodium; Thirst; Water Intoxication; Water-Electrolyte Balance; Weight Gain

Topics: Clozapine; Comorbidity; Humans; Male; Psychotic Disorders; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans

Topics: 1-Naphthylamine; Adult; Clozapine; Drug Therapy, Combination; Humans; Lithium; Male; Obsessive-Compulsive Disorder; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome; Valproic Acid

Topics: Age Factors; Aged; Clozapine; Dementia; Drug Administration Schedule; Humans; Psychotic Disorders

The authors' goal was to determine whether either of two 5-HT2A receptor polymorphisms, 102-T/C and 452-His/Tyr, are associated with clozapine response.. Brief Psychiatric Rating Scale (BPRS) ratings were obtained in 70 patients with schizophrenia or schizoaffective disorder to determine their response to clozapine compared with a typical neuroleptic. Patients were genotyped with the polymerase chain reaction and restriction fragment length polymorphism analysis.. Neither 102-T/C nor 452-His/Tyr was associated with clozapine response. There were no significant differences in BPRS scores among patients with different 5-HT2A genotypes at week 10 of clozapine administration.. Allelic variation in the 5-HT2A gene is not associated with individual differences in clozapine response.

Topics: Adult; Alleles; Clozapine; Female; Genetic Variation; Genotype; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Psychiatric Status Rating Scales; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia

Topics: Adult; Antipsychotic Agents; Bromocriptine; Clozapine; Dancing; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Humans; Male; Psychotic Disorders; Trihexyphenidyl; Vitamin E

The purpose of this study was to test the hypothesis that minor EEG abnormalities predict a favorable response to clozapine. Eighty-six psychotic clozapine-treated psychiatric inpatients with EEG records before starting clozapine were included in the study. When all diagnostic groups were combined, there were no significant differences in clinical outcome between patients with abnormal EEGs and patients with normal EEGs. However, female patients with abnormal EEGs had a significantly greater improvement in Global Assessment of Functioning (GAF) scores compared to female patients with normal EEGs. In addition, patients with major depressive episodes (bipolar, schizoaffective, unipolar) and abnormal EEGs had a significantly greater improvement in GAF scores compared to the same subgroup of patients with normal EEGs. The results suggest that EEG abnormalities before clozapine treatment many predict a favorable clinical response in specific groups of patients.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Depressive Disorder; Electroencephalography; Female; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Sex Factors; Single-Blind Method; Treatment Outcome

Topics: Antipsychotic Agents; Canada; China; Clozapine; Humans; Psychotic Disorders

Topics: Clozapine; Disorders of Excessive Somnolence; Drug Monitoring; Humans; Male; Methylphenidate; Middle Aged; Psychotic Disorders; Sleep Wake Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Neurologic Examination; Psychotic Disorders

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Clozapine; Diagnosis, Dual (Psychiatry); Female; Humans; Male; Middle Aged; Psychotic Disorders; Substance-Related Disorders

Topics: Adolescent; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Psychotic Disorders

Topics: Agranulocytosis; Antipsychotic Agents; Bone Marrow; Clozapine; Drug Monitoring; Female; Humans; Male; Psychotic Disorders; Risk Factors; Schizophrenia; Schizophrenic Psychology

The presence of the 5HT2C receptor allele, Ser23, has recently been reported to predict favorable response to the antipsychotic drug, clozapine. This finding is of interest as Ser23, compared with the more abundant Cys23, alters pharmacological characteristics of the receptor and therefore may provide insights into the mechanism of action of antipsychotic drugs. We determined 5HT2C receptor genotype at the Cys23Ser locus in 66 subjects participating in double-blind studies of clozapine. There was no relationship between Ser23 and clozapine response (p = 0.30, Fisher's exact) nor was there any effect of Ser23 upon absolute levels of psychiatric symptoms after 10 weeks of clozapine treatment (t = -0.57, p = 0.57). These data suggest that this 5HT2C receptor polymorphism is not associated with clozapine response.

Topics: Alleles; Antipsychotic Agents; Base Sequence; Clozapine; Cysteine; DNA Primers; Female; Genetic Carrier Screening; Homozygote; Humans; Male; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Predictive Value of Tests; Psychotic Disorders; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Schizophrenia; Serine

Topics: Acids; Adult; Antipsychotic Agents; Chlorpromazine; Clozapine; Cross Reactions; Drug Hypersensitivity; Humans; Male; Psychotic Disorders

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

Topics: Adult; Age Factors; Aged; Bradycardia; Cardiovascular Diseases; Clozapine; Drug Administration Schedule; Humans; Psychotic Disorders; Respiration Disorders

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Psychotic Disorders; Receptors, Dopamine; Receptors, Neurotransmitter; Risk Factors; Risperidone; Schizophrenia

While effective as a single agent in a significant proportion of treatment refractory patients, clozapine is often used in combination with other medications, including classical neuroleptics (1), mood stabilizers and antidepressants (2), benzodiazepines (3) and lithium (4). In Denmark, where clozapine has been in near continuous use since 1975, up to 60% of clozapine patients receive additional medication (4). Classical neuroleptics, often at antipsychotic levels, are the medications most frequently added, and are used in 30-35% of patients receiving clozapine (4,5). Clozapine, due to its low D2-blocking effect, may be therapeutically insufficient to contain symptoms and additional agents may be required (4). In controlled clinical trials risperidone has been shown to be superior to haloperidol (6), but has not yet been rigorously compared to clozapine. In light of its established efficacy and pharmacological profile (7) risperidone may be reasonably construed to be a medication with efficacy somewhere between clozapine and classical neuroleptics. As such, it may be especially well suited for use with clozapine as a part of an augmentation strategy. There are no reports in the literature describing the concurrent use of risperidone and clozapine. We present two cases demonstrating augmentation of clozapine's effects through combined use with clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Isoxazoles; Male; Piperidines; Psychotic Disorders; Risperidone; Schizophrenia, Paranoid; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Humans; Isoxazoles; Male; Piperidines; Psychotic Disorders; Risperidone

This study estimated rates of eligibility for treatment with clozapine among clients in a public mental health system using criteria with various degrees of restrictiveness.. A stratified, random cluster sample of 293 clients was selected from among all clients with schizophrenic disorders known to the mental health system of the city and county of San Francisco during 1991. Data on variables associated with eligibility for clozapine were abstracted from clinical records, and eligibility was estimated using broad and stringent criteria.. An estimated 42.9 percent of the clients were eligible for clozapine using broad eligibility criteria that included a diagnosis of schizophrenia or schizoaffective disorder, two previous neuroleptic trials of at least 600 mg per day chlorpromazine equivalents for at least four weeks or tardive dyskinesia, Global Assessment of Functioning score less than 61, and no contraindications. Eliminating eligibility due to tardive dyskinesia alone, excluding persons with schizoaffective disorder, requiring six-week medication trials, and requiring three adequate medication trials instead of two resulted in substantial reductions in the rate of eligibility.. Varying interpretations of the criteria for clozapine treatment listed in the medication package insert dramatically affect patients' eligibility for clozapine. Mental health agencies should endeavor to maintain a balance between restricting use of clozapine due to cost and providing it to the full spectrum of patients who might benefit from the medication.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Eligibility Determination; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Public Sector; San Francisco; Schizophrenia; Schizophrenic Psychology; United States; United States Food and Drug Administration

Clozapine is a novel antipsychotic that is effective in 30% to 50% of treatment-resistant schizophrenia. It is known to cause sialorrhea in 23% of patients. This phenomenon is paradoxical and poorly understood since clozapine is known to have potent anticholinergic effects. We have observed the development of transient salivary gland swelling in four patients on clozapine therapy. Although not clearly related to sialorrhea, this phenomenon may share a similar pathophysiology.. A retrospective chart review was performed on the 4 of 27 patients started on clozapine treatment during a 6-month period who developed salivary gland swelling.. Four patients, none of whom had previously complained of sialorrhea, developed salivary gland swelling after starting clozapine treatment. In all cases, the swelling resolved within days. A possible etiology may be the formation of a calculus that blocks the duct and causes swelling, which resolves when the stone passes.. Clinicians should be aware that salivary gland swelling may be a possible side effect of clozapine use.

Topics: Adult; Aged; Clozapine; Edema; Female; Humans; Psychotic Disorders; Retrospective Studies; Salivary Duct Calculi; Salivary Gland Diseases; Schizophrenia

1. Clozaril, an atypical antipsychotic, did not gain approval for use in Australia until 1992. Prior to its general release, a trial was conducted in three pilot sites to test the efficacy of a monitoring system. 2. Fear of litigation among hospital staff was reduced through educational sessions that reported on the low incidence of serious side effects and the efficacy of the monitoring system. 3. The most common side effect noted with initiation of Clozaril was sedation, which persisted for 4 to 6 weeks. Subsequent side effects included drowsiness, increased salivation, and tachycardia.

Topics: Attitude of Health Personnel; Australia; Clozapine; Cross-Cultural Comparison; Drug Monitoring; Humans; Nursing Assessment; Patient Care Team; Psychotic Disorders

Misidentification syndromes represent false, delusionally-based identification of self and/or others. These are variants of the Capgras Syndrome. Although the frequency of misidentification syndromes in schizophrenic populations has not yet been established, the authors believe this syndrome is more prevalent than previously described. Seven of twenty-five (28%) consecutive patients admitted to a chronic clozapine unit with a variant of misidentification syndrome will be described. Their symptoms are categorised according to traditional classification, and Silva's proposed nomenclature. Problems inherent in these classifications are discussed. The need for a more systematic classification of misidentification syndromes is emphasised. Longitudinal studies of misidentification syndrome, and the development of a standardised assessment tool for clinicians who treat chronically psychotic patients, are encouraged.

Topics: Adult; Capgras Syndrome; Clozapine; Delusions; Female; Hospitalization; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

The effects of clozapine administration on smoking were examined in chronic schizophrenic outpatients.. Twenty-nine of 30 schizophrenic outpatients enrolled in a university-affiliated Community Mental Health Center clozapine clinic were retrospectively surveyed by semistructured questionnaire regarding smoking before and after clozapine administration.. Smokers comprised 62% (N = 18) of patients, and within this group, there was a significant decrease in reported daily cigarette use during clozapine treatment compared with level of use when patients had been treated with typical neuroleptics (1.67 +/- 1.13 vs. 1.26 +/- 0.72 packs/day, p = .025).. Clozapine may alter smoking behaviors in chronic schizophrenics.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Chronic Disease; Clozapine; Coffee; Drinking; Female; Humans; Male; Middle Aged; Pilot Projects; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Smoking; Smoking Cessation; Smoking Prevention

This study was done to test the hypothesis that serum concentration of norclozapine is a risk factor for leukopenia during treatment with clozapine.. Maximum decreases in leukocyte counts in 44 unselected patients treated with clozapine were determined and then correlated with drug doses and serum concentrations of clozapine, norclozapine, and clozapine-N-oxide.. White cell and granulocyte counts decreased by up to 60%-73%, but there were no positive correlations between these decrements and drug dose, drug level, ratio of drug level to drug dose, or ratio of norclozapine level to clozapine level, nor were the decreases related to age or gender.. While these results do not suggest in vivo hemotoxicity of norclozapine, further study of patients with clinically significant leukopenia is required.

Topics: Clozapine; Female; Follow-Up Studies; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Psychotic Disorders; Risk Factors

This study was undertaken to evaluate the clinical response of geriatric patients with psychoses to the atypical neuroleptic drug, clozapine. Records of patients over 60 years of age (n = 12, all female) who had received clozapine over a 30-month period from selected hospitals in Western Pennsylvania were reviewed. Among the six patients who were rapidly titrated (300 mg/day in 3 weeks), none are currently receiving clozapine, while four patients who received a slower titration and lower dosage (range, 25 mg/day to 300 mg/day; mean, 150 mg/day) remain clinically improved on stable doses of clozapine. Postural hypotension affected seven patients, and was the reason for discontinuation of clozapine in five patients. One patient experienced nonfatal agranulocytosis, and one subject experienced leukopenia. One patient died from causes unrelated to clozapine. This retrospective study suggests both a low-dose and slow-titration strategy for initiating clozapine among elderly patients, similar to the use of other psychotropic drugs in the elderly, as well as close attention to postural hypotension, agranulocytosis, and drug interactions.

Topics: Aged; Aged, 80 and over; Clozapine; Female; Humans; Middle Aged; Pennsylvania; Psychiatric Status Rating Scales; Psychotic Disorders

Topics: Carbidopa; Clozapine; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Psychoses, Substance-Induced; Psychotic Disorders

Based on five case studies, the suggestion is that, if physiological myoclonus can be excluded, antidepressant - or neuroleptic-induced myoclonus must as a rule be presumed to be a most subtle indication of increased cerebral exitability, an epileptic fragment or, in some instances, a myoclonus epilepsy. In each of the reported cases EEG recordings reflected epilepsy-specific potentials. Whether, however, the scope of differences in the EEG recordings and the N1/P1 amplitude increase of the SSEP may be used as an additional diagnostic criterion to determine the risk of epileptic seizures, should depend on the type of myoclonus chiefly induced. This would require more extensive neurophysiological examinations which should mainly include the back-averaging to permit, beside the EEG, a better evaluation of the relatively easily obtainable SSEP findings.

Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Evoked Potentials; Female; Humans; Male; Maprotiline; Middle Aged; Psychotic Disorders; Trimipramine

Topics: Adult; Arousal; Bipolar Disorder; Clozapine; Confusion; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Lithium; Male; Orientation; Psychotic Disorders; Speech Disorders; Valproic Acid

The atypical antipsychotic medication clozapine is an effective treatment for refractory psychosis; however, the efficacy of clozapine when used in public mental health programs has yet to be fully characterized. This study assessed the outcome of clozapine treatment in a state hospital.. The medical records of the first 100 patients to receive clozapine in a state hospital, from six months before clozapine treatment through 18 months of treatment, were reviewed.. The patients had chronic psychotic disorders that had responded poorly to treatment with conventional antipsychotic medication. Eighteen months after beginning clozapine, 45 patients were much improved, and 18 were somewhat improved. All except one of the improved patients were continuing clozapine treatment. Forty patients were living in community settings, 59 remained hospitalized, and one had died of an illness unrelated to clozapine. Violent episodes in the hospital decreased during the first six months of clozapine treatment. Thirteen patients had one or two seizures while taking clozapine, 12 of whom successfully continued clozapine treatment. One patient developed agranulocytosis, and one developed leucopenia; each recovered fully after clozapine treatment was discontinued.. Clozapine was an effective treatment for refractory psychotic disorders when given as a part of routine state hospital treatment.

Topics: Activities of Daily Living; Adult; Clozapine; Female; Follow-Up Studies; Hospitals, Psychiatric; Hospitals, State; Humans; Male; Middle Aged; Patient Admission; Psychotic Disorders; Social Adjustment; Treatment Outcome

The purpose of this study was to determine if plasma clozapine levels were associated with treatment response.. To examine this question, neuroleptic nonresponsive patients with schizophrenia or schizoaffective disorder were given clozapine, which was titrated to 500 mg/day by day 14 of treatment, and the dose was held fixed at least through day 21. Subsequently, clozapine doses were adjusted as clinically indicated, up to a maximum of 900 mg/day. Plasma clozapine levels were obtained at weeks 3 and 6, and standard clinical ratings (Brief Psychiatric Rating Scale [BPRS] and Clinical Global Impression) were done at baseline and at weeks 3 and 6.. Data from 45 subjects were analyzed. There were no correlations between plasma clozapine levels and change in BPRS scores at treatment weeks 3 and 6. However, when the subjects were classified as responders or nonresponders, therapeutic response was associated with clozapine blood levels above 350 ng/ml.. This study suggest that clozapine blood levels are correlated with clinical response.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; False Positive Reactions; Female; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; ROC Curve; Schizophrenia; Sensitivity and Specificity; Treatment Outcome

Topics: Adult; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Psychotic Disorders

Topics: Adult; Clozapine; Deamino Arginine Vasopressin; Enuresis; Humans; Male; Psychotic Disorders

The authors hypothesized that patients who develop gross EEG abnormalities during clozapine treatment would have a less favorable outcome than patients who did not develop abnormal EEGs. The clinical EEGs and the Brief Psychiatric Rating Scale (BPRS) scores of 12 patients with schizophrenia and 4 patients with schizoaffective disorder were compared before and during treatment with clozapine. Eight patients developed significant EEG abnormalities on clozapine; 1 showed worsening of an abnormal pre-clozapine EEG; none of these subjects had clinical seizures. BPRS scores improved significantly in the group of patients who developed abnormal EEGs but not in the group who did not. Findings are consistent with previous reports of a high incidence of clozapine-induced EEG abnormalities and a positive association between these abnormalities and clinical improvement.

Topics: Adult; Cerebral Cortex; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Reference Values; Schizophrenia; Schizophrenic Psychology; Signal Processing, Computer-Assisted

Although not universally accepted, evidence exists that clozapine treatment may be associated with neuroleptic malignant syndrome (NMS). To date, 10 cases of NMS associated with the use of clozapine have been reported in the literature. We report two more cases of NMS in patients on clozapine treatment and review the clinical presentations, biochemical features, risk factors, treatment, and rechallenge with neuroleptics in all reported patients who developed NMS while receiving clozapine treatment. An update and critical review of clozapine-induced NMS are also presented. Clozapine treatment can cause NMS similar to that induced by conventional neuroleptics. A history of NMS, existing brain insults, low serum iron concentrations, and being a young male may be risk factors for the development of NMS associated with clozapine treatment. NMS most commonly occurs when clozapine is being used along with other psychotropics. Early recognition of the syndrome and cessation of clozapine when NMS occurs are advised. Supportive care and use of dopamine agonists and dantrolene may be helpful in treating clozapine-associated NMS. These results support the notion that clozapine can cause NMS. However, NMS associated with clozapine treatment is a rare event. When it happens, the clinical presentation, risk factors, and management appear to be similar to those of NMS associated with conventional neuroleptics.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Neuroleptic Malignant Syndrome; Psychotic Disorders; Schizophrenia

The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Hospitalization; Hospitals, Veterans; Humans; Leukocyte Count; Male; Middle Aged; Psychotic Disorders; Racial Groups; Schizophrenia; Substance-Related Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Readmission; Psychotic Disorders; Recurrence; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Clozapine; Drug Costs; Humans; Isoxazoles; Nursing Homes; Piperidines; Psychotic Disorders; Research; United States

A 20-year-old woman had for the preceding 11 weeks been receiving clozapine (225 mg/d) for an endogenous psychosis when she developed a urinary tract infection with fever. The blood count showed 2100 white cells/microliter without any neutrophils, the count having been normal 5 days previously. Physical examination was normal except for a fever of 39 degrees C and parodontitis. The red cell count was 3.9 mill/microliters, platelet count 443,000/microliters. Bone marrow biopsy revealed almost complete stop of proliferation and maturation in granulocytopoiesis so that granulocyte colony-stimulating factor (300 micrograms daily subcutaneously) had to be administered in addition to supportive measures. The granulocyte count at first fell to 1400 cells/microliter, but nine days after starting the drug myeloblasts, promyelocytes and myelocytes reappeared in peripheral blood for the first time. On the tenth day, administration of the growth factor was discontinued. An overshoot granulocytopoiesis occurred in bone marrow on the 13th day; on the 22nd day after treatment had been started the patient had a normal blood picture and was discharged.

Topics: Adult; Agranulocytosis; Blood Cell Count; Bone Marrow; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Psychotic Disorders; Urinary Tract Infections

Most reports of clozapine in treatment-refractory patients have dealt with outpatient and/or relatively less chronic samples. This report focuses on clinical outcome in an institutionalized sample, notable for chronicity, poor functioning, and representing the extreme segment of the treatment-refractory population. We analyzed the data for 50 persistently hospitalized patients referred for clozapine treatment in open trials. Dimensions of outcome assessed at baseline and periodically thereafter included psychopathology, cognitive performance, extrapyramidal side effects (EPS), and patient satisfaction. Certain features of clozapine response in institutionalized patients have been underemphasized (e.g., reduced use of restraint and seclusion, greater social interaction, reduced cost for care). Ninety-four percent of this sample showed some form of improvement with clozapine. Improvement ranged from modest (e.g., less EPS) to remarkable (e.g., discharge). An adequate clozapine trial may require more than 6 months.

Topics: Activities of Daily Living; Adult; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Long-Term Care; Male; Middle Aged; Neurologic Examination; Neuropsychological Tests; Patient Admission; Patient Satisfaction; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Social Behavior; Treatment Outcome

Three schizophrenic patients and one schizophreniform patient, all experiencing puerperal psychosis, required a drug-induced delactation (bromocriptine) simultaneously to neuroleptic treatment. Taking into account the pharmacodynamic effects, an exacerbation of symptoms following bromocriptine (a D-2 receptor agonist) and an impairment of delactation following neuroleptic treatment (bringing about the blockade of D-2 receptors) are to be expected. In three cases, we carried out a combined bromocriptine-haloperidol treatment and, in one case, a bromocriptine-clozapine treatment. The above mentioned complications were not observed in any of the cases. The problems which may result from using clozapine during the puerperal period are also discussed.

Topics: Adult; Antipsychotic Agents; Bromocriptine; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Haloperidol; Humans; Lactation; Psychotic Disorders; Puerperal Disorders; Schizophrenia; Schizophrenic Psychology

Urinary incontinence may occur in patients with severe mental illness. Psychosis and neuroleptic medication have both been implicated, but there has been a lack of systematic evaluation of the precise relationship between these phenomena. Incontinence has been recognized as a complication of clozapine treatment and we examined this in 16 consecutively treated patients. Thirteen were established on therapeutic doses, one of whom was excluded from further study due to pre-existing incontinence. Retrospective assessment revealed that nocturnal incontinence was experienced by five of the remaining 12 patients, occurring in the first 3 months of treatment and resolving spontaneously in all cases. Incontinence was documented in the case notes in only one of the five cases and there was a tendency for affected patients to be embarrassed and reluctant to report it to staff. Specific enquiry may be necessary to elicit this phenomenon and incontinence should be considered as a possible factor in poor compliance with clozapine.

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Enuresis; Female; Humans; Male; Middle Aged; Patient Compliance; Psychotic Disorders; Retrospective Studies; Urinary Incontinence

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Psychotic Disorders; Risk Factors; Schizophrenia; United States

Topics: Adult; Blood Pressure; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enalapril; Humans; Hypertension; Male; Psychotic Disorders; Resuscitation; Syncope

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Epilepsy, Tonic-Clonic; Female; Humans; Lithium Carbonate; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Among the tardive dyskinesia syndromes, dystonia can be the most difficult to treat. It may be severe to the point of being disabling, yet the patients may require antipsychotic medications for an even more disabling psychosis. Clozapine, an atypical neuroleptic drug that lacks extrapyramidal effects, may be the drug of choice for such patients. This report describes three patients with significant dystonia, previously disabled by their psychoses, who have been successfully managed with clozapine plus other agents for > 3 years.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Akathisia is a common side effect of traditional neuroleptic drugs and is associated with medication refusal and impulsive behavior. While our previous experience indicates that clozapine is effective in treating persistent akathisia, two controlled studies indicate vastly different prevalence rates of akathisia (7% vs. 40%) in patients receiving clozapine.. We used the Barnes Rating Scale for Drug-Induced Akathisia to estimate the prevalence of akathisia in patients receiving stable doses of clozapine alone (N = 29) in a state hospital. Measurements were also made of manifest psychopathology (Brief Psychiatric Rating Scale) and tardive dyskinesia (Abnormal Involuntary Movement Scale).. Two patients (6.8%) receiving clozapine were rated as having akathisia. Only 4 (28.6%) of the 14 subjects with a history of moderate-to-severe tardive dyskinesia on traditional neuroleptic drugs continued to show current evidence of tardive dyskinesia, and in 10 patients (71.4%) there was no evidence of the syndrome (p < .002). In the 4 subjects with tardive dyskinesia there was amelioration to a milder form of the syndrome. There were no new cases of tardive dyskinesia among clozapine-treated subjects.. These data support the low prevalence of akathisia in patients receiving stable doses of clozapine monotherapy. There is further support that clozapine has an ameliorating effect on tardive dyskinesia associated with traditional neuroleptic drugs. These and other data indicate the need for a controlled trial of clozapine in patients experiencing persistent and disabling akathisia on traditional neuroleptic drugs.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Disorders; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

A 45-year-old white male with a positive family history for various neurological disorders (not including dystonias), and a long history of neuroleptic exposure on account of a chronic schizoaffective illness, developed severe torsion trunkal movement to the left which were accompanied by inversion of the left arm and outward extension of the right arm, as well as left torticollis. The axial dystonia, which was refractory to treatment, was disabling interfering with the activities of daily living, posture and gait. Radiological studies revealed marked dextroscoliosis. The administration of clozapine in dosages of 200 mg p.o. in the morning and 250 mg p.o. at bedtime, resulted in a significant improvement of the neck and trunk dystonia. After the discontinuation of the clozapine, an exacerbation of the movement disorder back to baseline levels prior to the use of this agent, was observed. Subsequent therapy with thioridazine in a dosage of 600 mg/day did not mask or treat the dystonia. The clinical implications of these findings are discussed.

Topics: Clozapine; Dystonia; Humans; Male; Middle Aged; Psychotic Disorders

Some candidates for clozapine treatment may be unable to be given the drug. They may be so severely ill that they cannot or will not ingest a pill; their psychosis may have so compromised their physical status that use of clozapine, which produces a broad range of side effects, would be unsafe; and/or they may require a very rapid control of their behavior.. Two case reports are described of patients who, although candidates for clozapine, were unable to take or be given the drug. Initial treatment with electroconvulsive therapy (ECT) was tried in both patients prior to use of clozapine.. In the two cases described, treatment with ECT prior to clozapine stabilized the patients enough that clozapine could be administered. In both cases, the clozapine appeared to perpetuate the initial clinical response produced by the ECT.. These case reports suggest that a two-step strategy of ECT followed by clozapine treatment may both facilitate the use of clozapine in some patients and perpetuate the clinical stability produced by ECT alone.

Topics: Adult; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Middle Aged; Psychotic Disorders; Treatment Outcome

Topics: Adult; Clozapine; Cocaine; Comorbidity; Diagnosis, Dual (Psychiatry); Drug Therapy, Combination; Fluphenazine; Humans; Lithium; Male; Psychotic Disorders; Substance-Related Disorders; Treatment Outcome

The authors deal with the use of closapine during pregnancy. In their cases after the use of closapine during pregnancy, healthy children were born.

Topics: Adult; Apgar Score; Clozapine; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Psychopharmacology; Psychotic Disorders; Schizophrenia, Catatonic; Schizophrenic Psychology

Among 118 patients with DSM-III-R diagnoses of schizophrenia or schizoaffective disorder who received treatment with clozapine, 29 patients had an antecedent or current history of substance abuse. Substance abusers and nonabusers showed similar improvements on measures of psychopathology and psychosocial functioning after 6 months of clozapine therapy. The implications of this finding are discussed.

Topics: Adult; Clozapine; Comorbidity; Female; Humans; Male; Psychotic Disorders; Schizophrenia; Substance-Related Disorders

Cost-effective means different, sometimes competing things to different observers. In addition to well-known clinical benefits, large payors such as state governments think clozapine and similarly effective antipsychotic medications will yield immediate dollar savings. They do not consider the need to shift existing resources to community follow-up, the time required to phase out hospital units, and the backlogs of new patients. In today's financial climate, legislators and other elected officials are reluctant to invest in expensive medicines and then wait for long-term savings. We must convince those who hold the purse strings that acceptable antipsychotic drugs will be expensive for at least several years to come, until more new and generic drugs appear. We must tell them firmly that our patients, doctors, and mental health systems cannot afford to rely on older medications, even though they seem inexpensive. The drug cost "thermostat" should be reset so that payors and budget reviewers realize that safe and adequate antipsychotic medications often cost $5 to $25 a day. If new dollars are not available, existing budgets may have to be restructured. For most patients, anything else is substandard.

Topics: Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Delivery of Health Care; Humans; Psychotic Disorders; Schizophrenia; United States

The importance of persistent negative symptoms in schizophrenia as a limiting factor in psychosocial and vocational rehabilitation has been increasingly emphasized. As a result, treatment trials and new drug development programs are focusing more attention on negative symptoms. Unfortunately, there is enormous phenomenological overlap between negative symptoms and neuroleptic-induced parkinsonism. We report data from a cohort of 56 clozapine-treated patients demonstrating significant correlations between measures of akinesia and anergia. Despite an average drug washout of over 2 weeks, the persistence of drug-induced parkinsonism can confound the assessment of therapeutic drug effects on negative symptoms.

Topics: Adolescent; Adult; Basal Ganglia Diseases; Clozapine; Female; Humans; Male; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Clozapine; Deglutition Disorders; Dose-Response Relationship, Drug; Drug Therapy, Combination; Esophageal Motility Disorders; Humans; Male; Psychotic Disorders; Sialorrhea

Topics: Adult; Airway Obstruction; Circadian Rhythm; Clozapine; Deglutition Disorders; Humans; Male; Psychotic Disorders; Sialorrhea; Sleep Wake Disorders

We report a patient with severe axial tardive dystonia who has had dramatic improvement for 4 years after treatment with the atypical antipsychotic drug clozapine (625 mg/day). Clozapine differs from conventional neuroleptics in that it has higher affinity for D1 and lower affinity for D2 dopamine receptors than do conventional antipsychotics, which are relatively selective D2 antagonists. We propose that repetitive stimulation of the D1 receptor by endogenous dopamine, resulting in sensitization of the D1-mediated striatal output in the presence of D2 receptor blockade, is a fundamental mechanism mediating tardive dyskinesia, including the dystonic type. According to this hypothesis, it is primarily the D1 antagonist action of clozapine that accounts for its inability to cause tardive dyskinesia as well as its therapeutic effect in tardive dystonia. Regardless of its mechanism of action, the sustained improvement observed in this case suggests that clozapine should be tried in cases of severe refractory tardive dystonia.

Topics: Adult; Antipsychotic Agents; Clozapine; Corpus Striatum; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Dystonia; Follow-Up Studies; Humans; Long-Term Care; Male; Neurologic Examination; Psychotic Disorders; Receptors, Dopamine D1; Receptors, Dopamine D2

Topics: Clozapine; Cost Savings; Drug Monitoring; Health Services Accessibility; Humans; Patient Readmission; Psychotic Disorders; United States

Few investigators have focused on the response of individuals with mental retardation to clozapine. In the general population, some people who have responded to no other psychotropic have had a tremendous positive response, including increased positive scores "quality of life" measures. Clozapine, however, can cause fatal side effects. At least six people in the United States have died from agranulocytosis despite weekly blood counts. The use of clozapine in the general population was reviewed, potential difficulties in prescribing it for individuals with mental retardation discussed, and three relevant case histories presented.

Topics: Adult; Bipolar Disorder; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Intellectual Disability; Male; Middle Aged; Psychotic Disorders; Refractory Period, Psychological; Treatment Outcome

The process of conducting research protocols on clinical psychiatric units presents many challenges for research and clinical staff alike, challenges that are especially daunting when the clinical psychiatric unit is not designed for or dedicated to research. This article describes an attempt to bridge the gap between clinical and research needs through nursing collaboration, focusing on the specific issue of managing treatment-resistant psychotic patients in a neuroleptic-free state before trial on clozapine. It suggests that applying research methods to the process of research itself is as necessary as applying them to the specific protocols conducted within it.

Topics: Chronic Disease; Clinical Trials as Topic; Clozapine; Humans; Nursing Assessment; Nursing Research; Nursing, Team; Psychiatric Nursing; Psychotic Disorders; Retrospective Studies

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Neutropenia; Psychotic Disorders; Risk Factors; Survival Analysis; United Kingdom

The seizures associated with the atypical antipsychotic medication clozapine represent a serious side effect of treatment. In premarketing studies, seizures occurred at a crude rate of 3.5%. It is possible that the rate and character of seizures would vary in clinical settings because of differences in patient populations or differences in the manner in which treatment is administered. We studied the seizures that occurred during clozapine treatment in a state psychiatric hospital.. We reviewed the medical charts and pharmacy records of 100 sequential patients who were to start clozapine treatment. The review period covered 6 months pretreatment through 1 year of follow-up.. The patients were 55 men and 45 women, aged 20 to 61 years. Ten (5 men, 5 women) had at least one seizure during clozapine treatment. Seizures occurred at all dose ranges (0-299 mg/day, N = 6; 300-599 mg/day, N = 2; 600-900 mg/day, N = 2). Of 12 patients with histories of previous seizures, 4 (33%) had a seizure while taking clozapine and anticonvulsants. Of 9 patients with histories of head trauma but no seizures, 1 (11%) had a seizure. Of 79 patients without seizure disorder or a history of head trauma, 5 (6.3%) had a seizure. Nine of the patients who had a seizure continued on clozapine treatment with temporary dose reduction and/or addition of an anticonvulsant, 2 having one additional seizure.. Clozapine-associated seizures were more frequent in this group of state hospital patients than they were in premarketing studies. Clozapine-related seizures did not preclude successful treatment with clozapine.

Topics: Adult; Anticonvulsants; Clozapine; Cohort Studies; Delusions; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Hospitals, Psychiatric; Hospitals, State; Humans; Male; Middle Aged; Neurocognitive Disorders; Psychotic Disorders; Schizophrenia; Seizures; Treatment Outcome

This pharmaco-epidemiologic study was undertaken to determine if the combination of clozapine and valproate poses an increased risk of blood dyscrasias, liver function abnormalities, or other side effects and to develop dosing guidelines when the combination is utilized.. The charts of 55 patients receiving clozapine and valproate concurrently between May 8, 1989, and May 8, 1992, were reviewed to determine the indication for and length of time on each medication, abnormalities in liver function test results, blood cell dyscrasias, seizures, nausea, vomiting, sedation, sialorrhea, and enuresis. In addition, the efficacy of the combination was measured.. The combination of clozapine and valproate was efficacious and well tolerated in the majority of patients. Major adverse effects such as blood dyscrasias or seizures were not experienced by the study population. The side effect that led to discontinuation of the combination most frequently was sedation.. The combination of clozapine and valproate is safe and efficacious.

Topics: Adult; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Incidence; Leukopenia; Liver; Liver Function Tests; Male; Middle Aged; Psychotic Disorders; Seizures; Sleep; Treatment Outcome; Valproic Acid

To determine the efficacy and tolerance of long-term clozapine therapy in refractory affective illness.. Hospital records were reviewed for 193 treatment-resistant patients with a discharge diagnosis of bipolar disorder (N = 52), schizoaffective disorder (N = 81), unipolar depression (N = 14), schizophrenia (N = 40), or other disorders (N = 6) started on clozapine therapy as inpatients at McLean Hospital. An independent "best-estimate" diagnosis, based on DSM-III-R criteria, was established for each patient. Patients were contacted at least 6 months after clozapine initiation for structured follow-up interviews by raters blind to diagnosis. Patients were stratified by diagnosis, and a variety of patient characteristics and outcome measures were compared.. Subjects were followed up a mean of 18.7 months after clozapine initiation. Bipolar manic and schizoaffective bipolar subjects had significantly better outcomes than unipolar, bipolar, and schizoaffective depressed patients on a variety of measures. One or more episodes of depression prior to clozapine predicted clozapine discontinuation (p = .01). Affective and schizoaffective subjects had baseline measures of social functioning similar to that of the schizophrenics but had significantly greater improvement in scores at follow-up.. Clozapine is an efficacious and well-tolerated therapy for refractory affective illness. Manic symptomatology predicts a more favorable response than depression.

Topics: Adult; Affective Disorders, Psychotic; Bipolar Disorder; Clozapine; Depressive Disorder; Female; Follow-Up Studies; Humans; Male; Probability; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Treatment Outcome

The goals of this study were 1) to determine the extent of substance abuse in patients with treatment-resistant schizophrenia and 2) to assess the relevance of such abuse to subsequent response to treatment with clozapine.. The subjects were 118 treatment-resistant patients with DSM-III-R diagnoses of schizophrenia or schizoaffective disorder who underwent detailed demographic, clinical, and psychopathological evaluations before commencing treatment with clozapine. Lifetime and current histories of substance abuse were also systematically evaluated and characterized according to the Research Diagnostic Criteria and DSM-III-R. Response to clozapine treatment at 6 months was determined with measures of psychopathology and psychosocial function.. An antecedent or current history of substance abuse was determined for 29 patients. Although predominantly male, the abusers did not differ from the nonabusers on other demographic features. The substance abusers actually showed less psychopathology (negative and disorganization symptoms) and better psychosocial functioning at baseline; however, both groups attained similar improvements on these measures after 6 months of clozapine therapy.. A modest extent of previous or current substance abuse was observed among neuroleptic-resistant schizophrenic patients who subsequently received treatment with clozapine. This antecedent history of substance abuse did not appear to negatively influence subsequent response to clozapine treatment.

Topics: Adult; Clozapine; Comorbidity; Female; Humans; Male; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders; Treatment Outcome

Topics: Aged; Clozapine; Humans; Male; Parkinson Disease; Psychotic Disorders

Topics: Adult; Clozapine; Drug Interactions; Humans; Male; Nortriptyline; Psychotic Disorders

A 54-year-old woman with acute schizoaffective psychosis was treated with lithium carbonate (1,350 mg daily) and zuclopenthixol. On admission, clozapine was added (250 mg daily). Because extrapyramidal symptoms (rigor, akinesia) developed, she was additionally given biperiden retard (4 mg daily) from the fourth hospital day onwards. Eleven days after admission she began to complain of "unsteadiness" and "tremors" in her arms and she had asterixis (flapping tremor) on holding up her arms. The electromyogram showed electrical pauses of 60-120 ms, typical for asterixis. There were no significant metabolic or organic cerebral changes that could have accounted for the symptoms which presumably had been induced by the drugs even though their dosage was not unusual. The symptoms in fact regressed completely after the clozapine dose had been reduced, at first to 125 mg then to 50 mg. Previous experience has suggested that the risk of asterixis is particularly high when lithium and clozapine are taken together.

Topics: Biperiden; Clopenthixol; Clozapine; Drug Therapy, Combination; Electromyography; Female; Humans; Lithium Carbonate; Middle Aged; Psychotic Disorders; Tremor

The authors' aim was to assess the safety and efficacy of starting clozapine in a structured, long-term, partial hospitalization program that included protocols for detecting and managing side effects and adverse reactions to the drug as well as therapeutic programming to enhance patients' reintegration into community life.. Medical records of 47 patients with schizophrenia or schizoaffective disorder who were started on clozapine in the partial hospitalization program were analyzed. Data on incidence and management of adverse reactions, number of hospitalizations, status of symptoms, and changes in patients' social functioning for periods up to 12 months after initiation of clozapine were collected.. Although adverse reactions were common in the first weeks of treatment, they were managed with dosing strategies, monitoring, and concomitant medication so that no patient had to discontinue the medication. Psychotic symptoms and symptoms of tardive dyskinesia decreased significantly during the study period. At 12-month follow-up, most patients were able to attend school, hold paying or volunteer jobs, and live independently.. Clozapine can be safely initiated outside an inpatient setting. Partial hospitalization programs can enhance patients' reintegration into the community through a combination of treatment with clozapine and rehabilitative and psychotherapeutic programming.

Topics: Adolescent; Adult; Clozapine; Combined Modality Therapy; Day Care, Medical; Drug Monitoring; Female; Georgia; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Social Adjustment

Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.

Topics: Adult; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Psychotic Disorders

Topics: Aged; Antipsychotic Agents; Clozapine; Diagnosis, Differential; Humans; Male; Neurologic Examination; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Male; Psychotic Disorders

Topics: Antipsychotic Agents; Clozapine; Humans; Neuroleptic Malignant Syndrome; Neurologic Examination; Psychotic Disorders; Recurrence; Risk Factors

The authors attempted to determine if chronic exposure to clozapine can cause tardive dyskinesia.. Twenty-eight schizophrenic or schizoaffective patients with no prior history of definite tardive dyskinesia were treated with clozapine for at least 1 year, and their ongoing modified Simpson Dyskinesia Scale ratings were analyzed. These data were then compared with those of another group of similarly diagnosed patients who were treated with a conventional neuroleptic for at least 1 year.. Two patients in the clozapine-treated group (both of whom had ratings of questionable tardive dyskinesia at baseline) were later rated by the modified Simpson Dyskinesia Scale as having mild tardive dyskinesia on at least two consecutive ratings 3 months apart. Although there was uncertainty about whether clozapine definitely caused the tardive dyskinesia in those two patients, a survival analysis comparing the clozapine-treated group with the neuroleptic-treated group showed a lower risk of tardive dyskinesia developing in the clozapine-treated group.. This study was unable to definitively conclude whether clozapine causes tardive dyskinesia. However, if cases do develop, the risk of tardive dyskinesia is likely to be less with clozapine than with typical neuroleptics.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Incidence; Male; Prospective Studies; Psychotic Disorders; Schizophrenia

Topics: Adult; Australia; Clozapine; Drug Monitoring; Humans; Male; Psychotic Disorders

Topics: Adult; Clozapine; Drug Therapy, Combination; Humans; Male; Methylphenidate; Psychotic Disorders; Schizophrenia; Sleep

Eosinophilia associated with clozapine treatment has been reported in some studies and limited case reports. Because little is known regarding incidence, course, and relevance of this finding, clozapine therapy has been terminated prematurely in some patients with elevated eosinophil counts.. Records were reviewed on 118 consecutively hospitalized, acutely psychotic patients treated over a 1-year period with clozapine for at least 3 weeks. Demographic data were obtained on those patients, and white blood cell counts were analyzed. We reviewed the data for predisposing factors, associated medical findings, or clinical sequelae, and performed a two-sided Fisher's exact test to determine if sex or diagnosis was associated with a higher risk of developing eosinophilia. The literature pertaining to this blood dyscrasia and its relationship to clozapine was reviewed.. In our population, the cumulative incidence of eosinophilia among women was 23% (13/57), a statistically significant higher risk (p < .01) than that in men (7% [4/61]). In all cases, the eosinophilia was noted between Weeks 3 and 5 of treatment and resolved without medical or psychiatric complications.. Eosinophilia should be added to the list of commonly observed side effects of clozapine treatment. Women appear to be at significant risk. Eosinophilia usually occurs early in therapy, spontaneously resolves, and is not associated with any known complications. An otherwise healthy person with this blood dyscrasia may continue with treatment but should be monitored closely. Further investigation into this finding may provide insight into the mechanism of neutropenia and other adverse reactions to clozapine.

Topics: Acute Disease; Adult; Clozapine; Depressive Disorder; Eosinophilia; Female; Hospitalization; Humans; Incidence; Leukocyte Count; Male; Middle Aged; Psychotic Disorders; Risk Factors; Schizophrenia; Sex Factors

Studies in the literature that attempt to relate neuroleptic plasma levels to the development of tardive dyskinesia (TD) report inconsistent findings. As part of an open, long-term study, 60 schizophrenic and schizoaffective patients were started gradually on a b.i.d. schedule of the atypical antipsychotic drug clozapine. Blood samples were drawn weekly for 6 weeks and analyzed for a variety of constituents including clozapine plasma levels. Patients with higher levels of TD were found to have significantly higher levels of plasma clozapine and a higher ratio of plasma/dose than those with lower levels of TD. Our data suggests that schizophrenics with TD may have different pharmacokinetics, drug metabolism, and elimination processes than those without TD. Higher typical plasma neuroleptic levels may increase susceptibility to TD development. A second hypothesis implies that it is not the higher mean plasma level of a neuroleptic that is associated with TD but the greater fluctuations of plasma levels over time (i.e., a higher variance). This hypothesis is discussed in the context of our data.

Topics: Adult; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Psychotic Disorders; Schizophrenia

Topics: Clozapine; Humans; Psychotic Disorders

A 40-year-old woman suffering from major depression with psychotic features was unresponsive to conventional therapy. After the administration of a wide range of drug treatments and ECT, she received clozapine. Depressive symptoms improved and psychotic features disappeared. It is suggested that clozapine could be efficient in psychotic refractory depression.

Topics: Adult; Clozapine; Combined Modality Therapy; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Psychotic Disorders; Recurrence

Topics: Adult; Clozapine; Diarrhea; Fever; Humans; Male; Psychotic Disorders

Seven patients with idiopathic Parkinson's disease, aged 62 to 76 years, average duration of the disease approximately eleven years, suffering from severe hallucinosis and paranoid delusions of different degree, in whom conventional therapeutic strategies (administration of benzodiazepines and mild neuroleptics) had no antipsychotic effect, received clozapine, a non-classical highly potent neuroleptic, while blood count was strictly monitored. Paranoid ideas disappeared in all seven patients after a maximum of four days administration of 25-125 mg/day. No deterioration of parkinsonian symptoms, quantified according to UPDRS was seen. Given the protection of clozapine, we could increase the L-dopa dose in two cases, thereby improving the patients' motor function. Blood count showed no abnormalities in any of the patients during an average observation period of seventeen months. Our results support the assumption that clozapine has a potent antipsychotic effect in the treatment of psychotic decompensation in advanced Parkinson's disease in carefully selected patients. We saw no negative influence of the neuroleptic on extrapyramidal symptoms.

Topics: Aged; Benserazide; Blood Cell Count; Clozapine; Female; Hallucinations; Humans; Levodopa; Male; Middle Aged; Paranoid Disorders; Parkinson Disease; Psychotic Disorders

In a retrospective study, 1863 EEG recordings made during clozapine treatment of 283 patients with normal pretreatment EEG evaluations were analyzed. Furthermore, they were compared to the EEGs of the same patients without clozapine (i.e., during other neuroleptic medication). Moreover, the data of all patients who had seizures during treatment with clozapine were evaluated in case reports. Classical clinical EEG evaluation criteria for normal versus abnormal were used (including diffuse slowing and grouped alterations according to Jung 1953 and Kugler 1983). Of the 283 patients investigated, 61.5% (174) showed at least one abnormal EEG under clozapine according to these criteria. Evaluating all recorded EEGs of these patients in order to get some longitudinal information, we found a rate of 53.4% abnormal EEG recordings during clozapine treatment. Most of the EEG changes were evaluated as slight (22.5%) to moderate (10.1%) diffuse slowing and some as groups of nonparoxysmal waves (39.8%) or sharp waves (16.2%) rendering the EEGs abnormal according to the above criteria. Potential signs of increased bioelectrical cerebral reagibility such as paroxysmal activity (4.3%) or severe diffuse slowing (0.2%) were rare. A nearly linear correlation with the daily dose was found in the range up to 300 mg clozapine/day for both diffuse and grouped alterations. Possibly due to selection, adaptive mechanisms/habituation, and/or other unknown factors, the rate of alterations decreased slightly at doses above 300 mg and rose again sharply for doses over 600 mg/d. Three of the clozapine-treated patients, equivalent to 1.1%, developed seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Neurocognitive Disorders; Psychotic Disorders; Retrospective Studies; Schizophrenia; Seizures

A case report of clozapine-induced agranulocytosis in a patient treated concomitantly with lithium is reported. The possible role of lithium in the mechanism of clozapine myelosuppression is discussed.

Topics: Agranulocytosis; Clozapine; Drug Therapy, Combination; Female; Granulocytes; Humans; Leukocyte Count; Lithium; Middle Aged; Psychotic Disorders; Time Factors

Topics: Activities of Daily Living; Clozapine; Female; Humans; Psychotic Disorders; Sick Role

Topics: Ambulatory Care; Clozapine; Drug Monitoring; Humans; Psychotic Disorders; United Kingdom

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Leukopenia; Male; Middle Aged; Psychotic Disorders; Recurrence

Nine out of 4044 patients admitted to our institution between 1987 and 1990 suffered an episode of NMS. Neuroleptic rechallenge using clozapine for persisting psychiatric illness was tolerated by eight patients. Clozapine was discontinued in one older, high-risk patient because recurrence of NMS was anticipated. Clozapine should be considered a drug of choice for psychotic patients with a history of NMS.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders

The short- and long-term treatment tolerance of low-dose clozapine was retrospectively investigated in 18 psychogeriatric patients. Discontinued use of the drug because of side effects or inefficiency was required for only four patients. In the long-term treatment group leukopenia was not observed, and disturbances of liver function appeared to be very infrequent. A second group of seven severely demented psychogeriatric inpatients who were currently being treated with low-dose clozapine underwent a withdrawal study in order to evaluate the therapeutic efficacy of the drug, measured by the NOSIE and the SCAG scales. The results indicate that for patients such as these, with paranoid or socially disturbing behavior who also tend to develop severe neurological side effects with classical neuroleptics, a low-dose administration of clozapine is an acceptable alternative treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Clozapine; Dementia; Dementia, Multi-Infarct; Dose-Response Relationship, Drug; Female; Geriatric Assessment; Hospitalization; Humans; Hydrocephalus, Normal Pressure; Long-Term Care; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Social Behavior; Substance Withdrawal Syndrome

Topics: Adult; Clozapine; Electroencephalography; Epilepsy; Evoked Potentials; Humans; Male; Neurocognitive Disorders; Psychotic Disorders

Topics: Clozapine; Coma; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Middle Aged; Propranolol; Psychotic Disorders; Tachycardia

Topics: Acute Disease; Adult; Clozapine; Humans; Male; Pancreatitis; Psychotic Disorders

A retrospective study was conducted of 53 consecutive inpatients (through 1990) with psychotic disorders. The patients were between 13 and 18 years of age. In all cases this was the first time they had been treated with clozapine. The adverse effects seen under clozapine are discussed. During the use of clozapine assessments were made of liver enzymes, leukocytes, blood pressure and body temperature. There was an increase in liver enzyme values in 37.7% of the patients, leukopenia under 4000/mm3 in 15.1%, an increase in body temperature in 3.8% and bradycardia together with hypotensive dysregulation in 1.9%.

Topics: Adolescent; Austria; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Leukocyte Count; Liver Function Tests; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Risk Factors

Granulocytopenia and agranulocytosis are severe side effects of clozapine therapy. Even if these side effects are detected early and if clozapine is discontinued, patients suffering from agranulocytosis are extremely endangered by infectious diseases for up to 3 to 4 weeks until hematologic recovery. Therefore, any treatment that reduces this critical time span would decrease the risks of clozapine treatment.. The case of a patient in whom severe agranulocytosis developed after 7 weeks of clozapine treatment is presented.. After clozapine discontinuation, treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein that has been shown to stimulate the proliferation of precursor cells in the bone marrow and their differentiation into granulocytes and macrophages, was initiated. Under GM-CSF treatment, total granulocyte count rose from 63/cu mm to a value greater than 1500/cu mm within 5 days without complications or major side effects.. This case report suggests that treatment with GM-CSF may lower the risks associated with clozapine-induced agranulocytosis and therefore may indirectly improve the safety of clozapine therapy.

Topics: Adult; Agranulocytosis; Clozapine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Psychotic Disorders; Time Factors

The aim of this study was to determine the prevalence and clinical relevance of weight gain during clozapine treatment. Previous reports indicated clinically significant weight gain in 13% to 85% of patients and an average gain of 9.0 to 24.7 lb.. Twenty-one state hospital patients with treatment-resistant schizophrenia or schizoaffective disorder were weighed weekly for 12 weeks before clozapine treatment and during the first 16 weeks of treatment. Psychiatric symptoms were rated with a modified version of the Brief Psychiatric Rating Scale (BPRS).. The mean weight gain for the entire group was 13.9 lb, or 8.9% of body weight. During the 16 weeks of clozapine treatment, 38% of the patients experienced marked weight gains and 29% had moderate weight gains. The improvements in BPRS total score and composite negative symptom score were significantly greater for the eight patients with marked weight gains than for the other 13 patients.. Clozapine's propensity to induce weight gain may relate to the drug's efficacy and/or its unique neuropharmacologic effects. Increased attention to this phenomenon is important because of the morbidity associated with obesity.

Topics: Adult; Clozapine; Female; Humans; Male; Middle Aged; Obesity; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Weight Gain

This article reviews eight published studies that describe clozapine's effects on TD and examines the outcome of 30 patients with TD treated with clozapine for up to 36 months. These data indicate that TD response to clozapine is variable but that approximately 43% of cases, particularly those with dystonic features, improved after clozapine treatment. Methodological limitations of the studies described, however, preclude definitive conclusions, which must await appropriately controlled trials.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Neurologic Examination; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Topics: Aged; Clozapine; Female; Hallucinations; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders

Although growing research indicates that the atypical antipsychotic agent clozapine is effective in patients with schizophrenia, little is known about the efficacy of clozapine in patients with schizoaffective disorder or psychotic mood disorders. The purpose of this study was to assess whether or not clozapine is effective in some patients with schizoaffective disorder or psychotic mood disorders.. By surveying treating clinicians and chart data, we assessed treatment response in 85 consecutive patients, including 39 with schizophrenia, 25 with schizoaffective disorder, and 14 with bipolar disorder with psychotic features, who received clozapine for at least 6 weeks at our center.. All patients were either inadequately responsive to or unable to tolerate standard somatic therapies. Compared to patients with schizophrenia, patients with schizoaffective disorder and bipolar disorder with psychotic features displayed significantly higher response rates to clozapine.. Clozapine may be a useful drug in the treatment of patients with schizoaffective disorder or psychotic mood disorders who are treatment resistant or intolerant of side effects.

Topics: Adult; Bipolar Disorder; Clozapine; Drug Evaluation; Female; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Little is known about interactions of other drugs with the recently marketed antipsychotic clozapine. Two cases in which the addition of phenytoin caused a decrease in plasma clozapine concentrations and worsening of psychoses are described, and possible explanations are discussed.

Topics: Adult; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Phenytoin; Psychotic Disorders

Neuroleptic malignant syndrome (NMS), a rare but serious side effect of psychotropic drugs, is usually attributed to blockade of striatal and hypothalamic dopaminergic tracts. Clozapine is an atypical antipsychotic that has minimal extrapyramidal effects and might not be expected to cause NMS. The authors report the development of NMS in a 30-year-old white man after three 25-mg clozapine doses. To their knowledge, this is the first case of NMS linked with clozapine in which concurrent psychotropic medications cannot be implicated.

Topics: Adult; Catatonia; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Neuroleptic Malignant Syndrome; Psychotic Disorders

The efficacy and adverse effects of clozapine for patients who cannot be treated with conventional neuroleptics were evaluated by means of a retrospective chart review. The review showed that 85 percent of 503 inpatients experienced slight to nearly complete reduction in symptoms. Adverse effects occurred in 59 percent of patients, although only 7 percent had side effects severe enough to warrant discontinuation of the drug. Data for 70 outpatients treated with clozapine showed that the rate of rehospitalization was significantly lower than before treatment with the drug. These findings agree with those of other European studies and suggest that when hematological and other variables are carefully controlled, the benefits of clozapine therapy outweigh the risks.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dibenzazepines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Compliance; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

Topics: Adolescent; Clozapine; Humans; Obesity; Psychotic Disorders; Schizophrenia; Weight Gain

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Psychotic Disorders

Clozapine is a newly released antipsychotic that is associated with a higher prevalence of seizures than traditional neuroleptics. The authors describe four patients who developed seizure activity during clozapine treatment and provide recommendations for clinical management of this problem.

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Male; Psychotic Disorders; Schizophrenia; Seizures

Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furo[3,2-c]pyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings. Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response. In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furo[3,2-c]pyridine derivatives, the interaction of these molecules with the dopamine D2 receptor was weak. Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10. Despite the similarity these molecules share in their behavioral indices of antipsychotic activity, it is likely that the thieno- and furo[3,2-c]pyridine rings employ different mechanisms to achieve this convergence of biological effects.

Topics: Amphetamines; Animals; Avoidance Learning; Binding, Competitive; Catalepsy; Chemical Phenomena; Chemistry; Dioxanes; Female; Furans; Macaca; Male; Mice; Molecular Structure; Motor Activity; Piperazines; Psychoses, Substance-Induced; Psychotic Disorders; Pyridines; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Serotonin; Spiperone; Stereotyped Behavior; Structure-Activity Relationship; Thiophenes

Topics: Adult; Chronic Disease; Clozapine; Dibenzazepines; Female; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders

The effect of long-term treatment with clozapine in schizophrenia and schizoaffective disorder was evaluated in a retrospective study comprising 96 patients treated with the drug during the period 1974-1986 at the Psychiatric Research Center in Uppsala. All patients had previously been treated with different kinds of antipsychotic drugs but with insufficient clinical effect or distressing extrapyramidal side effects. When clozapine treatment was initiated, the mean duration of the illness was 8 years and 9 months. In 36% of the patients clozapine treatment was discontinued, the main reasons being lack of efficacy, poor compliance or temporary withdrawal from the market in 1975. Clinical evaluation of the effect revealed that 85% of the patients could be discharged from the hospital within a year and that 43% of the patients were significantly and 38% moderately improved compared to previous treatments. Of those patients who were still on clozapine 2 years after the treatment was initiated, 39% had employment compared to only 3% before clozapine. In ten patients a transient decrement in white blood cells (WBC) was noted but normalized during ongoing treatment. One patient developed leukopenia and one agranulocytosis, none with fatal outcome. Common side effects were sedation, hypersalivation, weight gain and obstipation. In one patient clozapine treatment was stopped because of grand mal seizures. No extrapyramidal side effects were observed or reported during clozapine treatment. It is concluded that clozapine offers particular advantages for many "therapy-resistant" schizophrenic patients when compared to classical neuroleptics.

Topics: Adult; Clozapine; Dibenzazepines; Drug Resistance; Female; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Schizophrenia; Sweden

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Male; Middle Aged; Psychotic Disorders; Substance Withdrawal Syndrome

Based on the results of two preliminary studies, we concluded that late-developing persistent drug-induced movement disorders are pharmacologically heterogeneous, and this heterogeneity is seen between individual patients (and groups of patients) as well as within body areas of individual patients; dystonic pathology has a distinct and more consistent response to pharmacologic stimulation than does nondystonic tardive dyskinesia (TD); and, although disturbances in dopamine and acetylcholine appear to be involved in these disorders, they do not in all cases exist in functionally opposite relationships. The observed pharmacologic heterogeneity in TD response reflects the limitations of the dopamine/acetylcholine model of TD, which oversimplifies the neuroanatomy of the basal ganglia and the pathophysiology of TD. The chemical and anatomical complexity of this region suggests that other neurotransmitter systems and neuronal circuits within and extending from the basal ganglia may be disturbed in the pathogenesis of TD.

Topics: Adult; Aged; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychotic Disorders; Time Factors

Clozapine, an atypical neuroleptic with unique clinical and preclinical properties, represents a potentially valuable addition to the psychopharmacopeia. Its development and use have been limited by its higher frequency, compared with other pharmacologic treatments, of the potentially fatal side effect of agranulocytosis. This article describes the natural history of five cases of agranulocytosis that occurred in the course of clozapine treatment. The cases were generally uniform as to onset, recovery, and hematologic features. No patient had hematologic reactions to treatment with psychotropic agents before or after clozapine treatment. These findings, along with other work in progress, suggest that clozapine's granulocytoxic effects are produced by a highly specific immune-mediated mechanism.

Topics: Adult; Agranulocytosis; Antibody Formation; Bone Marrow Cells; Clozapine; Dibenzazepines; Drug Hypersensitivity; Female; Humans; Leukocyte Count; Psychotic Disorders; Psychotropic Drugs

A retrospective study was performed to evaluate the effect of long-term treatment with clozapine in 96 schizophrenic or schizoaffective patients hospitalized at the Psychiatric Research Center in Uppsala during the period 1974-1986. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The mean duration of the disorder at the start of clozapine treatment was 8 years and 9 months and the mean duration of the treatment 3 years and 11 months. Clozapine treatment was discontinued in 36% of the patients, mainly due to lack of efficacy, poor compliance or temporary withdrawal of the drug from the market in 1975. In two patients the reason was leukopenia or agranulocytosis. In another 10 patients a transient decrement of WBC was seen, which was normalized during ongoing treatment. Four patients died when on clozapine during the follow-up period, but no causal relationship to the treatment could be established. Eighty-five per cent of the patients could be discharged from the hospital. Of the 62 patients who were still on clozapine after 2 years, 18% had full time and 21% half-time employment. A global evaluation of the clinical efficacy revealed a significant improvement in 43% and a moderate improvement in 38% of the patients compared to previous neuroleptic treatments. Common but usually mild side effects were sedation, hypersalivation, weight gain, and obstipation. Four patients had grand mal seizures. No extrapyramidal side effects were observed during clozapine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Clozapine; Dibenzazepines; Employment; Female; Humans; Leukopenia; Male; Psychotic Disorders; Retrospective Studies; Schizophrenia; Sweden

Topics: Adult; Clozapine; Dibenzazepines; Humans; Male; Psychotic Disorders; Recurrence; Schizophrenia; Substance Withdrawal Syndrome

Clozapin holds pharmacologically and clinically a special position among psychoactive drugs. By means of EEG examinations in 25 patients without and with Clozapin it could have been proved statistically that the distinctly marked changes can unambigously traced back to Clozapin medication. These role is in regard to localization explainable by pharmacologically assumed brain stem efficiency of the medicament. The increase of beta activity which was also found and which is not typical for neuroleptics can be explained in connection with the central anticholinerg action component.

Topics: Adult; Arousal; Brain; Brain Stem; Caudate Nucleus; Cerebral Cortex; Clozapine; Dibenzazepines; Electroencephalography; Evoked Potentials; Female; Humans; Male; Psychotic Disorders; Schizophrenia

In two patients with chronic schizophrenia, who were on clozapine medication for more than 6 months, a sudden withdrawal of the drug resulted in a very pronounced deterioration of the psychosis within 24-48 h. The most prominent symptoms were auditory hallucinations and persecutory ideas and one patient tried to commit suicide. These observations are interpreted as supersensitivity psychoses induced by the very effective clozapine treatment.

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Male; Psychotic Disorders; Schizophrenia; Substance Withdrawal Syndrome

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Psychotic Disorders

17 patients (13 males and 4 females) were examined for side effects due to long-term treatment with 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo(b,e)(1,4)diazepine (clozapine) with emphasis on alterations in bone marrow, liver, and kidney function. 16 patients were schizophrenic, one patient was diagnosed psychosis e causa dubia. The age range was 25-68 years, with an average of 38.2 years. The daily clozapine dose varied from 225 to 800 mg with a total intake during the trial period of 149.1-891.6 g yielding an average of 479.8 g. The treatment period varied from 20 to 51 months, with an average of 35.9 months. None of the patients had to discontinue the treatment because of side effects. The laboratory data including hematological, and nephrological parameters revealed no significant changes related to clozapine treatment within the treatment period. No changes were observed in ECG. 12 patients experienced side effects, 8 of them receiving concomitant psycholeptic medication. 9 patients complained of temporary fatigue and 5 of these experienced continuous drowsiness. There were 8 cases of nocturnal hypersalivation and two cases of increased appetite. One patient developed light tachycardia and one patient orthostatic hypotension. Clozapine is known to be an effective anti-psychotic drug, but due to reports of agranulocytosis in 16 Finnish patients the drug was withdrawn from the Danish market in 1975 although later its use was merely restricted to special cases. This study does not indicate that clozapine contains greater risk of clinical side effects than commonly used psycholeptic drugs.

Topics: Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Dibenzazepines; Female; Humans; Kidney Diseases; Male; Middle Aged; Psychotic Disorders; Time Factors

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Drug Administration Schedule; Female; Humans; Psychotic Disorders

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; alpha-Amylases; Aspartate Aminotransferases; Bilirubin; Blood Sedimentation; Chemical and Drug Induced Liver Injury; Clozapine; Creatinine; Dibenzazepines; Female; gamma-Glutamyltransferase; Hematologic Diseases; Hemoglobins; Humans; L-Lactate Dehydrogenase; Leukocytes; Male; Middle Aged; Psychotic Disorders

Cerebrospinal fluid 5-hydroxyindoleacetic acid level, and total blood serotonin content was measured in groups of manic and schizophrenic patients before and after 2, 4, 6, 10, 20, and 30 days of clozapine treatment. CSF 5-HIAA values were elevated after 2 and 4 days and returned to baseline levels after 6 days or more. Blood serotonin content, in contrast, increased gradually and remained high even after 30 days. Neither CSF 5-HIAA nor blood 5-HT correlated with age, drug dose, or clinical effectiveness, but some relationship between these and the sedative component of the clozapine action was observed.

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Hydroxyindoleacetic Acid; Leukocyte Count; Middle Aged; Psychotic Disorders; Serotonin; Time Factors

Topics: Animals; Autonomic Nervous System; Clozapine; Dibenzazepines; Humans; Nervous System Diseases; Psychotic Disorders

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Liver Function Tests; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Time Factors

The relationship between antipsychotic effect and side effects and plasma levels of clozapine were investigated in 26 patients. A significant linear correlation was found between dosage and plasma levels of clozapine. All patients were clearly improved. The degree of improvement was independent of the plasma levels in an average range of plasma levels (100 ng/ml-800 ng/ml). Sedation and orthostatic dysregulation occurred most pronounced on the third day of treatment. There was no relationship between plasma levels and these symptoms. After prolonged treatment the degree of both symptoms diminished. The development of tolerance of symptoms is concluded.

Topics: Adolescent; Adult; Clozapine; Dibenzazepines; Female; Humans; Hypotension, Orthostatic; Male; Middle Aged; Psychotic Disorders; Sleep

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Anthracenes; Clozapine; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Haloperidol; Homovanillic Acid; Humans; Limbic System; Male; Methyltyrosines; Psychotic Disorders; Psychotropic Drugs; Rats; Sulpiride; Thioridazine

An experimental analysis of the psychotropic activity of Leponex (in a chronic experiment on II cats) in conditions of a group interaction depicted that the preparation processes a definite tranquillizing and antipsychotic effect. In conditions of zoosocial interactions this drug promotes disappearance of neurotic reactions and a resocialization of animals in the zoosocial ierarchy. In tranquillizing doses the preparation has an antihypertensive effect and prevents the development of a long-term tonic hypertension due to emotional stress.

Topics: Animals; Antipsychotic Agents; Cats; Clozapine; Diazepam; Dibenzazepines; Disease Models, Animal; Haloperidol; Humans; Mental Disorders; Neurotic Disorders; Psychotic Disorders; Social Behavior; Tranquilizing Agents

Topics: Anti-Anxiety Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dibenzazepines; Handwriting; Humans; Psychiatric Status Rating Scales; Psychotic Disorders

Topics: Basal Ganglia Diseases; Clozapine; Dibenzazepines; Humans; Psychiatric Status Rating Scales; Psychotic Disorders

In a clinical study and with experiments in rats Clozapine showed a sedative effect, which diminished during the treatment, and indicated a development of tolerance. 5-HIAA in urine and CSF of patients was elevated after 10 days of treatment. 5-HT and 5-HIAA were elevated in the brains of rats in acute experiments as well as in chronic experiments.

Topics: Animals; Brain; Circadian Rhythm; Clozapine; Dibenzazepines; Humans; Hydroxyindoleacetic Acid; Male; Psychotic Disorders; Rats; Serotonin; Sleep Stages