clozapine and Chronic-Disease

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

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

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

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

Atypical antipsychotic drugs have less extra pyramidal side effects and are more effective to control the clinical manifestations of schizophrenia. However, their use may be associated to a higher incidence of weight gain, dyslipidemia, metabolic syndrome, glucose intolerance and type 2 diabetes mellitus. We performed a systematic literature search to evaluate the risk of type 2 diabetes mellitus incidence associated to the use of atypical antipsychotic drugs, compared to conventional treatment. If users of all types of atypical antipsychotic drugs are compared with users of conventional treatment, no significant differences in the incidence of type 2 diabetes mellitus were observed. If individual drugs are evaluated, clozapine and risperidone are associated with a higher risk of diabetes than haloperidol. Quetiapine is associated with a lower risk of diabetes than conventional treatment. The quality of the evidence found was low; therefore, new studies should been performed.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Diabetes Mellitus, Type 2; Humans; Mental Disorders; Risk Factors; Risperidone

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

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

Besides the well-known adverse effects of clozapine, such as granulocytopenia, tiredness and hypersalivation, acute pancreatitis is known to be a very rare complication of the drug. In the literature a total of five case reports have been published so far. We report a case of asymptomatic pancreatitis subsequent to clozapine treatment at therapeutic doses in a 38-year-old male patient with chronic paranoid-hallucinatory schizophrenia. The patient was rehospitalized after an acute exacerbation of the psychosis subsequent to an attempt to change medication on an outpatient basis. Treatment with clozapine was initiated again. During phases of progressively increasing the clozapine dose, serum levels of amylase and lipase were increased; after maintaining daily doses of clozapine of 300 mg and/or 600 mg the pancreatic enzymes normalized quickly within a few days. The patient did not report any pancreas-related complaints, nor did specific diagnostic studies produce any indicative result, only a minor thickening of the head and body of the pancreas in the ultrasound. It is assumed that the phenomenon of subclinical, asymptomatic pancreatitis during increasing dosage of clozapine occurs more often than previously supposed. The monitoring of serum amylase levels during slow increase in clozapine is recommended; if leukocytosis or eosinophilia is present, the possibility of even a subclinical and asymptomatic pancreatitis should be considered.

Topics: Adult; Amylases; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Monitoring; Hallucinations; Humans; Lipase; Male; Pancreatitis; Recurrence; Schizophrenia, Paranoid

Research on the impact of nicotine on schizophrenia and antipsychotic medications was reviewed to determine ways to improve treatment planning for patients with schizophrenia who smoke and to evaluate smoking cessation programs for this population.. All major research databases were searched. The review focuses on reports published since 1990.. Smoking improves processing of auditory stimuli (sensory gating) by patients with schizophrenia and may lessen negative symptoms by increasing dopamine in the nucleus accumbens and the prefrontal and frontal cortex. Use of traditional antipsychotics may result in patients' smoking more, whereas patients taking atypical antipsychotics may smoke less. Patients who smoke metabolize antipsychotics faster than nonsmoking patients. Smoking cessation programs for outpatients with schizophrenia report a success rate of about 12 percent after six months. No studies of cessation programs for chronically ill inpatients with schizophrenia have been published. Several hospitals have implemented smoking bans with equivocal results.. Nicotine affects both schizophrenia and antipsychotic medications. Neurobiological and psychosocial factors reinforce the high use of nicotine by patients with schizophrenia

Topics: Antipsychotic Agents; Auditory Perception; Chlorpromazine; Chronic Disease; Clozapine; Databases as Topic; Dopamine; Dose-Response Relationship, Drug; Frontal Lobe; Humans; Nicotine; Nucleus Accumbens; Prefrontal Cortex; Schizophrenia; Severity of Illness Index; Smoking Cessation

The unprecedented level of activity in the development of new antipsychotic medications can be traced to the 1989 approval of clozapine by the US Food and Drug Administration for treatment of refractory schizophrenia. This has encouraged the development of other new agents that share some of clozapine's receptor binding characteristics. A wide range of clinical trial designs are being used during the development of new antipsychotic medications. This article describes both basic designs and more innovative ones: flexible-dose designs that include placebo and conventional neuroleptic agents as controls; fixed-dose designs with multiple doses of experimental medication; and fixed-dose designs with multiple doses of the experimental and comparator medication. The strengths and weaknesses of each are identified. The need for long-term maintenance studies of newer agents is emphasized because psychotic disorders in general, and schizophrenia in particular, are chronic relapsing illnesses. The current status of four newer antipsychotic medications is considered: clozapine, risperidone, olanzapine, and sertindole. The importance of direct comparison among the newer antipsychotic medications in both short- and long-term trials is highlighted.

Topics: Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clinical Trials as Topic; Clozapine; Drug Administration Schedule; Drug Approval; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Placebos; Psychotic Disorders; Recurrence; Research Design; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States; United States Food and Drug Administration

The authors review the various methods of evaluating quality of life in schizophrenics and note the limitations of that type of method in terms of both form and content. In practical terms, the patients' cognitive disorders may constitute a bias when the questionnaire is addressed. Using a 'subjective quality of life profile' by Gerin et al., the authors interviewed 22 patients presenting with 'recalcitrant schizophrenia' and treated with clozapine for more than 3 years. The patients were asked to assess the change in their quality of life by comparison with previous neuroleptic chemotherapies. For all the items investigated, the responses were in favor of clozapine.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Patient Satisfaction; Psychiatric Status Rating Scales; Quality of Life; Recurrence; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Drug Therapy, Combination; Humans; Lithium; Psychotropic Drugs; Risperidone; Schizophrenia

Historically, first case-report of resistant schizophrenia were described under insulin therapy. Later on, the development of classical neuroleptics has permitted a better outcome but the persistence of a lack of improvement in certain patients has induced the individuation of treatment-refractory schizophrenia criteria. The difficulties in defining the refractory schizophrenic patients are described: variability of the schizophrenia diagnostic criteria, variability of outcome, lack of consensus about the good practices in neuroleptic treatment, difficulties in defining response criteria and the confusion between resistance, chronicity and severity. Three kinds of treatment refractory schizophrenia criteria are available: by Kane et al., May et Dencker, Brenner Dencker et al. There are few studies including resistant schizophrenic patients: their results are not homogeneous, perhaps because the prevalence of treatment-refractory schizophrenia is poorly known, with ranges from 5 to 25%. The following factors are hypothesized as being readily associated to a poor outcome and perhaps resistance: male sex, early illness beginning, severity of negative or formal thought disorder, absence of an affective syndrome, morphological CT scans abnormalities, pharmacological factors, late treatment initiation, variability of biodisposibility... Then the therapeutic point of view is considered under three main axes: neuroleptic drugs (NLP) are the basis of chemotherapy, but other therapeutic approaches complete the biological treatment: coherent institutional work and implication of family environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Social Environment

Clozapine's effectiveness in reducing symptoms and facilitating discharge among patients with chronic schizophrenia who were resistant to neuroleptics was studied.. All 169 such patients in a public psychiatric hospital were given clozapine. BPRS ratings (0-5 scale) were completed before treatment and 21 months later. Patients were followed for about 2.5 years.. Clozapine was discontinued in 37.8% of cases due to non-compliance, non-response, or side-effects. At follow-up 41% of clozapine recipients and 25.9% of the drop-outs were discharged and remained so, and 33% of recipients and 24.1% of drop-outs were being prepared for discharge. Longer treatment was associated with more improvement. Decline in average BPRS total scores of recipients was significantly more than drop-outs (32.7, s.d. 16.8 v. 12.1, s.d. 14.1, d.f. = 155, t = 7.5, P = 0.000).. Clozapine appears to be effective for treating some chronic neuroleptic nonresponding schizophrenic patients.

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Chronic Disease; Clozapine; Drug Resistance; Hospitalization; Humans; Middle Aged; Schizophrenia; Treatment Outcome

Clozapine holds great clinical promise for some chronic schizophrenic patients. However, limitations on access to the drug by the largest subgroup who need it, the indigent, are causing frustration for patients, their families, physicians, and public-sector mental health systems. The drug is available only through the manufacturer's proprietary monitoring system; many public-sector professionals and agencies feel that the system is overpriced, is unfairly exclusive, and has thus far kept the drug out of reach of most patients who need it. Arguments that patient improvement will lead to dollar savings in the long run seem overly optimistic. The ethical issue of access to treatment remains. The author discusses these and related issues and reports early experience from several public mental health systems.

Topics: Agranulocytosis; Chronic Disease; Clozapine; Cost-Benefit Analysis; Dibenzazepines; Health Services Accessibility; Humans; Medicaid; Medical Indigency; Risk Factors; Schizophrenia; Schizophrenic Psychology; United States

The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n=49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n=19], quetiapine [n=15], or risperidone [n=16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. ≥6 on the CDSS), using mixed models.. No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p<.01 for the whole sample and p=.01 for those with an MDE), and comparable to olanzapine and risperidone.. The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE.

Topics: Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Depressive Disorder, Major; Double-Blind Method; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

It has been proposed that a deficit of adenosinergic activity could contribute to the pathophysiology of schizophrenia. The authors undertook this study to further evaluate the level of adenosine deaminase (ADA) in patients with chronic schizophrenia treated with monotherapy of haloperidol, risperidone or clozapine and correlation between the ADA level with response to treatment.. The trial was a prospective, 8-week, double blind study of parallel groups of patients with chronic schizophrenia. Eligible participants in the study were 51 patients with chronic schizophrenia with ages ranging from 20 to 45 years. All participants were inpatients, in the active phase of illness, and met DSM-IV-TR criteria for schizophrenia. Patients were randomly allocated (17 patients in each group) to risperidone (6 mg/day) or haloperidol 15 mg/day or clozapine (300 mg/day). Serum ADA activity was measured at baseline and week 8.. The plasma levels of ADA in patients with chronic schizophrenia who received clozapine were significantly higher than patients who received haloperidol. In addition, response to treatment was positively correlated with plasma levels of ADA only in the clozapine group (r = 0.46 and p = 0.04).. The results indicate an increased activity of the enzyme ADA in the serum of schizophrenic patients being treated with clozapine and this increase may be correlated with clozapine's superior antipsychotic efficacy.

Topics: Adenosine; Adenosine Deaminase; Adult; Chronic Disease; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Prospective Studies; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

The limitations of antipsychotics for treatment of schizophrenia have led to investigation of the usefulness of pharmacological augmentation strategies. Clinical studies have provided evidence for glutamate abnormalities in schizophrenia. Topiramate is an anticonvulsant drug with alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist properties; therefore, the objective of the present study was to explore the therapeutic efficacy of topiramate as an adjunctive medication in schizophrenia.. A 17 week, double-blind, placebo-controlled clinical trial was performed on 80 patients (25 - 65 years) from 2005 - 2007. All were hospitalized in Mashhad psychiatric hospitals with chronic DSM-IV-TR-diagnosed schizophrenia. All participants received up to 300 mg/day of clozapine. In addition, participants randomly received either topiramate (200 - 300 mg/day) or placebo gradually added to their ongoing treatment. Efficacy of medication was measured by administering Positive and Negative Syndrome Scale at baseline and weeks 4, 8, 12, and 17.. During the study, 5 patients from the placebo group and 12 participants from topiramate group were excluded. Clozapine and topiramate group showed significant decreases in all three subscales of PANSS values from baseline, with the maximum efficacy in week 12. However, after tapering topiramate, the general psychopathology sign was the only subscale that showed a significant difference. The clozapine and placebo group showed a significant decrease in all three subscales of PANSS values compared to baseline. The significant efficacy for all subscales was obtained at the end point. No significant differences in PANSS scores from baseline to end point were noted between case and control groups.. Augmentation of clozapine and topiramate did not significantly decline patterns in any of the three subscales of PANSS compared to the clozapine and placebo group. Irct ID: IRCT138904014236N1

Topics: Adult; Aged; Anticonvulsants; Antipsychotic Agents; Chemotherapy, Adjuvant; Chronic Disease; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Topiramate; Treatment Outcome

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes.. Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments.. Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33-41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall).. Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Chronic Disease; Clozapine; Dibenzothiazepines; Female; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Perphenazine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

This study sought to examine the effect of ziprasidone on olanzapine or clozapine-associated medical morbidity such as insulin resistance, diabetes mellitus (DM) and impaired fasting glucose, obesity, and hyperlipidemia in patients with schizophrenia or schizoaffective disorder.. This was a 6-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in 21 schizophrenia or schizoaffective patients with DM, impaired fasting glucose, or insulin resistance.. Ten olanzapine-treated subjects and 11 clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week 6, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative, or depressive symptoms. QTc significantly increased at week 2 but not at week 6.. The addition of 160 mg/day of ziprasidone was well tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperglycemia; Insulin Resistance; Male; Middle Aged; Morbidity; Olanzapine; Piperazines; Schizophrenia; Thiazoles; Time Factors

Schizophrenia is associated with various abnormalities in the immune system. Suppression of inflammatory cytokines by cigarette smoke is well-established. The purpose of this study was to determine any differences in cytokine profiles in smokers and nonsmokers with schizophrenia and whether there were any relationships among altered cytokine profiles and psychopathological symptoms.. Serum interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha levels were measured in 96 male inpatients with DSM-IV schizophrenia: 66 smokers and 30 nonsmokers. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS).. The positive PANSS symptoms were lower in smokers than nonsmokers, while the negative symptoms were lower in those who smoked more cigarettes. Cytokine levels were positively correlated: IL-2 level with IL-6 and IL-6 with both IL-8 and TNF-alpha. Both IL-2 and IL-6, but not IL-8 or TNF-alpha, were significantly lower in smokers than nonsmokers (p < 0.002; p < 0.01). Lower IL-2 levels correlated with fewer negative symptoms and with smoking more cigarettes.. The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be associated with nicotine-induced suppression of some inflammatory cytokines.

Topics: Age Factors; Antipsychotic Agents; Chronic Disease; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Drug Administration Schedule; Humans; Interleukins; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Smoking; Smoking Cessation; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

This study examined the relative effects of the second-generation antipsychotic drugs and an older representative agent on psychosocial functioning in patients with chronic schizophrenia.. Consenting patients were enrolled in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. In phase 1, patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. Clozapine was included for patients who chose this pathway after discontinuing phase 1 due to inefficacy; all other patients received another second-generation antipsychotic. Psychosocial functioning was assessed using the Quality of Life Scale.. Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains.. All antipsychotic treatment groups in all phases made modest improvements in psychosocial functioning. There were no differences among them after 6, 12, or 18 months. More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions.

Topics: Adaptation, Psychological; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Dibenzothiazepines; Follow-Up Studies; Health Status; Humans; National Institute of Mental Health (U.S.); Olanzapine; Patient Dropouts; Perphenazine; Piperazines; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Thiazoles; Treatment Outcome; United States

Weight gain is a problem commonly encountered with antipsychotic treatment and has become more apparent with increasing use of the newer atypical antipsychotics. The adipocyte-derived hormone, leptin, has been associated with body weight and energy homeostasis, and abnormal regulation of leptin could play a role in weight gain induced by antipsychotics. We investigated whether a leptin gene promoter variant affected weight gain after long-term treatment with clozapine in chronic schizophrenia. Leptin G2548A polymorphism was genotyped in 102 Chinese Han inpatients with chronic schizophrenia treated with clozapine. Weight gains, expressed as change in body mass index (BMI), were monitored after long-term clozapine treatment. We found a significant relationship between the 3 leptin G/A genotypes and mean BMI gain (F(2,99) = 3.35, P = 0.039, r(2) = 0.09). Moreover, genotype had a strong effect on BMI gain in male (P = 0.004, r(2) = 0.16), but not in female patients (P > 0.05). Thus, variation in the leptin gene may be a risk factor for weight gain in male patients with schizophrenia on long-term clozapine treatment.

Topics: Antipsychotic Agents; Asian People; Body Mass Index; China; Chronic Disease; Clozapine; Female; Genotype; Humans; Leptin; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Promoter Regions, Genetic; Schizophrenia; Weight Gain

The development of therapeutic strategies for cognitive dysfunction remains one of the primary goals in the treatment of schizophrenia. The pharmacodynamic profile of mirtazapine, an antidepressant that enhances noradrenergic and serotonergic transmission, is based on a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism. Mirtazapine shares some pharmacological similarities with that of clozapine. This 8-week open label trial aimed to discover whether the addition of 30 mg mirtazapine could potentiate the effects on cognition of an ongoing stabilized clozapine therapy in 15 persons who met the criteria for chronic schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). Mirtazapine adjunction was well tolerated and induced a significant improvement in cognitive performance, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph, 1998) total score and by the subscales for immediate and delayed memory (p<.01). Since Hamilton Depression Rating Scale (HAM-D; Hamilton, 1967), Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962), and Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1989) scores at Week 8 did not show significant differences from baseline, the improvements in the effects of clozapine on cognition observed after the addition of mirtazapine seemed to be a direct rather than an indirect action of this drug (e.g., via mood or other psychopathological symptoms). These findings suggest a potential role for mirtazapine as a useful strategy to augment the efficacy of clozapine in the treatment of cognitive dysfunctions in chronic schizophrenia.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Cognition; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Drug Synergism; Female; Humans; Male; Mianserin; Mirtazapine; Schizophrenia; Time Factors

When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]).. Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation.. For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cross-Over Studies; Dibenzothiazepines; Drug Monitoring; Drug Resistance; Eosinophilia; Female; Follow-Up Studies; Humans; Male; Olanzapine; Piperazines; Prospective Studies; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

We report on dyspeptic complaints among patients hospitalized in the long-stay ward of a general psychiatric hospital.. A representative sample of the patients was interviewed using a structured questionnaire.. Eighty percent of the patients reported one or more symptoms of dyspepsia, and 68 % reported symptoms of reflux-like dyspepsia.. Significant positive associations were found for dyspepsia complaints and clozapine (OR = 3.4), laxatives (OR = 4.4), and heavy smoking (OR = 2.3).

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cathartics; Chronic Disease; Clozapine; Confidence Intervals; Dyspepsia; Female; Humans; Male; Mental Disorders; Middle Aged; Odds Ratio; Sex Factors; Smoking

Patients with chronic schizophrenia (DSM-IV criteria) often receive depot antipsychotic medications to assure longer administration and better compliance with their treatment regimen. This study evaluated whether patients stabilized on depot antipsychotic medication could be successfully transitioned to oral olanzapine.. In a 3-month open-label study, 26 clinically stable patients with schizophrenia taking depot antipsychotics for over 3 years were randomly assigned to continue on their current depot dose or to switch to oral olanzapine. Clinical ratings (Positive and Negative Syndrome Scale [PANSS], Global Assessment of Functioning [GAF] scale, and Clinical Global Impressions [CGI] scale) and side effect parameters (Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia Scale, AMDP-5 scale, vital signs, and weight) were obtained monthly.. Oral olanzapine patients (N = 13) demonstrated significant clinical improvement over the depot control group (N = 13) from baseline to 3-month endpoint (PANSS total, p =.012; PANSS general, p =.068; PANSS negative, p =.098; CGI-Improvement, p =.007; CGI-Severity, p =.026; GAF, p =.015). Side effect rating scales showed no statistical differences between the 2 groups (AIMS, Barnes Akathisia Scale, AMDP-5, vital signs). The depot control group showed no statistical superiority in any measure except weight change (p =.0005). After 3 months, all olanzapine patients preferred olanzapine to their previous depot medications and chose to continue on olanzapine treatment.. Clinicians may expect clinical improvement when switching chronically psychotic patients from traditional depot antipsychotic drugs to oral olanzapine. Switching may be completed within a 4-week period with relative compliance being maintained and patients preferring oral olanzapine to their previous depot medications.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Olanzapine; Patient Compliance; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Schizophrenia patients are known to manifest widespread, multifaceted cognitive deficits. There is now an increasing emphasis on the critical importance of cognitive deficits for the functional outcome in schizophrenia. Typical antipsychotics, although effective in reducing positive symptoms of the illness, have not shown much effect on cognitive functions. Atypical antipsychotics have shown promise of improving some cognitive functions.. This naturalistic study aimed to determine whether olanzapine and clozapine improve cognitive functioning in a sample of 48 patients with chronic schizophrenia who had either failed to show sufficient clinical improvements or suffered from distressing side effects with conventional antipsychotics and were switched to either olanzapine or clozapine for clinical reasons and, if so, whether the two drugs produce similar or different cognitive effects.. All patients completed a comprehensive battery of neuropsychological tests designed to index executive functioning, verbal learning, verbal and visual and memory, attention, working memory, and psychomotor speed at: (i) baseline, (ii) after 6 weeks and (iii) after 6 months of treatment with olanzapine or clozapine.. From the initial 48 patients who remained on olanzapine ( n=16) or clozapine ( n=14) for the entire duration with continuous participation, 30 provided data for this study. There were improvements over time (i.e. from baseline through 6 weeks to 6 months) in both treatment groups on verbal fluency, verbal learning and verbal and visual memory measures.. The findings indicate similar beneficial effects of olanzapine and clozapine on verbal learning and memory measures in patients showing a favourable clinical response to these drugs.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Female; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Olanzapine; Pirenzepine; Problem Solving; Schizophrenia; Time Factors; Treatment Outcome

The risk of suicide for schizophrenia patients is 20 to 50 times higher than that for the general population. Long-term treatment with clozapine, an atypical antipsychotic, has been shown to reduce the rate of suicide by 80% to 85%. The goal of the present study was to examine whether clozapine's effect on the reduction of suicidal behavior in chronic schizophrenic patients could be due to a reduction in impulsive-aggressive behavior.. 44 patients with chronic DSM-IV schizophrenia were treated with clozapine or haloperidol decanoate in an open prospective 6-month trial. Changes in measures of suicidality, impulsiveness, aggression, depressed mood, and positive and negative symptoms were assessed at baseline and at 6 months.. The clozapine-treated group (N = 18) had a significantly greater reduction on all outcome measures compared with the haloperidol decanoate-treated group (N = 26). Only in the clozapine-treated group did the reduction in measures of suicidality correlate significantly with a reduction in impulsiveness and aggression. The reductions in suicidality and impulsive aggression were not significantly correlated with reductions in depressed mood or positive and negative symptom scores in either group.. These data suggest that the reduction in suicidality following long-term clozapine treatment may be related to a reduction in impulsiveness and aggression.

Topics: Adolescent; Adult; Aggression; Antipsychotic Agents; Chronic Disease; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Disruptive, Impulse Control, and Conduct Disorders; Drug Administration Schedule; Female; Haloperidol; Humans; Male; Middle Aged; Schizophrenia; Suicide, Attempted

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

Despite the advent of new atypical antipsychotics, clozapine remains an important option in the treatment of patients with poor response to conventional antipsychotics. Clinicians would be well served if clinical characteristics could be identified that predict a favorable response to clozapine. A few studies addressing this issue have reported inconsistent results.. The association of clinical characteristics with a sustained response was investigated in 37 partially treatment-refractory outpatients with a DSM-III-R diagnosis of chronic schizophrenia who had been assigned to clozapine treatment in a double-blind, haloperidol-controlled, long-term (29-week) study of clozapine. Response was defined as a 20% decrease of the Brief Psychiatric Rating Scale (BPRS) psychosis factor score sustained over 2 consecutive ratings. Differences between responders and nonresponders with regard to selected baseline variables were analyzed with t tests and chi2 tests. In addition, Cox regression analyses were performed to identify variables that best predicted a response to clozapine treatment.. Clozapine responders were rated as less severely ill, showed a lesser degree of negative symptoms, and demonstrated fewer extrapyramidal side effects at baseline as compared with nonresponders. In addition, higher BPRS total scores--after controlling for the effects of the other variables--were associated with a response.. In a cohort of partially treatment-refractory outpatients, a favorable response to clozapine was associated with characteristics describing less severely ill patients. The history of patients did not affect their response to clozapine.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Basal Ganglia Diseases; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Probability; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome

This prospective, double-blind, multicenter, parallel-group study compared the efficacy and safety of therapeutic doses of clozapine and risperidone in patients with severe chronic schizophrenia and poor previous treatment response.. Male or female patients aged 18-65 years who met DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response (N=273) were randomly assigned to double-blind treatment with either clozapine or risperidone administered over 12 weeks in increasing increments. The primary efficacy measures were the magnitude of improvement in Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores. Adverse events were recorded throughout the study.. The magnitude of improvement in mean BPRS and CGI scores from baseline to end of the study was significantly greater in the clozapine group than in the risperidone group. Statistically significant differences in favor of clozapine were also seen for most of the secondary efficacy measures (Positive and Negative Syndrome Scale, Calgary Depression Scale, Psychotic Depression Scale, and Psychotic Anxiety Scale). The adverse event profile was similar for both treatment groups, with a lower risk of extrapyramidal symptoms in the clozapine group.. Clozapine showed superior efficacy over risperidone in this patient population. Both treatments were equally well tolerated as demonstrated through their adverse event profiles, although as expected clozapine was associated with a lower risk of extrapyramidal symptoms than risperidone.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Risk Factors; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents.. After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents.. Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone.. The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Human Growth Hormone; Humans; Hydrocortisone; Male; Parkinson Disease, Secondary; Prolactin; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Results presented in this article are focused on the variability in pharmacokinetics. The purpose of this study was (1) to investigate intra- and interindividual variabilities of pharmacokinetic parameters of clozapine and its two main metabolites in plasma after multiple oral administration in 8 chronic schizophrenic patients (Study 1) and (2) to gain more information regarding plasma concentrations of these drugs after multiple doses in a group of 25 treatment-responsive patients (Study 2). Patients were treated with clozapine in fixed daily doses (given every 8-12 hours) between 200 and 900 mg. Plasma drug concentrations were determined by high-performance liquid chromatography. The mean volume of distribution and the total plasma clearance of clozapine, uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The terminal elimination half-lives averaged 10.5 hours for clozapine, 19.2 hours for norclozapine, and 8.6 hours for the N-oxide metabolite. Significant relationships were observed between clozapine and norclozapine (or clozapine N-oxide) plasma concentrations. Large inter- and intrapatient variations in pharmacokinetics were observed. Clozapine was generally well tolerated by the patients, with sedation, hypersialorrhea, and tiredness as the most common side effects encountered.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Schizophrenia; Time Factors

The aim of this study was to evaluate the effect of long-term clozapine treatment on body weight changes in neuroleptic-resistant chronic schizophrenic patients and to compare it with that of classical antipsychotic agents. The body mass index (BMI) of 96 neuroleptic-resistant chronic schizophrenic patients was calculated before the beginning and after long-term (mean +/- SD 1.7 +/- 1.3 years) clozapine treatment. These data were compared to the BMI of 98 chronic schizophrenic patients maintained on classical antipsychotic agents for a similar duration (mean +/- SD 1.9 +/- 1.6 years). A significant elevation in BMI was detected in both groups during these periods (P < 0.0001 versus baseline, for both groups). The change in BMI (delta BMI) was similar in both groups (P < 0.9). We conclude that the increase in body weight caused by long-term (> 6 months) clozapine treatment is comparable to that obtained following long-term classical antipsychotic agents treatment.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Chronic Disease; Clozapine; Female; Humans; Male; Schizophrenia; Weight Gain

This study focused on the symptomatic and cognitive effects of the atypical antipsychotic clozapine in chronic hospitalized schizophrenia patients. Further, it explored how these effects might be related to discharge, an important functional outcome. Patients were assessed at baseline and at regular intervals with clinical instruments and a cognitive battery. Clozapine treatment produced symptomatic and cognitive improvements, positive changes that appeared to occur independently of one another. Baseline cognitive performance, as well as cognitive change with treatment, predicted discharge. Further investigation of the effects of clozapine and other atypical antipsychotics on cognition and functional outcome is warranted.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Cognition; Dose-Response Relationship, Drug; Female; Hospitalization; Hospitals, Psychiatric; Humans; Male; Middle Aged; Neuropsychological Tests; Psychomotor Performance; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients.. In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales.. Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness.. Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Chronic Disease; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Failure; Treatment Outcome

The pharmacokinetic parameters of clozapine and its two main metabolites, N-desmethylclozapine (norclozapine, active metabolite) and clozapine N-oxide, were evaluated, after oral administration, in 19 patients with chronic schizophrenia. Plasma and red blood cell (RBC) drug concentrations were determined by high-performance liquid chromatography. Large interpatient variations in pharmacokinetic parameters of clozapine and its two metabolites were observed. Plasma clozapine concentration peaked, on average, at 2.3 hours. The mean volume of distribution and the total plasma clearance, uncorrected for bioavailability, were 6 L/kg and 38 L/hr, respectively. The terminal elimination half-lives averaged 7.6 hours for clozapine, 13 hours for norclozapine, and 7 hours for the N-oxide metabolite. The mean RBC/plasma concentration ratios were 23, 61, and 81% for clozapine, N-desmethylclozapine, and clozapine N-oxide, respectively. From RBC concentration data, the mean elimination half-lives were 7.6 hours for clozapine, 16 hours for N-desmethylclozapine, and 8 hours for the N-oxide metabolite. The average value for blood clearance of clozapine was 54.7 L/hr. Significant correlations were observed between dose and maximum plasma concentrations and between dose and area under the curve concentrations; these results suggested linear steady-state pharmacokinetics over the range of concentrations studied.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Schizophrenia

Preliminary results of a double-blind clozapine study in a population of chronic psychotic patients at a state psychiatric facility are reported. Thirty "treatment-refractory" schizophrenic patients given a diagnosis according to DSM-III-R criteria (mean age of 44 +/- 9.1 years and a duration of illness of 24.9 +/- 8.8 years) who received 300 mg or 600 mg of clozapine and randomized in a double-blind fashion were analyzed. Subjects were evaluated using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale on a weekly basis for 16 weeks. Based on the changes in their CGI scores at week 16 of clozapine treatment, subjects were retrospectively categorized as "improvers" (N = 12) and "nonimprovers" (N = 18). The two groups were compared for changes in total BPRS and BPRS factor scores. In terms of total BPRS scores, we expected a difference between the two groups because they were categorized based on changes in their CGI scores. However, the total BPRS scores in improvers showed a significant decrease by week 6 of clozapine treatment. On analyzing the four BPRS factors, the improvers showed improvement in the thinking disturbance factor by week 1 that remained steady from week 7. On the hostility-suspiciousness factor, the improvers showed an improvement across time when compared with nonimprovers. The withdrawal-retardation factor showed improvement in both groups across time, whereas the anxiety-depression factor was least influenced by clozapine. These observations suggested that all BPRS symptom factors did not uniformly contribute to improvement in overall psychopathology, which was observed as a decrease in total BPRS scores.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; 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

Previous studies on the use of clozapine in neuroleptic-resistant chronic schizophrenic patients have demonstrated positive effects on tardive dyskinesia but were less conclusive about chronic akathisia and parkinsonism. The aim of the present study was to investigate the short-term (18 weeks) efficacy of clozapine in neuroleptic-resistant chronic schizophrenic patients with coexisting tardive dyskinesia, chronic akathisia, and parkinsonism.. Twenty chronic, neuroleptic-resistant schizophrenic patients with coexisting tardive dyskinesia, parkinsonism, and chronic akathisia were treated with clozapine. Assessment of tardive dyskinesia, parkinsonism, and chronic akathisia was made once weekly for 18 weeks with the Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Rating Scale for Extrapyramidal Side Effects, and Barnes Rating Scale for Drug-Induced Akathisia (BAS).. At the end of 18 weeks of clozapine treatment, improvement rates were 74% for tardive dyskinesia, 69% for parkinsonism, and 78% for chronic akathisia. A statistically significant reduction in the scores on the AIMS and Simpson-Angus Scale was achieved at Week 5 and on the BAS at Week 6 (p < .0001).. Relatively low doses of clozapine are effective for the treatment of neuroleptic-induced extrapyramidal syndromes in neuroleptic-resistant chronic schizophrenic patients. The relief of tardive dyskinesia, parkinsonism, and chronic akathisia in this group of patients occurs more rapidly than the reduction in psychotic symptoms. Disturbing, long-term extrapyramidal syndromes in chronic schizophrenic patients should be considered an indication for clozapine treatment.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Comorbidity; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Aggressive and impulsive behavior is frequently observed in schizophrenic patients. Previous studies suggest that impulsive aggression may be the most common behavioral correlate of central serotonergic system dysfunction. This study was aimed to determine if clozapine, an atypical antipsychotic agent with potent serotonergic antagonistic properties, can reduce impulsiveness and aggression in neuroleptic-resistant chronic schizophrenic patients. Fourteen neuroleptic-resistant chronic schizophrenic patients were treated with clozapine and prospectively evaluated for aggressiveness and impulsiveness for 18 weeks. Clozapine treatment induced a marked decrease in impulsiveness (32% on the Impulsivity Scale; p < 0.0001) and aggressiveness (98% on the Overt Aggression Scale; p < 0.0001). We conclude that clozapine treatment may be effective in reducing psychotic symptoms as well as in controlling aggressive and impulsive behavior in neuroleptic-resistant chronic schizophrenic patients.

Topics: Adult; Aggression; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Resistance; Female; Humans; Impulsive Behavior; Male; Middle Aged; Schizophrenia; Serotonin Antagonists

Plasma levels of clozapine and its major metabolites, N-desmethylclozapine and clozapine-N-oxide, were measured in 18 schizophrenic patients at different times (4, 6 and 24 weeks) during the course of treatment with multiple doses of the drug, by using high performance liquid chromatography (HPLC) with UV detection. Plasma levels of clozapine and N-desmethylclozapine were significantly higher in females than in males after 4 and 6 weeks, but not after 24 weeks, of treatment. No sex difference was found at any time with respect to plasma levels of clozapine-N-oxide.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Schizophrenia; Sex Factors; Time Factors

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

Forty-eight consecutive schizophrenic patients treated with clozapine (mean daily dose 436 mg) for at least 1 year (mean 7.6, range 2.2-14.8 years) were studied retrospectively. The most favourable changes in the course of illness were observed in 39 out-patients, whose duration of hospitalization per year continuously and significantly declined after the introduction of clozapine. The out-patients who continued with clozapine treatment for more than 10 years (n = 8) did not need hospitalization at all during the last year of the observation period. The improvement in social functioning in the out-patient group correlated positively with the duration of clozapine medication (r = 0.384, p = 0.016) and with the duration of hospitalization (r = 0.372, p = 0.020) after introduction of clozapine. Out-patients with disorganized schizophrenia (later called hebephrenic according to the Finish version of DSM-III) showed more noticeable clinical (U = 226, p = 0.032) and social (U = 233, p = 0.024) improvements than non-hebephrenic patients. There appears to be a subgroup of hebephrenic patients who benefit from clozapine more than patients with other types of schizophrenia.

Topics: Adolescent; Adult; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Outpatients; Schizophrenia; Time Factors; Treatment Outcome

Some treatment-resistant schizophrenic patients improve enough to remain out of the hospital but continue to have significant positive or negative symptoms.. The goal of this study was to assess the safety and potential efficacy of risperidone as an adjunct for schizophrenic patients treated with clozapine. In an open 4-week trial involving 12 DSM-III-R-diagnosed patients, the addition of risperidone to clozapine was well tolerated and did not affect serum clozapine concentrations significantly.. Total Brief Psychiatric Rating Scale (BPRS) scores and subscales measuring positive symptoms, negative symptoms, and depressive symptoms were significantly reduced from baseline. Ten of 12 participants had a 20% or greater reduction in the total BPRS score.. In this open trial, the addition of risperidone to clozapine was well tolerated and produced significant reduction of symptoms, suggesting that this may be a useful clinical approach. Because this was an open trial, the improvement we observed must be replicated in a controlled trial.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Traditional neuroleptic drugs like thioridazine and haloperidol have not proven to be systematically effective with the treatment of self-injurious behavior (SIB). These drugs may be ineffective because they primarily block D2 dopamine receptors. Based on research with humans and other animals, it appears that another dopamine receptor, D1, may be responsible for mediating some SIB. Clozapine, a neuroleptic recently introduced in the United States, has proven effective in treatment of refractory cases of schizophrenia and is known to have an affinity for blocking D1 receptors. The drug was used to complete a 93-week double-blind crossover trial with a client displaying chronic SIB. Though clozapine is known to affect other neurotransmitter systems, the successful treatment of the participant is consistent with the D1 hypothesis of self-injurious behavior and suggests the possibility that clozapine could be an effective pharmacological intervention for some cases of SIB.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Cross-Over Studies; Dopamine; Double-Blind Method; Humans; Male; Receptors, Dopamine D1; Receptors, Dopamine D2; Self-Injurious Behavior

Clozapine is an atypical neuroleptic with superior efficacy in severely ill, treatment-resistant inpatients with schizophrenia. To determine if clozapine's differential efficacy generalizes to less ill, outpatients populations, the authors examined the effects of clozapine on positive and negative symptoms in outpatients with schizophrenia.. Outpatients with schizophrenia who had histories of partial response to conventional neuroleptics and who had not responded to a prospective 6-week trial of fluphenazine participated in a 10-week, double-blind, parallel-groups comparison of clozapine and haloperidol. Thirteen men and six women were given clozapine, and 15 men and five women were given haloperidol. Clinical response rates were determined and effects on primary versus secondary negative symptoms were addressed. Doses of clozapine and haloperidol at the end of the 10-week trial were 410.5 mg/day (SD = 45.8) and 24.8 mg/day (SD = 5.5), respectively.. Clozapine was superior to haloperidol for treating positive symptoms. In addition, eight of the patients given clozapine and only one of the patients given haloperidol fulfilled clinical responder criteria. Clozapine was also superior to haloperidol for treating negative symptoms, although these effects were relatively minor. Negative symptoms were significantly affected in the subgroup of patients with nondeficit schizophrenia but not in the subgroup with deficit schizophrenia. Overall, clozapine was well tolerated.. Clozapine has superior efficacy for treating positive symptoms in partially responsive outpatients with chronic schizophrenia, suggesting that it has utility for a broad spectrum of patients with schizophrenia beyond the most severely ill.

Topics: Adult; Ambulatory Care; Chronic Disease; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Sialorrhea; Tachycardia

In order to assess the safety and some efficacy aspects of clozapine under UK conditions, 54 in-patients with severe treatment-resistant schizophrenic disorders were evaluated using several scales before and during treatment. Of the 54 evaluated, 26 completed the 26-week study. Of these patients, 20 showed improvement in psychopathology, often to a marked degree, involving both positive and negative symptoms. Some oral-facial extrapyramidal side-effects decreased as well. Two patients developed neutropenia, but recovered on discontinuation of clozapine. The most frequent adverse event was hypersalivation, and five patients suffered from seizures. It is concluded that clozapine is worth considering for the treatment of severe treatment-resistant patients in the UK.

Topics: Adult; Chronic Disease; Clozapine; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neutropenia; Schizophrenia; Schizophrenic Psychology; Sialorrhea; Treatment Outcome; United Kingdom

The purpose of the study was to examine the effects of clozapine in treating moderately ill schizophrenic outpatients and to determine the length of medication trial needed to identify responders and nonresponders.. Rates of clinical responses, relapses and hospitalizations, and levels of symptomatology and functioning were assessed for 30 chronic schizophrenic outpatients who received clozapine for one year. For some patients, data on relapse and hospitalization during treatment were compared with data from the year before treatment.. Eighteen of the 30 patients met criteria for sustained response; 17 of the responders were identified within the first four months of treatment. Patients experienced significantly fewer relapses and hospitalizations during treatment than in the previous year. Improvement in positive symptoms, general symptomatology, and levels of functioning reached a plateau during the first six months of treatment and remained at that level during the second six months. Negative symptoms and quality of life showed nonsignificant improvements at 12 months.. Results support the use of clozapine in treating chronic, residually symptomatic schizophrenic outpatients. A four-month clozapine trial may be adequate to detect clinical responders in this population.

Topics: Adult; Ambulatory Care; Chronic Disease; Clozapine; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; Male; Patient Readmission; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is a novel antipsychotic agent that selectively blocks mesolimbic--rather than nigrostriatal--dopamine receptors, causes fewer extrapyramidal symptoms than do other neuroleptics, and has superior antipsychotic efficacy in some patients. However, clozapine also causes agranulocytosis more frequently than do other neuroleptics. The evidence documenting the superior benefits obtained with clozapine has primarily involved short-term (4-6 weeks) trials, and the systematic evaluation of long-term clozapine use has been limited. In this study, 14 patients with refractory chronic schizophrenia were treated openly with clozapine up to 2 years; 8 did substantially better when given clozapine than they had when given other neuroleptics. That finding suggests that clozapine may provide a useful addition to the therapeutic armamentarium for the long-term treatment of schizophrenia, despite the increased risks and the need for frequent blood tests.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Clozapine; Dibenzazepines; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia.. To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD.. Two independent national cohorts including all persons diagnosed with schizophrenia (. For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24,. Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Recurrence; Schizophrenia; Substance-Related Disorders

Progressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine. Microglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry.. Iron impaired microglial function. Clozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS.

Topics: Animals; Antipsychotic Agents; Biomarkers; Cell Line; Chronic Disease; Clozapine; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Humans; Immunomodulation; Inflammation Mediators; Mice; Microglia; Oxidative Stress; Phagocytosis; Treatment Outcome

Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional "glial-neuron microcircuit" in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.

Topics: Animals; Anxiety Disorders; Astrocytes; Bone Density; Bone Resorption; Chronic Disease; Clozapine; Elevated Plus Maze Test; Emotions; Genes, Reporter; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gq-G11; Male; Mice; Mice, Inbred C57BL; Neurons; Open Field Test; Optogenetics; Proto-Oncogene Proteins c-fos; Random Allocation; Receptors, N-Methyl-D-Aspartate; Stress, Psychological; Ventromedial Hypothalamic Nucleus

Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.

Topics: Animals; Channelrhodopsins; Chronic Disease; Clozapine; Depressive Disorder, Major; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Genes, Reporter; Genetic Vectors; Hand Strength; Locomotion; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Optogenetics; Pars Reticulata; Receptor, Muscarinic M3; Recombinant Proteins; Rotarod Performance Test; Social Defeat; Stress, Psychological; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Despite its benefits, a major concern regarding antipsychotic treatment is its possible impact on the brain's structure and function. This study sought to explore the characteristics of white matter structural networks in chronic never-treated schizophrenia and those treated with clozapine or risperidone, and its potential association with cognitive function.. Diffusion tensor imaging was performed on a unique sample of 34 schizophrenia patients treated with antipsychotic monotherapy for over 5 years (17 treated with clozapine and 17 treated with risperidone), 17 never-treated schizophrenia patients with illness duration over 5 years, and 27 healthy control participants. Graph theory and network-based statistic approaches were employed.. We observed a disrupted organization of white matter structural networks as well as decreased nodal and connectivity characteristics across the schizophrenia groups, mainly involving thalamus, prefrontal, and occipital regions. Alterations in nodal and connectivity characteristics were relatively milder in risperidone-treated patients than clozapine-treated patients and never-treated patients. Altered global network measures were significantly associated with cognitive performance levels. Structural connectivity as reflected by network-based statistic mediated the difference in cognitive performance levels between clozapine-treated and risperidone-treated patients.. These results are constrained by the lack of random assignment to different types of antipsychotic treatment.. These findings provide insight into the white matter structural network deficits in patients with chronic schizophrenia, either being treated or untreated, and suggest white matter structural networks supporting cognitive function may benefit from antipsychotic treatment, especially in those treated with risperidone.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Cognitive Dysfunction; Diffusion Tensor Imaging; Female; Humans; Male; Middle Aged; Nerve Net; Risperidone; Schizophrenia; Treatment Outcome; White Matter

Cognitive impairment is core feature of schizophrenia. The impact of antipsychotics on cognition remains controversial. This study aimed to examine the effects of long-term use of different types of antipsychotics on cognitive impairment in schizophrenia patients.. We used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess the cognition of three groups of schizophrenia patients (318 on clozapine, 125 on risperidone, and 166 on typical antipsychotic drugs) and 399 healthy controls, and used the Positive and Negative Syndrome Scale to assess schizophrenia symptoms of patients.. Patients taking typical antipsychotics scored higher on the immediate memory and delayed memory index than those taking clozapine or risperidone (all p < 0.01). Patients taking clozapine scored higher on the language subscale than those taking risperidone (p < 0.05). Multiple regression analysis showed that the drug type was identified as an independent contributor to the immediate memory, language, and delayed memory index of RBANS (all p < 0.05).. Patients taking typical antipsychotics have better memory than those taking clozapine or risperidone. Patients taking clozapine have better language function than those taking risperidone.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Case-Control Studies; Chronic Disease; Clozapine; Cognition; Cross-Sectional Studies; Female; Humans; Language; Male; Memory; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; 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

We investigated whether negative symptoms, such as poor motivation or anhedonia, were associated with higher body mass index (BMI) in stable patients with schizophrenia chronically treated with antipsychotic medication.. 62 olanzapine- or clozapine-treated patients with illness duration of at least four years were selected from an international multicenter study on the characterization of negative symptoms. All participants completed the Brief Negative Symptom Scale (BNSS) and the Positive and Negative Syndrome Scale (PANSS). Bivariate correlations between BMI and negative symptoms (BNSS) were explored, as well as multiple regression analyses. We further explored the association of two principal component factors of the BNSS and BMI. Subsidiary analyses re-modeled the above using the negative symptoms subscale of the PANSS and the EMSLEY factor for negative symptoms for convergent validity.. Lower negative symptoms (BNSS score) were associated with higher BMI (r=-0.31; p=0.015). A multiple regression analysis showed that negative symptoms (BNSS score) and age were significant predictors of BMI (p=0.037). This was mostly driven by the motivation/pleasure factor of the BNSS. Within this second factor, BMI was negatively associated with anhedonia (r=-0.254; p=0.046) and asociality (r=-0.253; p=0.048), but not avolition (r=-0.169; p=0.188). EMSLEY score was positively associated with BNSS (r=0.873, p<0.001), but negatively associated with BMI (r=-0.308; p=0.015). The association between PANSS and BMI did not reach significance (r=-224, p=0.080).. We conclude that lower negative symptoms were associated with higher BMI (assessed using both the BNSS and EMSLEY) in chronic stable schizophrenia patients, mostly due to lower anhedonia and asociality levels.

Topics: Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Chronic Disease; Clozapine; Female; Humans; Male; Olanzapine; Principal Component Analysis; Psychiatric Status Rating Scales; Regression Analysis; Schizophrenia; Schizophrenic Psychology

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO

Topics: Adult; Antipsychotic Agents; Cardiovascular Diseases; Chronic Disease; Clozapine; Cross-Sectional Studies; Female; Haloperidol; Humans; Male; Oxygen Consumption; Physical Fitness; Schizophrenia

Upregulation of selenium binding protein 1 (SELENBP1) mRNA expression has been reported in schizophrenia, primarily in the dorsolateral prefrontal cortex. However, peripheral blood studies are limited and results are inconsistent. In this study, we examined SELENBP1 mRNA expression in whole blood and protein expression in plasma from patients with recent-onset schizophrenia (n = 30), treatment-resistant schizophrenia (n = 71) and healthy controls (n = 57). We also examined the effects of SELENBP1 genetic variation on gene and protein expression. We found lower SELENBP1 plasma protein levels in patients with recent-onset schizophrenia (p = 0.042) but not in treatment-resistant schizophrenia (p = 0.81). Measurement of peripheral mRNA levels showed no difference between treatment-resistant schizophrenia and healthy controls (p = 0.234) but clozapine plasma levels (p = 0.036) and duration of illness (p = 0.028) were positively correlated with mRNA levels. Genetic variation was not associated with mRNA or protein expression. Our data represent the first peripheral proteomic study of SELENBP1 in schizophrenia and suggest that plasma SELENBP1 protein is downregulated in patients with recent-onset schizophrenia.

Topics: Acute Disease; Adult; Antipsychotic Agents; Biomarkers; Chronic Disease; Clozapine; Down-Regulation; Drug Resistance; Female; Haplotypes; Humans; Male; Polymorphism, Single Nucleotide; Proteome; Proteomics; RNA, Messenger; Schizophrenia; Selenium-Binding Proteins; Time Factors; Young Adult

Cross-sectional data of inpatient residents of a rehabilitation center with schizophrenic psychosis diagnosis Abstract.. The objective of this study is to evaluate the level of neuropsychological functioning, quality of life, content of treatment, abnormal psychology as well as the level of functioning and medication in children and adolescents who suffer from a schizophrenia spectrum disorder, treated as rehabilitation inpatients.. Forty-two patients could be examined, therefore, the IRAOS, the WAIS-IV, the TMT-A/-B, the FBB-P (patient's version), the ILK-P, the SANS/SAPS, the BPRS, the BSCL, the GAF, the CGAS, and the CGI were used.. Patients' average age at onset of the disorder was 14.49 years (± 2.90). The total value of IQ was 87.00 (± 15.02), the value of TMT-A was 73.05 (± 14.51), and of the TMT-B 75.62 (± 15.15). The value for the content of treatment in the summary-score of the FBB-P was 3.05 (± 0.49). The value of the total-score in ILK-P was 2.10 (± 0.70). The summary-score of the SANS was 5.00 (± 2.90) and of the SAPS 3.00 (± 2.70). The BPRS-summary-score's value was 30.70 (± 7.80), the BSCL-GSI's value was 0.90 (± 0.50). GAF and CGAS were at 48.30 (± 12.80), respectively 51.00 (± 12.30). Clozapin has been prescribed in 25.0 % of the cases as first or second neuroleptic medication.. We investigated patients with VEOS and EOS living in a rehabilitation center. Usually, the course of their illness is much more severe and chronic than it is seen in a common department for child and adolescent psychiatry. Findings indicate a clear impairment in the level of neuropsychological and global functioning in contrast to rather low to moderate burden of positive/negative deficits. Satisfactory results of treatment and quality of life could be evaluated in spite of the aforementioned impairments. Medication did not conform to current guidelines, especially concerning Clozapin. Findings of the subsequent follow-up will show, if the impairment will improve under inpatient rehabilitation conditions.. Zusammenfassung. Fragestellung: Das Ziel der vorliegenden Untersuchung ist es, das neuropsychologische Funktionsniveau, die Behandlungszufriedenheit und die Medikation bei Kindern und Jugendlichen zu evaluieren, die an einer Psychose aus dem schizophrenen Formenkreis erkrankt sind und zum Zeitpunkt der Untersuchung an einer stationären Eingliederungsmaßnahme in dem Kinder- und Jugendwohnheim Leppermühle teilnahmen. Zusätzlich sollen bekannte Prädiktoren auf ihren Einfluss auf verschiedene Verlaufsvariablen hin untersucht werden. Methodik: Es konnten 42 Patienten (37.2 %) der insgesamt 113 Bewohner des Kinder- und Jugendwohnheims mit einer entsprechenden Diagnose untersucht werden. Ergebnisse: Die Patienten waren bei Erkrankungsbeginn durchschnittlich 14.5 Jahre alt und zum Zeitpunkt der Untersuchung waren sie im Mittel 20.0 Jahre alt. Für den Gesamtintelligenzquotient lag der Wert bei 87.0 Punkten, für den Trail Making Test Teil A (TMT-A) bei 73.1 Punkten und für den Trail Making Test Teil B (TMT-B) bei 75.6 Punkten. Die Behandlungszufriedenheit lag in allen Skalen und Subskalen des Fragebogens zur Beurteilung der Behandlung (FBB) bei 2.50 bis 3.50 Punkten, was einer guten Bewertung entspricht. Die Medikation entsprach nicht in allen Punkten den Leitlinien. Als Prädiktoren für das neuropsychologische Funktionsniveau konnte nur die prämorbide kognitive Leistungsfähigkeit bestätigt werden. Schlussfolgerungen: Die gefundenen Ergebnisse im Wechsler Adult Intelligence Score IV (WAIS-IV) und im TMT-A/B sprechen für eine deutliche Beeinträchtigung der Patienten im neuropsychologischen Funktionsniveau und decken sich überwiegend mit den Werten bisher durchgeführter Studien.

Topics: Adolescent; Adult; Age of Onset; Antipsychotic Agents; Brief Psychiatric Rating Scale; Child; Chronic Disease; Clozapine; Cross-Sectional Studies; Female; Germany; Guideline Adherence; Humans; Male; Neuropsychological Tests; Patient Admission; Psychometrics; Quality of Life; Rehabilitation Centers; Schizophrenia; Social Adjustment; Young Adult

Topics: Adult; Antipsychotic Agents; Case-Control Studies; Chronic Disease; Clozapine; Cross-Sectional Studies; Female; Hospitals, Psychiatric; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Schizophrenia is a severe and debilitating psychiatric disorder. Pharmacological interventions aim to ameliorate symptoms and reduce the risk of relapse and costly hospitalisation. Despite the established efficacy of antipsychotic medication, compliance to treatment is poor, particularly with oral formulation. The emergence of long acting injectable (LAI) antipsychotic formulations in recent years has aimed to counteract the poor compliance rates observed and optimise long term patient outcomes.. To estimate the cost-effectiveness of aripiprazole once-monthly 400mg (AOM 400) vs. risperidone long acting injectable (RLAI), paliperidone long acting injectable (PLAI) and olanzapine long acting injectable (OLAI) in the maintenance treatment of chronic, stable schizophrenia patients in the United Kingdom.. A Markov model was developed to emulate the treatment pathway of a hypothetical cohort of patients initiating maintenance treatment with LAI antipsychotics. The economic analysis was conducted from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a 10 year time horizon. Efficacy and safety probabilities were derived from mixed treatment comparisons (MTCs) where possible. Analyses were conducted assuming pooled dosing from randomised clinical trials included in the MTCs.. The model estimates that AOM 400 improves clinical outcomes by reducing relapses per patient comparative to other LAIs over the model time horizon (2.38, 2.53, 2.70, and 2.67 for AOM 400, RLAI, PLAI and OLAI respectively). In the deterministic analysis, AOM 400 dominated PLAI and OLAI; an incremental cost-effectiveness ratio (ICER) of GBP 3,686 per QALY gained was observed against RLAI. Results from the univariate sensitivity analyses highlighted the probability and cost of relapse as main drivers for cost-effectiveness. In the probabilistic sensitivity analysis, AOM 400 demonstrated a marginally higher probability of being cost-effective (51%) than RLAI, PLAI and OLAI (48%, 1% and 0%, respectively) at a willingness to pay threshold of GBP 20,000.. The model was built to accommodate results of an adjusted MTC analysis. Furthermore the model effectively captures repercussions of deteriorating compliance to treatment by incorporating three levels of compliance with elevated risks of relapse for partial compliance and non-compliance. Limitations of the analysis include the limited number of studies incorporated in the MTC, the extrapolation of short term clinical data and the exclusion of the wider societal burden.. Comparative to other atypical antipsychotics, AOM 400 represents value for money in the maintenance treatment of chronic, stable schizophrenia; however, in light of the PSA findings and comparable cost-effectiveness (i.e. against RLAI), the product profile and wider benefits of the respective treatments must be taken into account when prescribing antipsychotics.. Future research should assess the use of LAI antipsychotics earlier in the disease course of schizophrenia to see whether improved compliance and outcomes shortly following the onset of psychosis has the potential to alter the disease trajectory. Moreover it should be assessed whether changes in the disease trajectory can alleviate cost and resource pressures placed on national health services.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Chronic Disease; Clozapine; Computer Simulation; Cost-Benefit Analysis; Delayed-Action Preparations; Drug Administration Schedule; Humans; Injections, Intramuscular; Markov Chains; Models, Economic; Olanzapine; Paliperidone Palmitate; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; State Medicine; United Kingdom

Depression interferes with the human ability to make decisions. Multiple criteria have been adopted for the diagnosis of depression in humans, but no clear indicators are available in animal models to reflect the depressive mood, involving higher cognitive functions. The act of foraging is a species-specific behaviour which is believed to involve the decision-making and higher cognitive functions. We previously established a method to detect the foraging behaviour of rodents, in which our results demonstrated that NMDA and dopamine receptors were involved. Conversely, increased NMDA receptors and reduced dopamine have been reported in depression model rodents. However, we hypothesise that foraging activities may also be impaired in depression. To test the theory, we successfully established a mouse model of depression using the chronic unpredictable mild stress (CUMS) paradigm. Most interestingly, the food foraging activity of mice after CUMS was significantly reduced. In addition, the treatment of anti-depressant fluoxetine reversed most depressive symptoms and reduced glial fibrillary associated protein (GFAP) expression in the hippocampus, but was less effective in the reduction of foraging activities. However, clozapine reversed all symptoms of CUMS-exposed mice including reduction of GFAP expression in the hippocampus and impaired foraging activity. Our findings of GFAP expression as a marker to validate the CUMS protocol provide further validation of our hypothesis, that the reduced food foraging is probably a new behavioural finding of depression in which the serotoninergic system could not be singly involved. Our study suggests that NMDA receptors, serotoninergic and dopaminergic systems are differentially involved in these food foraging behaviours. Our data suggest that the foraging test in rodents can be a useful tool to assess the ability of decision-making in depression.

Topics: Animals; Antidepressive Agents; Appetitive Behavior; Body Weight; Cerebral Cortex; Chronic Disease; Clozapine; Depressive Disorder; Disease Models, Animal; Exploratory Behavior; Feeding Behavior; Fluoxetine; Freezing Reaction, Cataleptic; Glial Fibrillary Acidic Protein; Hippocampus; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Stress, Psychological

Topics: Antipsychotic Agents; Blood Glucose; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Middle Aged; Schizophrenia; Triglycerides; Weight Gain

We investigated the associations of the LEP-2548A/G and HTR2C-759C/T polymorphisms with long-term clozapine-induced weight changes and baseline BMI in chronic patients with schizophrenia.. A total of 113 patients receiving clozapine for at least 1 year were enrolled. Body weight was measured cross-sectionally and data on body weight just before starting clozapine were retrospectively extracted from medical records.. Clozapine-induced change in BMI was correlated inversely with the baseline BMI (P<0.001, ρ=-0.347). The LEP-2548A/G polymorphism was associated significantly with the change in BMI (F=4.380, P=0.015) during clozapine use; those with the AA genotype had the highest BMI gain (1.4±3.1 kg/m), followed by those with the AG (-0.2±3.3 kg/m) and GG (-1.6±3.4 kg/m) genotypes. We also found a significant association between the leptin genotype and BMI at baseline (F=3.499, P=0.034); those with the AA genotype had the lowest baseline BMI (23.4±4.3 kg/m), followed by those with the AG (24.1±4.4 kg/m) and GG (28.8±7.3 kg/m) genotypes. In the case of the HTR2C-759C/T polymorphism, we found a trend in which T alleles were more prevalent in male patients with up to 7% increase in BMI than in those with a greater than 7% increase in BMI [12/54 (22.7%) vs. 1/27 (3.7%); Fisher's exact test: P=0.051].. This study shows an inverse correlation between the baseline BMI and change in BMI during long-term clozapine use in patients with schizophrenia, and the LEP-2548A/G polymorphism was associated significantly with both these measures.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Chronic Disease; Clozapine; Humans; Leptin; Middle Aged; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Schizophrenia; Weight Gain

Topics: Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Follow-Up Studies; Humans; Injections, Intramuscular; Leukocyte Count; Male; Medication Adherence; Middle Aged; Neutropenia; Neutrophils; Schizophrenia, Paranoid

To examine the prevalence and correlates of diabetes in a large sample of Chinese patients with schizophrenia on long-term clozapine treatment, because this population previously has received little systematic study.. Two hundred and six inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizophrenia criteria were recruited in a cross-sectional naturalistic study, and compared with 615 healthy control subjects matched for age, sex, education, and body mass index (BMI). The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Diagnoses of diabetes were established through review of medical records and fasting blood glucose testing, or an oral glucose tolerance test.. Diabetes mellitus was more common in patients than in the normal controls (22.3% vs 6.2%) (odds ratio = 4.37, confidence interval (CI) 2.76-6.92, p < 0.001). The prevalence of diabetes increased with age across five age-groups as compared with normal controls (X(2) = 18.0, df = 4, p = 0.001). The PANSS total score and sub-scores showed no differences between the diabetic and non-diabetic groups. Logistic regression in the patients revealed significant associations between diabetes and a family history of diabetes (p < 0.001), age (p < 0.01), and BMI (p < 0.05).. Long-term clozapine treatment was associated with an increased and clinically important risk of diabetes mellitus in Chinese chronic schizophrenic patients, which is consistent with previous reports in Western populations.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Blood Glucose; Body Mass Index; China; Chronic Disease; Clozapine; Cross-Sectional Studies; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Logistic Models; Male; Middle Aged; Prevalence; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia

The aim of this study was to identify the prevalence of metabolic syndrome and its putative precursors in a naturalistic study of non-acute inpatients at a psychiatric hospital.. Anthropometric and biochemical data collected from the hospital's annual cardiometabolic survey, along with information about prescribed medications, were used to assess the prevalence and predictors of physical health problems in patients with schizophrenia.. Of the 167 patients included in the survey, 52.4% met criteria for metabolic syndrome. A shorter duration of hospital admission and clozapine use were significant predictors of metabolic syndrome. Age, gender, duration of admission and clozapine use were all predictors of individual cardiometabolic risk factors.. The findings from this naturalistic study reinforce the high prevalence of physical health problems in patients with schizophrenia and the important influence that psychiatric treatments can have on physical health. The impact of clozapine on cardiometabolic health appears to occur early in the course of treatment and emphasizes the need for proactive monitoring and interventions from the outset of management.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Prevalence; Risk Factors; Schizophrenia; Sex Factors; Treatment Outcome

Cardiovascular disease (CVD) mortality in schizophrenia is more frequent than in the general population. Whether second-generation antipsychotics (SGAs) increase risk of CVD morbidity and mortality has yet to be determined.. We conducted a retrospective cohort study using an administrative database to identify patients with DSM-III- or DSM-IV-diagnosed schizophrenia, treated in Maryland, who started clozapine treatment (n = 1,084) or were never treated with clozapine (initiated on risperidone; n = 602) between 1994 and 2000. Deaths between 1994 and 2004 were identified by the Social Security Death Index, and death records were obtained.. During the 6- to 10-year follow-up period, there were 136 deaths, of which 43 were attributed to CVD. Cardiovascular disease mortality in patients aged younger than 55 years at medication start was approximately 1.1% (clozapine, 1.1%; risperidone, 1.0%) in both groups at 5 years and 2.7% (clozapine) and 2.8% (risperidone) at 10 years (chi(2)(1) = 0.12, P = .73). Patients who started treatment at ages >or= 55 years had CVD mortality of 8.5% (clozapine) and 3.6% (risperidone) at 5 years and 16.0% (clozapine) and 5.7% (risperidone) at 10 years (chi(2)(1) = 2.13, P = .144). In a Cox regression model, patients aged >or= 55 years were at greater risk of mortality than younger patients (hazard ratio = 4.6, P < .001); whites were at greater risk than nonwhites (HR = 2.1, P = .046); however, SGA treatment (HR = 1.2; 95% CI, 0.6-2.4; P = .61) and sex (HR = 0.9, P = .69) were not statistically significant predictors of CVD, nor was there a significant age x clozapine interaction (chi(2)(1) = 1.52, P = .22). Age-, race-, and gender-adjusted standardized mortality ratios were significantly elevated (clozapine, 4.70; 95% CI, 3.19-6.67; risperidone, 2.88; 95% CI, 1.38-5.30) compared to year 2000 rates for the Maryland general population but did not differ by antipsychotic group (chi(2)(1) = 1.42, P = .23).. The risk of CVD mortality in schizophrenia does not differ between clozapine and risperidone in adults despite known differences in risk profiles for weight gain and metabolic side effects. However, we cannot rule out an increased risk of CVD mortality among those starting treatment at ages 55 years or older.

Topics: Adult; Age Distribution; Age Factors; Aged; Antipsychotic Agents; Cardiovascular Diseases; Chronic Disease; Clozapine; Cohort Studies; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Maryland; Middle Aged; Outcome Assessment, Health Care; Prevalence; Psychiatric Status Rating Scales; Retrospective Studies; Risk Factors; Schizophrenia; United States

Clozapine is an important second-generation antipsychotic that is reserved for patients with refractory schizophrenia. Unfortunately, clozapine is also associated with a number of adverse effects, with agranulocytosis being one of the chief concerns. Interestingly, patients who receive clozapine treatment may occasionally experience elevations in their total white blood cell count (WBC). In some of these patients, the leukocytosis may be persistent. We report the case of a patient with refractory schizophrenia who is treated with clozapine and who experienced chronic leukocytosis. A brief review of the literature addressing clozapine-associated leukocytosis follows the case report.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Leukocyte Count; Leukocytosis; Male; Schizophrenia, Paranoid

Nicotinic receptor decreases in the frontal cortex and hippocampus are important mediators of cognitive impairment in both schizophrenia and Alzheimer's disease. Drug treatments for these diseases should take into account the impacts of compromised brain function on drug response. This study investigated the impact of compromised nicotinic receptor activity in the frontal cortex in rats on memory function. Since both Alzheimer's disease and schizophrenia can involve psychosis, antipsychotic drugs are often given. The impacts of antipsychotic drugs on cognitive function have been found to be quite variable. It is the hypothesis of this and previous studies that the cognitive effects of antispychotic drugs on cognitive function depend on the integrity of brain systems involved in cognition. Previously in studies of the hippocampus, we found that chronic inhibition of beta2-containing nicotinic receptors with dihydro-beta-erythrodine (DHbetaE) impaired working memory and that this effect was attenuated by the antipsychotic drug clozapine. In contrast, chronic hippocampal alpha7 nicotinic receptor blockade with methyllycaconitine (MLA) potentiated the clozapine-induced memory impairment which is seen in rats without compromised nicotinic receptor activity. The current study determined medial frontal cortical alpha7 and beta2-containing nicotinic receptor involvement in memory and the interactions with antipsychotic drug therapy with clozapine. Chronic DHbetaE and MLA infusion effects and interactions with systemic clozapine were assessed in female rats tested for memory on the radial-arm maze. Antipsychotic drug interactions with chronic systemic nicotine were investigated because nicotinic procognitive treatment has been proposed. The same local infusion DHbetaE dose that impaired memory with hippocampal infusion did not impair memory when infused in the medial frontal cortex. Frontal DHbetaE infusion potentiated clozapine-induced memory impairment, whereas previously the memory impairment caused by hippocampal DHbetaE infusion was attenuated by clozapine. Frontal cortical MLA infusions at a dose that previously was found to potentiate the clozapine-induced memory impairment with hippocampal infusion had no significant effect when infused into the medial frontal cortex. The location and subtype of nicotinic receptor underactivity are critical determinates for clozapine effects on memory. Patients with hippocampal beta2-containing nicotinic receptor loss may

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Cerebral Cortex; Chronic Disease; Clozapine; Dihydro-beta-Erythroidine; Female; Maze Learning; Memory Disorders; Memory, Short-Term; Microinjections; Nicotinic Antagonists; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic

Topics: Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition Disorders; Dementia; Drug Resistance; Humans; Korsakoff Syndrome; Male; Middle Aged; Neuropsychological Tests; Psychomotor Agitation; Schizophrenia

S100B is a calcium-binding protein, mainly produced and secreted by astrocytes, and it mediates the interaction among glial cells and between glial cells and neurons. Recently, several studies have shown increased serum 100B levels in patients with schizophrenia, suggesting that S100B might be relevant to the pathophysiology of schizophrenia. To examine the potentially differential effect of clozapine compared to typical antipsychotics on serum S100B and the relationship between S100B levels and psychopathology in patients with schizophrenia, 63 physically healthy patients with schizophrenia were compared with 50 age-, sex-matched normal controls. The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum S100B levels were measured by sandwich ELISA. The results showed that S100B levels were significantly elevated in chronic patients with schizophrenia than in healthy controls (p<0.0001). As compared with healthy controls, there was a significant increase in S100B levels in patients treated with both clozapine and typical antipsychotics (both p<0.0001). However, no significant difference in S100B was found between patients treated with clozapine and typical antipsychotic subgroups (p>0.05). Furthermore, there was no significant correlation between S100B and standardized drug doses or the duration of taking neuroleptic medications (both p>0.05). In addition, no significant correlation was observed between S100B and PANSS total score and its subscale scores (all >0.05). These findings suggest that serum S100B levels in chronic schizophrenia under antipsychotic medication may be increased, suggesting that a dysfunction of astrocytes and/or oligodendrocytes may play a role in the pathogenesis of schizophrenia. Long term treatment with both typical and atypical antipsychotics may produce similar effects on the S100B serum levels, which however remains to be characterized in a large sample of first-episode, medication-naïve patients with schizophrenia using a longitudinal design.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Nerve Growth Factors; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Obesity; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Tumor Necrosis Factor-alpha

Topics: Adult; Aggression; Anticonvulsants; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Humans; Lamotrigine; Male; Schizophrenia, Disorganized; Triazines

Several lines of evidence suggest that central brain-derived neurotrophic factor (BDNF) modulates food intake, metabolism, and increases in body weight. Reports have also shown that serum BDNF is altered in schizophrenic patients treated with antipsychotics. This study aimed to determine if there was a relationship between BDNF and antipsychotic-induced weight gain in patients with chronic schizophrenia. Serum BDNF was measured in 124 schizophrenia patients chronically treated with clozapine (n=57), risperidone (n=23) or typical antipsychotics (n=44) and 50 healthy control subjects. To further assess group differences in serum BDNF, additional analyses were performed in a subset of patients and controls individually matched for body mass index (BMI). BDNF levels were lower in patients with schizophrenia than normal controls. However, this difference was not present when controlling for current BMI. In the individually BMI-matched sample, no differences in serum BDNF levels were observed in schizophrenic patients compared to BMI-matched healthy controls. BDNF levels negatively correlated with BMI gain in female but not in male patients when gender was considered. Antipsychotic class exerted differential effects over BDNF levels and BMI gain. Our findings suggest that decreased BDNF levels may be associated with weight gain in female schizophrenic patients on long-term antipsychotic treatment.

Topics: Antipsychotic Agents; Brain-Derived Neurotrophic Factor; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Risperidone; Schizophrenia; Serum; Weight Gain

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Leukocytosis; Male; Middle Aged; Retrospective Studies

Topics: Adult; Allopurinol; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Gout; Gout Suppressants; Hallucinations; Humans; Piperazines; Psychoses, Substance-Induced; Recurrence; Schizophrenia, Paranoid; Thiazoles

Impaired ability to detect and correct errors may contribute to poor cognitive and social function in schizophrenia.. To test the hypothesis that impairment in error monitoring contributes to impaired executive function in schizophrenia.. 56 schizophrenia patients and 77 healthy individuals were tested with the Penn Conditional Exclusion test (PCET), a computerised test of executive function which allowed collection of accuracy and latency performance parameters. Error monitoring was assessed by analyzing reaction times for correct (RTC) and incorrect (RTI) responses. Tests of face recognition, working memory (WM) and processing speed were also administered.. Executive error-monitoring effort (EXER), calculated by dividing the difference between RTI and RTC by the sum of RTC and RTI, was significantly smaller in patients than controls. A regression model with the executive function (PCET total errors) as dependent variable showed independent contributions of EXER, verbal WM and spatial WM to test performance and explained 35% of the variance. EXER showed significant association with error-monitoring effort for face recognition in patients but not controls.. Impaired error-monitoring contributes to poor executive function in schizophrenia. Independent contributions of error-monitoring effort and verbal WM to executive functions may reflect distinct contributions of prefrontal and medial frontal cortical dysfunctions. Error-monitoring mechanisms in different cognitive domains may share more neural resources in schizophrenia than in healthy individuals, reflecting inefficient processing.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Male; Memory, Short-Term; Neuropsychological Tests; Olanzapine; Piperazines; Reaction Time; Risperidone; Schizophrenia; Self Efficacy; Severity of Illness Index; Thiazoles

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

Clozapine is a well-known antipsychotic to cause fatal agranulocytosis but there are only a few case reports about the risk of leukopenia and agranulocytosis associated with other atypical antipsychotics. Olanzapine has structural pharmacological similarities to those of clozapine and reports about haematological adverse effects of olanzapine include three groups: the first group includes cases of olanzapine-induced neutropenia, the second informing that olanzapine is safe after clozapine induced agranulocytosis and the third group forms prolongation of clozapine-induced leukopenia with olanzapine use. The aim of this paper is to report a case of prolongation of clozapine-induced leukopenia despite olanzapine treatment and discuss leukopenia caused by atypical antipsychotic use in the light of recent and limited literature.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Humans; Leukopenia; Male; Olanzapine; Schizophrenia

Risperidone, olanzapine, and clozapine are three atypical antipsychotic medications commonly used in the management of chronic schizophrenia. While they offer advantages with regard to clinical efficacy and side-effect profile, few studies have compared them in a naturalistic prospective observational manner. This study therefore investigated their comparative efficacy over 12 weeks including illness characteristics and adverse effects. One hundred thirty-one patients (76 M, 55 F) with DSMI-V schizophrenia or schizoaffective disorder were treated with risperidone (n = 38), olanzapine (n = 38), or clozapine (n = 55). All patients showed a significant decrease of Positive and Negative Syndrome Scale (PANSS)-positive scores. Decreases in tardive dyskinesia and impulsivity scores were noted with clozapine and olanzapine, respectively. No differences between the medications were noted on depression, anxiety, EPS, or overt aggression scores. Olanzapine and clozapine appeared to be more effective in females. Males showed a decreased sexual performance irrespective of the medication and those treated with risperidone and clozapine showed greater proportional reduction of overt aggression. Clozapine-treated patients showed significant increased weight, increased glucose levels, and lowered sexual performance. Risperidone patients tended to exhibit reduced cholesterol levels. Higher creatine kinase (CK) levels were noted in risperidone-treated patients. While cautious given the nature of the study design, results suggest differences in the response to various atypical antipsychotic medications regarding efficacy and side-effect susceptibility.

Topics: Adolescent; Adult; Aged; Aggression; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Chronic Disease; Clozapine; Creatine Kinase; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Risperidone; Schizophrenia; Sex Factors; Triglycerides

The present study aimed to elucidate the effectiveness of clozapine treatment in reducing the disabling period of chronically ill schizophrenic patients by investigating their rehospitalization status. Of 232 schizophrenic patients with a history of clozapine use who were recruited from the clinic at Seoul National University Hospital, 117 were selected who had been followed up for more than 1 year with respect to rehospitalization. To obtain information about the period before the clozapine change, a chart review of these 117 patients was conducted. The number and length of hospitalizations of the patients significantly decreased after clozapine treatment compared to the same period before clozapine treatment. The hospital days per year of the patients were also decreased significantly after clozapine introduction. By analysing 38 patients who were followed up for more than 5 years, it was suggested that the decrease in the number and length of hospitalizations was substantially sustained for up to 5 years after clozapine treatment. This study showed that the number and length of hospitalizations are significantly decreased by long-term clozapine treatment and that this effect can positively affect the social outcome of schizophrenic patients.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Length of Stay; Long-Term Care; Male; Middle Aged; Patient Readmission; Psychiatric Status Rating Scales; Recurrence; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The present study investigated clozapine dosage, plasma clozapine and metabolite levels, clinical and side-effect profiles in Asian versus Caucasian patients with chronic schizophrenia who were on stable maintenance treatment. Twenty Asian patients from Singapore and 20 Caucasian patients from Australia were systematically evaluated with the following rating scales: Positive and Negative Syndrome Scale for Schizophrenia, drug attitude scale (DAI-10), drug adverse reaction profile (Liverpool University Neuroleptic Side-effect Rating Scale), extrapyramidal side-effects scales (Abnormal Involuntary Movement Scale, Simpson and Angus Scale). Cigarette and caffeine consumption were recorded and steady-state plasma clozapine and metabolites levels were measured. Although Asian patients received a significantly lower mean clozapine dose (176 mg/day) than the Caucasian group (433 mg/day, P<0.001), plasma clozapine levels were similar between the groups. As a result, Asian patients had more than twice the effective clozapine concentration to dose ratio (P<0.001). The findings remained significant even after controlling for gender, body mass index, cigarette, alcohol and caffeine use. Conversely, the plasma metabolites (desmethylclozapine and clozapine N-oxide) to clozapine ratios were higher in the Caucasian patients (P<0.01). Compared to Caucasian patients, Asian patients appeared to have a lower dosage requirement for clinical efficacy. Hence, appropriate dose adjustment should be considered in Asian patients receiving maintenance clozapine therapy in clinical practice.

Topics: Adult; Aged; Antipsychotic Agents; Asian People; Chronic Disease; Clozapine; Diet; Ethnicity; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Singapore; Treatment Outcome; White People

In schizophrenia, elevations of serum and CSF S100B levels have been reported and related to state of the disease and negative symptoms. In elderly chronic schizophrenic inpatients with stable medication, S100B may be increased and correlated to psychopathology and neuropsychological deficits. We have measured serum levels of S100B in 41 elderly, chronic schizophrenic patients and 23 age- and gender-matched controls using an immunoluminometric assay. In patients, we assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine and its two main metabolites desmethylclozapine and clozapine metabolite N-oxid by HPLC. S100B levels were increased in elderly chronic schizophrenic patients compared to healthy controls. In patients, levels were negatively correlated with deficit symptoms and positively with age. There were no significant differences of S100B between medication groups and no correlation with serum levels of antipsychotics or neuropsychological scores. Elevations of S100B in elderly chronic schizophrenic patients may be related to an active disease process lasting until old-age. Correlations point to the impact of S100B in neuroplasticity and ageing. Post-mortem studies should clarify the presence of altered S100B function in the brain and its relationship to neuroplastic or neurodegenerative processes.

Topics: Aged; Antipsychotic Agents; Chronic Disease; Clozapine; Cognition Disorders; Depressive Disorder, Major; Female; Haloperidol; Humans; Male; Middle Aged; Nerve Growth Factors; Neuropsychological Tests; Psychological Tests; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

The effects of atypical antipsychotic treatment on the brain volume deficits associated with schizophrenia are poorly understood. We assessed the brain volumes of eleven healthy controls and 29 patients with schizophrenia, using magnetic resonance imaging at baseline and at follow-up after two years of treatment with atypical neuroleptics. Two groups of patients were analyzed: treatment-naïve patients (n = 17) and chronic treatment-resistant patients (n = 12). Treatment-naïve patients received risperidone during the follow-up period, whereas chronic patients received clozapine. Gray matter (GM) and white matter (WM) volumes in the frontal, parietal, occipital, and temporal lobes were measured. Contrary to the controls, both groups of patients presented GM increases and WM decreases in the parietal and occipital lobes (p < .005). Frontal GM also increased in the chronic group with clozapine. There was a significant (p < .001) inverse relationship between the baseline volumes (GM deficit/WM excess) and the longitudinal change. These GM and WM changes were not related to changes in weight. Thus, treatment with risperidone and clozapine in schizophrenia may have an effect on gray and white matter volume and needs further exploration.

Topics: Adult; Antipsychotic Agents; Atrophy; Brain; Chronic Disease; Clozapine; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Risperidone; Schizophrenia

Topics: Adult; Anti-Obesity Agents; Chronic Disease; Clozapine; Humans; Hyperglycemia; Lactones; Male; Obesity; Orlistat; Schizophrenia

Respiratory long-term facilitation (LTF), a serotonin-dependent, persistent augmentation of respiratory activity after episodic hypoxia, is enhanced by pretreatment of chronic intermittent hypoxia (CIH; 5 min 11-12% O2-5 min air, 12 h/night for 7 nights). The present study examined the effects of methysergide (serotonin 5-HT1,2,5,6,7 receptor antagonist), ketanserin (5-HT2 antagonist), or clozapine (5-HT2,6,7 antagonist) on both ventilatory LTF and the CIH effect on ventilatory LTF in conscious male adult rats to determine which specific receptor subtype(s) is involved. In untreated rats (i.e., animals not exposed to CIH), LTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O2) separated by 5-min normoxic intervals, was measured twice by plethysmography. Thus the measurement was conducted 1-2 days before (as control) and approximately 1 h after systemic injection of methysergide (1 mg/kg ip), ketanserin (1 mg/kg), or clozapine (1.5 mg/kg). Resting ventilation, metabolic rate, and hypoxic ventilatory response (HVR) were unchanged, but LTF ( approximately 18% above baseline) was eliminated by each drug. In CIH-treated rats, LTF was also measured twice, before and approximately 8 h after CIH. Vehicle, methysergide, ketanserin, or clozapine was injected approximately 1 h before the second measurement. Neither resting ventilation nor metabolic rate was changed after CIH and/or any drug. HVR was unchanged after methysergide and ketanserin but reduced in four of seven clozapine rats. The CIH-enhanced LTF ( approximately 28%) was abolished by methysergide and clozapine but only attenuated by ketanserin (to approximately 10%). Collectively, these data suggest that ventilatory LTF requires 5-HT2 receptors and that the CIH effect on LTF requires non-5-HT2 serotonin receptors, probably 5-HT6 and/or 5-HT7 subtype(s).

Topics: Animals; Chronic Disease; Clozapine; Hypoxia; Ketanserin; Male; Methysergide; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Respiration; Respiratory Mechanics; Serotonin Antagonists

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Cohort Effect; Cohort Studies; Haloperidol; Humans; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Research Design; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The effect of mirtazapine on steady-state plasma concentrations of the newer atypical antipsychotics clozapine, risperidone and olanzapine was investigated in 24 patients with chronic schizophrenia. In order to treat residual negative symptoms, additional mirtazapine (30 mg per day) was administered for six consecutive weeks to nine patients stabilized on clozapine therapy (200-650 mg per day), eight on risperidone (3-8 mg per day) and seven on olanzapine (10-20mg per day). There were only minimal and statistically insignificant changes in mean plasma concentrations of clozapine and its metabolite norclozapine, risperidone and its metabolite 9-hydroxyrisperidone, and olanzapine during the study period. Mirtazapine co-administration with either clozapine, risperidone or olanzapine was well tolerated. In the overall sample, a slight improvement in negative symptomatology, as assessed by the Scale for Assessment of Negative Symptoms, was observed at final evaluation (P<0.01) and six patients (two in each treatment group) were classified as responders. While double-blind, controlled studies are needed to evaluate the potential clinical benefits of mirtazapine in chronic schizophrenia, our findings indicate that mirtazapine has a negligible effect on the metabolism of clozapine, risperidone and olanzapine and can be added safely to an existing treatment with these antipsychotics.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clinical Trials as Topic; Clozapine; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Italy; Male; Mianserin; Middle Aged; Mirtazapine; Olanzapine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Time Factors

Topics: Agranulocytosis; Anticonvulsants; Chronic Disease; Clozapine; Drug Therapy, Combination; Humans; Male; Middle Aged; Schizophrenia, Paranoid; Serotonin Antagonists; Valproic Acid

The atypical antipsychotic clozapine causes EEG alterations, and may lead to memory impairments due to its anticholinergic properties. The relationships between clozapine serum level, quantitative EEG parameters and performance in vigilance and memory tasks were studied in a group of 17 chronically ill schizophrenic patients under maintenance treatment with clozapine at stable dosages. There were negative correlations between clozapine serum levels and the amount of high-frequency EEG activity and positive correlations between high-frequency EEG activity and memory performance. These findings may suggest that clozapine treatment brings about dose-dependent impairments of vigilance and memory, for which a reduction of high-frequency EEG activity is indicative.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Female; Humans; Male; Memory; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Half-Life; Humans; Male; Schizophrenia; Suicide, Attempted

Atypical neuroleptics share a common feature, showing higher affinity for 5-HT2 receptors than for D2 dopamine receptors, but show considerable differences in their clinical and pharmacological properties. In clinical doses, they occupy serotonergic receptors near saturation, but show considerable differences regarding the D2 receptor occupancies, with clozapine showing the lowest degree of occupation. We assessed serotonergic and dopaminergic receptor responsiveness in two groups of male schizophrenic patients, one treated with the atypical neuroleptic clozapine (14 patients, doses 200-600 mg/d) and the other treated with olanzapine (11 patients, doses 10-30 mg/d). We measured the prolactin responses to the acute administration of a serotonergic drug, clomipramine, and a dopaminergic one, haloperidol. Tests were first performed in the drug-free state, and were repeated after the patients had been treated with stable doses of either drug for six weeks. Clomipramine administration induced significant increases of prolactin in the drug-free state. These responses were eliminated after treatment of the patients with either drug, thereby indicating a high 5-HT receptor occupancy by both clozapine and olanzapine. The prolactin responses to haloperidol were not altered after treatment with clozapine, but were significantly reduced after the olanzapine treatment. The baseline prolactin levels were not influenced by clozapine treatment, and were moderately but significantly increased after treatment with olanzapine. The results indicate that there is a difference between the two drugs in their capacity to block dopamine receptors at the hypothalamus-pituitary level, and match the results obtained by SPECT receptor binding studies for striatal dopamine receptors.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clomipramine; Clozapine; Haloperidol; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Olanzapine; Pirenzepine; Prolactin; Psychiatric Status Rating Scales; Receptors, Dopamine D2; Receptors, Serotonin; Schizophrenia; Treatment Outcome

Topics: Anti-Infective Agents; Bipolar Disorder; Chronic Disease; Clozapine; Drug Synergism; Female; Humans; Middle Aged; Neutropenia; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Thrombocytopenia; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Chronic Disease; Clinical Competence; Clozapine; Female; Humans; Male; Psychiatry; Schizophrenia; Schizophrenic Psychology; Specialization; Treatment Outcome

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

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

The high acquisition cost of the atypical antipsychotics has prompted their closer clinical and economic evaluation. This study aims to examine the financial implications of using atypical antipsychotics in a defined catchment area sample of patients with schizophrenia.. Service costs over a 10-month period were compared between groups of patients fulfilling DSM-IV criteria for schizophrenia who were taking different atypical antipsychotic agents.. All patients studied were taking clozapine (N = 31). risperidone (N = 19), or olanzapine (N = 41). Clozapine was used in more chronic patients, while risperidone and olanzapine were prescribed in both chronic and recently diagnosed cases. After background group differences were controlled for, patients on risperidone treatment incurred the lowest costs. The monthly costs for the clozapine and olanzapine groups were higher than for risperidone by US $246 and US $566, respectively.. Clozapine was reserved for more severe forms of schizophrenia, but its cost impact was relatively low. Risperidone, as prescribed in ordinary practice, may be more cost-effective than olanzapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cost-Benefit Analysis; Dose-Response Relationship, Drug; England; Female; Humans; Long-Term Care; Male; Middle Aged; Olanzapine; Patient Readmission; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

The authors performed a MRSI study of the anterior cingulate gyrus in 19 schizophrenic patients under stable medication and 16 controls in order to corroborate previous findings of reduced NAA in the anterior cingulate region in schizophrenia. Furthermore, correlations between NAA in the anterior cingulate gyrus and age or illness duration have been determined. A decreased NAA signal was found in the anterior cingulate gyrus of patients compared to controls. Subdividing the patient group into two groups depending on medication revealed that the group of patients receiving a typical neuroleptic medication showed a lower mean NAA in comparison to the group of patients receiving atypical antipsychotic drugs. No significant group differences in the creatine and phosphocreatine signal or the signal from choline-containing compounds were found. The NAA signal significantly correlated with age, and therefore, individual NAA values were corrected for the age effect found in the control group. The age-corrected NAA signal in schizophrenia correlated significantly with the duration of illness. The detected correlations of NAA decrease with age and illness duration are consistent with recent imaging studies where progressing cortical atrophy in schizophrenia was found. Further studies will be needed to corroborate a possible favorable effect of atypical antipsychotics on the NAA signal.

Topics: Adult; Antipsychotic Agents; Aspartic Acid; Chronic Disease; Clozapine; Creatine; Female; Gyrus Cinguli; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Reference Values; Risperidone; Schizophrenia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Body Weight; Chronic Disease; Clozapine; Fructose; Humans; Male; Neuroprotective Agents; Obesity; Schizophrenia, Paranoid; Topiramate; Weight Loss

A 37-item survey covering a variety of somatopsychic domains was constructed to explore patients' subjective response to treatment with clozapine. The survey was administered to 130 patients with diagnoses of chronic schizophrenic or schizoaffective disorders who were on a stable clozapine regimen. The majority reported improvement in their level of satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness. Most patients reported worsening in nocturnal salivation, and smaller numbers reported worsening in various gastrointestinal and urinary symptoms and weight gain. This general health survey highlights the patients' positive regard for clozapine, despite adverse bodily experiences. Subjective reports are a useful component of outcome measures of drug treatment.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Patient Compliance; Patient Satisfaction; Quality of Life; Schizophrenia; Schizophrenic Psychology

In 200 inpatients on regular neuroleptics, point prevalence of extrapyramidal syndromes, including Parkinson syndrome, akathisia and tardive dyskinesia (TD), was studied and found to be 20, 11 and 22%, respectively. A total of 46 patients have currently, and for a longer time, (average about 3years, median over 1year) been treated with clozapine, and 127 with typical neuroleptics (NLs). Comparing both groups, higher TD scores were found in the clozapine sample. Investigating the influence of a set of seven clinical variables on the TD score with the help of multiple regression analysis, the influence of the treatment modality disappeared, whereas the age proved to be the only significant variable. Studying the role of past clozapine therapy in patients currently on typical NLs and comparing 10 matched pairs of chronic patients with and without TD in whom a complete life-time cumulative dose of NLs was identified, a relationship between TD and length of current typical NL therapy and life-time typical NL dosage could be demonstrated. On the whole, long-term relatively extensive use of clozapine has not markedly reduced the prevalence of extrapyramidal syndromes in our psychiatric inpatient population. In particular, we failed to demonstrate a beneficial effect of clozapine on prevalence of TD. There are certainly patients who suffer from TD in spite of a long-term intensive clozapine treatment.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Disorders; Middle Aged; Prevalence; Time Factors

Clozapine is an atypical antipsychotic that is associated with certain adverse effects that limit its usefulness. Published case reports have associated clozapine with impairment of glucose tolerance, including the onset or exacerbation of diabetes mellitus. We report two patients who experienced diabetes mellitus associated with the agent.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Middle Aged; Schizophrenia

Concomitant fluvoxamine use can potentially reduce the dosage of clozapine needed in treatment-refractory patients with schizophrenia. Previous reports have shown that fluvoxamine can increase plasma clozapine concentrations by inhibition of cytochrome P450 (CYP) 1A2. We evaluated the safety and efficacy of fluvoxamine, 50 mg/day, coadministration with clozapine, 100 mg/day, in refractory schizophrenic patients.. In this prospective study, 18 treatment-refractory patients with DSM-IV schizophrenia (10 nonsmokers and 8 smokers) were treated with clozapine at a target dose of 100 mg h.s. After steady-state conditions of clozapine had been reached, 50 mg/day of fluvoxamine was then added. Plasma levels of clozapine, norclozapine, and clozapine N-oxide were measured prior to fluvoxamine addition and on days 14 and 28 during combined treatment. Side effects and efficacy were monitored with standardized rating instruments.. After 14 days of combined treatment, the mean +/- SD plasma clozapine level increased 2.3-fold to 432.4+/-190.9 ng/mL without further elevation on day 28. All patients completed the study without significant adverse side effects. Twelve of the 18 patients achieved plasma clozapine concentrations of at least 350 ng/mL. While plasma norclozapine levels also rose (but to a smaller extent), plasma clozapine N-oxide levels remained unchanged after the add-on therapy. Patients who smoked had 34% lower plasma clozapine concentrations than nonsmokers (NS). Three of the 4 patients who did not reach clozapine plasma levels of at least 300 ng/mL were smokers. Plasma norclozapine/clozapine ratios, especially in smokers, declined significantly with fluvoxamine addition.. The addition of fluvoxamine, 50 mg/day, to low-dose clozapine, 100 mg/day, can raise plasma clozapine levels to at least 300 ng/mL in most patients. Only slight dosage adjustments with clozapine may be needed after fluvoxamine coadministration in some patients who smoke. Plasma clozapine levels remained stable after 14 days of fluvoxamine addition. The combined treatment was well tolerated, and clinical improvement was observed in our patients. Further long-term studies with this drug combination are needed to determine its economic impact.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Comorbidity; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Smoking; Treatment Outcome

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; History, 20th Century; Humans; Outpatients; Psychiatry; Schizophrenia

The atypical antipsychotic, clozapine, has been reported to reduce smoking in schizophrenic patients. We sought to determine whether other atypical antipsychotics would also be associated with a decreased prevalence of smoking in this population. Data were obtained from three groups of chronic, hospitalized, schizophrenic patients, receiving either a typical antipsychotic (n=15), clozapine (n=6), or another atypical antipsychotic (n=18). In addition to smoking prevalence, the groups were compared with regard to demographics (age, education), medication (doses, duration of treatment, side-effects), clinical (diagnosis, duration of illness) and behavioral (Wide-Range Achievement Test, Wechsler Adult Intelligence Scale) variables. Smoking prevalence differed significantly among the three groups (P<0.001). Clozapine was associated with a significantly lower incidence of smoking than either typical drugs (P<0.003) or other atypical antipsychotics (P=0. 042). The groups did not differ on demographic or other medication variables or on any of several behavioral measures. However, a diagnosis of paranoid schizophrenia was also significantly correlated with smoking (P<0.01), but not with medication class. Although the cause is still unknown, these results are consistent with reports that clozapine reduces smoking and provide new data on smoking prevalence associated with other atypical agents.

Topics: Acute Disease; Adult; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Female; Hospitalization; Hospitals, Psychiatric; Humans; Male; Prevalence; Schizophrenia; Serotonin Antagonists; Smoking; Wechsler Scales

Topics: Adult; Atropine; Chronic Disease; Clozapine; Female; Humans; Ophthalmic Solutions; Schizophrenia; Sialorrhea

Clozapine is an atypical antipsychotic agent for the treatment of schizophrenic patients whose symptoms do not respond to traditional antipsychotic drugs. The emergence of obsessive-compulsive symptoms during treatment of clozapine has been reported in some case studies. We report on the case of a 31-year old man with chronic schizophrenia who had shown obsessive-compulsive symptoms during treatment with clozapine.. A 31-year old patient with treatment refractory schizophrenia was treated with clozapine. During clozapine treatment, positive symptomatology decreased, but after 4 months after starting clozapine the patient showed obsessive and compulsive symptoms. This symptomatology had previously not been a feature of this patient's illness.. Obsessive-compulsive symptoms were observed during treatment of clozapine in a schizophrenic patient. This may be explained either by the serotonin-receptor antagonism of clozapine or its atypical dopaminergic receptor effects.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Male; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Clozapine is an "atypical" antipsychotic agent for treating previously resistant schizophrenic patients. Its main advantages over "typical" neuroleptics are low incidence of extrapyramidal side effects and its capacity to induce therapeutic response in previously treated refractory patients. However, withdrawal from clozapine has been observed to lead to "atypical" clinical characteristics or a "rebound phenomenon," manifested in two interwoven clinical forms: (1) psychotic exacerbation, and (2) cholinergic rebound. The underlying pathophysiological mechanism of this phenomenon is postulated to be a result of cholinergic supersensitivity. In this paper, the "rebound phenomenon" will be discussed and exemplified by three case histories in which abrupt cessation of clozapine led to serious deterioration and psychotic exacerbation, and one case in which gradual titration from the drug was employed in order to preempt this hazardous occurrence.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Schizophrenia; Substance Withdrawal Syndrome

This study investigated the incidence of clozapine-associated urinary incontinence (UI) in schizophrenic patients, the percentage of these patients with persistent urinary incontinence (PUI), and the possible factors affecting the occurrence of UI.. A total of 61 Chinese in-patients with schizophrenia (according to DSM-IV) treated with clozapine for more than 3 months were assessed retrospectively for the occurrence of UI. Patients who still had UI at the time of assessment were classified as having PUI. Patients whose UI had resolved at the time of assessment were classified as having self-limited urinary incontinence (SUI). We compared the characteristics of UI and non-UI cases and of PUI and SUI cases.. The results showed that urinary incontinence developed at some time in 27 of 61 patients (44.3%), and that it was persistent in 15 of 61 patients (25%). There were no statistically significant differences in age, sex, clozapine dose, duration of clozapine use, duration of index admission, duration of illness, age at onset of schizophrenia, or concurrent treatment with other psychiatric medications between the UI and non-UI groups and between the PUI and SUI groups.. Clozapine-associated urinary incontinence may be persistent in some patients, and it should be cautiously monitored in every patient taking clozapine.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Ethnicity; Female; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Schizophrenia; Taiwan; Urinary Incontinence

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Exanthema; Female; Humans; Pleural Effusion; Schizophrenia, Paranoid; Skin Diseases, Papulosquamous

The tricyclic antidepressants amitriptyline (CAS 549-18-8), amitriptylinoxide (CAS 4317-14-0) and doxepine (CAS 1229-29-4) as well as the atypical neuroleptic clozapine (CAS 5786-21-0)--all of them substances with well-established clinical efficacy--were investigated in order to elucidate their effect on N-methyl-D-aspartate (NMDA) receptor-mediated events. Modulation of NMDA receptor function was studied using the model of NMDA-evoked [3H]-acetylcholine ([3H]-ACh) release in slices of rat caudatoputamen. All substances reduced [3H]-ACh release in a concentration dependent manner. Significant inhibition occurred in the low micromolar range with the exception of amitriptylinoxide which was less potent in vitro (amitriptylinoxide is not being metabolized in vitro). Amitriptyline and clozapine at 10 mumol/l both decreased the maximum effect of NMDA by around 17%, but left its EC50 unchanged. This suggests a "classical" non-competitive antagonism and excludes an uncompetitive or "use-dependent" antagonism. Considering the important role of NMDA receptor-mediated effects in spinal nociception the analgesic properties of tricyclic antidepressants may partly be explained by their inhibitory action on spinal NMDA receptors, in addition to their enhancement of monoaminergic transmissions in the dorsal horn.

Topics: Acetylcholine; Algorithms; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Caudate Nucleus; Chronic Disease; Clozapine; Doxepin; Excitatory Amino Acid Agonists; Male; N-Methylaspartate; Pain; Putamen; Rats; Rats, Wistar

The effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites was studied in 10 schizophrenic patients with residual negative symptoms. Patients stabilized on clozapine therapy (200-450 mg/day) received additional fluoxetine (20 mg/day) for eight consecutive weeks. During fluoxetine administration, mean plasma concentrations of clozapine, norclozapine and clozapine N-oxide increased significantly by 58%, 36% and 38%, respectively. There was no difference in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, and the drug combination was generally well tolerated. The concomitant elevation in plasma levels of clozapine and its major metabolites suggests that fluoxetine inhibits the metabolism of clozapine by affecting pathways other than N-demethylation and N-oxidation. Close monitoring of clinical response and, possibly, plasma clozapine levels is recommended whenever fluoxetine is given to patients stabilized on clozapine therapy.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Biotransformation; Chronic Disease; Clozapine; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2D6 Inhibitors; Depression; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fluoxetine; Humans; Male; Middle Aged; Schizophrenia

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Pregnancy; Schizophrenia; Treatment Outcome

Functional neuroimaging studies in schizophrenia have often been confounded by various factors including medication status. To explore the effects of antipsychotic medications on relative regional cerebral perfusion, we scanned a group of 33 persons with schizophrenia twice, while receiving a stable dose of antipsychotic and after being off antipsychotics for 3 weeks, using technetium-99m hexamethyl-propyleneamine oxime single photon emission computed tomography (Tc-99m HMPAO-SPECT. We found that antipsychotic significantly increased the mean relative cerebral perfusion in the left basal ganglia. Additionally, patients receiving thiothixene (n = 9) had a significantly greater increase in relative cerebral perfusion in the basal ganglia than patients receiving haloperidol (n = 12). These findings indicate that antipsychotics lead to regional increases in cerebral perfusion and that antipsychotic status must be controlled for in functional neuroimaging studies. Functional neuroimaging techniques such as SPECT may be useful in furthering our understanding of the mechanism of antipsychotics.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Brain; Brain Mapping; Cerebellum; Cerebral Cortex; Chronic Disease; Clozapine; Female; Haloperidol; Humans; Male; Organotechnetium Compounds; Oximes; Psychiatric Status Rating Scales; Regional Blood Flow; Schizophrenia; Schizophrenic Psychology; Technetium Tc 99m Exametazime; Thiothixene; Tomography, Emission-Computed, Single-Photon; Trifluoperazine

The surface EEGs of 32 medicated chronic schizophrenic patients, 12 unmedicated chronic schizophrenics and 35 matched healthy controls were analyzed by adaptive segmentation of continuous EEG during a rest condition, a mental arithmetic task, and a CNV paradigm. Results indicate increased duration of brain microstates in both unmedicated and medicated schizophrenics as well as reduced topographic variability. These findings did not vary across the different tasks. Comparing different cognitive tasks, schizophrenics and controls alike showed task-related changes of electric field topography, of EEG microstate duration and of the number of very short microstates (single-peak segments). However, the topography of the microstates during the tasks differed significantly in both medicated and unmedicated schizophenics from that of controls. Age, sex and educational levels did not influence these findings. Neuroleptic medication correlated negatively with microstate duration in a dose-dependent way. There was an inverse relationship between topographic variability and negative symptoms as well as BPRS scores. It is concluded that the temporo-spatial characteristics of brain electric activity indicate an impoverished array of functional modes and enhanced stability of brain electrical microstates in schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Cognition Disorders; Electroencephalography; Female; Humans; Male; Reaction Time; Schizophrenia; Schizophrenic Psychology

Topics: Chronic Disease; Clozapine; Drug Therapy, Combination; Humans; Middle Aged; Paroxetine; Risperidone; Schizophrenia

Topics: Adult; Animals; Chronic Disease; Clozapine; Drug Synergism; Drug Therapy, Combination; Humans; Male; Ondansetron; Psychiatric Status Rating Scales; Rabbits; Schizophrenia; Severity of Illness Index

The aim of this study was to evaluate the clinical response to clozapine of 11 treatment-resistant patients with schizophrenia. Nine male and two female inpatients of a state psychiatric hospital, with at least a 2-year history of unresponsiveness to adequate trials of at least three antipsychotics and from chemically distinct groups, were challenged with clozapine. Clinical assessment involved baseline and repeated post-baseline ratings using the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impressions Scale (CGI), the Nurses Observation Scale for Inpatient Evaluation (NOSIE-30), and the Abnormal Involuntary Movement Scale (AIMS). Progression to lower categories of care was used as an additional outcome measure. Statistically significant reductions were achieved in global symptomatology, positive psychotic symptoms, and hostility. A statistically significant improvement occurred on the Social Interest factor; however, improvements in the remaining negative symptoms were not statistically significant. Reductions in psychopathology enabled eight patients to progress to lower categories of care with five patients moving to community care. The results indicate that clozapine was effective in treating hospital patients with a very severe form of mental illness.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Hospitals, Psychiatric; Hospitals, State; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome

A haloperidol-treated patient with chronic schizophrenia had a near-arrhythmic circadian rest-activity cycle, whereas rhythms of 6-sulphatoxy-melatonin and core body temperature were of normal amplitude and phase-advanced. Sleep electroencephalography measured throughout a 31-h 'constant-bedrest' protocol revealed a phase-delayed sleep-wake propensity cycle, low sleep continuity (ultradian 'bouts'), and very little slow-wave sleep and slow-wave activity (0.75-4.5 Hz). Switching treatment to the atypical neuroleptic clozapine improved both the circadian organization of the rest-activity cycle and the patient's clinical state. This observation can be conceptualized in terms of the two-process model of sleep regulation. High-dose haloperidol treatment may have lowered the circadian alertness threshold, whereas clozapine augmented circadian amplitude (perhaps through its high affinity to dopamine D4 and serotonin 5HT7 receptors in the suprachiasmatic nuclei). Measurement of the circadian rest-activity cycle may be a useful non-invasive method to follow functional consequences of neuroleptic treatment.

Topics: Adult; Antipsychotic Agents; Bed Rest; Body Temperature; Catatonia; Chronic Disease; Circadian Rhythm; Clozapine; Haloperidol; Humans; Male; Melatonin; Motor Activity; Recurrence; Rest; Schizophrenia; Sleep; Time Factors

Topics: Adult; Chronic Disease; Clozapine; Eosinophilia; Eosinophils; Humans; Leukocyte Count; Male; Neutropenia; Schizophrenia

Gender differences in neuroleptic-refractory chronic schizophrenic disorder patients were examined to determine whether a superior or equivalent antipsychotic response in women vs. men existed similar to that of the general schizophrenic population. Sixty-nine DSM-III schizophrenic patients (47 males and 22 females) were treated with clozapine using a standardized medication regime. The gender differences in these neuroleptic-nonresponsive chronic schizophrenic disorder patients differed from those previously observed in the general schizophrenic population in that an equivalent antipsychotic treatment response in females versus males was not found. These treatment-refractory women appear to be a severely ill subgroup of female schizophrenics with distinct onset of illness, course and treatment response characteristics.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prolactin; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sex Factors; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Schizophrenia; Substance Withdrawal Syndrome

Topics: Activities of Daily Living; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Combined Modality Therapy; Female; Humans; Motivation; Psychotherapy; Rehabilitation, Vocational; Schizophrenia; Schizophrenic Psychology; Travel; Treatment Outcome

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Leukocyte Count; Psychiatric Status Rating Scales; Recurrence; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Suicide, Attempted

This study examined the combined effectiveness of clozapine and a comprehensive inpatient psychosocial rehabilitation program on the clinical functioning and aggressive behaviors of patients with chronic schizophrenia.. Two groups of 11 subjects each were selected from among patients being treated in the social learning program at Fulton (Mo.) State Hospital. Group 1 subjects were placed on clozapine at various times after the introduction of the program, while group 2 subjects remained on traditional antipsychotics throughout the study period. Group 1 and group 2 subjects were matched on clinical functioning as measured by the Time-Sample Behavioral Checklist (TSBC). For each subject, scores on six TSBC subscales were examined at five time points. Data were analyzed using repeated-measures multiple analysis of variance and univariate analyses of variance. Data on frequency of aggressive behaviors were aggregated into three six-month time periods and were analyzed using Wilcoxon signed-rank tests.. Both groups demonstrated significant improvement on several measures. However, the addition of clozapine resulted in accelerated improvement for group 1 subjects, especially in aggressive behaviors.. Comprehensive psychosocial treatment programming resulted in significant improvements in clinical functioning for many inpatients. Clozapine may enhance responsiveness to such programming for some patients.

Topics: Activities of Daily Living; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Combined Modality Therapy; Disabled Persons; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology; Social Behavior; Socioenvironmental Therapy; Token Economy

Muscle dysfunction related to clozapine treatment is largely unrecognized. We evaluated weekly creatine kinase (CK) levels in 37 consecutive clozapine-treated outpatients with chronic psychotic disorders. Those with CK elevations underwent clinical neurologic evaluation, electromyography (EMG), and nerve conduction studies. Patients with probable myopathy had a quadriceps muscle biopsy. Twenty control patients had a single CK level determination. Twenty-nine of 37 clozapine-treated patients had CK elevations. Three patients had extreme CK elevations (> 20,000 IU/L), without myoglobinuria. Mean CK levels were significantly greater in clozapine patients (194 IU/L) than in control patients (142.3, p = 0.033). Of 18 clozapine-treated patients evaluated clinically, 6 had mild proximal weakness. EMG in 13 patients was myopathic in 5, normal in 5, and neurogenic in 3. Muscle biopsy in 5 patients showed rare regenerating myofibers and mild acute denervation (1), mild type II fiber atrophy (1), minimal acute denervation (1), and normal muscle (2). In conclusion, clozapine therapy may be associated with CK elevations and, rarely, mild myopathy.

Topics: Chronic Disease; Clozapine; Creatine Kinase; Electromyography; Humans; Muscles; Neural Conduction; Prospective Studies; Psychoses, Substance-Induced

A prospective, open-label study in a 400-bed state psychiatric hospital evaluated change in therapeutic response among ten patients with treatment-resistant schizophrenia who were switched from clozapine to risperidone. Drug effects were examined before discontinuation of clozapine and at three, six, nine, and 12 weeks of risperidone treatment. No patients improved, and five discontinued treatment due to exacerbation of psychosis or adverse effects. Changes in scores on the Positive and Negative Syndrome Scale, the Brief Psychiatric Rating Scale, and the Barnes Akathisia Scale indicated clinically significant worsening of symptoms. The findings do not support replacing clozapine with risperidone for patients with treatment-resistant schizophrenia.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neurologic Examination; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

A total of 107 drug-free schizophrenic patients (76 males and 31 females) were consecutively admitted to an emergency ward and rated for psychotic symptoms by means of 32 items from the Comprehensive Psychopathological Rating Scale (CPRS). They were followed prospectively with ratings of social functioning by use of Strauss-Carpenter's outcome scale at 1, 3 and 5 years after index admission with the aim of determining possible early symptoms that are predictors of social outcome. In total, 59 of the patients were first admissions and had never been treated. At index admission, no difference was found in total CPRS scores between first-admission patients and chronic readmitted patients, or between male and female subjects. When subscales for positive symptoms (flights of ideas, feeling controlled, disrupted thoughts, auditory hallucinations, ideas of persecution) and negative symptoms (indecision, withdrawal, reduced speech, lack of appropriate emotions, slowness of movements) from the CPRS were applied, no relationship between the two subscales and outcome scores was found. However, in patients with a duration of the disorder of less than 24 months before index admission, high scores on both negative and positive subscales were significantly correlated with a poor 5-year outcome. No correlation was found in the group with a duration of illness of more than 24 months before index admission. It is concluded that symptoms at index admission have a predictive value for outcome in schizophrenic patients. Negative symptoms measured by use of a subscale of the CPRS have a predictive value for outcome up to 5 years after index admission, but high scores on both positive and negative symptoms are more strongly associated with a poor outcome. The duration of the symptoms before admission, as well as the kind of neuroleptic treatment given (clozapine vs. classical neuroleptics), seem to be important factors for prediction of outcome. Our data support the view that early negative symptoms in particular have a predictive value for the prognosis in schizophrenia for up to 5 years.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Follow-Up Studies; Humans; Male; Patient Admission; Patient Readmission; Prognosis; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Treatment Outcome

In order to investigate the biological mechanisms underlying the clinical efficacy of clozapine, 200 mg/day of clozapine was added to the drug regimens of 19 patients with chronic, anti-psychotic-resistant schizophrenia, and the plasma homovanillic acid (HVA), clozapine concentrations, anti-dopamine D2 and anti-serotonin 5-HT2 receptor activities were measured. After 28 days, six patients showed an improvement of more than 20% over baseline Brief Psychiatric Rating Scale (BPRS) scores. Mean plasma HVA concentrations and anti-D2 receptor activities did not change significantly in the entire group or in the six patients showing improvement. However, anti-5-HT2 receptor activities increased significantly in all 19 patients. Changes in BPRS scores did not correlate significantly with changes in plasma HVA or with changes in clozapine concentrations, or with anti-D2 and anti-5-HT2 receptor activities.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dopamine; Homovanillic Acid; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Radioligand Assay; Receptors, Dopamine D2; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Chronic Disease; Clonidine; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Middle Aged; Receptors, Adrenergic, alpha-2; Schizophrenia; Sialorrhea

Agranulocytosis is the most serious side effect of clozapine therapy, occurring in approximately 1% of all treated patients. Despite careful blood monitoring, a significant number of cases of agranulocytosis and resulting fatalities have occurred. Strategies are needed to manage clozapine-induced agranulocytosis more safely.. This report describes the management of three state hospital inpatients who developed clozapine-induced agranulocytosis. All patients were diagnosed as having chronic paranoid schizophrenia according to DSM-III-R criteria and had previously failed to respond to treatment with standard antipsychotic medications. After onset of agranulocytosis, all patients were transferred to a medical service in a university hospital and treated with recombinant granulocyte colony-stimulating factor (filgrastim).. White blood count and absolute neutrophil count returned to within normal limits in each patient after 5 to 8 days of treatment with filgrastim 300 micrograms/day subcutaneously. No side effects were observed during filgrastim treatment.. Treatment with filgrastim appears to be safe and effective in decreasing the duration of clozapine-induced agranulocytosis. While further studies are necessary to establish the safety and effectiveness of this treatment, filgrastim should presently be considered a treatment of choice for clozapine-induced agranulocytosis.

Topics: Adult; Agranulocytosis; Chronic Disease; Clozapine; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Recombinant Proteins; Schizophrenia, Paranoid; Treatment Outcome

Clozapine has been shown to be effective in treating schizophrenic patients. In this study we compare the efficacy of clozapine in two groups of treatment resistant psychotics (among the most severe inpatients). 5 chronic schizophrenics (CS). Age 49.6 +/- 12 (paranoid, disorganized residuals). 14 "mixed" patients (MP). Age 34.6 +/- 13, between: major affective disorders (MAD) with mood incongruent psychotic features; schizo affective disorders (SAD). 19 patients (11 females -8 males) have been involved in our trial. They receive 400 up to 800 mg/day of clozapine for a minimum of 12 months and a maximum of 38 months. Treatment responders were defined on the evaluation of the following criteria: scores PANSS-CGI-MADRS (not for the first patients); number of relapses; response to socialisation (exit); quality of life. The results even if based on small sample sizes were classified as: Improvement -->reduction of all major symptoms: patient exit. CS:2/5 (40%); MP:5/14 (35%). Improvement++-->decrease of most major symptoms. CS:1/5 (20%); MP:5/14 (35%). Improvement+-->decrease of one or few major symptoms. CS:2/5 (40%); MP: 1/14 (8%). Failure-->3 from the MP subgroup (16%), 1 leucopenia, 1 worsening, 1 non responder). These finding show that affective disorders and schizoaffective patients are as likely to respond to clozapine as the schizophrenic patients: 60% of the CS and 70% of the MP were very much ( ) and much improved (++). The data also suggest that in the subtype of MP high scores of response occur with the youngest and most recently ill patients (< 30 years, < 18 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Chronic Disease; Clozapine; Cohort Studies; Depression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; 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 paper examines the clinical and demographic data of patients in the Clozapine Distribution System in Metropolitan Toronto in the first year after its inception. One hundred and thirty-seven patients were approved for funding during the year. They tended to be young, chronically and markedly ill patients suffering from schizophrenia, primarily with treatment resistance as the reason for clozapine therapy. Only 55 patients completed at least six months of therapy; 15 patients discontinued clozapine before six months of treatment, mainly because of side-effects and/or patients' noncompliance with bloodwork. Three patients discontinued clozapine because of haematological compromise. Clozapine was efficacious for the majority of patients who took it for at least six months, with improvement in all six clinical dimensions examined in the study. Nevertheless, the number of early discontinuation patients significantly lowered the overall effectiveness of clozapine in actual clinical practice.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Clozapine; Drug Monitoring; Female; Humans; Male; Middle Aged; Ontario; Patient Compliance; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Urban Population

Topics: Adult; Anticonvulsants; Chronic Disease; Clozapine; Drug Interactions; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Schizophrenia; Schizophrenic Psychology

Topics: Chronic Disease; Clozapine; Dermatitis, Photoallergic; Dermatitis, Phototoxic; Humans; Male; Middle Aged; Photosensitivity Disorders; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Humans; Male; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Cost Control; Delivery of Health Care; Diffusion of Innovation; Feeding and Eating Disorders; Heroin Dependence; Humans; Quality Assurance, Health Care; Schizophrenia; United Kingdom

Topics: Chronic Disease; Clozapine; Humans; Patient Compliance; Risperidone; Schizophrenia

In the run-up to a prospective intervention study to assist the preparation of psychoeducational therapeutic measures, schizophrenic out-patients were questioned on their experiences with two oral neuroleptics, Clozapine and Perazine. The two drugs, which are known to have similar side effects, find equal acceptance among patients. Subjective attitudes to medication and general evaluations of drug therapy are extremely positive. Numerous patients had already modified their neuroleptic dosage on their own initiative, in most cases discontinuing their medication but in some cases increasing or reducing the dose. These experiences can be used in designing a psychoeducational intervention directed towards individual needs.

Topics: Adaptation, Psychological; Administration, Oral; Adult; Ambulatory Care; Chronic Disease; Clozapine; Female; Humans; Male; Patient Acceptance of Health Care; Patient Education as Topic; Perazine; Recurrence; Schizophrenia; Schizophrenic Psychology; Sick Role

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

A patient with refractory chronic schizophrenia having severe polydipsia and hyponatremia was treated with clozapine. There followed a dramatic improvement in the polydipsia and correction of the hyponatremia. This improvement has been sustained throughout a 6-month follow-up.

Topics: Adult; Chronic Disease; Clozapine; Compulsive Behavior; Dose-Response Relationship, Drug; Drinking; Drug Administration Schedule; Humans; Hyponatremia; Male; Mental Status Schedule; Schizophrenia, Disorganized; Water-Electrolyte Balance

Longitudinal assessments (every six weeks for one year) were made of plasma norepinephrine, dopamine, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG) in 40 adolescents with schizophrenia, 20 on clozapine therapy and 20 on conventional medication. In addition to the plasma catecholamine determinations, serum levels of 5-HT were determined as a measure of serotoninergic status. All analyses were performed by HPLC-ECD (high-performance liquid chromatography with electrochemical detection). Clinical ratings of symptomatology were obtained with the Brief Psychiatric Rating Scale (BPRS) and the Andreasen scales for negative and positive symptoms (SANS and SAPS). Compared with the typical neuroleptic medication, clozapine administration was accompanied by a significant increase in plasma norepinephrine and MPHG and serum serotonin levels. The fluctuations in the biogenic amines were closely associated with the observed symptomatology. Plasma MHPG was linked to depressive symptoms (BPRS), and negative symptoms (SANS) were related to changes in the serum serotonin levels. The pathophysiological implications and clinical consequences of these findings are discussed.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Depressive Disorder; Dopamine; Epinephrine; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Methoxyhydroxyphenylglycol; Neurotransmitter Agents; Norepinephrine; Prospective Studies; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Serotonin; Treatment Outcome

Topics: Adult; Chronic Disease; Clozapine; Female; Humans; Hyponatremia; Male; Middle Aged; Schizophrenia; Water Intoxication

To investigate the association of clozapine treatment and weight gain, we studied short- and long-term weight gain, correlation of weight gain with treatment response, and risk factors for weight gain in 82 patients with chronic schizophrenia who received clozapine treatment for up to 90 months.. Weight values were obtained through retrospective chart review. Clozapine was titrated over an average of 3 to 5 weeks up to a dose of 500 to 600 mg/day. Psychopathology was assessed with the Brief Psychiatric Rating Scale and the Clinical Global Impressions scale.. A clinically significant weight gain occurred mostly during the first 6 to 12 months, but continued well into the third year of treatment. Weight gain and treatment response were not correlated, and early weight gain was not a predictor of response. The cumulative incidence of patients becoming substantially overweight exceeded 50%. Being underweight at baseline correlated with maximum amount gained (p = .000), and being overweight at baseline correlated with percentage above ideal weight (p = .006).. Treatment with clozapine is associated with a high incidence of substantial weight gain, posing a potential long-term health risk. Studies are needed of the underlying mechanisms of weight gain, as well as the treatment for this side effect.

Topics: Adult; Chronic Disease; Clozapine; Female; Follow-Up Studies; Humans; Incidence; Male; Obesity; Psychiatric Status Rating Scales; Retrospective Studies; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

Topics: Adult; Chromatography, High Pressure Liquid; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Metabolic Clearance Rate; Schizophrenia, Paranoid; Schizophrenic Psychology

This study addressed the unique clinical properties attributed to the atypical antipsychotic clozapine, including its efficacy in patients with treatment-refractory psychosis and against negative symptoms, its lack of acute extrapyramidal side effects, and the longer time course of its therapeutic effects.. The clinical responses of 84 schizophrenic inpatients (66 with treatment-refractory illness and 18 who were intolerant of antipsychotic treatment) were examined. After all previous antipsychotic medications had been withdrawn, the patients were treated with clozapine according to a standardized titration and dosage schedule. Patients who tolerated and responded to treatment were discharged and maintained on a regimen of clozapine for up to 52 weeks. Patients were evaluated for behavioral response and side effects after weeks 3, 6, 12, 26, 39, and 52 of treatment.. Fifty percent of the patients with treatment-refractory illness and 76% of the treatment-intolerant patients responded to clozapine in up to 52 weeks. The optimal period for a trial of clozapine appeared to be 12-24 weeks. Clozapine exhibited therapeutic effects on negative symptoms, but these were not clearly independent of its effects on positive symptoms and extrapyramidal side effects. Several variables, including early age at onset of illness and female gender, were found to be predictors of poor response to treatment. Predictors of good response included the presence of extrapyramidal side effects during previous treatment with classic neuroleptics and a diagnosis of paranoid schizophrenia.. These findings have important implications for the use of clozapine and our understanding of the pathophysiology of treatment-resistant schizophrenia.

Topics: Adolescent; Adult; Age of Onset; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Female; Humans; Male; Probability; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sex Factors; 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; Cause of Death; Chronic Disease; Clozapine; Drug Monitoring; Humans; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; Survival Analysis

The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half-life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng.hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza-pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.

Topics: Adult; Chronic Disease; Clozapine; Dextromethorphan; Half-Life; Homovanillic Acid; Humans; Male; Metabolic Clearance Rate; Middle Aged; Phenotype; Schizophrenia

Topics: Adult; Chronic Disease; Clozapine; Drinking; Female; Humans; Male; Middle Aged; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Water Intoxication

Topics: Adult; Chronic Disease; Clozapine; Humans; Male; Schizophrenia, Paranoid; Substance-Related Disorders

The authors' aim was to determine whether clozapine was associated with a decrease in state hospital bed-days for patients with chronic schizophrenia.. Patients were started on clozapine in a state facility and were followed while taking the medication for 1.5 years (N = 172), two years (N = 86), and 2.5 years (N = 53). Patients' number of bed-days before starting clozapine was compared with those during the follow-up period.. Bed-days were reduced by an average of 132 days per year after 1.5 years, 166 days per year after two years, and 201 days per year after 2.5 years (p < .001). During the final 180 days of each follow-up period, only 23 to 30 percent of patients were continuously hospitalized, compared with 56 to 64 percent before clozapine. Forty to 57 percent of patients had no hospital days at all during the last 180 days of follow-up.. Based on hospital costs of $250 per patient per day, this reduction in bed-days could result in gross savings of about $33,000 per patient per year at 1.5 years, $41,500 per patient per year at two years, and $50,250 per patient per year at 2.5 years. Hospital patients are conspicuous targets for clozapine funding, since bed-days represent an easily measured expense. Nevertheless, community treatment should be an even higher priority, since most chronic mentally ill persons are outpatients.

Topics: Adult; Aged; Chronic Disease; Clozapine; Cost Savings; Female; Follow-Up Studies; Hospitals, Psychiatric; Hospitals, State; Humans; Length of Stay; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology; Texas

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: Adult; Antipsychotic Agents; Attitude of Health Personnel; Chronic Disease; Clozapine; Contraindications; Drug Monitoring; Drug Prescriptions; Humans; Informed Consent; Male; Patient Education as Topic; Schizophrenia, Paranoid; Schizophrenic Psychology

The authors present data from a national survey of state departments of mental health showing that two years after reaching the U.S. market, clozapine is available to only a small fraction of the patients whom it might benefit. The primary continuing hurdle for the public sector, where most schizophrenic patients get their care, is funding. Several arguments support the use of clozapine in state mental health systems: it is the most effective or only effective medication for many patients, it can decrease the enormous costs of schizophrenia and related disorders, and access to the medication has become an important issue for advocacy groups and other mental health activists. Two years of experience with clozapine in the Texas mental health system have shown that availability of clozapine in the community is a vital factor for successful use of the drug in hospitals. The authors discuss ways to encourage outpatient clozapine programs that are critical to successful treatment in both the hospital and the community.

Topics: Chronic Disease; Clozapine; Community Mental Health Services; Drug Utilization; Financing, Government; Hospitals, Psychiatric; Hospitals, Public; Humans; Schizophrenia; Schizophrenic Psychology; State Health Plans; United States

Topics: Adult; Chemical and Drug Induced Liver Injury; Chronic Disease; Clozapine; Female; Humans; Liver Function Tests; Schizophrenia, Paranoid

A retrospective chart review was used to assess weight changes in 36 chronic schizophrenic inpatients who were treated with clozapine after being treated with standard neuroleptics. The average weight gain during 6 months of clozapine treatment was 16.9 lb; 75.0% of the patients gained at least 10 lb. The results confirm previous findings of clozapine-associated weight gain.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Hospitalization; Humans; Male; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Weight Gain

Treatment-refractory schizophrenia is a major clinical problem for which there is relatively little scientific information, and no consensus has been reached on approaches to treatment. The pharmacotherapy used for 103 patients with a diagnosis of schizophrenia or schizoaffective disorder at one psychiatric hospital was examined. Data were gathered on neuroleptic choice and dose, the use of adjunctive treatments and serum neuroleptic levels. The daily neuroleptic dose was compared with that of random samples of patients receiving outpatient maintenance treatment, and short-stay patients receiving acute treatment. The patients in our sample received high doses of neuroleptics despite a persistent lack of response to treatment, and despite the fact that these were in excess of the recommended maximum beneficial dose. The appropriateness of this therapy is discussed.

Topics: Activities of Daily Living; Antipsychotic Agents; Chlorpromazine; Chronic Disease; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Humans; Incidence; Long-Term Care; Ontario; Psychiatric Status Rating Scales; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology

Clozapine, an atypical neuroleptic, is an effective medication in a subgroup of schizophrenic patients who have either failed to respond to the typical neuroleptics or experienced intolerable side effects such as neuroleptic malignant syndrome and disabling tardive dyskinesia. Its efficacy for persistent and disabling akathisia is less clear. Akathisia, especially the chronic and disabling form, can be a treatment dilemma for the clinician and the patient.. We describe three representative case illustrations of schizophrenic patients who had severe, persistent treatment-resistant akathisia. Two of them had refractory psychoses and the third had multiple disabling side effects during treatment with typical neuroleptics. Two had tardive dyskinesia. These patients were treated with clozapine while other neuroleptics were discontinued.. During a 2-year follow-up, these patients made impressive social and vocational strides coinciding with a fairly rapid remission of akathisia (under 3 months) and a lesser though notable improvement in the psychoses. Tardive dyskinesia also remitted, though over a period of 6 to 12 months.. Our experience leads us to suggest a trial of clozapine in a subgroup of schizophrenic patients, who in addition to refractory psychoses have persistent disabling akathisia. However, given the risk of agranulocytosis with clozapine, we suggest that the usual treatment strategies for akathisia be tried before clozapine is initiated in the approved manner. Future controlled trials of clozapine that specifically investigate persistent akathisia may answer this question more conclusively.

Topics: Adult; Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychomotor Agitation; Schizophrenia; Schizophrenic Psychology; Social Adjustment

The effects of clozapine, an unconventional neuroleptic drug, on the use of restraint and seclusion in patients have not been extensively reported on in the United States.. The records of 107 patients receiving clozapine in Missouri state mental hospitals were reviewed over a 13-month period for frequency and duration of restraint and seclusion.. During clozapine treatment, patients had fewer episodes of restraint and seclusion than previously. The duration of restraints and seclusions also decreased, starting the second month after the initiation of clozapine treatment.. For patients who were restrained or secluded before clozapine treatment, the decrease in the number and duration of restraint and seclusion episodes was dramatic.

Topics: Chronic Disease; Clozapine; Hospitalization; Humans; Restraint, Physical; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Social Isolation

Clozapine differs from other currently available antipsychotics in its prominent serotonin blockade. We explore the relationship between clozapine and obsessive compulsive symptoms, which have been linked to deficient serotonin.. We reviewed our experience in treating 49 chronic schizophrenic patients with clozapine.. Five patients were identified who experienced either de novo obsessive compulsive symptoms or exacerbation of preexistent symptoms. Clinical details are provided for each case.. Clozapine may produce or unmask obsessive compulsive symptoms. This may reflect a variation on the normal course of clinical improvement, or may more specifically result from clozapine's atypical pattern of CNS receptor antagonism. Further attention to this issue is warranted.

Topics: Adult; Chronic Disease; Clozapine; Female; Humans; Male; Obsessive-Compulsive Disorder; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology

Topics: Aged; Chlorpromazine; Chronic Disease; Clonazepam; Clozapine; Depressive Disorder; Desipramine; Diphenhydramine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Neurologic Examination

Topics: Chronic Disease; Clozapine; Delusions; Hallucinations; Humans; Psychotherapy; Schizophrenia; Schizophrenic Psychology

Cimetidine may decrease concomitant medication clearance by inhibiting the oxidative system of cytochrome P-450. The authors report increased serum clozapine levels and adverse side effects during clozapine and cimetidine treatment but not during clozapine and ranitidine treatment in a patient with chronic paranoid schizophrenia.

Topics: Adult; Chronic Disease; Cimetidine; Clozapine; Drug Interactions; Drug Therapy, Combination; Humans; Male; Ranitidine; Schizophrenia, Paranoid

Topics: Administration, Oral; Adult; Brain; Chronic Disease; Clozapine; Female; Fenfluramine; Humans; Male; Norfenfluramine; Prolactin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists

Topics: Chronic Disease; Clozapine; Financing, Government; Health Services Accessibility; Humans; Monitoring, Physiologic; Schizophrenia; Schizophrenic Psychology; United States

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: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Meige Syndrome; Schizophrenia; Schizophrenic Psychology

The criteria for treatment refractoriness for the use of clozapine are necessarily set at a high level because of the potential risk of agranulocytosis with this treatment. However, a more liberal definition should be considered to better appreciate the limitations of current therapies and prepare for switching to the next generation of clozapine-like drugs that do not cause agranulocytosis. It is suggested that failure of therapy to bring about the best premorbid level of functioning be considered as a starting point for treatment-resistance.

Topics: Chlorpromazine; Chronic Disease; Clozapine; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Chronic Disease; Clozapine; Community Mental Health Services; Cost Control; Cost-Benefit Analysis; Dibenzazepines; Humans; Leukocyte Count; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Aftercare; Chronic Disease; Clozapine; Community Mental Health Services; Cost-Benefit Analysis; Dibenzazepines; Dose-Response Relationship, Drug; Female; Humans; Length of Stay; Male; Psychiatric Status Rating Scales; Referral and Consultation; Schizophrenia; Schizophrenic Psychology

Clozapine, an effective but expensive drug treatment for patients with severe, chronic schizophrenia who are unresponsive to conventional antipsychotics, is associated with a high risk of agranulocytosis, which is sometimes fatal. Weekly blood tests to detect evidence of this side effect are required. To estimate the number of potential candidates for this treatment and the national cost of administering the drug to this population, the authors used data from three recent patient surveys conducted in New York State. Depending on the criteria used to exclude unsuitable candidates, between 133,000 and 189,000 individuals will be eligible for treatment with clozapine nationally at a cost of $1.2 to $1.7 billion annually.

Topics: Adult; Affective Disorders, Psychotic; Aftercare; Agranulocytosis; Chronic Disease; Clozapine; Community Mental Health Services; Cost Control; Cost-Benefit Analysis; Dibenzazepines; Female; Humans; Length of Stay; Male; Middle Aged; New York; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Chronic Disease; Clozapine; Community Mental Health Services; Cost Control; Dibenzazepines; Hospitals, Psychiatric; Hospitals, State; Humans; Leukocyte Count; Schizophrenia; Schizophrenic Psychology; United States

Three ethical constructs of distributive justice--utilitarianism, Marxism, and the theories of John Rawls--are applied to selection of patients for treatment with clozapine. Elements of an ethical selection process include a means of monitoring the clinical effectiveness of the drug so that it is not wasted and procedures for ensuring that patients' rights to advocacy and due process are met. The authors suggest that a disproportionate number of patients with tardive dyskinesia may receive clozapine because clinicians and hospitals risk litigation if these patients continue to receive standard neuroleptics and experience worsening side effects.

Topics: Chronic Disease; Clozapine; Cost Control; Dibenzazepines; Ethical Theory; Ethics, Medical; Health Care Rationing; Humans; Mentally Ill Persons; Patient Rights; Patient Selection; Philosophy, Medical; Resource Allocation; Risk Assessment; Schizophrenia; Schizophrenic Psychology; United States

The long-term efficacy of clozapine therapy and its effect on health care costs were examined over a two-year period. Patients on clozapine showed marked clinical improvement as measured by the Brief Psychiatric Rating Scale. They also had significantly lower rates of rehospitalization and hospitalization costs than a comparison group of schizophrenic patients who received standard neuroleptic treatment and who were considerably less psychotic at hospital admission. By the second year of the study, savings on mental health care costs averaged $20,000 for each patient on clozapine therapy. The savings were due largely to the patients' change in residence from costly inpatient facilities to less expensive settings in the community.

Topics: Agranulocytosis; Chronic Disease; Clozapine; Cohort Studies; Cost Control; Dibenzazepines; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Patient Readmission; Schizophrenia; Schizophrenic Psychology; Seizures

The sudden improvement in long-term schizophrenic patients after treatment with clozapine is frequently disconcerting to their families. In many cases the patients appear to have increased hostility toward their families because of the alleviation of negative symptoms such as apathy and blunted affect. The authors believe that psychoeducational intervention can help families adjust to the change in their family members and describe such intervention with three families. They emphasize the importance of recognizing that a patient's improvement can be a stressor in the family relationship and the need for devising appropriate interventions.

Topics: Adult; Chronic Disease; Clozapine; Combined Modality Therapy; Dibenzazepines; Family; Family Therapy; Female; Halfway Houses; Home Nursing; Humans; Male; Patient Discharge; Professional-Family Relations; Schizophrenia; Schizophrenia, Paranoid; Schizophrenic Psychology; Social Adjustment; Social Environment; Social Support

Topics: Adult; Chronic Disease; Clozapine; Dibenzazepines; Female; Humans; Male; Psychiatric Status Rating Scales; Psychotic Disorders

The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.

Topics: Administration, Oral; Adult; Chronic Disease; Clozapine; Dibenzazepines; Humans; Injections, Intravenous; Male; Schizophrenia

Topics: Adult; Antipsychotic Agents; Chlorpromazine; Chronic Disease; Clozapine; Female; Humans; Male; Schizophrenia; Sulpiride; Syndrome

Data were obtained from 14 chronically schizophrenic women (age 40-59) living in the same ward of a psychiatric hospital (Marburg, FRG), and having been treated with clozapine (450-600 mg/day) during the last 2 years. The uncontrolled study was initiated by the addition of sodium valproate (900 mg/day) for 3 months. The observation commenced after the discontinuation of the valproate medication with the evaluation of the symptoms (Brief Psychiatric Rating Scale, BPRS) and the visually evoked potentials (VEP). The VEP were recorded after 3, 12 and 30 days and the rating was repeated after 4 weeks. No significant changes in symptomatology were obtained with the BPRS in patients under combination therapy in comparison with the scores 30 days after discontinuation of the valproate medication. On the other hand, after single flash stimulation, the amplitudes of the components N110, P260, and N300 of the VEP were significantly (p less than 0.05) increased during the same time interval. These findings are interpreted as an expression of an inhibiting action of the GABA system on the reactivity of the visual system in chronic schizophrenics induced by the comedication of sodium valproate.

Topics: Adult; Brain; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Dibenzazepines; Drug Therapy, Combination; Evoked Potentials, Visual; Female; gamma-Aminobutyric Acid; Humans; Middle Aged; Schizophrenia; Valproic Acid

The authors studied a prolonged (3--5 years) use of leponex in 23 patients with the most progressive forms of schizophrenia (hebephrenic, paranoid and close to them attack-like). The study included the influence on the frequency and duration of relapses, on the dynamics of the so-called productive and negative disorders and social adaptation. The achieved data indicate that leponex possesses certain advantages compared to other neuroleptical drugs in prolonged maintenance therapy. Leponex has a rather "universal" psychopharmacological effect which includes a capability of arresting acute psychoses, exerts a psychoregulating influence on the general behaviour, contacts and socio-working adaptation, distinctly alleviates the clinical signs and frequency of relapses. Due to the absence of motor disturbances and minimum of other side-effects leponex is quite convenient for prolonged use and promotes a higher quality of remissions.

Topics: Adult; Chronic Disease; Clozapine; Dibenzazepines; Female; Humans; Male; Middle Aged; Recurrence; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Social Adjustment; Syndrome; Time Factors

Topics: Administration, Oral; Adult; Brain; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Dibenzazepines; Dopamine; Drug Evaluation; Female; Humans; Limbic System; Male; Middle Aged; Receptors, Dopamine; Schizophrenia

Fifty-two mental hospital cases of acute and chronic schizophrenia and gross behaviour disorders were investigated and observed for 6-12 months during treatment with clozapine. Three-quarters of the acute cases recovered with full occupation capacity. Two-thirds of the chronic cases improved markedly. Antisocial behaviour was controlled in 12 out of the 13 behaviour-disordered group. The improvement in initiative and social capacity was striking and appeared to be due to improved awareness of the environment and the acquisition and handling of useful knowledge. The response to clozapine appears to be specific and relapses occurred when maintenance medication was stopped. It is of value in treating temper states in epilepsy and has the advantage of not causing extrapyramidal symptoms and side-effects are slight after the first week. Maximum improvement may not be reached before 8 weeks. Thereafter the maintenance dose can be small and fluctuations in the illness do not seem to occur. The dosage, side-effects and precautions are discussed. A rating system to display the effect of clozapine on individual parameters as well as on the over-all state was devised for this study.

Topics: Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Clozapine; Dibenzazepines; Epilepsy; Female; Humans; Male; Middle Aged; Recurrence; Schizophrenia; Social Behavior Disorders