clozapine and Body-Weight

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

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

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

Highly variable plasma concentrations are found in patients receiving the same dose of clozapine. Therefore, rational dose adjustment of clozapine that is guided by therapeutic drug monitoring (TDM) can improve efficacy while reducing risk of toxicity. As a background to the discussion of the use of TDM for clozapine, the pharmacodynamics and pathways of clozapine biotransformation are first reviewed, in particular the role of the primary enzymes involved. These are CYP1A2, the primary enzyme involved in converting clozapine to norclozapine, and CYP3A4, the primary enzyme involved in converting clozapine to clozapine-N-oxide. The factors that can influence plasma levels of clozapine are next reviewed; these include dose, gender, smoking, age, body weight, caffeine intake, and drug-drug interactions. The authors then examine the concentration-dependent toxicity of clozapine based on a review of published data. Finally, the authors present four cases illustrating the issues involved and how TMD can be used to improve clinical care of patients being treated with clozapine, both in terms of improving efficacy and minimizing potential toxicity.

Topics: Adult; Aged; Antipsychotic Agents; Biotransformation; Body Weight; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Middle Aged; Sex Factors; Smoking

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

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

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

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

After the introduction of the so-called "atypical antipsychotics" in the clinical experience hyperglycemia as well as increased triglyceride and cholesterol serum levels were reported in patients treated with some of these agents. In this article, the recently published population-based studies are reviewed.. According to the available data, the risk to develop type 2 diabetes mellitus or hyperlipidemia in patients treated with clozapine and olanzapine is increased. The underlying pathomechanism still remains widely unclear. Since overweight is a known risk factor for type 2 diabetes mellitus, the weight-inducing effect of atypical antipsychotics may play an important role.. Since metabolic disorders often lead to severe diseases, these side effects of antipsychotics should be paid more attention.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Humans; Hypercholesterolemia; Hypertriglyceridemia; Olanzapine; Pirenzepine; Risk

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

Schizophrenia is associated with a lowered bone mineral density. The antidiabetic and body weight lowering glucagon-like peptide-1 receptor agonist liraglutide has shown to mitigate overweight and impaired glucose tolerance associated with olanzapine and clozapine. As liraglutide has been proposed to affect bone metabolism, we evaluated the effect of liraglutide on bone turnover markers (BTM) in patients with prediabetes and schizophrenia treated with olanzapine or clozapine. Patients diagnosed with a schizophrenia spectrum disorder treated with the antipsychotic compounds clozapine and/or olanzapine, having prediabetes and a BMI above 27 kg/m

Topics: Adult; Antipsychotic Agents; Biomarkers; Body Weight; Bone and Bones; Bone Density; Bone Remodeling; Clozapine; Collagen Type I; Fasting; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Olanzapine; Overweight; Prediabetic State; Schizophrenia

Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period.. One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels.. From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide.. The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Weight; C-Peptide; Clozapine; Denmark; Fasting; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipid Metabolism; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Overweight; Placebos; Prediabetic State; Schizophrenia; Young Adult

This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia.. Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12.. Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (- 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; - 26 ± 76 vs - 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100).. In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. CLINICALTRIALS.. NCT00981526.

Topics: Adult; Antipsychotic Agents; Body Composition; Body Mass Index; Body Weight; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Insulin; Male; Middle Aged; Olanzapine; Schizophrenia; Telmisartan; Treatment Outcome; Triglycerides

Numerous studies have demonstrated that fluvoxamine has considerable pharmacokinetic and pharmacodynamic interactions with clozapine. We conducted a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia.. We recruited 85 patients who received a DSM-IV diagnosis of schizophrenia. Eligible patients were randomized to receive fluvoxamine 50mg/day plus clozapine 100mg/day or clozapine 300mg/day. We studied metabolic parameters, psychopathology, and drug levels at baseline and 4, 8, and 12weeks after the intervention. Plasma levels of clozapine, norclozapine, clozapine N-oxide, and fluvoxamine were determined using high-performance liquid chromatography with ultraviolet detection.. No significant difference was observed in baseline characteristics between the two groups. Clozapine-fluvoxamine combined treatment significantly attenuated the increments in body weight, insulin resistance, and levels of insulin, glucose, and triglycerides compared with clozapine monotherapy. Both groups exhibited significant improvements in their Positive and Negative Syndrome Scale (PANSS) total and negative scores. The combined treatment group showed significant reduction in the PANSS general psychopathology scores compared with the monotherapy group. No difference was observed in the plasma clozapine level between the two groups. The monotherapy group showed higher levels of norclozapine and clozapine N-oxide than the combined group.. Compared with clozapine monotherapy, treatment with adjunctive fluvoxamine with clozapine for 12weeks can alleviate body weight gain and metabolic abnormalities in patients with schizophrenia, without sacrificing the clinical effect. Clinicians should interpret these findings cautiously considering the short duration of this study. The study was registered at www.clinicaltrials.gov (NCT01401491).

Topics: Antipsychotic Agents; Antisocial Personality Disorder; Body Weight; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fluvoxamine; Follow-Up Studies; Humans; Leukocytes; Male; Metabolic Diseases; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome

Omega-3 fatty acid (FA) supplementation has been reported to improve several cardio-metabolic risk factors. We aimed to assess the efficacy of omega-3 fatty acids on metabolic and inflammatory indices in patients with schizophrenia who were taking clozapine and sodium valproate. All patients were on a stable dose of 300-400mg of clozapine for 3 months. Subjects were randomized to treatment with either omega-3 fatty acid (4gr/day) or a placebo for 8 weeks. Height, weight, abdominal circumference, serum lipid profile, fasting blood glucose (FBG), and serum high sensitivity-C-reactive protein (hs-CRP) were determined at baseline and after 8 weeks of treatment. Fifty six subjects were recruited into the study. Patients with schizophrenia who were in the group receiving omega-3 FA capsules had an improvement in some anthropometric indices including weight, BMI, wrist and waist circumference, compared to the placebo group. Only changes in waist circumferences remained significantly different after adjustment for serum fasted TG. Our results showed omega-3 FA supplementation can improve some anthropometric indices in patients with schizophrenia who are taking clozapine pharmacotherapy.

Topics: Adult; Anthropometry; Antipsychotic Agents; Body Mass Index; Body Weight; C-Reactive Protein; Clozapine; Dietary Supplements; Double-Blind Method; Fasting; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Schizophrenia; Treatment Outcome; Triglycerides; Valproic Acid; Waist Circumference

Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation.. A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants.. Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds.. ACTRN12617001547336; Pre-results.

Topics: Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Metabolic Syndrome; Metformin; Obesity; Research Design; Schizophrenia; Secondary Prevention; Treatment Outcome; Weight Gain; Weight Loss

Some therapeutic drug monitoring studies suggest that increased weight is associated with small increases in clozapine concentrations. The goal of this study was to reanalyze a US double-blind study using a sophisticated statistical model to test whether weight gains from baseline or increases in percentage of body fat from baseline, computed from a published equation, are associated with increased total plasma clozapine concentrations after controlling for the effects of smoking and sex.. Using data from a multidosage randomized double-blind US clozapine trial previously published, a random intercept linear model of steady-state total plasma clozapine concentrations was fitted to 424 concentrations from 47 patients.. After adjusting for sex and smoking, (1) a 1-kg gain in body weight during clozapine treatment was significantly associated with a 1.4% increase in total plasma clozapine concentrations (95% confidence interval = 0.55 to 2.3) and (2) a 1-point increase in percentage of body fat during clozapine treatment was significantly associated with a 5.4% increase in total clozapine concentration (2.5 to 8.3) in females and 1.4% (-1.1 to 4.0) in males.. As hypothesized, weight increases during clozapine treatment, which probably reflect increases in fat tissue, were associated with increases in total plasma concentrations. Pending further replication in other samples, it seems likely that clozapine may deposit in body fat and that this may decrease clozapine clearance. This change may be small in most patients but may be clinically relevant in females with major gains in body fat.

Topics: Adipose Tissue; Adult; Antipsychotic Agents; Body Weight; Clozapine; Data Analysis; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Statistical; Weight Gain

Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics.. We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales.. In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients.. These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

Topics: Adolescent; Adult; Antipsychotic Agents; Betahistine; Body Mass Index; Body Weight; Child; Clozapine; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Olanzapine; Schizophrenia; Treatment Outcome; Weight Gain; Young Adult

Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. The lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. This study was designed to determine whether metformin at 500 mg/d and 1000 mg/d is effective in improving the metabolic profiles of clozapine-treated patients with pre-existing metabolic abnormalities, and whether its effectiveness depends on metformin dosage.. In this 12-week, randomized, double-blind, placebo-controlled trial, metformin at 500 mg/d or 1000 mg/d was prescribed to clozapine-treated patients with schizophrenia who had pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at weeks 4, 8, and 12. The outcomes were any changes in metabolic traits.. Among the 96 clozapine-treated patients with schizophrenia screened for the trial, 55 patients with pre-existing metabolic abnormalities were randomly assigned to placebo (n = 18), metformin dosage at 500 mg/d (n = 18), and metformin dosage at 1000 mg/d (n = 19) groups. The body weight (BW) of patients in the metformin 1000 mg/d group significantly decreased, by a mean of 0.97 kg over the 12 week trial period. Moreover, patients in the metformin at 500 mg/d and 1000 mg/d groups had a significant decrease in body mass index (BMI) after 12 weeks, with the mean decrease being 0.70 and 0.50 kg/m2, respectively. No significant changes were observed in the other metabolic parameters of patients in the three groups.. Our results demonstrated that a low metformin dosage of either 500 mg/d or 1000 mg/d for 12 weeks slightly reduced the BW and BMI of clozapine-treated patients with pre-existing metabolic abnormalities. A longer period of treatment with a larger sample is warranted to determine the factors that influence the metformin treatment response.. ClinicalTrials.gov NCT02751307.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Schizophrenia; Treatment Outcome

Many studies have shown that metformin can decrease body weight and improve metabolic abnormalities in patients with schizophrenia. Whether or not the beneficial effects can be sustained after discontinuation of metformin needs to be evaluated. We conducted a 24-week randomized, double-blind, placebo-controlled study to evaluate the effect of metformin on metabolic features in clozapine-treated patients with schizophrenia and followed their body weight after stopping the intervention for at least 24 weeks.. The study was conducted between September 2008 and July 2011. We recruited patients with DSM-IV diagnosis of schizophrenia or schizoaffective disorder who had been taking clozapine for more than 3 months, were overweight or obese, or fulfilled at least 1 criteria of metabolic syndrome. Eligible patients were randomized to receive metformin 1,500 mg/d or placebo. We followed metabolic features at baseline and at weeks 2, 4, 8, 16, and 24 and rechecked body weight when the patients stopped the trial after at least 24 weeks.. A total of 55 subjects (28 in the metformin and 27 in the placebo group) were enrolled. There were no significant differences in all baseline characteristics between the 2 groups, except that patients in the metformin group had higher fasting plasma glucose levels (P = .03). After the 24-week intervention, body weight (P < .0001), body mass index (P < .0001), fasting plasma glucose (P < .0001), high-density lipoprotein cholesterol (P = .03), insulin level (P = .01), and homeostasis model assessment index (P = .02) had significant changes in the metformin group. At the end of the intervention, 8 patients (28.57%) lost more than 7% of their body weight in the metformin group. Mean body weight returned to baseline after patients stopped the intervention in the metformin group.. Metformin can significantly reduce body weight and reverse metabolic abnormalities in clozapine-treated patients with schizophrenia and preexisting metabolic abnormalities. However, the beneficial effects of metformin on body weight disappeared after discontinuing this medication.

Topics: Adult; Body Weight; Clozapine; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Metabolic Syndrome; Metformin; Middle Aged; Obesity; Overweight; Psychotic Disorders; Schizophrenia; Time Factors; Treatment Outcome

In first-episode patients with psychosis, clozapine may be potentially valuable as an initial treatment seeking to limit early on clinical and cognitive deterioration. Nevertheless, until recently its restricted use has limited the study of this possibility. Our research group is developing a non-commercial, multicentric and open label study on the differential efficacy between clozapine and risperidone in first-episode schizophrenia. In this paper, we present the results related to clinical variables after a one-year follow-up. So far, we have recruited 30 patients diagnosed with schizophrenia or schizophreniform disorder with illness duration of less than two years. The patients had not received any previous treatment and they were randomized to treatment with clozapine or risperidone. Our results indicate that on average, patients on clozapine adhered to their original treatment for a longer time period than patients on risperidone. By last observation carried forward (LOCF) analysis, patients on clozapine and risperidone displayed similar clinical improvements, although marginally greater improvements in positive and total symptoms scores were found in the clozapine group. At the 12-month point we observed a marginal improvement in negative symptom scores in patients on clozapine. Subjective secondary effects, as measured with the Udvalg for KliniskeUndersøgelser (UKU) scale, correlated negatively with negative symptoms at follow-up. Our data, although preliminary, suggest that clozapine may have a slightly superior efficacy in the initial year of treatment of first-episode treatment-naïve patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Body Weight; Clozapine; Electrocardiography; Female; Follow-Up Studies; Glycemic Index; Humans; Lipid Metabolism; Male; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Time Factors; Treatment Outcome; Young Adult

In recent years, several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics. While there has been some success, in general, results have not been compelling. Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression. Therefore, we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or olanzapine.. The study was a double-blind, placebo-controlled trial. All participants received the same psychosocial platform: a structured support and exercise group. People with schizophrenia or schizoaffective disorder, on olanzapine or clozapine, who had gained at least 7% of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week, randomized, parallel group, double-blind comparison of adjunctive atomoxetine or placebo.. Thirty-seven participants (20 atomoxetine, 17 placebo) were randomized and 26 participants (14 atomoxetine, 12 placebo; 70.2%) completed the study. There were no significant group differences in baseline BMI (atomoxetine: 34.5±4.9; placebo: 35.7±7.0) or weight (atomoxetine: 102.2±15.7 kg; placebo: 104.3±17.5 kg). Both treatment groups showed modest, not significant, trends in weight loss, averaging about 2 kg. Gender or baseline antipsychotic treatment did not modify treatment effects on weight. Secondary outcomes included neuropsychological assessments, symptom assessments (BPRS, SANS) and safety assessments. Of these, only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine.. Atomoxetine is not effective for weight loss in this population, but both olanzapine and clozapine participants can lose weight with structured group support and exercise.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Appetite Depressants; Atomoxetine Hydrochloride; Attention; Benzodiazepines; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Clozapine; Combined Modality Therapy; Diet, Reducing; Double-Blind Method; Exercise; Female; Humans; Life Style; Male; Maryland; Middle Aged; Neuropsychological Tests; Obesity; Olanzapine; Propylamines; Psychotic Disorders; Schizophrenia

A positive relationship between cholesterol levels and cognition has been reported in various human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol.. This was a double-blind randomized prospective 12-week study. Participants received a baseline evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were evaluated at the end of 12 weeks. A general cognitive index (GCI) derived from the cognitive battery was the primary variable.. 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There was a statistically and clinically significant positive association between change in cholesterol levels and change in GCI. This association was especially pronounced for verbal memory. There was no interaction between medication grouping and cholesterol level; the positive association was observable separately in each medication group. It was very robust and remained significant after we controlled for glucose and triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications, and pre-study antipsychotic medications.. Cholesterol levels show a strong association with cognition in schizophrenia in all medication groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core deficit of schizophrenia.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Clozapine; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Triglycerides; Young Adult

Sedation is a common side effect of clozapine treatment and may exacerbate metabolic consequences of poor diet and exercise habits that are common in patients with schizophrenia. Modafinil has been proposed as a treatment for clozapine-induced sedation and metabolic abnormalities.. To estimate the effect sizes and person-to-person variation in anthropometric measures, glucose and lipid metabolism, and diet on modafinil treatment for future randomized control trials.. A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted, adding modafinil up to 300 mg/day to stabilized schizophrenia outpatients receiving clozapine. Blood pressure, weight, BMI, laboratory assays, and dietary intake were tracked to monitor changes in metabolic markers.. Thirty-five participants were randomly assigned to treatment with study drug or placebo and were included in the analysis. Modafinil did not improve blood pressure, weight, BMI, glucose or lipid metabolism compared to placebo. Modafinil was well tolerated and did not worsen psychosis.. Results of this pilot trial do not support routine use of modafinil to counteract increased weight and metabolic diseases in patients taking clozapine. However, the effects of modafinil on weight and insulin regulation warrant further investigation with effect sizes of 0.4 to 0.6.

Topics: Adult; Analysis of Variance; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Weight; Clozapine; Double-Blind Method; Female; Follow-Up Studies; Humans; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Modafinil; Neuroprotective Agents; Retrospective Studies; Schizophrenia; Time Factors

Clozapine is associated with significant weight gain and metabolic disturbances. This multicentre, randomized study comprised a double-blind, placebo-controlled treatment phase of 16 wk, and an open-label extension phase of 12 wk. Outpatients who met DSM-IV-TR criteria for schizophrenia, who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or =2.5 kg while taking clozapine, were randomized (n=207) to aripiprazole at 5-15 mg/d or placebo, in addition to a stable dose of clozapine. The primary endpoint was mean change from baseline in body weight at week 16 (last observation carried forward). Secondary endpoints included clinical efficacy, body mass index (BMI) and waist circumference. A statistically significant difference in weight loss was reported for aripiprazole vs. placebo (-2.53 kg vs. -0.38 kg, respectively, difference=-2.15 kg, p<0.001). Aripiprazole-treated patients also showed BMI (median reduction 0.8 kg/m(2)) and waist circumference reduction (median reduction 2.0 cm) vs. placebo (no change in either parameter, p<0.001 and p=0.001, respectively). Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein (LDL) cholesterol. There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigator's Assessment Questionnaire scores favoured aripiprazole over placebo. Safety and tolerability were generally comparable between groups. Combining aripiprazole and clozapine resulted in significant weight, BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine. Improvements may reduce metabolic risk factors associated with clozapine treatment.

Topics: Adolescent; Adult; Aged; Aripiprazole; Body Mass Index; Body Weight; Chemotherapy, Adjuvant; Cholesterol; Clozapine; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Quinolones; Schizophrenia; Treatment Outcome; Young Adult

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Weight; Clozapine; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Italy; Lipids; Male; Middle Aged; Patient Compliance; Piperazines; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Thiazoles; Young Adult

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

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

Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration.. In a double-blind, parallel group protocol, 61 patients (94.4% with schizophrenia) receiving clozapine (196.8+/-132 mg daily, range: 25-500) for more than 3 consecutive months (86.5+/-40.6 months, range: 4-168) were randomly allocated to extended release MET (n=31; 500 to 1000 mg daily) or placebo (n=30) group for 14 weeks. The BW, the body mass index, waist circumference, serum glucose, insulin, lipids, glycated hemoglobin (HBA1c), leptin and cortisol, and the HOMA-IR index were assessed at baseline, and weeks 7 and 14.. MET was well tolerated and the mental state was not impaired during the study. The protocol was completed by all the placebo subjects and by 24 MET-treated patients. In a complete analysis at week 14, without including data of the 7 dropouts, the MET group lost -1.87+/-2.9 kg, whereas the placebo group had a stable BW: 0.16+/-2.9 kg, p=0.01 for the between group comparisons (effect size: 0.70). Leptin levels also tended to decrease after MET (p=0.08). Insulin and the triglyceride-HDL-C ratio significantly decreased (p<0.05, effect size 0.59 and 1.99 respectively) and the HDL-C significantly increased (p=0.001, effect size 0.95) after MET.. MET improves metabolic control during prolonged clozapine administration.

Topics: Adult; Anthropometry; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol, HDL; Clozapine; Double-Blind Method; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Schizophrenia; Statistics, Nonparametric; Waist Circumference

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or= 80, and CGI-S score >or= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Weight; Clozapine; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucose; Humans; Italy; Lipids; Male; Middle Aged; Patient Compliance; Piperazines; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Thiazoles; Young Adult

This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine-associated weight gain.. This was a 12-week double-blind, placebo controlled, randomized trial of sibutramine for weight loss in obese clozapine-treated schizophrenia or schizoaffective disorder subjects.. Ten patients were enrolled into the placebo group and 11 patients into the sibutramine group. There were no significant baseline differences between the two groups on age, gender, education, ethnicity, diagnosis, weight, body mass index (BMI), and blood pressure. At week 12, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, Hba1c, fasting glucose, or cholesterol levels.. Sibutramine treatment did not show significant weight loss compared with placebo in clozapine-treated patients with schizophrenia or schizoaffective disorder. Further research with a larger sample size and longer follow-up duration is warranted.

Topics: Adult; Anthropometry; Antipsychotic Agents; Appetite Depressants; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Clozapine; Cyclobutanes; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Hemoglobins; Humans; Male; Obesity; Psychotic Disorders; Schizophrenia; Weight Gain

Atypical antipsychotics (SGA) have the propensity to induce weight gain.. The aim was to evaluate early changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels.. We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study.. Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University.. Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months.. At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals.. Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Body Weight; Clozapine; Female; Ghrelin; Glucose Tolerance Test; Hormones; Human Growth Hormone; Humans; Insulin; Male; Metabolic Networks and Pathways; Neurosecretory Systems; Peptide Hormones; Risperidone; Schizophrenia; Weight Gain

Investigators have reported that weight gain attributed to clozapine is associated with its clinical response. However, weight gain is a nonspecific physiological variable that, in itself, does not explain the mechanism underlying this relation. Alternatively, other biological variables that are often associated with weight gain, such as serum lipids, may assist in explaining this observation. The primary objective of this study was to determine whether an increase in serum lipids is associated with improvement in schizophrenia symptoms during steady state treatment with clozapine.. The data for this study represent a subset of data from a randomized, double-blinded trial that evaluated subjects with schizophrenia who demonstrated a poor treatment response to clozapine. While continuing their clozapine therapy, subjects were randomly assigned to receive either risperidone 3 mg daily or placebo for 8 weeks. This course of treatment was followed by an optional (open-label) 18 weeks of augmentation with risperidone. In the present study, we included all subjects from the previously reported trial who had fasting lipid analyses and Positive and Negative Syndrome Scale (PANSS) scores from days 7 and 63 (n = 55). For the primary analyses, we used multiple regression to examine the association between serum lipid concentrations and PANSS scores, after controlling for weight.. The analyses showed that the change in serum lipid concentration predicted change in symptoms over that of change in weight. Specifically, an increase in serum triglyceride concentration was associated with a decrease in the total PANSS score (p = 0.037). In addition, an increase in either serum total cholesterol concentration (p = 0.007), serum triglyceride concentration (p = 0.017) or their combined effect (p = 0.010) was associated with a decrease in PANSS negative subscale scores.. Elevation of serum lipids is associated with an improvement in schizophrenia symptoms in subjects treated with clozapine. Although the mechanism is unclear, serum lipids may play a role in influencing clozapine's therapeutic activity.

Topics: Antipsychotic Agents; Body Weight; Clozapine; Data Interpretation, Statistical; Double-Blind Method; Humans; Lipids; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triglycerides

We conducted this 6-week open-label trial to examine the effects of adjunctive aripiprazole in clozapine-treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia.. Ten clozapine-treated subjects received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. Eighty percent were male, the mean age was 38.7 +/- 8.9 years and the mean clozapine dose was 455 +/- 83 mg daily.. There was a significant decrease in weight (P = 0.003), body mass index (P = 0.004), fasting total serum cholesterol (P = 0.002) and total triglycerides (P = 0.04) comparing baseline to study endpoint. There was no significant change in total Positive and Negative Syndrome Scale scores.. This combination may be useful for clozapine-associated medical morbidity and must be studied in placebo-controlled double-blind randomized trials to determine efficacy and safety.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Aripiprazole; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Clozapine; Community Mental Health Centers; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Psychotic Disorders; Quinolones; Schizophrenia; Triglycerides

Metabolic side effects have been found earlier during treatment with second-generation antipsychotics. Among those disturbances serum lipids are less investigated. We conducted a prospective, open study in schizophrenia patients in order to compare body weight and serum lipids during treatment with amisulpride, ziprasidone, clozapine or olanzapine over a period of 4 weeks. Body mass index, total cholesterol and triglycerides increased in patients treated with clozapine and olanzapine whereas high-density lipoprotein cholesterol decreased in those patients. In patients treated with amisulpride or ziprasidone, we found a decrease in body mass index and total cholesterol whereas high-density lipoprotein cholesterol increased. Our results indicate that treatment with ziprasidone and amisulpride is more favourable than treatment with clozapine and olanzapine with respect to the risk to induce weight gain and hyperlipidaemia. These results are important with regard to the increased risk for cardiovascular complications in patients with schizophrenia.

Topics: Adolescent; Adult; Aged; Amisulpride; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Clozapine; Humans; Lipids; Middle Aged; Olanzapine; Piperazines; Prospective Studies; Schizophrenia; Sulpiride; Thiazoles; Time Factors; Triglycerides

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Body Weight; Clozapine; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia

Some, but not all, previous studies have indicated that weight gain is associated with greater improvement in psychopathology during clozapine treatment. Possible reasons for the inconsistent results include failure to adjust for initial body weight and level of psychopathology, differences in trial duration, outcome measures, reliability of assessment, concomitant medications and clozapine dosage. The purpose of this study was to test the hypothesis that clozapine-induced weight gain is related to antipsychotic efficacy at 6 weeks and 6 months after adjusting for initial body weight and severity of illness.. Weight and psychopathology were determined in 74 patients with schizophrenia or schizoaffective disorder at baseline and after 6 weeks and 6 months of open treatment with clozapine monotherapy. The primary measures of psychopathology were the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms subscales, Schedule for Assessment of Negative Symptoms (SANS), Schedule for Assessment of Positive Symptoms (SAPS) and Global Assessment of Function Scale (GAFS).. Significant improvement in the key measures of psychopathology was noted at 6 weeks and 6 months. Mean weight gains at 6 weeks and 6 months were 3.7+/-5.7 S.D. and 7.3+/-7.9 S.D. kg, respectively, with the increase between 6 weeks and 6 months being significant. Age, but not gender, initial body weight, clozapine dosage or plasma levels predicted weight gain at both time points. At 6 weeks and 6 months, after adjustment for age, initial weight and level of psychopathology, the percentage change in weight significantly predicted the improvement in the BPRS Total and Positive symptoms subscale, the SANS Global score, as well as other measures of psychopathology.. Increase in weight with clozapine predicted improvement in psychopathology. This suggests that effects of clozapine on neurotransmitters which influence weight gain, e.g. 5-HT(2C) and 5-HT(1a) antagonism, in association with individual variations in these receptors and others molecules, e.g. peptides and transporters, due to polymorphisms or post-translational editing of mRNAs, may also contribute to the improvement in psychopathology.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Weight; Clozapine; Female; Humans; Male; Prospective Studies; Regression Analysis; Schizophrenia; Schizophrenic Psychology; Sex Factors; Time Factors; Weight Gain

The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest.. The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the "noninferiority" of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total).. Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the "noninferiority" of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p =.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients.. Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinically eligible for treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Clozapine; Double-Blind Method; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Olanzapine; Patient Compliance; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Time Factors

Clozapine treatment is associated with side-effects such as blood cell dyscrasias and weight gain. Increased plasma levels of the cytokines and soluble cytokine receptors leptin, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, as well as toxic metabolites of clozapine, have been suggested as the basis for these side-effects,. This study examined whether the coadministration of the selective serotonine reuptake inhibitor fluvoxamine, which interferes with clozapine's hepatic metabolism, affects the immunomodulation by clozapine and some of its side-effects.. The following parameters were measured: circulating levels of the cytokines and soluble receptors, plasma concentrations of clozapine and its metabolite N-desmethylclozapine, body weight and blood cell counts in 11 and 12 schizophrenic inpatients on combined and monotherapy, respectively, before and during the first 6 weeks of medication.. On the basis of comparable plasma levels of clozapine and N-desmethylclozapine, the coadministration of fluvoxamine 1) attenuated and delayed the clozapine-induced increase in TNF-alpha plasma levels, 2) enhanced and accelerated the clozapine-induced increase in leptin plasma levels without significant effect on clozapine-induced weight gain, and 3) decreased granulocyte counts.. As clozapine, its metabolite N-desmethylclozapine and fluvoxamine are unlikely to make these differences, other metabolites might be responsible. The coadministration of clozapine and fluvoxamine offers the opportunity to investigate further the putative associations between certain metabolites, immunomodulation and these side-effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Cell Count; Body Weight; Clozapine; Cytokines; Drug Interactions; Drug Therapy, Combination; Female; Fluvoxamine; Granulocytes; Humans; Leptin; Male; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors

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

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

Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I.. A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication.. Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 lb (4.5 kg) was significantly greater in patients treated with olanzapine.. These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Bipolar Disorder; Body Weight; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lithium; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Retrospective Studies; Risperidone; Treatment Outcome; Valproic Acid

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

Serum concentrations of clozapine and its main metabolite demethylclozapine were measured in 44 schizophrenic inpatients, of whom ten were non-smokers and 34 smokers. When comparing their clozapine dose and body weight-related serum drug levels, we found that clozapine and demethylclozapine concentrations were about 40% lower in the smoking than in the non-smoking group, probably due to an inducing effect of smoking on the cytochrome P450 (CYP) 1A2, which is involved in the metabolism of clozapine. We conclude that dosage adjustment may be necessary in clozapine-treated smokers.

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Female; Humans; Male; Schizophrenia; Smoking

Patients treated with clozapine have been reported to gain weight. We hypothesized that patients would also experience an increase in body mass, which can be more directly related to cardiovascular morbidity.. Forty-two patients who had been treated with clozapine for at least 1 year were weighed and measured, and waist-hip ratios (WHR) and body mass index (BMI), measured as kg/m2, were calculated. Patients were also asked about a series of factors potentially related to change in body mass.. Female patients gained both weight and body mass. Their WHR after 37 months of clozapine therapy was .83, with a significant increase in BMI from 23.2 to 29.1 kg/m2 (p = .001). Male subjects also gained weight and body mass. Their WHR after 39 months of clozapine therapy was .93, with a significant increase in BMI from 26.4 to 29.7 kg/m2 (p < .001). Stepwise multiple-regression analysis showed that factors related to final body mass were initial body mass, dose of clozapine, and decrease in smoking. Baseline BMI contributed most to the final BMI, but the addition of dose and decrease in smoking made significant contributions to the model.. Both female and male patients treated with clozapine gain body mass. This may place them at greater risk for cardiovascular morbidity.

Topics: Adult; Anthropometry; Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Female; Follow-Up Studies; Humans; Male; Sex Characteristics

With the aim of exploring putative correlations between serum and CSF levels of clozapine and its demethyl metabolite, lumbar puncture was performed on four male and five female schizophrenic patients during long-term treatment with clozapine. Three consecutive 6-ml fractions were collected after at least 8 h of bedrest and fasting. On comparing serum and CSF levels, a correlation was found for norclozapine in the third (13-18 ml) CSF fraction. Norclozapine in the first (0-6 ml) CSF correlated significantly with height. The CSF/serum ratio of clozapine in the first fraction was correlated significantly with body weight. No correlations were found between serum levels of clozapine and norclozapine, or between the serum and CSF levels of clozapine. The study suffers from a small number of patients (for ethical reasons), but the present results might be explicable if the first (0-6 ml) CSF fraction represents a cul-du-sac of the CSF, mirroring the previous day's drug levels. The second fraction, then, will represent the CSF level in the steady state during the night.

Topics: Adult; Antipsychotic Agents; Biotransformation; Body Weight; Clozapine; Dealkylation; Female; Humans; Male; Middle Aged; Pilot Projects; Schizophrenia

The adverse drug reaction profile of 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine -NB 106-689), a possible successor drug of clozapine, is presented based on, first, the results of the open multicentre trial of the AMDP group, and second, on two open multicentre trials initiated by the manufacturers. In general, side-effects of fluperlapine seem to be very similar to those of clozapine, i.e. anticholinergic and sedative effects as well as marked EEG-changes can be observed in most of the patients. However, in contrast to clozapine, so far no evidence for the occurrence of hypersalivation, or increase of body temperature has been obtained, although an increased white blood cell count around day 15 could be seen in quite a number of patients. Hypotensive effects were less than expected from corresponding trials with clozapine.

Topics: Animals; Antipsychotic Agents; Appetite; Blood Pressure; Body Weight; Clinical Trials as Topic; Clozapine; Depression; Electrocardiography; Electroencephalography; Hematopoietic System; Humans; Hypnotics and Sedatives; Lipids; Liver Function Tests; Mental Disorders; Parasympatholytics; Rats; Schizophrenia

Dysregulation of body weight maintenance and opioid dependence are often treated as independent disorders. Here, we assessed the effects of both acute and long-term administration of morphine with and without chemogenetic activation of agouti-related peptide (AGRP)-expressing neurons in the arcuate nucleus (ARC

Topics: Agouti-Related Protein; Analgesics, Opioid; Animals; Body Weight; Clozapine; Eating; Ghrelin; Mice; Morphine Derivatives; Neurons; Opioid-Related Disorders; Receptors, Opioid

Olanzapine and clozapine are atypical antipsychotics (AAPs) with the greatest risk of weight gain, and changes in feeding behavior are among the most important underlying mechanisms. However, few studies have investigated the role of diet-alone interventions in improving individuals' weight gain by taking AAPs. In closed management mental hospitals of China, family members are allowed to bring food to patients regularly, causing patients to have caloric intake added to their 3 daily meals. However, during the global pandemic of coronavirus disease 2019 (COVID-19), bringing food to the hospital was temporarily prohibited in mental health institutions in China to prevent the spread of the virus. This study sought to compare the body weight and body mass index (BMI) changes of patients taking olanzapine or clozapine undergoing diet-alone interventions caused by this prohibition.. A retrospective self-controlled study was conducted on 90 patients with schizophrenia from a single-center treated with olanzapine or clozapine monotherapy, or combined with aripiprazole or ziprasidone which has a small metabolic impact. A paired-samples t-test was used to compare the changes in body weight and BMI before and after the 3-month prohibition, and general linear regression was used to analyze the effects of gender, age, disease course, duration of drug exposure, and equivalent dose on the BMI improvement. Also, the percentage of people who lost weight and that of individuals who lost 5% of their pre-prohibition body weight were calculated.. Paired-samples t-test showed that after 3-month prohibition, the patients' body weight (71.68±6.83 vs. 66.91±7.03, P<0.001) and BMI (26.43±2.11 vs. 24.63±1.81, P<0.001) decreased significantly. Weight loss rate accounted for 99.1%, and weight loss of 5% from the pre-prohibition body weight accounted for 71.8%. General linear regression showed that the duration of drug exposure (β =-0.678, P<0.001) was significantly and negatively correlated with the BMI changes. No significant correlation of gender, age, disease course, or equivalent dose with BMI changes was found.. Diet-alone interventions facilitate weight loss in chronically hospitalized schizophrenia patients taking AAPs. Conduction of dietary intervention in the early stages of medication may yield greater benefits.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; China; Clozapine; COVID-19; Humans; Olanzapine; Pandemics; Retrospective Studies; Risperidone; SARS-CoV-2; Schizophrenia

The low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D

Topics: Animals; Behavior, Animal; Body Weight; Clozapine; Disease Models, Animal; Drug Interactions; Feeding Behavior; Metformin; Receptors, Dopamine D1; RNA, Messenger; Schizophrenia; Time Factors

Parasympathetic nervous system (PNS) innervates with several peripheral organs such as liver, pancreas and regulates energy metabolism. However, the direct role of PNS on food intake has been poorly understood. In the present study, we investigated the role of parasympathetic nervous system in regulation of feeding by chemogenetic methods. Adeno associated virus carrying DREADD (designer receptors exclusively activated by designer drugs) infused into the target brain region by stereotaxic surgery. The stimulatory hM3Dq or inhibitory hM4Di DREADD was over-expressed in selective population of dorsal motor nucleus of the vagus (DMV) neurons by Cre-recombinase-dependent manners. Activation of parasympathetic neuron by intraperitoneal injection of the M3-muscarinic receptor ligand clozapine-N-oxide (CNO) (1 mg/kg) suppressed food intake and resulted in body weight loss in ChAT-Cre mice. Parasympathetic neurons activation resulted in improved glucose tolerance while inhibition of the neurons resulted in impaired glucose tolerance. Stimulation of parasympathetic nervous system by injection of CNO (1 mg/kg) increased oxygen consumption and energy expenditure. Within the hypothalamus, in the arcuate nucleus (ARC) changed AGRP/POMC neurons. These results suggest that direct activation of parasympathetic nervous system decreases food intake and body weight with improved glucose tolerance.

Topics: Animals; Body Weight; Clozapine; Dependovirus; Eating; Energy Metabolism; Feeding Behavior; Hypothalamus; Mice; Mice, Transgenic; Neurons; Parasympathetic Nervous System; Vagus Nerve

Antipsychotic-induced weight gain has been especially related to clozapine and olanzapine. Underlying mechanisms in relation to food preferences with an increased food craving and consumption of specific nutrients have not been extensively studied in patients with serious mental illness (SMI). We aim to describe specific food preferences (craving) and subsequent food consumption in SMI patients starting clozapine, as well as their possible relation to weight and body mass index (BMI).. An observational prospective follow-up study (18 weeks) was conducted in a cohort of 34 SMI patients who started clozapine due to resistant-psychotic symptoms. Anthropometric measures, Food Craving Inventory (FCI), and a food consumption frequency questionnaire were evaluated at baseline, weeks 8 and 18 of treatment. Statistical analysis included generalized estimating equations models with adjustment for potential confounding factors.. No longitudinal changes over time were found across the different food craving scores after 18 weeks of treatment. However, adjusted models according to BMI status showed that the normal weight (NW) group presented an increased score for the "complex carbohydrates/proteins" food cravings (- 0.67; 95% CI [- 1.15, - 0.19]; P = 0.010), while baseline scores for "fast-food fats" cravings were significantly higher in the overweight/obese (OWO) group in comparison with NW patients (NW, 2.05; 95% CI [1.60, 2.49]; OWO, 2.81, 95% CI [2.37, 3.25]; P = 0.016). When considering if food craving could predict weight gain, only increments in "fast-food fats" cravings were associated (β = - 5.35 ± 1.67; 95% CI [- 8.64, - 2.06]; P = 0.001).. No longitudinal differences were found for any of the food craving scores evaluated; however, in the NW group, food craving for "complex carbohydrates/proteins" changed. Thus, changes in "fast-food fats" cravings predicted weight increase in this sample. Interventions targeting food preferences may help to mitigate weight gain in patients starting treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Cohort Studies; Craving; Eating; Female; Follow-Up Studies; Food Preferences; Humans; Longitudinal Studies; Male; Mental Disorders; Middle Aged; Prospective Studies; Treatment Outcome; Weight Gain; Young Adult

Ramadan is a religious month dedicated to prayer, fasting and feasting. Recently, there has been an increased interest among healthcare providers regarding possible health-related complications as a consequence of religious fasting such as that seen during Ramadan. In , a 34-year-old female patient with a diagnosis of schizoaffective disorder, depressive type, was admitted for inpatient hospitalization to an inpatient psychiatric hospital in Buffalo, New York. The earliest date of initial diagnosis is unclear; however, the patient reports an increase in symptoms during her early twenties. Upon admission, the patient was continued on haloperidol, lithium and fluphenazine decanoate which had been initiated prior to this admission. Medication administration and meal times were adjusted to accommodate her observance of Ramadan. Despite efforts to mitigate the potential impact, the patient complained of dizziness and weakness following initiation and titration of clozapine. Due to psychiatric exacerbation, inpatient hospitalization and continuous monitoring, clozapine titration occurred quickly. Upon admission, the patient's blood pressure was 137/85 mmHg, which decreased to a low of 87/58 mmHg as her clozapine dose was increased, leaving the patient requesting bedrest due to significant dizziness and weakness. On the 21st day of Ramadan, the patient broke her fast due to substantial adverse effects. Five days after breaking her fast, the patient's blood pressure increased and returned to baseline. Individuals participating in Ramadan tend to have disrupted sleep cycles, including nocturnal sleep reduction and broken sleep patterns, which can impact overall health. Additional health-related complications that have been reported include dehydration and changes in blood glucose, blood pressure, lipid panel, body weight and exacerbation of psychiatric symptoms. These adverse effects can result in serious complications in fasting individuals with acute medical and psychiatric illness. Clozapine was initiated and rapidly titrated during the patient's observance of Ramadan. She exhibited signs and symptoms of hypotension, which were also subjectively reported by the patient. The significant drop in blood pressure while fasting, and rapid increase once the fast was broken, confirm that medication changes implemented during religious fasting, such as that seen during Ramadan, can increase a patient's risk of serious adverse effects.

Topics: Adult; Affective Disorders, Psychotic; Blood Pressure; Body Weight; Clozapine; Fasting; Female; Humans; Polypharmacy

Overeating is a serious issue in modern society, causing many health problems, including obesity. Although the hypothalamus has been previously identified as the key brain structure that regulates body weight homeostasis, the downstream pathways and non-canonical neural circuitry involved in feeding behavior remain largely uncharacterized. Here, we discover that suppressing the activity of GABAergic cells in the anterior ventrolateral periaqueductal gray (vlPAG), whether directly or through long-projection GABAergic inputs from either the bed nucleus of the stria terminalis (BNST) or the lateral hypothalamus (LH), is sufficient to promptly induce feeding behavior in well-fed mice. In contrast, optogenetic activation of these cells interrupts food intake in starved mice. Long-term chemogenetic manipulation of vlPAG GABAergic cell activity elicits a corresponding change in mouse body weight. Our studies reveal distinct midbrain GABAergic pathways and highlight an important role of GABAergic cells in the anterior vlPAG in feeding behavior.

Topics: Animals; Antipsychotic Agents; Body Weight; Central Amygdaloid Nucleus; Clozapine; Feeding Behavior; GABA-A Receptor Agonists; GABAergic Neurons; Hypothalamic Area, Lateral; Mice; Muscimol; Neural Pathways; Optogenetics; Periaqueductal Gray; Septal Nuclei

Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D

Topics: Animals; Antipsychotic Agents; Body Weight; Chemistry Techniques, Synthetic; Drug Design; Ether-A-Go-Go Potassium Channels; Heterocyclic Compounds; Memory; Mice; Piperazine; Rats; Schizophrenia; Structure-Activity Relationship; Tissue Distribution

Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment.. Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined.. Liraglutide co-treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine-induced glucose intolerance.. Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs.

Topics: Adiposity; Animals; Body Weight; Clozapine; Eating; Glucose Tolerance Test; Hypoglycemic Agents; Liraglutide; Locomotion; Male; Maze Learning; Memory, Short-Term; Olanzapine; Rats; Recognition, Psychology; Weight Gain

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRP

Topics: Adenomatous Polyposis Coli Protein; Animals; Anorexia; Behavior, Animal; Body Weight; Cachexia; Calcitonin Gene-Related Peptide; Carcinoma, Lewis Lung; Clozapine; Energy Metabolism; Female; Illness Behavior; Male; Metalloendopeptidases; Mice; Mice, Transgenic; Neoplasms; Parabrachial Nucleus; Tetanus Toxin; Tumor Cells, Cultured

Metabolic syndrome (obesity, glucose intolerance, insulin resistance and dyslipidaemia) is a well-known adverse effect of most antipsychotics. It is particularly common in patients treated with olanzapine and clozapine. Currently, the mechanisms underlying its development are not completely understood.. We present a case of improved body composition (reduced amount of total body fat and visceral adipose tissue), anthropometric measurements (body weight, waist, abdominal and hip circumferences) and lipid profile in a 31-year-old man with schizophrenia following discontinuation of clozapine. During a combined treatment with clozapine, flupentixol and ziprasidone, a routine laboratory test revealed a severe dyslipidaemia (triglycerides > 1800 mg/dL; > 20.3 mmol/L), despite previous lipid-lowering therapy. This abnormality completely recovered after clozapine has been discontinued.. Clozapine may cause severe, but reversible metabolic abnormalities, including obesity and hypertriglyceridaemia. Atypical antipsychotic-related lipid abnormalities may have a very rapid onset, occur in relatively young patients, with severe lipid derangements and have potential serious complications. This case confirms how important is to monitor metabolic parameters in patients taking antipsychotics. Discontinuation or switching to another antipsychotic medication may improve components of the metabolic syndrome.

Topics: Adult; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Humans; Hypertriglyceridemia; Insulin Resistance; Lipids; Male; Metabolic Syndrome; Schizophrenia; Withholding Treatment

To investigate the developmental effects of clozapine and other atypical antipsychotics on infants who were exposed to as fetus.. The developmental progress of 33 infants who were exposed to clozapine as fetus was compared to 30 infants who were exposed to risperidone, olanzapine or quetiapine as fetus by assessing Apgar scoring, birth weight at birth, body weight, height, and the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at months 2, 6 and 12 of age. Five subscale scores of BSID-III including cognitive, language, motor, social-emotional, and adaptive behavior were also compared. Student's t test and Chi-square analysis were used as appropriate. Repeated measurements were evaluated by analysis of covariance.. Of the 63 infants, 58 (92.1%) completed a 12-month study period. At the age of 2 and 6 months, mean adaptive behavior scores of BSID-III were significantly lower in clozapine-exposed infants than infants who exposed to other atypical antipsychotic at 2 and 6 months of age. More clozapine-exposed infants had delayed development (defined as the subscale score of <85) for adaptive behavior at 2 and 6 months of age. There was no difference between the two groups for cognitive, language, motor, social and emotional at 2, 6 and 12 months of age. More infants who were exposed to clozapine as fetus (25 of 33, 75.8%) had disturbed sleep and a labile state than those who were exposed to other atypical antipsychotics (8 of 30, 26.7%) during 2 months of age (P<0.001).. These results suggest that clozapine has more adaptive behavior effects on infants who were exposed to as a fetus than other atypical antipsychotics at 2 and 6 months of age.. ClinicalTrials.gov NCT01479400.

Topics: Adult; Antipsychotic Agents; Body Height; Body Weight; Child Development; Clozapine; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Maternal Exposure; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Risk Factors

Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.

Topics: Animals; Antipsychotic Agents; Body Weight; Clozapine; Disease Models, Animal; Eating; Glucose Intolerance; Glucose Tolerance Test; Insulin Resistance; Intra-Abdominal Fat; Male; Random Allocation; Rats, Sprague-Dawley; Risperidone; Vitamin D Deficiency

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

Chronic treatment with the atypical antipsychotics clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia and insulin resistance diabetes. The present study mainly aimed to investigate possible mechanisms underlying clozapine-induced hyperglycemia. Male Wistar albino rats were randomly divided into two groups (each consists of 12 rats). The first group received clozapine orally at a dose of 10mg/kg body weight daily for 6 weeks, while the other group received the drug vehicle only and served as the control group. At the end of the six weeks, hyperglycemia, hyperinsulinemia and insulin resistance, as indicated by Homeostatic model assessment of insulin resistance (HOMA-IR), were observed in the clozapine group as compared with the control group. This disturbance in glucose regulation was associated with non-significant changes in body weight, serum cortisol level, and hepatic glycogen content. The Clozapine group showed a significant increase in hepatic phosphorylase activity and in the gene expression level of hepatic glucose-6-phosphatse (G6Pase) enzymes compared to the control group. It can be concluded that clozapine-induced hyperglycemia and insulin resistance occur in a manner mostly independent of weight gain, and may be attributed to an increase in hepatic phosphorylase activity and increased expression level of G6Pase.

Topics: Animals; Antipsychotic Agents; Body Weight; Clozapine; Hyperglycemia; Insulin Resistance; Male; Rats; Rats, Wistar

Mitochondria are the main source of energy for neurons and have a role in many vital neuronal functions. Mitochondrial dysfunction has been described in schizophrenia, and antipsychotics such as clozapine and olanzapine have been associated with differences in gene expression in mitochondria. We investigated the hypothesis that nuclear-encoded mitochondrial genes, particularly those involved in oxidative phosphorylation or involved in oxidative stress, mitochondrial biogenesis, inflammation, and apoptosis, would be associated with antipsychotic-induced weight gain (AIWG). In total, we selected 28 genes and analyzed 60 SNPs (50 are functional), in 283 schizophrenia subjects, treated with atypical medications for up to 14 weeks. Association between AIWG (as measured by the % of weight gain from baseline) and SNP genotypes were tested using linear regression with treatment duration, baseline body weight, and medication type as covariates. We observed a significant association between rs6435326 in the NDUFS1 gene and AIWG in the subset of European patients (N=150, Pcorrected=0.02). The haplotype carrying the risk alleles of rs6435326 and two other SNPs (rs1053517 and rs1801318) in NDUFS1 was also nominally associated with percentage of weight gain (T-C-G vs A-T-A, P=0.005). In addition, stepwise linear regression was performed to select important variables predictive of the outcome, and a gene-gene interaction analysis was carried out. We observed a significant interaction between the TT risk genotype of rs6435326 in NDUFS1 and AG genotype of rs3762883 in COX18 (Pcorrected=0.001). A permutation-based test of all 60 SNPs jointly showed significant association with weight gain (P=0.02). Finally, our replication study of rs6435326, rs1053517 and rs1801318 in NDUFS1 using samples from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that rs1801318 was significantly associated with AIWG (N=200, Pcorrected=0.04), and the three SNPs were collectively associated with AIWG (P=0.04). In conclusion, our findings suggest an association between NDUFS1 and AIWG in schizophrenia subjects. To the best of our knowledge, this is the first study to explore genetic variation in the mitochondrial genes in the context of AIWG.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Female; Genes, Mitochondrial; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Linkage Disequilibrium; Male; Membrane Proteins; Mitochondrial Proteins; Models, Biological; NADH Dehydrogenase; Olanzapine; Polymorphism, Single Nucleotide; Risk; Schizophrenia; Time Factors; Weight Gain

The immunomodulatory effects of clozapine (CLZ), antipsychotic drug, were investigated in vivo using female Balb/c mice. The main aim of this study was to evaluate the immunomodulatory effects of CLZ, antipsychotic drug, following daily intraperitoneal injection to female Balb/c mice over a period of 21 days.. Mice were divided into five groups, eight animals per group. Group I, served as a control group, received only the vehicle. Groups II-V received a daily intraperitoneal dose of CLZ (1, 5, 10 and 20 mg/kg, respectively) over a period of 21 days.. CLZ has shown a significant decrease in the animal body weight, and it showed a significant decrease in the percentage of circulating neutrophils and lymphocytes while circulating monocytes were increased. The immunotoxicity has been also assessed by evaluating spleen cellularity, humoral immune response to a foreign antigen using sheep red blood cells and delayed-type hypersensitivity reaction. The results showed a marked suppression in these responses in CLZ-treated mice compared with the control group. Detectable changes have also been noticed in the histology of the footpad tissue and spleen.. Results showed significant immunomodulatory effects of CLZ when used in Balb/c mice.

Topics: Animals; Antipsychotic Agents; Body Weight; Clozapine; Dose-Response Relationship, Drug; Female; Hypersensitivity, Delayed; Immunity, Humoral; Immunologic Factors; Lymphocytes; Mice; Mice, Inbred BALB C; Neutrophils; Sheep; Spleen

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

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

The present study was undertaken to determine if patients with schizophrenia on clozapine monotherapy have lower serum levels of peptide YY [PYY(1-36)], which is an endogenous inhibitor of food intake, comparing to healthy controls.. Data for 24 patients (mean age 38.8 years) with paranoid schizophrenia on clozapine monotherapy and 24 healthy subjects (gender- and age-matched; mean age 39.9 years) were analyzed.. Fasting serum levels of PYY(1-36) were lower in the clozapine group (178.4±138.4 vs. 277.4±218.1 pg/mL, p=0.034). In the whole study sample PYY(1-36) levels were lower in subjects with body mass index≥25 kg/m(2) (p=0.03) and in subjects with abdominal obesity defined using International Diabetes Foundation criteria (p=0.04). There were no significant differences for metabolic syndrome, smoking, impaired fasting glucose, dyslipidemia, and homeostatic model assessment (HOMA) defined insulin resistance.. RESULTS suggest that weight is asso-ciated with levels of PYY. Patients on clozapine had higher body mass index, but not fat mass index or body weight, therefore lower levels of PYY(1-36) in patients taking clozapine may result from clozapine-induced weight gain and central -obesity.

Topics: Adult; Antipsychotic Agents; Body Composition; Body Mass Index; Body Weight; Clozapine; Electric Impedance; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Peptide YY; Schizophrenia; Smoking

CART (cocaine- and amphetamine-regulated transcript) is an endogenous inhibitor of food intake. We compared fasting serum CART levels in subjects with schizophrenia on clozapine monotherapy (n=24) with sex- and age-matched healthy controls (n=24). CART levels were higher in the clozapine group (262.76±359.91 vs. 90.40±169.90 pg/mL). CART levels were higher in subjects with metabolic syndrome compared to subjects without metabolic syndrome in the clozapine group (415.63±416.93 vs. 122.62±237.17 pg/mL, n=12 and 12, respectively) and in the whole study group (377.73±401.09 vs. 88.58±172.35 pg/mL, n=16 and 32, respectively). In the control group CART levels were higher in subjects with total body fat lower than the target maximum compared to subjects with total body fat below the target maximum (121.71±154.91 vs. 66.32±182.96 pg/mL, n=14 and 10, respectively). CART levels did not correlate with age, weight, BMI, abdominal, waist and hip circumferences, WHR, blood pressure, laboratory tests, clozapine dose, antipsychotic or clozapine treatment duration, body composition, and markers of insulin resistance in the study group. Further studies are required to confirm whether increased levels of circulating CART are compensatory in response to treatment-induced weight gain and abdominal obesity or a primary feature of schizophrenia.

Topics: Adult; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Female; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Nerve Tissue Proteins; Schizophrenia; Weight Gain

Topics: Antipsychotic Agents; Body Weight; Clozapine; Humans; Male; Middle Aged; Schizophrenia; Weight Loss

Alcohol use disorder, characterized by modest levels of alcohol use, commonly occurs in patients with schizophrenia and dramatically worsens their course. Recent data indicate that the atypical antipsychotic clozapine, but not the typical antipsychotic haloperidol, decreases alcohol drinking both in patients with schizophrenia and also in the Syrian golden hamster, an animal model of moderate alcohol drinking. The present study was designed to assess the comparative effects of clozapine and haloperidol in the alcohol-preferring (P) rat, an animal model of alcoholism. First, the study investigated the comparative effects of clozapine and haloperidol on initiation of alcohol consumption in P rats, which models the early stage of alcoholism. Second, the study assessed the comparative effects of clozapine and haloperidol on maintenance of chronic alcohol consumption in P rats to provide a clue as to whether either drug may also limit alcohol consumption in alcohol-dependent patients. Clozapine attenuated the initiation of alcohol drinking and development of alcohol preference while haloperidol did not. However, neither clozapine nor haloperidol attenuated maintenance of chronic alcohol drinking. Taken together, the current data suggest that clozapine, but not haloperidol, may be effective at reducing alcohol abuse or non-dependent drinking and the P rat, used within an alcohol initiation paradigm, and may differentiate the effects of clozapine and haloperidol on alcohol drinking.

Topics: Alcohol Drinking; Alcoholism; Animals; Antipsychotic Agents; Body Weight; Clozapine; Dose-Response Relationship, Drug; Drinking; Eating; Haloperidol; Male; Rats; Rats, Inbred Strains

Clozapine is used in children and adolescents to treat early onset schizophrenia, but data on efficacy and on the plasma clozapine concentrations attained are limited.. We studied data from a clozapine therapeutic drug monitoring (TDM) service, patients in the UK and Eire aged <18 years, 1994-2010. Multiple linear regression analysis was performed to investigate the relationship between plasma clozapine concentration and dose, age, sex, body weight, plasma clozapine:norclozapine ratio (clozapine metabolic ratio (MR)) and smoking habit.. There were 1408 samples from 454 patients, 267 (59%) males aged at time of first sample (median = 17; range = 8-17 years) and 187 (41%) females aged 16 (10-17) years. The plasma clozapine concentration was <0.35 mg L(-1) in 36%, and ≥0.60 mg L(-1) in 31% of samples (6.4% samples ≥1.0 mg L(-1) ). Although plasma clozapine was broadly related to prescribed dose, there was much variation: 10% of samples had plasma clozapine >0.60 mg L(-1) at prescribed clozapine doses of 50-150 mg d(-1) (66% <0.35 mg L(-1) ), while 12% of samples had plasma clozapine <0.35 mg L(-1) at doses ≥650 mg d(-1) (62% >0.6 mg L(-1) ). The covariates studied in the 16-17-year-olds had proportionately similar influences to those observed in adults. Together they explained 48% of the variance observed in plasma clozapine, with dose, smoking habit, MR and sex being major influences. In the younger patients, there were very few smokers, and the influence of sex did not reach statistical significance.. As in adults, clozapine TDM may help in assessing adherence and in dose adjustment, for example if smoking habit changes.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Body Weight; Child; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Schizophrenia; Sex Characteristics; Smoking

An increased risk for metabolic syndrome has been described for patients with psychotic disorders. Antipsychotic drugs possibly contribute to metabolic changes.. Haloperidol or clozapine was orally fed to male and female Sprague Dawley rats for 12 weeks, and body weight gain, food and water intake were measured. The serum levels of fasting glucose, HbA1c, triglycerides, cholesterol, HDL and LDL, insulin, leptin, adiponectin and ghrelin were determined. Gonadal and perirenal fat pads were removed and weighed.. We found increased body weight in the male clozapine group, but decreased ones in the male haloperidol group. Clozapine-treated male and female animals had higher fasting glucose, adiponectin, leptin, ghrelin, cholesterol, HDL and LDL levels, whereas haloperidol caused increased levels of insulin and decreased values of HbA1c, cholesterol, HDL and LDL.. Both antipsychotic drugs cause sex-dependent metabolic changes, which are risk factors for the metabolic syndrome, be it hyperinsulinemia under haloperidol treatment or hyperglycemia, hyperleptinemia and hyperlipidemia under clozapine.

Topics: Adiposity; Animals; Antipsychotic Agents; Blood Glucose; Body Weight; Clozapine; Drinking; Eating; Female; Haloperidol; Hormones; Insulin; Lipids; Male; Metabolic Syndrome; Motor Activity; Rats; Rats, Sprague-Dawley; Sex Characteristics; Weight Gain

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

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

Administration of atypical antipsychotics often induces significant weight gain and metabolic changes. Little is known about subjective weight-related parameters in adolescent patients. Therefore, this cross-sectional, explorative study aimed to assess these parameters and their relationship with biological weight-related parameters.. 74 patients (mean age: 19.9 [SD ± 2.3] years; 66.2% male) with schizophrenia under clozapine or olanzapine treatment were examined. Subjective well-being, eating behavior, body perception and social functioning were assessed, using the Three-Factor-Eating-Questionnaire, FKB-20 Body Perception Questionnaire, Subjective Well-being under Neuroleptics, Short Form and Global Assessment of Functioning. Patients' biological weight-related parameters were measured as well. Gender differences as well as associations between subjective and biological weight-related parameters were evaluated.. Female patients reported significantly worse negative body appraisal and physical functioning than males. An elevated BMI was associated with impaired physical functioning in females and with negative body appraisal and hunger in males.. In our sample of young patients with schizophrenia unter treatment with atypical antipsychotics, an elevated BMI was associated with impaired physical functioning and negative body appraisal, respectively. Bearing in mind the high risk of obesity in this population, the mentioned impairments should be accounted for, especially in terms of compliance and quality of life.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Image; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Feeding Behavior; Female; Ghrelin; Humans; Hunger; Leptin; Male; Obesity; Olanzapine; Physical Fitness; Schizophrenia; Schizophrenic Psychology; Sex Factors; Social Adjustment; Young Adult

Although weight gain is one of the most widely studied adverse effects of second-generation antipsychotics, only relatively few studies have specifically evaluated the long-term effect of switching antipsychotic medication on body weight. We aimed to evaluate the impact of switching antipsychotics on body mass index (BMI) during a 6-month follow-up period in a large cohort of patients with schizophrenia.. Data came from a 6-month prospective naturalistic survey in 6007 patients with schizophrenia.. We prospectively studied the effect on BMI of initiating or switching antipsychotic medication after 6 months of treatment among 3801 patients with schizophrenia in a real-life setting. Patients who were being treated with clozapine or olanzapine at baseline were more likely to experience a decrease in BMI during the follow-up period than the patients who were being treated with a conventional antipsychotic (odds ratio, 2.25 and 1.68, respectively). Patients treated with aripiprazole and, to a lesser extent, those treated with risperidone were more likely to experience a decrease in BMI during follow-up than patients treated with conventional antipsychotics (odds ratio, 2.96 and 2.06, respectively).. Our findings suggest that switching antipsychotics could be an effective strategy for reducing or preventing weight gain.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Cohort Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Piperazines; Prospective Studies; Quinolones; Risperidone; Schizophrenia; Weight Loss

Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Body Weight; Clozapine; Disease Susceptibility; Eating; Female; Gene Expression Regulation; Hormones; Hypothalamus; Male; Malnutrition; Nervous System; Obesity; Piperazines; Pregnancy; Prenatal Nutritional Physiological Phenomena; Quinolones; Rats; Rats, Wistar; Schizophrenia

Melperone is an atypical antipsychotic drug that has been reported to be effective in treatment-resistant schizophrenia and L-DOPA psychosis. There are limited data concerning its effect on weight or body mass index (BMI). Weight and BMI were retrospectively compared in patients with schizophrenia treated with melperone (n=34), clozapine (n=225), or typical neuroleptics (n=74) for up to 3 months. Clozapine resulted in significant increases in weight and BMI from baseline to 6 weeks and 3 months. Neither melperone nor typical neuroleptics resulted in significant weight gain at either time point. Melperone did not result in significant increases in BMI. Weight and BMI were significantly lower with melperone compared with clozapine, but similar to typical neuroleptics. The proportion of melperone patients who experienced a >or=7% weight increase was lower than that in patients treated with clozapine and similar to that in patients treated with typical neuroleptics. Percent change in weight and BMI predicted improvement in BPRS total scores at 3 months in the clozapine group, but not in the melperone or typical neuroleptic groups. Because of the relationship between BMI and cardiovascular risk, melperone deserves further study as both a first line treatment and as an alternative to clozapine in refractory schizophrenia.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Mass Index; Body Weight; Butyrophenones; Clozapine; Female; Humans; Male; Schizophrenia; Time Factors

Abnormal lipid profiles have been reported in the central nervous system (CNS) in individuals with schizophrenia, although the etiology of these changes remains to be elucidated. While treatment with second-generation antipsychotics has been associated with alterations in peripheral lipid levels and changes in erythrocyte membrane composition, the relationship between peripheral and CNS lipid levels is complex and the effect of antipsychotics on CNS lipid regulation is not yet understood. In this study we investigated whether sub-chronic administration of the second-generation antipsychotic clozapine and the first-generation antipsychotic haloperidol alters brain membrane lipid composition in male Sprague-Dawley rats. The relationship between brain membrane lipid composition and plasma cholesterol concentrations was also assessed. Our results indicate that brain lipid composition and plasma cholesterol concentrations are not altered following administration of antipsychotics. No correlation was observed between plasma and brain membrane cholesterol levels. Our findings suggest that observed alterations in brain lipid profiles in individuals with schizophrenia are not a consequence of treatment with antipsychotic medications.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Body Weight; Brain Chemistry; Cholesterol; Clozapine; Haloperidol; Male; Phospholipids; Rats; Rats, Sprague-Dawley

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain (BWG), which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the dopamine receptor D2 (DRD2) gene may be associated with body weight change after AAP treatment.. The study included 479 schizophrenic patients treated with clozapine (n=239), olanzapine (n=70) or risperidone (n=170) for an average of 48.2+/-27.8 months. BWG was defined as an increase of more than 7% of the baseline body weight during AAP treatment. Thirteen common single nucleotide polymorphisms of the DRD2 gene were chosen as tagging single nucleotide polymorphisms.. In single-marker-based analysis, the DRD2 rs4436578-C homozygous genotype was found to be associated with a significantly increased risk of BWG [P=0.001, adjusted odds ratio=3.36 (95% confidence interval=1.62 - 7.00)]. In addition, haplotype analysis further showed that the rs4436578-C-allele-related haplotype was more frequent in those patients with BWG than those without (P=0.01 - 0.00019).. Our findings confirm the importance of genetic factors in body weight change induced by long-term AAP treatment in patients with schizophrenia and indicate a role of DRD2 in body weight regulation during long-term AAP treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Female; Genes; Genotype; Haplotypes; Humans; Long-Term Care; Male; Middle Aged; Odds Ratio; Olanzapine; Receptors, Dopamine D2; Risperidone; Schizophrenia; Weight Gain

The prevalence of smoking is high in persons with serious mental illness (SMI) despite associated health risks. Persons with SMI die on average 25 years earlier than the general population and an increased focus on wellness, including smoking cessation, has been a goal of federal, state, and municipal governments.. The primary objective of this study was to evaluate the effects of smoking cessation on symptom severity in psychiatric inpatients at a New York State psychiatric facility 1 year after a smoke-free policy had been implemented. The secondary objective of this study was to evaluate cardiometabolic risk factors.. A retrospective chart review of 26 adult psychiatric inpatients receiving either clozapine, olanzapine, or both at any time between January 2006 and December 2007 was conducted. In addition to Brief Psychiatric Rating Scale (BPRS) scores and cardiometabolic measures (body weight, body mass index [BMI], and blood pressures before and after implementation of the smoke-free policy), other information collected included age, gender, diagnosis, the frequency of psychiatric medications used on an as-needed (p.r.n.) basis, immediate-need (stat) medication use, medication dosing, number of psychiatric emergencies, Global Assessment of Functioning (GAF) scores, privilege status, and time in special observation. Patients were compared on their own pre- and post-smoking cessation parameters and data were analyzed using a dependent t-test with p < 0.01 chosen as indicating significance.. Data analysis revealed a small but statistically significant decrease in GAF scores (p < 0.01), but no other significant difference between values pre- and post-smoking cessation.. Analysis demonstrated no change in psychiatric symptomatology or cardiometabolic factors 1 year post-smoking cessation in individuals with schizophrenia taking clozapine, olanzapine, or both. Further investigation is needed before concluding that smoking cessation has no impact on symptoms or on cardiometabolic risk factors. Despite a slight but statistically significant worsening in GAF scores, the health benefits of smoking cessation should continue to form the basis of encouraging smoking cessation in persons with SMI while longer term and methodologically more rigorous assessments on psychiatric and general health status are undertaken.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Brief Psychiatric Rating Scale; Clozapine; Comorbidity; Cross-Sectional Studies; Female; Hospitalization; Humans; Male; Middle Aged; Olanzapine; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Smoking; Smoking Cessation

Numerous reports have linked atypical antipsychotics, especially clozapine and olanzapine, to the development of cardiovascular risk factors. In this retrospective chart review study, we investigated the blood pressure changes in Korean schizophrenic inpatients treated with clozapine or olanzapine.. We reviewed the medical record of schizophrenic patients treated with clozapine or olanzapine for 8 weeks. A total of 167 patients were included in the study; 70 patients in clozapine group and 97 patients in olanzapine group. Systolic and diastolic blood pressures prior to medication and at post-treatment (8-week) were assessed, and changes in blood pressure were analyzed. The prevalence of hypertension at the time of study period was assessed and compared between the two groups.. There was a significant difference in hypertension prevalence in comparisons between the clozapine and olanzapine group. The systolic and diastolic blood pressures in the clozapine group were significantly increased after treatment, but systolic and diastolic blood pressures in olanzapine group did not change significantly.. Our findings suggest that clozapine treatment may be associated with increased blood pressure and higher prevalence of hypertension, which may have a significant impact on medical morbidity and mortality.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Cardiovascular Diseases; Clozapine; Cross-Sectional Studies; Female; Humans; Hypertension; Male; Middle Aged; Olanzapine; Republic of Korea; Retrospective Studies; Risk Factors; Schizophrenia

Metabolic syndrome is currently the research topic of several studies. Although physical manifestations of metabolic syndrome have been described, the psychological and psychiatric impact of metabolic syndrome has not been studied to date. We report the first case of antipsychotic-induced metabolic syndrome which was associated with development of delusions of pregnancy in a post-menopausal woman.

Topics: Antipsychotic Agents; Body Weight; Cholesterol, HDL; Clozapine; Delusions; Diagnosis, Differential; Female; Humans; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Pseudopregnancy; Schizophrenia, Paranoid; Triglycerides; Waist Circumference

To explore the impact of premorbid and baseline body mass indices (BMIs) as well as BMI of patient's parents and associated variables on the prediction of antipsychotic-induced body weight gain.. Retrospective/cross-sectional data of 65 patients receiving clozapine, olanzapine and/or risperidone were assessed according to a systematic categorization of the long-term (7.3+/-9.2 years) weight course and evaluated using descriptive, explorative correlation and regression analyses.. Increased values of parents' BMI (p=0.041) and patients' BMI at premorbid stage (p=0.039) and prior to first antipsychotic treatment (p=0.032) as well as female gender (p=0.012), younger age (p=0.005) and non-smoking (p=0.047) have the most predictive value on body weight gain under antipsychotic treatment including pre-treatment with typical antipsychotics. Weight gain under atypical antipsychotics (pre-treatment excluded) is predicted by an increased premorbid BMI (p=0.019). Conversely, a low BMI prior to first antipsychotic treatment predicts a higher acceleration of BMI change (p=0.008) in vulnerable individuals, but not total BMI change itself. Furthermore, a diagnosis of a schizophrenia spectrum disorder showed a trend towards the prediction of an increased atypical DeltaBMI (p=0.067), possibly due to a longer treatment duration with atypical antipsychotics (p<0.001).. The study indicates increased parents' BMI and patients' premorbid BMI, female gender, younger age and - as a trend - the diagnosis of a schizophrenia spectrum disorder to be predictors for antipsychotic-induced body weight gain involving atypical antipsychotics. Data contribute to the assumption of a strong impact of predispositional factors on weight gain, besides treatment-related factors.

Topics: Adolescent; Adult; Age Factors; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Olanzapine; Parents; Retrospective Studies; Risk Factors; Risperidone; Sex Factors; Smoking; Time Factors; Weight Gain; Young Adult

Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se.. Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored.. Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism.. Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Dibenzothiazepines; Dietary Fats; Disease Models, Animal; Eating; Exenatide; Food Preferences; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Obesity; Peptides; Pyrazines; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Triazoles; Venoms

Atypical antipsychotics (AA) are generally associated with weight gain. We determined body mass index (BMI) change in Parkinson's disease (PD) before and after taking AA and compared against PD controls and Alzheimer's disease (AD) patients on AA. In 66 consecutive PD subjects started on AA who had accurate weights for more than 6 months before and after initiation of AA, we compared weight change before and after AA use, against a control group of sixty-one sex-matched PD subjects, and against twenty-eight AD subjects taking AA. A linear regression model was created to compare weight changes. Fifty-nine PD subjects had complete data, quetiapine (n=53) and clozapine (n=6). The mean BMI change in the period before starting AA was 0.00 kg/m(2)/month over 1.95+/-1.41 years. After starting AA, subjects lost 0.03 kg/m(2)/month (95% CI 0.62-1.21, P<0.0001), comparing PD before AA to the same PD patients after AA. In 61 PD controls, the mean BMI loss was 0.01 kg/m(2)/month (95% CI 0.15-0.94, P=0.007) comparing PD on AA vs. PD controls. The BMI for 28 AD subjects on AA increased 0.01 kg/m(2)/month (95% CI 0.26-0.83, P<0.0001), comparing PD on AA vs. AD on AA. The weight loss seen in the PD/AA group, compared to AD, suggest uniquely altered weight homeostasis in PD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Body Mass Index; Body Weight; Case-Control Studies; Clozapine; Confidence Intervals; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Odds Ratio; Parkinson Disease; Quetiapine Fumarate

We aimed to determine the effectiveness of a hand-held record (the 'Blue Card') for seriously mentally ill consumers by investigating effects on consumer knowledge of physical health risk factors, consumer involvement in care and communication with healthcare professionals.. Consumers were given and educated in the use of the Blue Card, which contained information regarding their physical health. Consumers completed a pre- and post-knowledge questionnaire and commented on the effectiveness of the Blue Card with respect to their knowledge of physical health risks.. Statistically significant improvements in consumer knowledge were shown at the 3-month follow-up, with high retention of the Blue Card being demonstrated. Consumers that used the card described their use of the card positively.. The results are very encouraging. Further studies of this low-cost intervention are warranted to establish its effectiveness and utility.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Clozapine; Comorbidity; Female; Follow-Up Studies; Health Knowledge, Attitudes, Practice; Health Status; Humans; Male; Medical Records; Middle Aged; New South Wales; Patient Acceptance of Health Care; Patient Satisfaction; Program Evaluation; Risk Assessment; Schizophrenia

Rats exposed during prenatal life to methylazoxymethanol (MAM) display in postnatal age structural and behavioral deficits resembling those observed in schizophrenic patients. These deficits are associated with significant changes in brain nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), particularly in the hippocampus and entorhinal cortex. In the present study, we used the MAM model to investigate in young rats the effect of antipsychotics, Clozapine and Haloperidol, on brain and blood NGF and BDNF presence. Young animals were used because administration of antipsychotics during adolescence is a common feature of intervention. The results showed that administration of Clozapine and Haloperidol causes significant changes in the concentration of NGF and BDNF in the brain and bloodstream of MAM-treated rats. These findings indicate that these drugs may affect the synthesis and release of neurotrophins in the central nervous system and in the blood circulation. In addition, the MAM model can be a useful tool to investigate the biochemical and molecular mechanisms regarding the effects of antipsychotics.

Topics: Alkylating Agents; Animals; Antipsychotic Agents; Body Weight; Brain Chemistry; Clozapine; Entorhinal Cortex; Female; Granulocytes; Haloperidol; Hippocampus; Methylazoxymethanol Acetate; Nerve Growth Factors; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley

Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine.. This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229).. None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration.. Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Mental Disorders; Middle Aged; Olanzapine; Outliers, DRG; Receptors, Leptin; Schizophrenia; Sex Factors; Weight Gain

Lipid accretion is one of the major side effects of clozapine pharmacotherapy of schizophrenia that made clozapine into an interesting obesity drug model.. Ingenuity Pathway Analysis (IPA) engine was used for core analysis and building the networks of weight regulation.. The examination of molecules that were selected into 'clozapine neighborhood' identified them as multifunctional signals that appear to orchestrate vascular and tissue functions plausibly implicated in adiposity side effect.. It is hypothesized that clozapine unmasks the functional and morphological phenotype of microvascular deficit that facilitates shunting nutrients from utilization toward storage.

Topics: Adipose Tissue; Antipsychotic Agents; Body Weight; Clozapine; Humans; Microcirculation; Models, Biological; Neurotransmitter Agents; Obesity; Schizophrenia

The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various ant

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Dose-Response Relationship, Drug; Eating; Female; Hyperinsulinism; Hyperphagia; Models, Animal; Olanzapine; Rats; Rats, Wistar; Research Design; Sex Factors; Weight Gain; Weight Loss

Topics: Antipsychotic Agents; Body Weight; Clinical Trials as Topic; Clozapine; Cognition; Health Policy; Humans; Perphenazine; Schizophrenia

The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Haloperidol; Humans; Olanzapine; Protein Binding; Radioligand Assay; Receptors, Cell Surface

Around 40-70% patients with treatment-resistant schizophrenia fail to respond to clozapine. Though combining antipsychotics is commonly practised with non-responders, there is little evidence for its use.We carried out a retrospective review of case notes of patients with treatment-resistant schizophrenia on clozapine-aripiprazole combination at our clozapine clinic. We report changes in psychotic symptoms, social function, weight, total cholesterol, serum glucose, HDL, CGI and GAF score pre- and post-aripiprazole augmentation. Clozapine-aripiprazole combination was associated with 22% reduction of clozapine dose. Eighteen out of 24 (75%) lost a mean weight of 5.05 kg. There was improvement in positive and negative symptoms, social functions, weight loss and a moderate increase in HDL. Our findings suggest that clozapine-aripiprazole is a safe and tolerable combination; however, control trials are needed to validate our findings.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Blood Glucose; Body Weight; Cholesterol; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Male; Piperazines; Quinolones; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Clozapine; Female; Humans; Male; Mental Disorders; Olanzapine; Risperidone; Weight Gain

To our knowledge, a suitable animal model to investigate how atypical antipsychotics may induce diabetes in patients has not received much attention.. We investigated the effects of acute as well as subchronic administration of clozapine on food intake, body weight gain, glucose tolerance and insulin secretion in response to glucose in Sprague-Dawley rats. We then evaluated the effects of clozapine on corticosterone secretion and 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) and phosphoenolpyruvate carboxykinase (PEPCK) expression in the liver. We investigated the in vitro effects of clozapine on glucose uptake and development of differentiated myotubes in skeletal muscle cell (C2C12) cultures.. Clozapine administration caused hyperglycemia (p < 0.05) in female rats. In male rats, the increase of plasma glucose levels after clozapine injection was not statistically significant. The increase of plasma insulin concentrations and the intraperitoneal glucose tolerance test results proved that clozapine reduced insulin sensitivity in female rats. These endocrine and metabolic effects of clozapine were not related to changes in feeding behavior of fat accumulation. We observed a stimulatory effect of clozapine on corticosterone (p < 0.01) secretion in both female and male rats. Chronic clozapine administration upregulated PEPCK and 11beta-HSD-1 expression in rat liver. Clozapine did not inhibit basal and insulin-induced glucose transport in murine myotubes but it was able to antagonize the stimulatory effect of alpha-methyl-5-hydroxytryptamine on glucose uptake.. Clozapine induces sex-related alterations of glucose homeostasis and insulin sensitivity in rodents. We discussed the possible contribution of clozapine-induced activation of HPA and clozapine antagonistic activity at peripheral 5-HT(2A) receptors to the observed metabolic alterations.

Topics: Animals; Antipsychotic Agents; Blood Glucose; Body Weight; Clozapine; Corticosterone; Eating; Female; Glucose; Glucose Tolerance Test; Haloperidol; Homeostasis; Hypothalamo-Hypophyseal System; Male; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Time Factors

An important goal of current neuroleptic research is to develop antipsychotic compounds with the low incidence of extrapyramidal side effects. The therapeutic success and less side-effect of atypical anti-psychotics such as clozapine and risperidone has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptics-associated extrapyramidal side effects. The present study compares the effect of chronic administration of typical and atypical antipsychotics on neurochemical profile in rat forebrain. The study was planned to study changes in extracellular levels of norepinephrine, dopamine and serotonin in forebrain region of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements (VCM's), tongue protrusions and facial jerking) in rats, hall mark of chronic extrapyramidal side-effect of neuroleptic therapy tardive dyskinesia. Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in significant increase in orofacial hyperkinetic movements where as clozapine and risperidone showed less significant increase in orofacial hyperkinetic movements as compared to control. There were also significant decrease in the extracellular levels of neurotransmitters dopamine, norepinephrine and serotonin in fore-brain as measured by HPLC/ED after chronic administration of haloperidol and chlorpromazine. Chronic administration of atypical neuroleptics clozapine and risperidone resulted in the decrease in extracellular concentration of dopamine and norepinephrine but the effect was less significant as compared to typical drugs. However, treatment with atypical neuroleptics resulted in 3 fold increase in serotonin levels as compared to forebrain of control rats. Typical and atypical neuroleptics showed varying effects on neurotransmitters, especially serotonin which may account for the difference in their profile of side effects (Tardive dyskinesia).

Topics: Animals; Antipsychotic Agents; Body Weight; Chlorpromazine; Clozapine; Dopamine; Dyskinesia, Drug-Induced; Haloperidol; Male; Norepinephrine; Prosencephalon; Rats; Rats, Wistar; Risperidone; Serotonin

Treating primary 'negative symptoms' of schizophrenia with a combination of a typical antipsychotic and a selective serotonin reuptake inhibitor, is more effective than with antipsychotic alone and is similar to the effect of the atypical antipsychotic, clozapine. The mechanism of this treatment combination is unknown and may involve changes in dopaminergic and serotonin systems. We studied dopamine and serotonin metabolism in different rat brain areas at 1.5 and 24 h after the last dosage of chronic treatment (30 days), with haloperidol plus fluvoxamine, each drug alone, and clozapine. Haloperidol-fluvoxamine combination, haloperidol, and clozapine treatments increased striatal and frontal cortex dopamine turnover and reduced striatal tyrosine hydroxylase activity at 1.5 h. At 24 h both dopamine turnover and tyrosine hydroxylase activity were reduced. Thus, in chronically treated animals, release of striatal dopamine increases following a drug pulse and returns to baseline by 24 h. Serotonin and 5-hydroxyindoleacetic acid concentrations were decreased at 1.5 h in haloperidol-fluvoxamine and clozapine groups and returned to normal levels by 24 h. A limited behavioral assessment showed that treatment with haloperidol plus fluvoxamine reduced motor activity compared to haloperidol, and increased sniffing compared to haloperidol, fluvoxamine and clozapine. These findings indicate that combining antipsychotic with SSRI results in specific changes in dopaminergic and serotonergic systems and in behavior. The possibility that these may be relevant to the mechanism underlying the clinical effectiveness of augmentation treatment warrant further study.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Body Weight; Brain; Clozapine; Dopamine; Dopamine Antagonists; Drug Interactions; Fluvoxamine; Haloperidol; Immunohistochemistry; Male; Motor Activity; Neostriatum; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Tyrosine 3-Monooxygenase

To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.. Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.. Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.. A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Clozapine; Disease Models, Animal; Energy Intake; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Dopamine; Sex Factors

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

We evaluated the behavioral effects of chronic haloperidol (HAL) and clozapine (CLO) during gestation and CNS development, compared with transient treatments that stopped 1-3 weeks before the test.. 1) Chronic HAL (6 mg/l in drinking water) but not HAL-withdrawal caused hypo-activity in open-field test on postnatal days (PNDs) 35, 42 and 56. However, hyper-activity was found in both CLO (90 mg/l) and CLO-withdrawal pups. 2) In the step-through test, retention performance was significantly higher in HAL-treated mice than in the controls on PND 42, as well as in withdrawal mice on PNDs 35 and 42. However, both chronic CLO (90 mg/l) exposure and CLO-withdrawal tended to improve the acquisition of memory. Furthermore, chronic CLO (180 mg/l) ameliorated scopolamine (3 mg/kg)-induced impairment of memory on PND 56. 3) In the water-maze test, both chronic HAL and HAL-withdrawal treatments significantly impaired performance on the 4th training day at PND 35, but not PNDs 42 and 56. Neither chronic CLO exposure nor CLO-withdrawal affected spatial memory. 4) Body weight following HAL/CLO administration decreased when compared with the controls during PND 21-35, but approached control levels at PND 40.. HAL doesn't elicit permanent behavioral changes in offspring. By contrast, CLO had longer-lasting effects than HAL. The pups at age before PND 35 seem more sensitive to HAL/CLO than elder pups.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Body Weight; Central Nervous System; Clozapine; Female; Haloperidol; Male; Maternal Exposure; Maze Learning; Memory; Mice

While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes.. To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test.. A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis.. Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis.. Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness.. The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapineolanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Olanzapine; Risperidone; Schizophrenia

Atypical antipsychotics, like clozapine, have fewer extrapyramidal side effects compared with typical antipsychotics, however, such treatment is associated with several adverse metabolic effects such as weight gain, hyperglycemia and hyperlipidemia in patients with schizophrenia. In this study, we investigated the effects of 30-day clozapine treatment on weight change, and serum fasting glucose, cholesterol and triglyceride levels in male BALB/c mice. The results demonstrate that 10.0 mg/kg clozapine group gained significantly less weight but had higher cholesterol compared with controls and the 2.0 mg/kg clozapine group. Our findings indicate the possibility of using mice to study the mechanisms of body weight change and lipid dysregulations induced by clozapine.

Topics: Animals; Antipsychotic Agents; Blood Glucose; Body Weight; Cholesterol; Clozapine; Injections, Intraperitoneal; Lipids; Male; Mice; Mice, Inbred BALB C; Triglycerides

This retrospective study compared the prevalence of diabetes mellitus/hyperglycemia between patients receiving treatment with clozapine (n = 24) and patients receiving treatment with depot (n = 27) neuroleptics in a Department of Veterans Affairs outpatient mental health clinic in the Mid-Atlantic region. Of the clozapine cases without a history of diabetes/hyperglycemia, 27.7% developed diabetes after initiation of clozapine. There were no new cases of diabetes/hyperglycemia in the depot group after initiation of depot neuroleptic. All patients receiving neuroleptic treatment should be monitored for changes in weight, lipid, and glucose levels so that appropriate preventive and therapeutic measures can be promptly initiated.

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Delayed-Action Preparations; Diabetes Mellitus; Drug Monitoring; Female; Health Services Needs and Demand; Humans; Hyperglycemia; Male; Mass Screening; Mid-Atlantic Region; Middle Aged; Nurse's Role; Prevalence; Retrospective Studies; Risk Factors; Schizophrenia; United States; United States Department of Veterans Affairs; Veterans

Resting energy expenditure (REE) is lower than predicted in persons taking atypical antipsychotic medication, and weight management is a significant clinical challenge for some of them. However, to date there have been no published guidelines to assist clinicians in choosing appropriate prediction equations to estimate energy expenditure in persons taking atypical antipsychotic medications. The objectives of this study were to measure REE in a group of men taking the atypical antipsychotic clozapine and to determine whether REE can be accurately predicted for this population using previously published regression equations. REE was measured using indirect calorimetry via a ventilated hood on eight men who had completed at least 6 months of treatment with clozapine. Comparisons between measured REE and predicted REE using five different equations were undertaken. The commonly-used Harris-Benedict and Schofield equations systematically overestimated REE. Predictions of REE from other equations were too variable for clinical use. When estimating energy requirements as part of a weight-management program in men who have been taking clozapine for 6 months, predictions of REE from the equations of Harris-Benedict and Schofield should be reduced by 280 kcal/day.

Topics: Adult; Antipsychotic Agents; Basal Metabolism; Body Weight; Calorimetry, Indirect; Clozapine; Humans; Male; Mathematics; Predictive Value of Tests; Regression Analysis; Schizophrenia, Paranoid; Weight Gain

Prepulse inhibition (PPI) of the acoustic startle reflex is a commonly used measure of preattentive sensorimotor gating. Disrupted PPI in rodents represents an animal model of the sensorimotor gating deficits characteristic of schizophrenia. The neurotensin (NT) system is implicated in the pathophysiology of schizophrenia, and NT has been hypothesized to act as an endogenous antipsychotic. In rats, NT receptor agonists restore PPI disrupted by dopamine receptor agonists and N-methyl-D-aspartate receptor antagonists, and pretreatment with an NT receptor antagonist blocks restoration of isolation rearing induced deficits in PPI by some antipsychotic drugs. The current studies further scrutinized the role of the NT system in the regulation of PPI and in antipsychotic drug-induced restoration of PPI using NT-null mutant mice (NT-/-). NT-/- mice exhibited significantly higher pulse alone startle amplitudes and disrupted PPI compared with NT+/+ mice. Haloperidol (0.1 mg/kg) and quetiapine (0.5 mg/kg) administered 30 min before PPI testing significantly increased PPI in NT+/+ mice but had no effect on PPI in NT-/- mice. In contrast, clozapine (1.0 mg/kg) significantly increased PPI in both NT-/- and NT+/+ mice, whereas olanzapine (0.5 mg/kg) had no effect on PPI in either NT-/- or NT+/+ mice. In a separate experiment, amphetamine (2.0 mg/kg i.p.) significantly disrupted PPI in NT+/+ mice but not NT-/- mice. These results provide evidence that the effects of antipsychotic drugs (APDs) may be differentially affected by the state of NT neurotransmission and, moreover, that APDs differ in their dependence on an intact NT system.

Topics: Amphetamine; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Dibenzothiazepines; Female; Haloperidol; Male; Mice; Mice, Inbred C57BL; Neurotensin; Olanzapine; Quetiapine Fumarate; Reflex; Reflex, Startle

Schizophrenia is a chronic and debilitating disease which is thought to arise from a neuro-developmental disorder. Both the stable tubule-only polypeptide (STOP) protein and the N-methyl-D-aspartate (NMDA) NR1 subunit are involved in neuronal development and physiology. It has therefore been postulated that transgenic mice lacking either the STOP or the NMDAR1 gene would show a 'schizophrenic-like' phenotype. Here, STOP knockout and NMDA NR1 hypomorphic mice were assessed in a behavioural measure that can be used to detect schizophrenic-like phenotypes: a change in sensorimotor gating, measured through prepulse inhibition (PPI). STOP knockout mice were further assessed in another measure of 'schizophrenic-like behaviour': hyperlocomotion. The PPI deficit exhibited by both the STOP knockout and NMDA knockdown mice could not be reversed by acute treatment with the atyptical antipsychotic, clozapine (1 mg/kg, i.p.) but the hyperlocomotion shown by the STOP knockout mice was reversed with the same acute dose of clozapine.

Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Body Temperature; Body Weight; Clozapine; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Enzyme Inhibitors; Gait Disorders, Neurologic; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Motor Activity; Neural Inhibition; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Reflex, Acoustic; Rotarod Performance Test; Somatosensory Cortex; Swimming; Time Factors

A novel method of oral drug administration was used in a neuroleptic animal study. Seventy male Sprague-Dawley rats were randomly subdivided into four groups, which were treated with clozapine, haloperidol, diazepam or a vehicle solution (5% sucrose solution). Oral drug treatment was achieved by training the rats to drink the drug of choice mixed with five percent sucrose or vehicle solution from a syringe. Within 3-4 weeks the haloperidol group developed vacuous chewing movement, which did not disappear with discontinuation of the drug. Significant weight gain was observed for all drug groups in relation to the control group, whereas only the diazepam group showed a significant increase in response latency on the disengage test of sensorimotor function, which disappeared with drug withdrawal. A novel means of testing the motivational status showed that all drug-treated groups engaged in eating chocolate before grooming (t=11.69, p<0.001), whereas the control group showed no specific tendency towards either task. Furthermore, there was a significant delay in grooming for the haloperidol group compared to the other drug groups and controls. In conclusion, a novel method of oral drug administration with minimum stress was introduced that was sufficient to cause the described changes in behavioural parameters. Additionally, the combination of tests used provided an efficient discrimination between the behavioural effects of clozapine, haloperidol and diazepam in rodents.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Behavior, Animal; Body Weight; Brain; Clozapine; Diazepam; Disease Models, Animal; Dyskinesia, Drug-Induced; Grooming; Haloperidol; Male; Mastication; Motivation; Motor Activity; Rats; Rats, Sprague-Dawley; Reaction Time

Patients treated with atypical antipsychotic drugs commonly gain excess weight. Because obesity is associated with considerable morbidity and decreased life expectancy, treatment of weight gain in these patients is critical. Topiramate, a fairly new anticonvulsant, promotes bodyweight loss in healthy obese subjects, patients with bipolar disorder, and patients with eating disorder. However, there are very few reports about the efficacy of topiramate for weight management in schizophrenic patients. We present the cases of three Taiwanese patients with schizophrenia whose bodyweight increased as a result of atypical antipsychotics treatment, then was controlled by topiramate without aggravation of their psychotic symptoms.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Child, Preschool; Clozapine; Dibenzothiazepines; Female; Fructose; Humans; Male; Olanzapine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Taiwan; Topiramate; Weight Gain

The measurement of plasma clozapine concentrations is useful in assessing compliance, optimizing therapy, and minimizing toxicity. We measured plasma clozapine and norclozapine (N-desmethylclozapine) concentrations in samples from 3782 patients (2648 male, 1127 female). No clozapine was detected in 291 samples (227 patients, median prescribed dose 300 mg/d). In 4963 (50.2 %) samples (2222 patients); plasma clozapine concentration ranged from 10 to 350 ng/mL.Step-wise backward multiple regression analysis (37 % of the total samples) of log10 plasma clozapine concentration against log10 clozapine dose (mg/d), age (year), sex (male = 0, female = 1), cigarette smoking habit (nonsmokers = 0; smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (clozapine metabolic ratio, MR) showed that these covariates explained 48% of the observed variation in plasma clozapine concentration (C = ng/mL x 10-3) (P < 0.001) according to the following equation: log 10 (C) = 0.811 log 10 (dose) + 0.332 (MR) + 69.42 X 10 (-3) (sex) + 2.263 x 10 (-3) (age) + 1.976 x 10(-3) (weight) - 0.171 (smoking habit) - 3.180. This model and its associated confidence intervals were used to develop nomograms of plasma clozapine concentration versus dose for male and female smokers and nonsmokers. Predicted plasma clozapine changes by +48% in nonsmokers, +17% in females, +/-8 % for every 0.1 change in MR (reference 1.32), +/-4% for every 5 years (reference 40 years), and +/-5 % for every 10 kg body weight (reference 80 kg). The nomograms can be used (i) to individualize dosage to achieve a given target plasma clozapine concentration, and (ii) for quantitative evaluation of adherence by estimating the likelihood of an observed concentration being achieved by a given dosage regimen. The model has been validated against published data.

Topics: Adult; Aging; Algorithms; Body Weight; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Forecasting; Humans; Male; Models, Biological; Patient Compliance; Retrospective Studies; Sex Factors; Smoking; Treatment Outcome; United Kingdom

The purpose of this pilot study is to determine if an association exists between clozapine-associated weight gain and resting metabolic rate (RMR). In doing so, we used a "pretest-posttest" single group design in which we measured resting metabolic rate and total body weight prior to implementing clozapine therapy and then again approximately 1 month after initiating clozapine therapy. The results of three patients treated with clozapine revealed an inverse relationship between resting metabolic rate and total body weight. Resting metabolic rates were notably reduced by 10.3-16.0% whereas total body weights had increased between 2.9 and 9 kg. To our knowledge, this is the first documentation of an antipsychotic medication being associated with the reduction in resting metabolic rate.

Topics: Adult; Antipsychotic Agents; Basal Metabolism; Body Weight; Clozapine; Humans; Male; Middle Aged; Pilot Projects; Rest; Schizophrenia

Clozapine has been linked to significant weight gain and increase in serum lipids and appears to negatively impact glucose metabolism. In this retrospective chart review study, we examine changes in systolic and diastolic blood pressure and treatment for hypertension in clozapine-treated patients.. Data on demographics and systolic and diastolic blood pressure were examined for up to 5 years (September 1987 to September 1992) in 82 patients treated with clozapine. Rates of hypertension treatment in clozapine-treated patients were compared with patients receiving conventional antipsychotics (N = 56) and other atypical antipsychotic agents (N = 102).. The mean age of the 82 patients at the time of clozapine initiation was 36.4 +/- 7.8 years, with 22 (27%) female, 75 (91%) white, 3 (4%) black, 3 (4%) Hispanic, and 1 (1%) Asian. The baseline weight was 175.5 +/- 34.0 lb (79.0 +/- 15.3 kg) and baseline body mass index was 26.9 +/- 5.0 kg/m(2). There was a significant increase in systolic blood pressure (p =.0004) and diastolic blood pressure (p =.0001). Overall, 22 patients (27%) received treatment for hypertension following clozapine initiation. Only 2 (4%) of 56 patients in the conventional antipsychotic group and 9 (9%) of 102 patients in the other atypical antipsychotic group (olanzapine, N = 6; risperidone, N = 3) received treatment for hypertension.. Our findings suggest that long-term clozapine treatment is associated with increased rates of hypertension, which may have a significant impact on medical morbidity and mortality.

Topics: Adult; Antihypertensive Agents; Antipsychotic Agents; Blood Pressure; Body Mass Index; Body Weight; Clozapine; Diastole; Female; Humans; Hypertension; Male; Medical Records; Psychotic Disorders; Retrospective Studies; Schizophrenia; Systole

Several studies postulated an interaction of clozapine with N-methyl-D-aspartate (NMDA) receptor-mediated transmission. We previously showed that acute clozapine application on rat prefrontal cortex (PFC) slices increased NMDA receptor-dependent long-term potentiation (LTP) in the prelimbic (PL) area. The present study explores the effects of subchronic clozapine treatment on LTP in the same brain area. After 21 days of treatment (30 mg/kg per day, via drinking water), rats were sacrificed and slices from the PFC were prepared for electrophysiological investigations. To this end, extracellular field potentials in the layer II-V pathway were recorded. In contrast to our previous study with acute application on the slice, subchronic clozapine treatment attenuated LTP as compared to non-treated animals. We interpret these findings to suggest that prolonged treatment with clozapine might result in a compensatory response to the acute facilitating action of clozapine on LTP-mediating processes.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Body Weight; Clozapine; Dose-Response Relationship, Drug; Drinking; Drug Administration Routes; Electric Stimulation; Excitatory Amino Acid Antagonists; GABA Antagonists; Long-Term Potentiation; Male; Prefrontal Cortex; Rats; Rats, Sprague-Dawley

Weight gain frequently occurs during treatment with clozapine. However, the pathophysiology of clozapine-induced weight gain remains unclear. The aim of this study was to investigate the influence of clozapine on hormones leptin and insulin in relation to body weight and composition measures to determine their contribution to clozapine-induced weight gain.. Data are reported on 19 patients with schizophrenia (11 women and 8 men) who completed 10 weeks of treatment with clozapine. Insulin levels, weight measurements, body mass index (BMI), and body composition measurements were evaluated at baseline and at the end of treatment. Leptin levels were assessed at baseline and after 4 and 10 weeks of treatment. Analysis of variance with repeated measures was used to evaluate changes in weight, body composition measures, leptin, and insulin. The Pearson correlations were used to assess the relationships between changes in hormone levels and weight along with body composition measurements. The correlations of change in Positive and Negative Syndrome Scale (PANSS) score with changes in hormone levels, weight gain and body composition measures were evaluated with Pearson correlations.. Leptin and insulin levels did not show any significant alterations across time. The use of clozapine was associated with significant increases in BMI (F=19.8, P<.001), lean muscle mass (F=8.2, P=.01), and fat mass (F=15.4, P=.001), while total body fluid percentage (F=4.1, P=.05) significantly decreased. Improvement in PANSS scores was not correlated to change in leptin, insulin, weight, BMI, or body composition measurements. The change in leptin levels was correlated to change in body fat mass.. The role of leptin in weight gain induced by clozapine might be a regulatory mechanism rather than being etiologic.

Topics: Adult; Analysis of Variance; Body Composition; Body Weight; Clozapine; Female; Humans; Insulin; Leptin; Male; Middle Aged; Schizophrenia

Tumor necrosis factor alpha (TNF-alpha), a potent immunomodulator and proinflammatory cytokine, has been implicated in schizophrenia pathogenesis and clozapine response. Two studies have established an association between schizophrenia and the TNF-alpha gene -308G/A polymorphism; however, both increased and decreased -308A allele frequency have been reported in two analogous investigations. The present study examined the hypothesis that the TNF-alpha gene -308G/A polymorphism confers susceptibility to schizophrenia in 205 patients with schizophrenia compared with 192 controls. A subgroup of 99 clozapine-treated schizophrenia patients was also tested for the genetic effects of this polymorphism, as evidenced by clinical manifestation, and clozapine-related therapeutic outcome and body-weight change. The results of these investigations suggest that the TNF-alpha gene -308G/A variants do not play a major role in susceptibility to, clinical manifestations for, or clozapine response in, schizophrenia.

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Genetic; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Tumor Necrosis Factor-alpha

Weight gain is one side effect of many antipsychotic drugs (APDs). A small number of lateral hypothalamic/perifornical area (LH/PFA) neurons express the orexins, peptides that are critically involved in body weight regulation and arousal. We examined the ability of APDs to activate orexin neurons, as reflected by induction of Fos. APDs with significant weight gain liability increased Fos expression in orexin neurons, but APDs with low or absent weight gain liability did not. The weight gain liability of APDs was correlated with the degree of Fos induction in orexin neurons of the lateral LH/PFA. In contrast, amphetamine, which causes weight loss, increased Fos expression in orexin neurons of the medial but not lateral LH/PFA. We compared the effects of amphetamine and clozapine, an APD with weight gain liability, on orexin neurons innervating the prefrontal cortex. Clozapine induced Fos in 75% of the orexin neurons that project to the cortex, but amphetamine induced Fos in less than a third of these cells. These data suggest that APD-induced weight gain is associated with activation of distinct orexin neurons and emphasize the presence of anatomically and functionally heterogeneous populations of orexin neurons.

Topics: Amphetamine; Animals; Antipsychotic Agents; Body Weight; Carrier Proteins; Cell Count; Central Nervous System Stimulants; Clozapine; Dopamine Antagonists; Fornix, Brain; Haloperidol; Hypothalamic Area, Lateral; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Neurons; Neuropeptides; Orexins; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Weight Gain

Clozapine treatment frequently causes body weight gain that may impair health and may affect patient compliance. While the histamine-1 (H1) receptor may play a major role in the mechanism of the clozapine-induced body weight change, we tested the relationship between the genetic variant (Glu349Asp) of the H1 receptor and the clozapine-induced body weight change. Eighty-eight schizophrenic patients treated with clozapine were included in this study. Analysis of body weight change after 4 months of clozapine treatment showed no relationship with the H1 genotype. Further exploration of the other H1 genotypes and the antipsychotic-induced body weight change may help in the understanding of the mechanisms of antipsychotic-induced body weight gain and in the choice of patient's antipsychotic regimens.

Topics: Adolescent; Adult; Aged; Amino Acid Substitution; Body Weight; Clozapine; DNA Primers; Female; Genetic Variation; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Histamine H1; Schizophrenia; Serotonin Antagonists

The aim of this study was to examine the effects of different doses of typical antipsychotics, chlorpromazine (0.25-1 mg/kg) and haloperidol (0.25-1 mg/kg), and atypical antipsychotics, clozapine (0.5-2 mg/kg), olanzapine (0.25-1 mg/kg), risperidone (0.5-2 mg/kg), sulpiride (10-40 mg/kg) and dopamine D1 antagonist, SCH 23390 (0.25-1 mg/kg) on feeding behavior at different time intervals after acute administration. The study further investigated the central dopamine and serotonergic receptor involvement in clozapine-induced hyperphagia using SKF 38393, quinpirole and quipazine. Then, the authors also examined the effect of subchronic treatment for 21 days with fluoxetine on clozapine-induced hyperphagia and modulation of body weight and fat pad weights. The feeding behavior was assessed in nondeprived mice by presenting the palatable chow to different groups of mice in glass petri dishes and recording the food consumed at different time intervals. After acute administration, significant (P<.05) increase in food intake was observed at different time intervals with different doses of both typical and atypical antipsychotics. Further, clozapine-induced hyperphagia was significantly (P<.05) reversed after treatment with SKF 38393 (dopamine D1 agonist), quinpirole (dopamine D2 agonist) and quipazine (5-HT1B, 5-HT2 and 5-HT3 agonist). In subchronic study, treatment with fluoxetine (10 mg/kg) significantly (P<.05) antagonized the increase in body weight and food intake induced by clozapine (2 mg/kg). The current investigations underscore the reported increases in food intake and body weight gain observed with antipsychotics. The study further confirms the involvement of dopamine D1, D2 and serotonergic receptor involvement in clozapine-mediated hyperphagia. Further, the serotonergic agents may prove useful to counteract antipsychotic-induced obesity.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adipose Tissue; Animals; Antipsychotic Agents; Body Weight; Clozapine; Eating; Feeding Behavior; Female; Fluoxetine; Hyperphagia; Mice; Mice, Inbred Strains; Organ Size; Quinpirole; Quipazine; Selective Serotonin Reuptake Inhibitors; Weight Gain

To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA.. A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA.. Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale.. The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.

Topics: Adult; Antipsychotic Agents; Autoimmune Diseases; Blood Glucose; Body Weight; Clozapine; Diabetic Ketoacidosis; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Male; Schizophrenia, Paranoid

The goal of this study was to identify adverse effects of the atypical neuroleptic clozapine on liver function and lipid metabolism.. Data which included serum levels of clozapine and its hepatic metabolite N-desmethyl clozapine were collected from medical records of patients treated with clozapine and controls.. We identified a clozapine-associated marked elevation of plasma cholinesterase (ChE) with unchanged levels of AST, ALT or g-GT. ChE was correlated to the serum level of clozapine and even closer to N-desmethyl clozapine. For the total patient group we observed significant correlations of ChE with the body-mass index and body weight. However, clozapine-treated patients and controls did not differ with regard to body-mass index, triglycerides, and cholesterol.. We report for the first time a clozapine-associated and dose-dependent elevation of plasma ChE, which may be related to clozapine-associated effects on hepatic lipid metabolism or ChE enzyme induction.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Cholesterol; Cholinesterases; Clozapine; Female; Humans; Lipid Metabolism; Liver Function Tests; Male; Middle Aged; Outpatients; Psychotic Disorders; Retrospective Studies; Triglycerides

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

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

Topics: Animals; Antipsychotic Agents; Area Under Curve; Behavior, Animal; Biotransformation; Body Weight; Chromatography, High Pressure Liquid; Clozapine; Cytochrome P-450 CYP1A2; Dyskinesia, Drug-Induced; Half-Life; Mice; Mice, Knockout; Spectrophotometry, Ultraviolet

Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin.. Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12).. In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment.. Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization.

Topics: Adipose Tissue; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Haloperidol; Hospitalization; Humans; Leptin; Mental Disorders; Olanzapine; Pirenzepine; Proteins; Weight Gain

Previous reports concerning the effects of gender and age on steady-state plasma concentrations of clozapine and its major metabolites, norclozapine and clozapine-N-oxide, have been controversial. Since the frequency distribution of the plasma levels is asymmetrical and skewed to the right, the statistical methods (such as analysis of variance and regression analysis) used earlier are actually inappropriate for analyzing the effects of the variables on the concentrations and might contribute to the inconsistent results. The goal of the present study, with befitting statistics, is to measure the potential effect of dose, gender, age, and body weight on plasma levels of clozapine and its 2 major metabolites.. We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxide levels that was conducted in a large group of Chinese schizophrenic inpatients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The daily doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD value of 379.5 +/- 142.2 mg. Plasma concentrations had been measured using high-performance liquid chromatography with ultraviolet detection. Multiple linear regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the dependent variable to overcome the skewness problem.. After adjusting the effects of gender, age, and body weight by multiple linear regression, each 1-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% higher norclozapine, with other variables being controlled. No sex differences were demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and clozapine-N-oxide by 1.0%. Body weight could not influence the levels of these compounds.. The present results suggest that women possess higher plasma levels (about one third higher) of clozapine and norclozapine, but not the N-oxide metabolite. Each addition of 1 year in age elevated clozapine and either metabolite's levels by about 1%. Furthermore, every 1-mg increase in the daily dose raised clozapine and norclozapine concentrations by approximately 0.3%. These findings could assist clinicians in optimizing clozapine dosing strategies.

Topics: Adult; Age Factors; Body Weight; Chromatography, High Pressure Liquid; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Linear Models; Male; Retrospective Studies; Schizophrenia; Sex Factors

Weight gain is a major side-effect of treatment with clozapine. In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment. Serum clozapine levels and levels of its metabolites were simultaneously assessed. Alterations of body weight and body composition were determined. During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001). During the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. The maximal relative increase over baseline was 536%. Low doses of clozapine were sufficient to induce this effect. Within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. Based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion.

Topics: Adipose Tissue; Antipsychotic Agents; Body Composition; Body Mass Index; Body Weight; Clozapine; Humans; Leptin; Proteins; Schizophrenia; Time Factors; Weight Gain

Topics: Adult; Body Weight; Clozapine; Drug Interactions; Fluvoxamine; Humans

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Long-Term Care; Male; Middle Aged; Prognosis; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Both acute and long-term effects of haloperidol and clozapine on Fos-like immunoreactive nuclei in several rat forebrain areas were quantified. Rats were treated with saline (1 ml/kg.day, control), haloperidol (1 mg/kg.day) and clozapine (20 mg/kg.day) i.p. for 21 days. Two hours before perfusion fixation a single (acute treatment) or last (long-term treatment) dose of the drug was given. Drug-induced catalepsy and gain in body weight were also measured. A single dose of haloperidol produced large increases in Fos-like immunoreactive nuclei in the striatum, the nucleus accumbens and central amygdala. Following long-term treatment these increases were reduced in all nuclei studied, except the lateral septum. Acute clozapine treatment had slight (if any) effects on the number of Fos-like immunoreactivity-expressing nuclei in the striatum, but the increases in the nucleus accumbens, the lateral septum, the paraventricular and supraoptic nuclei of the hypothalamus and the central amygdala were substantial. Long-term clozapine treatment reduced the acute response significantly in all the areas except the nucleus accumbens. Both haloperidol and clozapine treatment reduced the weight gain of the rats. Haloperidol, but not clozapine, induced catalepsy that remained maximal during the long-term haloperidol treatment. These results indicate that in most brain areas high Fos-protein levels are not necessary to maintain antipsychotic activity or side-effects. The persisting effect of clozapine in the nucleus accumbens may be of significance to the efficacy of this drug in treatment-refractory schizophrenia.

Topics: Animals; Body Weight; Catalepsy; Clozapine; Haloperidol; Immunohistochemistry; Male; Prosencephalon; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Weight Gain

This report describes a method for determination of clozapine and its major metabolites N-desmethylclozapine and clozapine N-oxide in serum samples of adolescent schizophrenic patients during maintenance therapy. The method includes deproteinization and subsequent high-performance liquid chromatography with electrochemical detection. The method shows sufficient sensitivity to quantitate clozapine, clozapine N-oxide and N-desmethylclozapine accurately at 0.5, 5, and 0.5 ng/ml, respectively. We were able to demonstrate for 16 patients receiving fixed doses of clozapine that the individual mean values calculated from six consecutive measurements revealed a strong linear dosage and serum level relationship (Pearson's coefficient of correlation): clozapine (r = 0.82, p = 0.0001); N-desmethylclozapine (r = 0.81, p = 0.0001); clozapine N-oxide (r = 0.91; p = 0.0001). Preliminary pharmacokinetic data are presented and dose-response relationship are discussed.

Topics: Administration, Oral; Adolescent; Adult; Body Weight; Chromatography, High Pressure Liquid; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Schizophrenia

Clozapine has an unusual profile of adverse effects; among them, gastrointestinal (GI) side effects are important management concerns. The charts of patients in a state hospital who received clozapine for at least 3 months were reviewed. We compared the pre- and post-clozapine weights and changes in frequency and intensity of use of drugs prescribed for gastrointestinal symptoms for each subject (n = 99). There were statistically significant increases in the use of antacids (p < 0.02) and both bulk and non-bulk laxatives (p < 0.05, p < 0.03). Seventy-three percent of patients gained weight, of whom 27% gained over 10% body weight. This study confirms clozapine's association with weight gain, constipation, and upper GI symptoms. The literature concerning weight gain, and the mechanisms underlying GI adverse effects were reviewed.

Topics: Adult; Antacids; Antipsychotic Agents; Body Weight; Cathartics; Clozapine; Constipation; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Weight Gain; Weight Loss

Previous reports have shown that long-term administration of typical and atypical neuroleptics induced obesity in female but not in male rats. It has been suggested that impaired ovarian steroidogenesis related to neuroleptic-induced hyperprolactinemia is necessary to observe the body weight changes. This hypothesis was tested with clozapine, an atypical neuroleptic that produces in rats a shorter increase in serum prolactin levels than do other neuroleptics. The effects of clozapine on body weight and food intake were assessed in female and male rats under treatment with any of the following doses: 0.5, 1, 2.5, 5, 10, and 20 mg/kg IP for 21 days. Vaginal cycle under clozapine treatment, as an indirect indicator of ovarian steroidogenesis, was also assessed. Obesity was not observed in any group. By contrast, clozapine at the doses of 10 and 20 mg/kg significantly decreased body weight and feeding in male rats. Clozapine at the doses of 5 and 10 mg/kg IP induced permanent diestrus. The failure of clozapine to induce obesity in female rats, despite impaired vaginal cycle, can be considered indirect evidence that drug-induced hyperprolactinemia is not sufficient to observe neuroleptic-induced obesity in rats.

Topics: Animals; Body Weight; Clozapine; Depression, Chemical; Eating; Estrus; Female; Male; Ovary; Rats; Rats, Wistar

The authors investigated the clozapine plasma levels of 148 psychiatric inpatients. Multiple regression analysis revealed a linear relationship between dose of clozapine and plasma concentrations. The analysis showed a significant influence of dose, sex, smoking, weight, and age on the plasma concentrations of clozapine under clinical conditions. These results remained significant when clozapine doses below 150 mg/day and above 500 mg/day were excluded from the analysis.

Topics: Adult; Age Factors; Analysis of Variance; Body Weight; Clozapine; Dose-Response Relationship, Drug; Female; Hospitalization; Humans; Male; Mental Disorders; Sex Factors; Smoking

Six of seven patients treated with clozapine gained 6-69 lb. Because of clozapine's anticipated availability in the United States, clinicians should be aware of this possible side effect, which, to the authors' knowledge, has not been reported previously.

Topics: Adult; Body Weight; Clozapine; Dibenzazepines; Female; Humans; Male; Middle Aged; Obesity; Schizophrenia; Weight Gain

Rats were administered haloperidol, clozapine, raclopride, or no drug for either 28 days or 8 months and then withdrawn from drug treatment for 3 weeks. Oral movements were repeatedly recorded, both by a human observer and by a computerized video analysis system which determined mouth openings and closings, or computer-scored movelets (CSMs). Four weeks of neuroleptic administration produced no changes in CSMs in any drug-treated group. Long-term administration induced distinctively different patterns of oral activity in the three drug groups, both in number of CSMs and the form of these movements. The oral movements which developed in the haloperidol-treated rats fit a previously described syndrome of late-onset oral dyskinesias which increased upon drug withdrawal. The clozapine- and raclopride-treated rats did not show the increased oral movements seen in the haloperidol animals, but each exhibited uniquely different CSM characteristics compared to controls. The results from this rodent model imply that haloperidol, but not clozapine or raclopride, produces late-onset oral dyskinesias in rats that fit the pattern expected for tardive dyskinesia.

Topics: Animals; Behavior, Animal; Body Weight; Clozapine; Dibenzazepines; Disease Models, Animal; Drinking; Dyskinesia, Drug-Induced; Female; Fourier Analysis; Haloperidol; Raclopride; Rats; Rats, Inbred Strains; Salicylamides

Some atypical neuroleptics have been shown to exert selective effects on the nigrostriatal or mesolimbic dopamine systems as assessed by behavioral, biochemical and electrophysiological measures. This specificity appears to occur using chronic or acute schedules of drug administration. This study examined the effect of chronic administration of haloperidol, clozapine, sulpiride and metoclopramide on stereotypy and locomotor activity elicited by direct injection of dopamine in to the striatum or nucleus accumbens, respectively. Each rat was pre-treated with a neuroleptic drug or vehicle control for 21 days. Five days after the termination of drug treatment, each rat was injected with 10 micrograms dopamine bilaterally, and stereotypy or locomotor activity was measured. Rats pre-treated with metoclopramide exhibited an enhanced stereotypy response, and rats pre-treated with haloperidol, clozapine or sulpiride exhibited enhanced locomotor activity compared to controls. The extent to which these results demonstrate the selective action of these drugs in sensitizing dopamine systems is discussed.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Body Weight; Clozapine; Corpus Striatum; Dopamine; Haloperidol; Humans; Injections; Metoclopramide; Motor Activity; Nucleus Accumbens; Rats; Rats, Inbred Strains; Stereotyped Behavior; Sulpiride

Drug monitoring in psychiatry is of increasing interest due to compliance problems, side effects of psychoactive drugs and the search for adequate dosage. In the present study, plasma levels of clozapine, as determined by high performance liquid chromatography, were investigated in 148 patients receiving a daily dose between 12.5 and 700 mg clozapine. Regression analysis revealed a linear relationship between dose and plasma concentrations. Plasma concentrations at a given dose (level divided by dose and body weight) in male patients reached only 69.3% of the concentrations in female patients (Mann-Whitney U Test P less than 0.001). When the patients were divided into smokers and non-smokers, the corresponding plasma levels were also found to be linearly dose dependent in each of the two groups. However, the average plasma concentration at a given dose was only 81.8% in smokers, compared to non-smokers. This difference was statistically significant (variance analysis P = 0.022). Dividing female patients into smokers and non-smokers, the smokers reached nearly the same plasma levels as the non-smokers. Male smoking patients reached average plasma concentrations which were only 67.9% of those of non-smokers. This difference was statistically significant (Mann-Whitney U Test P = 0.0083). The plasma levels of the different age groups at a given dose per kg body weight were compared using the Mann-Whitney U Test. Significant differences were found between group 1 (18-26) and group 4 (45-54) (P less than 0.01) and group 2 (27-35) and group 4 (P less than 0.01) showing higher plasma levels in the older age group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aging; Body Weight; Clozapine; Dibenzazepines; Female; Humans; Male; Sex Factors; Smoking

Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and 3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific 3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for 3H-flunitrazepam binding to cerebellar membrane preparations was decreased by 12 months administration of all drug treatments. The dissociation constant (Kd) for 3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25-100 microM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific 3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.

Topics: Animals; Body Weight; Brain; Clozapine; Flunitrazepam; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Haloperidol; Kinetics; Male; Psychotropic Drugs; Rats; Rats, Inbred Strains; Sulpiride; Time Factors

The effect of chronic neuroleptic treatment, using haloperidol or clozapine, on immunoreactive dynorphin peptide and substance P levels in basal ganglia of rats was examined. The drugs were administered i.p. in daily doses for 10 days (haloperidol 1 mg/kg and clozapine 10 mg/kg). Dynorphin A, dynorphin B and substance P were measured in substantia nigra, striatum, globus pallidus and hypothalamus using specific radioimmunoassays. The most prominent effects were observed with with clozapine which increased levels of all measured peptides in substantia nigra. Haloperidol only affected nigral substance P levels which declined, while nigral dynorphin peptide levels remained unchanged. In striatum, haloperidol slightly reduced dynorphin peptides while substance P was unaffected. Clozapine increased striatal substance P but the dynorphin peptides were not affected. Minor changes in dynorphin peptides found in globus pallidus and hypothalamus were not statistically reliable. Substance P was not changed in these structures after either of the two drugs. High molecular weight fragments (greater than or equal to 5,000) from the dynorphin precursor, proenkephalin B, were measured in substantia nigra and striatum using trypsin digestion and subsequent analysis of generated Leu-enkephalin-Arg6. These high molecular weight fragments were found to be affected in the same manner as the dynorphin peptides. This study indicates that the two types of neuroleptic drugs have different modes of interaction on peptide systems in basal ganglia of rats. Dynorphin peptides and substance P were also differentially affected.

Topics: Animals; Basal Ganglia; Body Weight; Clozapine; Dibenzazepines; Dynorphins; Haloperidol; Injections, Intraperitoneal; Male; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred Strains; Substance P

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.

Topics: Acetylcholine; Animals; Apomorphine; Body Weight; Clozapine; Corpus Striatum; Dibenzazepines; Haloperidol; Humans; Male; Mastication; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spiperone; Stereotyped Behavior; Thioxanthenes; Tritium

Rats were administered 10 mg/kg SC of clozapine (C) or vehicle solution (S) daily from day 1 after birth until 20 days of age. At 60 days of age (40 days after the postnatal treatment with C or S was interrupted) the stereotyped behaviour and the effects on locomotor activity elicited by apomorphine in S- and C-pretreated rats were investigated. The intensity of stereotyped behaviour as well as the decrement in locomotion induced by apomorphine (0.5--1 mg/kg SC) were not influenced by chronic C administration during development. Finally, at 80 days of age (60 days after the postnatal treatment with C or S was interrupted) rats were subjected to a differential reinforcement of low rates schedule (DRL15s). The results indicate that the acquisition of the DRL task performance criterion (Rs/Rf less than or equal to 2.5) was significantly more rapid in S-pretreated rats than in C-pretreated ones. In parallel biochemical experiments, homovanillic acid (HVA) content was measured in striatum in rats at 60 days of age (40 days after the postnatal treatment with C or S was interrupted). The results indicate that even if an acute challenge dose of 10 mg/kg C shows a certain degree of tolerance a single dose of 20 mg/kg C is still able to increase striatal HVA concentration in chronic C-pretreated animals. These data indicate that early postnatal administration of a non-cataleptogenic neuroleptic, like C, induces, in the adult rat, behavioural and biochemical changes which significantly differ from those elicited by a cataleptogenic neuroleptic, like haloperidol.

Topics: Animals; Apomorphine; Behavior, Animal; Body Weight; Brain Chemistry; Clozapine; Corpus Striatum; Dibenzazepines; Dopamine; Homovanillic Acid; Humans; Male; Motor Activity; Rats; Rats, Inbred Strains; Reinforcement Schedule; Stereotyped Behavior

Topics: Aging; Animals; Body Weight; Clozapine; Dibenzazepines; Male; Mice; Mice, Inbred C57BL; Motor Activity; Sleep