clozapine and Obesity

Clozapine is the most effective antipsychotic, but its use is tempered by adverse metabolic effects such as weight gain, glucose intolerance and type II diabetes. Current interventions do not facilitate compelling or sustained improvement in metabolic status. Recent studies suggest that glucagon-like peptide-1 (GLP-1) may play a key role in clozapine's metabolic effects, possibly suggesting that clozapine-associated obesity and diabetes are mediated independently through reduced GLP-1. As a result, GLP-1 agonists could show promise in reversing antipsychotic-induced metabolic derangements, providing mechanistic justification that they may represent a novel approach to treat, and ultimately prevent, both diabetes and obesity in patients on clozapine. GLP-1 agonists are already used for diabetes, and they provide a unique combination of glycaemic improvement and metabolically relevant weight loss in diabetic and non-diabetic patients, in the context of a currently favourable safety profile. Using GLP-1 agonists for clozapine-associated obesity and diabetes could be a potentially effective intervention that may reduce cardiometabolic morbidity and mortality in this vulnerable patient population.

Topics: Animals; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Obesity

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

Metabolic complications are commonly found in people treated with clozapine. Reviews on the management of this problem have generally drawn conclusions by grouping different types of studies involving patients treated with various different antipsychotics. We carried out a systematic review and meta-analysis of pharmacological and non-pharmacological treatments for clozapine-induced obesity or metabolic syndrome. Two researchers independently searched PubMed and Embase for randomised controlled trials (RCTs) of treatments for clozapine-induced obesity or metabolic syndrome. All other types of studies were excluded. We only included RCTs where more than 50% of participants were taking clozapine. We identified 15 RCTs. Effective pharmacological treatments for clozapine-induced obesity and metabolic syndrome include metformin, aripiprazole, and Orlistat (in men only). Meta-analysis of three studies showed a robust effect of metformin in reducing body mass index and waist circumference but no effects on blood glucose, triglyceride levels, or HDL levels. In addition, there is limited evidence for combined calorie restriction and exercise as a non-pharmacological alternative for the treatment of clozapine-induced obesity, but only in an in-patient setting. Rosiglitazone, topiramate, sibutramine, phenylpropanolamine, modafinil, and atomoxetine have not shown to be beneficial, despite reports of efficacy in other populations treated with different antipsychotics. We conclude that randomised-controlled trial data support the use of metformin, aripiprazole, and Orlistat (in men only) for treating clozapine-induced obesity. Calorie restriction in combination with an exercise programme may be effective as a non-pharmacological alternative. Findings from trials in different populations should not be extrapolated to people being treated with clozapine.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Clozapine; Humans; Metabolic Syndrome; Obesity; Randomized Controlled Trials as Topic

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

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

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Histamine H1 Antagonists; Humans; Hypothalamus; Obesity; Olanzapine; Receptors, Histamine H1; Weight Gain

The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects.

Topics: Animals; Antipsychotic Agents; Appetite Regulation; Benzodiazepines; Clozapine; Glucose; Histamine; Histamine Antagonists; Humans; Models, Biological; Muscarinic Antagonists; Obesity; Olanzapine; Receptors, Histamine; Vagus Nerve; Weight Gain

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

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

The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle.

Topics: Adiponectin; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Diabetes Mellitus; Humans; Leptin; Obesity; Olanzapine; Piperazines; Quinolones; Receptor, Muscarinic M3; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Histamine; Serotonin 5-HT1 Receptor Agonists; Thiazoles; Weight Gain

Atypical antipsychotics are emerging as the first-line pharmacologic treatment for irritability (i.e., aggression, self-injurious behavior, and severe tantrums) in children and adolescents with autistic and other pervasive developmental disorders. Results from placebo-controlled and open-label studies of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole in this subject population are reviewed. Additional placebo-controlled trials and studies of longer-term safety and tolerability are needed.

Topics: Adolescent; Aggression; Antipsychotic Agents; Aripiprazole; Autistic Disorder; Benzodiazepines; Child; Child Development Disorders, Pervasive; Child, Preschool; Clozapine; Dibenzothiazepines; Disorders of Excessive Somnolence; Humans; Obesity; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles

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

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

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

Weight overload and obesity became these last years a major health problem. However gain weight is a frequent side effect of a large number of psychotropics. This article proposes to discuss this potential while reviewing various molecules. This reveals that the atypical antipsychotics are most likely to induce weight gain, in particular clozapine and olanzapine. The tricyclic antidepressants and mirtazapine come next, with the majority of the mood stabilizers. The old antipsychotics seem to involve less gain of weight. The SSRI make lose weight in the first weeks of treatment, but induce a moderate weight gain on the long term.

Topics: Adolescent; Adult; Amisulpride; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Child; Clozapine; Dibenzothiazepines; Double-Blind Method; Female; Fructose; Haloperidol; Humans; Imidazoles; Indoles; Male; Obesity; Olanzapine; Piperazines; Placebos; Psychotropic Drugs; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Risperidone; Socioeconomic Factors; Sulpiride; Thiazoles; Time Factors; Topiramate; Valproic Acid; Weight Gain

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

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

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

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

Clozapine is associated with obesity and type 2 diabetes. Glucagon-like-peptide-1 (GLP-1) receptor agonists such as exenatide can counter clozapine-associated GLP-1 dysregulation. Our 24-week randomized, controlled, open-label, pilot trial of once-weekly extended-release subcutaneous exenatide or usual care (CODEX) (n = 28), found exenatide was associated with significantly greater weight loss. We examined whether this effect was maintained at 12-months post-intervention. We followed up CODEX trial participants at 12-months post trial endpoint, collecting information on weight, BMI, waist circumference, blood pressure, fasting glucose, HbA1c, and use of metformin. The primary outcome of interest was change in weight from trial baseline to 12-months post endpoint and trial endpoint to 12-months post endpoint compared between former exenatide and usual care participants. Only HbA1c differed between baseline and 12-months post endpoint between the exenatide and control groups. From endpoint to 12-month follow up there were significantly greater increases among the former exenatide versus former usual care participants for weight, BMI, HbA1c and proportion with >5% weight gain. Stratifying results by whether participants used metformin post trial did not alter proportion with >5% weight gain. Although there were no significant differences in weight and BMI between baseline and 12-month post endpoint, there were significant increases in weight and BMI in the 12 months post endpoint for the former exenatide group. This was irrespective of metformin use and is in keeping with studies of other GLP-1RA agents. Further studies on GLP-1RAs use beyond 24 weeks for people with clozapine associated weight gain are needed.

Topics: Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Obesity

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

Topics: Adolescent; Adult; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Humans; Male; Middle Aged; Obesity; Pilot Projects; Schizophrenia; Weight Loss; Young Adult

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

Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.. To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.. This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.. Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.. The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.. Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.. Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.. clinicaltrials.gov Identifier: NCT01845259.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Outcome Assessment, Health Care; Overweight; Prediabetic State; Schizophrenia

Increased body weight and hyperlipidemia caused by antipsychotics may be associated with improved antipsychotic efficacy in schizophrenia. If this association has a causal interrelationship via a genuine pathophysiological mechanism, then body weight loss in antipsychotic-treated patients would be accompanied by worsened psychopathology. This could have clinical implications.. To explore whether the decreased body weight in these patients is associated with a worsened psychopathology.. In our previously published study, a 16 week treatment period with add-on orlistat (but not placebo) resulted in body weight loss in male (but not female) clozapine- or olanzapine-treated overweight or obese patients. In the current study, we investigated whether body weight loss in those male patients could worsen psychosis. Changes in the Positive and Negative Syndrome Scale (PANSS) scores within groups and body weight changes and lipid profiles over the treatment period were analysed by the paired samples t-test. Between-group comparisons were analysed by the independent samples t-test.. Over the treatment period body weight decreased by 2.56 ± 3.25 kg from initial 106.02 ± 12.61 kg (p = 0.04) for the orlistat group, with no statistically significant changes for the placebo group. Lipid levels did not change in either group. The orlistat-induced weight decrease was not associated with worsening in the PANSS scores.. Weight loss was not associated with a worsening of psychosis. The interrelationship between the antipsychotic-induced weigh gain and improved schizophrenia psychopathology observed in earlier studies appears to be indirect. Orlistat treatment in our study did not worsen psychopathology in this population.

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Humans; Lactones; Lipid Metabolism; Male; Middle Aged; Obesity; Olanzapine; Orlistat; Psychiatric Status Rating Scales; Psychopathology; Schizophrenia; Weight Loss

Obesity-related genetic variants, including TMEM18 (rs6548238), SH2B1 (rs7498665), and GNPDA2 (rs10938397), have been shown to be associated with obesity in the general population. Our study aimed to test whether these genetic variants are associated with metabolic profiles and metformin treatment response in clozapine-treated schizophrenic patients. We recruited 107 clozapine-treated patients who were genotyped and measured their metabolic profiles. Fifty-five subjects, who had at least 1 metabolic abnormality in a range of measures, were subsequently randomized to a 24-week trial of metformin (n = 28) or placebo (n = 27). We examined the associations between TMEM18, SH2B1, GNPDA2 genetic variants and metabolic profiles at baseline in all patients and metabolic changes in the trial groups. We found a significant association between SH2B1 and blood pressure at baseline in all patients. In the metformin group, TMEM18 minor allele carriers had a greater reduction in insulin levels (P = 0.04). A significantly higher proportion of TMEM18 and GNPDA2 minor allele carriers (60% and 40%) lost more than 7% of their body weight after metformin treatment as compared with their homozygous counterparts (21.7% and 15.4%, P = 0.02 and 0.004, respectively).There were trends toward favorable metabolic changes in minor allele carrier groups. In the placebo group, no association between genetic variants and changes in metabolic profiles was found. In conclusion, the study results suggest that these genes might be associated with metabolic abnormalities and response to metformin in clozapine-treated patients with schizophrenia.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aldose-Ketose Isomerases; Alleles; Antipsychotic Agents; Clozapine; Double-Blind Method; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Membrane Proteins; Metabolic Diseases; Metformin; Middle Aged; Obesity; Schizophrenia

Metabolic disturbances, obesity and life-shortening cardiovascular morbidity are major clinical problems among patients with antipsychotic treatment. Especially two of the most efficacious antipsychotics, clozapine and olanzapine, cause weight gain and metabolic disturbances. Additionally, patients with schizophrenia-spectrum disorders not infrequently consume alcohol. Glucagon-like peptide-1 (GLP-1) has shown to improve glycaemic control and reduce alcohol intake among patients with type 2 diabetes.. To investigate whether the beneficial effects of GLP-1 analogues on glycaemic control and alcohol intake, in patients with type 2 diabetes, can be extended to a population of pre-diabetic psychiatric patients receiving antipsychotic treatment.. Trial design, intervention and participants: The study is a 16-week, double-blinded, randomised, parallel-group, placebo-controlled clinical trial, designed to evaluate the effects of the GLP-1 analogue liraglutide on glycaemic control and alcohol intake compared to placebo in patients who are prediabetic, overweight (body mass index ≥27 kg/m(2)), diagnosed with a schizophrenia-spectrum disorder and on stable treatment with either clozapine or olanzapine.. The primary endpoint is the change in glucose tolerance from baseline (measured by area under the curve for the plasma glucose excursion following a 4 h 75 g oral glucose tolerance test) to follow-up at week 16. The secondary endpoints include changes of dysglycaemia, body weight, waist circumference, blood pressure, secretion of incretin hormones, insulin sensitivity and β cell function, dual-energy X-ray absorption scan (body composition), lipid profile, liver function and measures of quality of life, daily functioning, severity of the psychiatric disease and alcohol consumption from baseline to follow-up at week 16. Status: Currently recruiting patients.. Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations.. ClinicalTrials.gov: NCT01845259, EudraCT: 2013-000121-31.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clinical Protocols; Clozapine; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Olanzapine; Prediabetic State; Research Design; Schizophrenia

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

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

Constipation is a common and potentially fatal side effect of clozapine treatment. Another important side effect of clozapine may also be significant weight gain. Orlistat is a weight-control medication that is known to induce loose stools as a common side effect. This study aimed to explore whether orlistat used to control clozapine-induced weight gain can simultaneously tackle clozapine-related constipation. In this 16-week randomized-controlled study, clozapine-treated patients received add-on orlistat (n=30) or add-on placebo (n=24). Colonic function was measured using the Bristol Stool Form Scale. There was a significant (P=0.039) difference in the prevalence of constipation in favor of orlistat over placebo in completers (n=40) at the endpoint. A decrease in the prevalence of constipation within the orlistat group (P=0.035) was observed (vs. no statistically significant changes in the placebo group). In clozapine-treated patients, orlistat may be beneficial not only for weight control but also as a laxative. As no established treatments for clozapine-induced constipation exist, orlistat can be considered for this population, although more studies are required.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Colon; Constipation; Cross-Sectional Studies; Diarrhea; Double-Blind Method; Finland; Humans; Incidence; Lactones; Laxatives; Obesity; Olanzapine; Orlistat; Overweight; Patient Dropouts; Prevalence; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Weight Loss

To explore long-term effects of orlistat in adult clozapine- or olanzapine-treated patients with DSM-IV-diagnosed schizophrenia and overweight or obesity who tolerate orlistat.. Orlistat or placebo was added to clozapine or olanzapine in stable doses in a 16-week randomized controlled trial. Open-label orlistat was added to the antipsychotics during a 16-week extension phase for those completing the double-blind phase. No low-calorie diet or participation in behavioral programs was required. Body weight (primary outcome) and some metabolic parameters were measured prospectively. Analyses were performed for those completing both phases (ie, population differing from that reported earlier). The study was conducted from 2004 through 2005.. During the open-label phase, the 44 patients experienced mean ± SD body weight loss of -1.29 ± 3.04 kg, P = .007. During both phases, men (but not women) showed a weight loss of -2.39 ± 5.45 kg, P = .023. Some subgroups showed desirable changes in several metabolic parameters. Prolonged (32 weeks) orlistat treatment yielded no additional benefits as compared to short (16 weeks) treatment.. In clozapine- or olanzapine-treated overweight or obese patients able to take orlistat on a long-term basis, the drug, with no concomitant hypocaloric diet or behavioral interventions, caused moderate weight loss only in men. However, some metabolic benefits may be achieved independently of weight changes. In patients who do not respond to orlistat within the first 16 weeks, continuation treatment may provide no additional benefits.. controlled-trials.com Identifier: ISRCTN65731856.

Topics: Adult; Anti-Obesity Agents; Antipyretics; Benzodiazepines; Cholesterol; Cholesterol, LDL; Clozapine; Double-Blind Method; Female; Humans; Lactones; Male; Obesity; Olanzapine; Orlistat; Schizophrenia; Sex Factors; Treatment Outcome; Weight Loss

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

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

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

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

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

Overweight and obesity are common concerns in individuals with severe mental disorders. In particular, antipsychotic drugs (AP) frequently induce weight gain. This phenomenon lacks current management and no previous controlled studies seem to use cognitive therapy to modify eating and weight-related cognitions. Moreover, none of these studies considered binge eating or eating and weight-related cognitions as possible outcomes.. The main aim of this study is to assess the effectivity of cognitive and behavioural treatment (CBT) on eating and weight-related cognitions, binge eating symptomatology and weight loss in patients who reported weight gain during AP treatment.. A randomized controlled study (12-week CBT vs. Brief Nutritional Education) was carried out on 61 patients treated with an antipsychotic drug who reported weight gain following treatment. Binge eating symptomatology, eating and weight-related cognitions, as well as weight and body mass index were assessed before treatment, at 12 weeks and at 24 weeks.. The CBT group showed some improvement with respect to binge eating symptomatology and weight-related cognitions, whereas the control group did not. Weight loss occurred more progressively and was greater in the CBT group at 24 weeks.. The proposed CBT treatment is particularly interesting for patients suffering from weight gain associated with antipsychotic treatment.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Body Mass Index; Bulimia Nervosa; Clozapine; Cognitive Behavioral Therapy; Combined Modality Therapy; Diagnostic and Statistical Manual of Mental Disorders; Female; Health Education; Humans; Male; Middle Aged; Obesity; Weight Gain

Patients with schizophrenia treated with clozapine often gain weight. This study evaluated the effects of dietary control and physical activity among obese inpatients with schizophrenia being treated with clozapine.. Fifty-three clozapine-treated obese patients with schizophrenia in a veterans hospital in eastern Taiwan who had a body mass index greater than 27 (weight divided by height in meters squared) and who were taking clozapine were randomly assigned to a study group of 28 or a control group of 25. The study group was placed on a diet that reduced calorie intake by 200 to 300 kcal per day (to 1,300 to 1,500 kcal per day for women and to 1,600 to 1,800 kcal per day for men) and a six-month regimen of regular physical activity in which participants used approximately 600 to 750 kcal per week (level walking and walking on stairs for 60 minutes three days per week). Anthropometric, metabolic, and hormonal parameters were measured after three and six months by using anthropometry, an enzyme autoanalyzer, immunoassay, and enzyme-linked immunosorbent assay.. Compared with the control group, the study group showed a significant decrease in body weight, body mass index (5.4% reduction), waist circumference (3.3 cm), and hip circumference (3.3 cm) after three months and after six months. Triglyceride and insulin-like growth factor-binding protein-3 (IGFBP-3) decreased significantly only after six months.. A program of dietary control and regular physical activity can significantly reduce body weight and improve metabolic profiles of insulin, triglyceride, and IGFBP-3 among obese inpatients taking clozapine for the treatment of schizophrenia.

Topics: Adult; Anthropometry; Antipsychotic Agents; Body Mass Index; Clozapine; Diet, Reducing; Exercise; Female; Follow-Up Studies; Hospitalization; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Male; Middle Aged; Obesity; Schizophrenia; Taiwan; Triglycerides; Veterans

Topics: Adult; Antipsychotic Agents; Chlorpromazine; Clozapine; Female; Humans; Male; Middle Aged; Obesity; Phytotherapy; Plant Extracts

Antipsychotic medications are associated with weight gain and metabolic dysregulation, yet little is known about the management of obesity among individuals with severe and persistent mental illness. Thus we sought to evaluate the potential utility of a behavioral weight control program for this population.. Outpatients receiving psychiatric care at a university medical center who had a body mass index (BMI; weight in kg/[height in m](2)) >or= 30 and were currently taking antipsychotic medication participated in a 12-week group behavioral weight control program. A medical chart review was conducted for each participant's body weight over the 10 months prior to beginning the program. A multiple baseline design was used to determine the impact of the intervention on BMI through 12-month posttreatment follow-up. We also assessed self-reported eating behavior, physical activity, and health-related quality of life. Data were collected from October 2000 to July 2003.. Among 35 patients who began the program, 29 (83%) completed treatment, with mean (+/- SD) weight loss of 5.04 (+/- 7.52) pounds (p = .001) and improvements in eating, activity, and quality of life. At 3-month posttreatment follow-up (N = 27; 77%), total mean weight loss was 7.14 (+/- 11.47) pounds (p = .003). Results of a longitudinal model based on general estimating equations indicated that, relative to the pretreatment period, BMI decreased significantly during treatment and remained stable through 12-month posttreatment follow-up.. Behavioral weight control is a promising approach to the treatment of obesity among outpatients taking antipsychotic medications, but longer and more robust interventions are needed.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Behavior Therapy; Body Mass Index; Clozapine; Comorbidity; Feasibility Studies; Feeding Behavior; Female; Health Status; Humans; Male; Mental Disorders; Obesity; Quality of Life; Treatment Outcome; Weight Loss

Few studies have examined gender differences in the propensity to gain weight on clozapine. Weight gain increases risk for many medical illnesses and is of particular concern for people with schizophrenia who are more overweight than the general population. Long-stay patients in Connecticut state hospitals were randomly assigned to switch to open-label treatment with clozapine (n = 138) or to continue receiving first generation (conventional) antipsychotic medications (n = 89). Using survival and random regression models, we examined percentage of body weight gained during 2 years for patients assigned to clozapine versus those who continued taking first generation antipsychotic medications. We also examined the impact of gender on weight gain. Patients who switched to clozapine gained a greater percentage of weight (13 pounds, 7%) than did patients remaining on first generation medications (5 pounds, 4%) at the end of 2 years. Normal-weight patients on clozapine were more likely to become obese (body mass index [BMI] > or = 30). Patients gained weight whether they switched to clozapine or remained on first generation antipsychotic medications, but weight gain was significantly greater (1 BMI unit) in the clozapine-treated group, particularly among women.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Obesity; Schizophrenia; Severity of Illness Index; Time Factors; Weight Gain

Weight gain is a common side effect of clozapine treatment and may expose patients to obesity-associated health risks. We proposed that concomitant treatment with an appetite suppressant such as phenylpropanolamine (PPA) would lead to a decrease in appetite and therefore loss of weight.. This was a 12-week, double-blind, randomized, placebo-controlled trial of PPA, 75 mg/day, in outpatients with treatment-refractory schizophrenia (DSM-IV) who were stable on clozapine treatment for at least 4 months and had gained > 10% of their baseline body weight since starting clozapine. Patients were evaluated for adverse effects and weighed weekly. A Positive and Negative Syndrome Scale (PANSS) assessment, a short dietary quiz, and blood indices were completed monthly.. Sixteen patients were equally randomly assigned to receive PPA or placebo. The groups did not differ in mean age, baseline weight, dose of clozapine, baseline PANSS scores, or the percent of weight gained since the start of clozapine. There was no significant effect of treatment on weight (t = 0.219, df = 10, p = .831). There was no significant change in either the total PANSS scores (t = -0.755, df = 10, p = .468), the positive or negative symptom cluster scores, or any of the remaining variables.. Phenylpropanolamine 75 mg/day was well tolerated but was not effective in reversing established weight gain associated with clozapine treatment in stable outpatients with schizophrenia.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Appetite Depressants; Clozapine; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Obesity; Phenylpropanolamine; Pilot Projects; Placebos; Psychiatric Status Rating Scales; Research Design; Schizophrenia; Treatment Outcome; Weight Gain; Weight Loss

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

We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain.. Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated.. Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04).. Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Haloperidol; Humans; Imidazoles; Indoles; Male; Obesity; Olanzapine; Pirenzepine; Placebos; Retrospective Studies; Risperidone; Schizophrenia; Weight Gain

Antipsychotic medications increase the risk of abnormal glucose metabolism. However, in clinical practice, it is difficult to predict this risk because it is affected by medication-related and background factors. This study aimed to identify the risk factors for abnormal glucose metabolism during antipsychotic treatment. We conducted a multicenter, prospective, cohort study in patients with schizophrenia, schizoaffective disorder, or bipolar disorder. Of these patients, those with prediabetes or possible diabetes were excluded. Finally, 706 patients were included in the analysis. The hazard ratio (HR) for each factor was calculated for events of progression to hyperglycemia using time-dependent Cox regression analysis stratified according to facility type and adjusted for available background and drug-related factors. Treatments with olanzapine (HR = 2.06, 95% confidence interval [CI] = 1.05-4.05), clozapine (HR = 4.25, 95% CI = 1.56-11.60), and chlorpromazine (HR = 4.48, 95% CI = 1.21-16.57), overweight and obesity (HR = 1.57, 95% CI = 1.02-2.41), and hypertriglyceridemia (HR = 1.72, 95% CI = 1.02-2.88) were associated with a significantly higher occurrence of hyperglycemic progression. The number and daily dose of antipsychotics were not associated with their occurrence. Our study demonstrated that more careful monitoring is necessary during olanzapine, clozapine, and chlorpromazine treatment because of the higher occurrence of abnormalities in glucose metabolism. Furthermore, patients with obesity or hypertriglyceridemia warrant monitoring for the occurrence of abnormal glucose metabolism, regardless of the type of antipsychotic medication.

Topics: Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; Cohort Studies; Glucose; Humans; Hypertriglyceridemia; Obesity; Olanzapine; Prospective Studies; Risk Factors

Objectives: Clozapine-induced myocarditis may be a hypersensitivity reaction due to titration that was too rapid for a patient's clozapine metabolism. Obesity, infections, and inhibitors (e.g., valproate) may lead to clozapine poor metabolizer (PM) status. The hypothesis that 4 patients with clozapine-induced myocarditis from two United States hospitals were clozapine PMs was tested by studying their minimum therapeutic clozapine doses and titrations. Methods: Using methodology from a prior myocarditis case series of 9 Turkish patients, we studied: 1) the concentration-to-dose (C/D) ratio; 2) minimum therapeutic dose required to reach 350 ng/ml (a marker for PM status); and 3) titration speed. Results: All 4 patients were possible clozapine PMs (their respective minimum therapeutic doses were: 134, 84, 119 and 107 mg/day). The identified possible contributors to clozapine PM status were: 1) valproate in Cases 1, 2 and 4; 2) obesity and a urinary tract infection in Case 2; and 3) obesity and very rapid titration in Case 4. Case 3, who was given a normal US titration, appeared to be a genetic clozapine PM. He developed clozapineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after rechallenge using 12.5 mg/day > 3 months later. The results were similar to 9 Turkish cases, all of which were PMs (6 on valproate, 4 with obesity, 1 with infection and 1 possibly genetic). Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced myocarditis could be explained by lack of individualized titration. (Neuropsychopharmacol Hung 2022; 24(1): 29-41).

Topics: Antipsychotic Agents; Clozapine; Hospitals; Humans; Male; Myocarditis; Obesity; Schizophrenia; Valproic Acid

Metabolic syndrome and related cardiovascular risk factors are well-known comorbidities among patients with schizophrenia. Biomarkers of these antipsychotic-associated metabolic adverse effects and antipsychotic-induced weight gain are needed. Glucagon-like peptide-1 (GLP-1) is involved in insulin secretion, regulation of satiety, inhibition of food intake, and inhibition of gastric emptying. GLP-1 also induces reduction in body weight. Visfatin/ NAMPT/ PBEF is an adipocytokine secreted by several cells and tissues. Increased plasma visfatin levels have been associated with overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases, low grade inflammation, and proinflammatory markers. Associations between antipsychotic-induced weight gain and serum visfatin and GLP-1 levels have been little studied in patients with schizophrenia. The aim of the present study was to test the possible role of serum GLP-1 and visfatin level alterations as markers of weight gain in association with metabolic and inflammatory markers in 190 patients (109 male, 81 female) with schizophrenia on clozapine treatment. High serum levels of GLP-1 correlated significantly with higher levels of visfatin, leptin, insulin, HOMA-IR, higher BMI, and weight change among men. Associations between serum visfatin levels and BMI or weight change were not found in the present patients. Serum GLP-1 level seems to be a marker of metabolic risk factors among men with schizophrenia on clozapine treatment. Female patients may be more sensitive to suppressive effects of clozapine on GLP-1 secretion. Patients on clozapine would benefit from GLP-1 agonists as preventive treatment.

Topics: Clozapine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Male; Obesity; Weight Gain

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

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

Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Yet, the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss. We hypothesized that increased activity in the subset of VTA DA neurons expressing neurotensin receptor-1 (NtsR1) might promote weight loss behaviors. To test this, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate VTA NtsR1 neurons in normal weight and diet-induced obese mice. Acute activation of VTA NtsR1 neurons (24hr) significantly decreased body weight in normal weight and obese mice by reducing food intake and increasing physical activity. Moreover, daily activation of VTA NtsR1 neurons in obese mice sustained weight loss over 7 days. Activating VTA NtsR1 neurons also suppressed how much mice worked to obtain sucrose rewards, even when there was high motivation to consume. However, VTA NtsR1 neural activation was not reinforcing, nor did it invoke liabilities associated with whole-body NtsR1 agonism such as anxiety, vasodepressor response or hypothermia. Activating VTA NtsR1 neurons therefore promotes dual behaviors that support weight loss without causing adverse effects, and is worth further exploration for managing obesity.

Topics: Animals; Clozapine; Dopaminergic Neurons; Mice; Obesity; Receptors, Neurotensin; Reward; Ventral Tegmental Area; Weight Loss

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased

Topics: Adipocytes; Animals; Biomarkers; Body Weights and Measures; Chromium; Clozapine; Disease Models, Animal; Fatty Acid-Binding Proteins; Fluorescent Antibody Technique; Gene Expression; Gene Expression Regulation; Glucose Intolerance; Immunohistochemistry; Insulin; Kidney Diseases; Liver; Mice; Mice, Obese; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Obesity; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Retinal Diseases; Sterol Regulatory Element Binding Protein 1

Clozapine, an antipsychotic developed in 1958, is considered the gold standard and the treatment of choice in treatment-resistant schizophrenia despite its side effects and despite 40-70% of these patients not responding to clozapine. In the last decade, new antipsychotics, such as paliperidone palmitate (PP), have emerged as well as its long acting-injectable (LAI) formulations, available as PP-1-monthly (PP1M) and the newest PP-3-montlhy (PP3M). Despite paliperidone having shown a similar efficacy as others antipsychotics for the treatment of schizophrenia, and that PP3M has been shown to reduce relapses compared to oral formulations, no study has been carried out in treatment-resistant schizophrenia. The aim of our study was to carry out an exploratory evaluation of endocrine and hepatic profiles as well as the concomitant treatments associated to PP3M vs. clozapine, the gold standard, in patients with treatment-resistant schizophrenia. We designed a retrospective study. A total number of 33 patients previously diagnosed as schizophrenics treatment-resistant, who were prescribed clozapine followed by PP1M and PP3M when available, were selected. Demographic data, BMI, hepatic enzymes (glutamic oxaloacetic transaminase, glutamate-pyruvate transaminase and gamma-glutamyl transferase (GGT)], thyroid function (thyroid stimulating hormone), blood platelets and both white and red blood cells as well as the use of concomitant antipsychotics, benzodiazepines and biperiden were compared under treatment with clozapine and PP3M. Antipsychotics and benzodiazepines dosages were compared using by the defined daily dose (DDD) method and haloperidol or diazepam dose equivalents. All statistical analyses were performed using the paired Student t-test for repeated measures. Our data showed that patients under treatment with PP3M showed a significant decrease in BMI (P < 0.01), glucose (P < 0.01), cholesterol (P < 0.05) and triglycerides (P < 0.01) when compared with basal values under treatment with clozapine. Hepatic cholestasis enzyme, GGT, were significantly elevated (P < 0.05) under treatment with clozapine when compared to PP3M. Switching clozapine to PP3M led to a significant lower pharmacological exposure to antipsychotics, by both the DDD (P < 0.05) and haloperidol dose equivalents (P < 0.001) methods without increasing the dose of benzodiazepines while biperiden was more used under PP3M. Finally, antipsychotic monotherapy was higher and less polypharmacy was use

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Substitution; Dyslipidemias; Female; Humans; Hyperglycemia; Male; Middle Aged; Obesity; Paliperidone Palmitate; Retrospective Studies; Schizophrenia; Spain

Clozapine is effective in treatment-resistant schizophrenia; however, adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; therefore, the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. In low CYP3A4 expressers, significant correlation was detected between fasting glucose level and clozapine concentration; moreover, the incidence of abnormal glucose level was associated with exaggerated clozapine concentrations (> 600 ng/ml). In low CYP3A4 expressers, exaggerated concentrations were more frequently observed than in normal/high expressers. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and consequently with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Obesity; Pharmacogenomic Testing; Schizophrenia; Young Adult

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

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

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

Topics: Antipsychotic Agents; Clozapine; Humans; Liraglutide; Obesity; Olanzapine; Overweight; Prediabetic State; Schizophrenia; Weight Gain

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

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

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Obesity; Schizophrenia; Sex Factors; Treatment Outcome

People with severe mental illness have a 20-year life-expectancy shortfall. The majority of antipsychotic medications are associated with obesity and heightened diabetes risk. People with severe mental illness less frequently achieve benchmarked diabetes care, often attributed to poor adherence, lower clinical attendance and documented medical biases in treatment. This case is presented to highlight the profound effect medication change can have on diabetes control.. A 56-year-old man with a 42-year history of schizophrenia had required clozapine treatment for the preceding 14 years. Type 2 diabetes and obesity occurred within 4 years of clozapine instigation. Glycaemic control had been continuously poor, despite frequent contact with diabetes services and multiple medications, including insulin at a dose exceeding 200 IU daily. Request for consideration of antipsychotic review and close interaction with the psychiatry team was initiated at the diabetes outpatient clinic. A gradual medication switch from clozapine to aripiprazole was associated with a reduction in HbA(1c) from 80 to 50 mmol/mol (9.5 to 6.7%) over 4 months, associated with a weight loss of 10 kg. Over the ensuing 2 years, the improvement in HbA(1c) has endured, with total weight loss of 13 kg and halving of insulin requirements.. This case illustrates the benefits of engagement between endocrinologists and psychiatrists to achieve the shared goal of improved physical health in severe mental illness. Greater interdisciplinary collaboration will help bridge the life-expectancy gap in severe mental illness and may assist in preventing disabling diabetes complications in this vulnerable patient group.

Topics: Antipsychotic Agents; Aripiprazole; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Piperazines; Quinolones; Schizophrenia; Treatment Outcome; Weight Loss

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

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

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

Overweight and obesity are common in patients with bipolar disorder. Rates of up to 70% are described in scientific publications. There is sufficient evidence that these conditions are associated with a worse course of the disease (more episodes, higher suicide and hospitality rates, worse response to lithium, somatic comorbidities). Most of the mood stabilisers lead to weight gain. This is also true for clozapine, which can be effective in therapy-refractory courses of bipolar disorder. This case report demonstrates the complexity of the treatment of bipolar disorder. A young patient in depressive stupor following a severe suicide attempt after 5 months of hospital treatment was sent to our department to perform ECT. This was not possible because of the severity of his injuries. We were able to cure the acute condition and interrupt the course of rapid cycling with a combination of clomipramine, lithium and clozapine. A stable course of four years under this medication and psychoeducation has been achieved. In this period the patient was able to lower his body mass index from 38 to 26 because of a consequent lifestyle modification.

Topics: Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Humans; Male; Obesity; Overweight; Suicide, Attempted; Young Adult

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Liraglutide; Middle Aged; Obesity; Receptors, Glucagon; Schizophrenia; Weight Loss

Clozapine is a uniquely effective antipsychotic, but is very toxic in clozapine-naïve subjects. A 34-year-old male patient in a mental health facility, who was not prescribed clozapine, took 350 mg clozapine obtained from another patient at night. He was found dead the next morning. The presence of cardiomegaly related to obesity may have increased the risk of suffering an acute cardiac event after ingestion of clozapine. The medication prescribed to the patient was not thought to have contributed to the fatal outcome. Post mortem femoral blood clozapine and norclozapine concentrations were 0.48 and 0.20mg/L, respectively. By way of comparison, audit of 104,127 plasma samples (26,796 patients) assayed for therapeutic drug monitoring purposes 1993-2007, showed plasma clozapine 0.35 mg/L or more in 57.5% samples (8.4% 1mg/L or more). Those involved in the investigation of clozapine-associated deaths need to be aware that that death in an adult may occur after a single 'therapeutic' dose. A diagnosis of fatal clozapine poisoning cannot be made solely on the basis of a post mortem blood clozapine measurement.

Topics: Adult; Antipsychotic Agents; Clozapine; Fatal Outcome; Fatty Liver; Humans; Hypertrophy, Left Ventricular; Male; Obesity

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

Polyunsaturated fatty acids (PUFAs) are bimodally distributed in acute schizophrenia, suggesting two endophenotypes. We intended to characterize these endophenotypes clinically. Our a priori hypothesis was that low PUFA patients have more negative symptoms.. Patients (aged 18-39) with schizophrenia, schizoaffective or schizophreniform disorders were recruited at hospital admission during an acute episode. The baseline Positive and Negative Syndrome Scale, vital signs and biochemical variables were measured in 97 patients with available RBC PUFA levels. Adjustment for multiple testing was not performed.. The median Negative Subscale score was higher (p=0.04) in the low PUFA (25 points, n=30) than in the high PUFA group (19 points, n=67). Among 95 patients with measurements of serum triglycerides, hypertriglyceridaemia was more prevalent (p=0.009) among low PUFA patients (66%) than high PUFA patients (36%). PUFA modified the effect of antipsychotics on triglycerides (p=0.046). Serum glucose and mean corpuscular haemoglobin were higher (p=0.03, 0.001, respectively) in low PUFA than in high PUFA patients. Low PUFA men were heavier (p=0.04) than high PUFA men.. During an acute episode of schizophrenia, patients with low RBC PUFA have more negative symptoms and more metabolic and haematological abnormalities than those with high PUFA. This indicates that PUFA levels define two clinically distinct endophenotypes of the disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Clozapine; Dibenzothiazepines; Endophenotypes; Erythrocytes; Fatty Acids, Unsaturated; Female; Humans; Hypertriglyceridemia; Linear Models; Logistic Models; Male; Obesity; Olanzapine; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology

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

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

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

Consumers with a mental illness have a significantly higher risk of physical health problems than the general population. The role of health behaviour beliefs and their part in the health of consumers with a mental illness has been poorly explored in the literature.. To understand the relationship between physical health risk factors and health behaviour beliefs in consumers with schizophrenia.. A cross-sectional survey study design using the European Health and Behaviour Survey and assessing (n=99) consumer's blood pressure, waist circumference, body mass index, smoking history, exercise levels, demographics, family history of diabetes and cardiovascular disease was used.. The study was conducted in a 76-bed psychiatric facility located within a 550-bed metropolitan generalist hospital in Sydney, Australia.. Patients attending an outpatient clozapine clinic at the mental health service were asked to participate in the survey by a nurse working in the clinic during the study period.. Of the 163 consumers asked to be involved in the study, n=99 agreed to participate. Mean waist circumference and body mass index for both males and females were significantly above normal population limits. Overall, consumer's beliefs toward their health on the European Health and Behaviour Survey were positive, having statistically significantly more positive attitudes to the statements 'avoiding too much sugar', 'drinking no alcohol' and 'yearly blood pressure checks' than a previously published non-mental health consumer sample. Whilst having positive attitude toward their healthcare, consumers' physical health risk parameters were higher than general population norms.. Consumers with a mental illness have a significantly higher risk for serious physical health problems, yet possess high positive attitudes toward their physical health care. Models of care need to explore this contradiction within mental health services to improve patient outcomes.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Attitude to Health; Cardiovascular Diseases; Clozapine; Cross-Sectional Studies; Female; Health Behavior; Humans; Hypertension; Life Style; Male; Mental Disorders; Models, Psychological; New South Wales; Obesity; Outpatients; Risk Assessment; Risk Factors; Self Care; Smoking; Surveys and Questionnaires

Although there are well-established psychiatric procedures available concerning switching of antipsychotic drugs, in practice we often face a situation where we have to consider not only the patient's demands, but also requests from relatives. In this article we describe a case where we encountered this situation. Our patient was a 48-year-old married man suffering from paranoid schizophrenia with extreme obesity. We had to consider the modification of the antipsychotic treatment because of the patient's persistent residual symptoms (significant lack of initiative, serious under-motivation, emotional plainessness, considerable passivity) his overweight and its consequences (metabolic syndrome). In our paper we describe the psychoeducational process and the clozapine/aripiprazol switch.

Topics: Ambulatory Care; Antipsychotic Agents; Aripiprazole; Clozapine; Depressive Disorder, Major; Drug Administration Schedule; Humans; Interpersonal Relations; Male; Middle Aged; Obesity; Patient Education as Topic; Patient Satisfaction; Piperazines; Quinolones; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Spouses

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

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

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

We studied the dynamics of serum leptin level and some anthropometric values in patients with schizophrenia treated with risperidone, olanzapine, and clozapine showed gender-dependent specific correlations between the studied parameters.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Leptin; Male; Obesity; Olanzapine; Risperidone; Schizophrenia, Paranoid; Sex Factors; Young Adult

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

Obese patients with schizophrenia being treated with clozapine and non-psychiatric obese are often assumed to share the same physiological changes in obesity. The aim of this study was to identify possible metabolic and hormonal differences between non-psychiatric obese subjects (OB) and obese patients with schizophrenia being treated with clozapine (OSC).. Fifty-one normal healthy subjects (Nor, body mass index (BMI):23.2+/-0.3), 50 OB (BMI:31.7+/-0.7) and 71 OSC (BMI:30.4+/-0.5).. Anthropometric, metabolic and hormonal parameters were determined by anthropometry, enzyme autoanalyzer, immunoassay and enzyme-linked immunosorbent assay.. Triglyceride, total cholesterol divided by high-density lipoprotein (HDL) cholesterol (TC/HDL) and leptin levels were significantly higher whereas the HDL and the molar ratio of insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein (IGFBP)-3 levels were significantly lower in both OB and OSC groups than those in the Nor group. Compared to normal subjects, insulin and homeostasis model assessment (HOMA) index levels were significantly higher in OSC, and, in OSC, insulin sensitivity and insulin-like growth factor (IGF)-1 were significantly lower. Although the anthropometric parameters in the OB and OSC groups were similar, in the OSC group the waist-to-hip ratio (WHR), insulin levels and HOMA index were significantly higher, while insulin sensitivity, cholesterol, low-density lipoprotein (LDL) cholesterol, TC/HDL, LDL/HDL, IGF-1 and IGF-1/IGFBP-3 molar ratio were lower, than those of the OB group.. Insulin homeostasis and lipid profiles in clozapine-treated schizophrenic obesity were different from those in non-psychiatric obesity with similar anthropometric parameters, body weight and BMI. Among the three groups, the highest fasting insulin, the lowest insulin sensitivity and the highest HOMA index occurred in the OSC group. The OSC group was characterized by impaired glucose-insulin homeostasis, abnormal lipid profiles and hormonal changes in the GH-IGF-IGFBP axis and in leptin.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Mass Index; Body Weights and Measures; Clozapine; Enzyme-Linked Immunosorbent Assay; Female; Homeostasis; Humans; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leptin; Lipids; Male; Middle Aged; Obesity; Schizophrenia

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

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

To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs).. Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment.. Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [chi(2) = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3-725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine.. Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.

Topics: Adolescent; Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Brain; Bulimia Nervosa; Clozapine; Feeding Behavior; Female; Humans; Male; Middle Aged; Obesity; Olanzapine; Recurrence; Surveys and Questionnaires

The case of a 35-year-old female patient who was diagnosed as schizophrenia treated with psychotrophic drugs nearly for 15 years is presented here. After the disease was diagnosed, the patient quit her university education and began to live inactively far from her social environment, usually spending lazy time at home. During this period, due to either the effects of drugs which have to be used on hormones affecting appetite and body weight or her decreased physical activity, her body weight increased by nearly 30 kg. Anthropometric measurements, biochemical parameters and food diaries were evaluated at the beginning of the nutritional counseling and then repeated periodically. Upon obtaining biochemical findings, collaboration with other units started. The patient was educated on nourishing healthy and controlling body weight, also to bring about lasting behavioral changes. At the beginning of the therapy, among the biochemical measurements, insulin resistance was defined and metformin treatment was begun. Metformin therapy contributed to the patient's adaptation to the diet and improved glucose tolerance. In this way, it was possible to cope with the insulin resistance caused by anti-psychotic pharmacotherapy (clozapine) and the obesity which had developed as a result of clozapine. During the 18-month therapy the patient lost 27 kg, her body fat was reduced by 10% (18 kg) and BMI returned to normal levels. It is known that, many medications used in psychiatric disorders affect appetite and body weight. As seen in our patient metformin therapy causes weight loss and decreases insulin resistance. Both the illness and the medications used for treatment could affect the hormones which play a part in controlling body weight and the cytokines, as a result could change food preference and eating behavior which ultimately pave the way to obesity.

Topics: Adult; Antipsychotic Agents; Behavior Therapy; Clozapine; Female; Humans; Insulin Resistance; Metformin; Obesity; Schizophrenia

Weight gain is a frequently observed adverse event in the treatment with atypical antipsychotics that significantly affects the patients' physical health and treatment compliance.. We report on a treatment-resistant schizophrenic patient who received an add-on treatment with the low-affinity NMDA antagonist memantine because of cognitive disturbances.. During this treatment we observed a marked decrease of clozapine-induced weight gain. The causal relationship to memantine could be demonstrated using an on-off-on design with a significant increase of weight after discontinuation and again a substantial weight loss after re-exposition with memantine. Beside weight, also negative symptoms improved.. Prospective controlled trials evaluating the safety and possible positive effects of memantine on antipsychotic induced weight gain are needed.

Topics: Adult; Antipsychotic Agents; Clozapine; Dopamine Agents; Humans; Male; Memantine; N-Methylaspartate; Obesity; Schizophrenia

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

Topics: Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Delivery of Health Care; Humans; Metabolic Syndrome; Obesity; Risk Factors; Schizophrenia; Weight Gain

The aim of this study was to test whether the initial antipsychotic response to clozapine is related to subsequent weight change.. This study was an 8-year retrospective chart review of 96 hospitalized patients with schizophrenia. Data on monthly weight change, initial clinical response, age, gender, clozapine dose, and concomitant use of mood stabilizers and other antipsychotics were analyzed.. Fifty-five (57.3%) of the patients received clozapine over the entire 8-year period; these subjects experienced an average weight gain of 11.7 kg (SD=1.6). Seventeen of these patients (30.9%) who had a significant initial clinical response (CGI improvement rating of 1 or 2 during the first 14 months) gained significantly more weight (13.8 kg [SD=8.4]) than did the 38 patients without a significant initial response (4.5 kg [SD=12.0]). Multiple linear regression analysis showed significant initial clinical response and lower baseline body mass index were associated with significantly more weight gain.. The results show that initial antipsychotic response to clozapine is associated with subsequent long-term weight gain as measured over 8 years.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Clozapine; Female; Hospitalization; Humans; Longitudinal Studies; Male; Obesity; Prognosis; Psychiatric Status Rating Scales; Recurrence; Retrospective Studies; Schizophrenia; Treatment Outcome; Weight Gain

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

Association has been reported between the C allele of a -759C/T polymorphism in the promoter of the 5-HT2C receptor gene (HTR2C) and antipsychotic-induced weight gain, suggesting that polymorphic HTR2C expression influences this phenotype. The authors tested this polymorphism, and other promoter variants, for effects on HTR2C transcription.. Six HTR2C promoter haplotypes constructed from four polymorphisms were cloned into a luciferase reporter gene plasmid. Their transcriptional activities were then compared in two human cell lines.. All haplotypes containing the -759C allele showed less transcriptional activity than haplotypes containing the -759T allele. The A allele of a -997G/A polymorphism was also associated with reduced expression.. These findings suggest that the -759C allele is functional and results in relative underexpression of HTR2C. Reduced expression of HTR2C mRNA may underlie vulnerability to weight gain following antipsychotic treatment.

Topics: Alleles; Antipsychotic Agents; Body Mass Index; Cell Line; Clozapine; Gene Expression; Genetic Markers; Haplotypes; Humans; Obesity; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Schizophrenia; Transcription, Genetic; Transfection; Weight Gain

Weight gain, leading to further morbidity and poor treatment compliance, is a common consequence of treatment with clozapine. The substantial interindividual and interracial differences in drug-induced weight gain suggest that genetic factors may be important. Several studies showed that alpha-2, adrenoceptor may related to feeding behavior with rat or lipolytic activity of human adipocyte tissue, they are related to body weight change. In the study, we try to test the possible relation of clozapine-induced weight gain and adrenergic receptor alpha 2a -1291C>G genetic polymorphism in a long term follow up (14.0 +/- 6.2 months). Our results show the genotype GG (8.45 +/- 7.2 Kg) with higher mean body weight gain than genotype CC (2.79 +/- 6.1 Kg) (p = 0.023). The finding identify a genetic factor associated with clozapine-induced weight gain in schizophrenic patients.

Topics: Adult; Antipsychotic Agents; Base Sequence; Clozapine; Cytosine; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Guanine; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Obesity; Point Mutation; Polymorphism, Genetic; Receptors, Adrenergic, alpha-2; Weight Gain

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

Second generation antipsychotics (SGA) are obesitogenic and diabetogenic. Role of ghrelin (RIA), resistin and TNF-alpha (ELISA) in weight gain and insulin resistance (fasting plasma insulin, HOMA, ELISA) was studied in Hungarian psychiatryic patients (n=60) treated with SGA (clozapine, olanzapine, risperidone, quetiapine, 15 each). After 1 year, 80% of patients became overweight/obese (BMI > 27/30) and 35% (n= 21/60) presented impaired glucose tolerance (13/60) or diabetes (8/60). Ghrelin (1.3 +/- 0.6 ng/ml), resistin (9.8 +/- 3.7 ng/ml), TNF-alpha (5.8 +/- 1.7 pg/ml), insulin (10.4 +/- 7.6 U/ml, HOMA A: 2.5 +/- 1.8, HOMA B: 133 +/- 62.5) were significantly higher in patients than in healthy matched controls. Resistin and TNF-alpha positively correlated with each other, insulin, HOMA, and negatively with ghrelin. Ghrelin contributes to weight gain, resistin and TNF-alpha to insulin resistance. A negative feedback regulation may exist between adipocytokines and ghrelin production. SGA drugs enhance ghrelin production despite the suppressive effect of adipocytokines. All four SGA drugs are equally obesitogenic and diabetogenic.

Topics: Antipsychotic Agents; Benzodiazepines; Carbohydrate Metabolism; Case-Control Studies; Clozapine; Dibenzothiazepines; Female; Ghrelin; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Obesity; Olanzapine; Overweight; Peptide Hormones; Quetiapine Fumarate; Resistin; Risperidone; Tumor Necrosis Factor-alpha; Weight Gain

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Clozapine; Diabetes Complications; Haloperidol; Humans; Obesity; Olanzapine; Piperazines; Quinolones; Risk Factors; Schizophrenia; Weight Gain

Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain.. The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002.. Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups.. Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Dibenzothiazepines; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Leptin; Male; Obesity; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Treatment Outcome; Triglycerides; Weight Gain

Topics: Antipsychotic Agents; Body Mass Index; Clozapine; Comorbidity; Female; Humans; Male; Middle Aged; Obesity; Schizophrenia; Sleep Apnea, Obstructive; Weight Gain

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Follow-Up Studies; Humans; Male; Obesity; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Weight Gain

Individuals with schizophrenia have standardised mortality rates which are double that of the general population. In addition to suicide, high rates of cardiovascular and respiratory disease contribute to this raised mortality rate. Although clozapine has been reported to improve psychotic symptoms and decrease suicide rates, attention has recently focussed on its potential to increase cardiovascular risk factors including obesity, dyslipidemia and diabetes mellitus. This study aimed to ascertain the prevalence of these risk factors in a cohort of Irish outpatients treated with clozapine.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Cholesterol; Clozapine; Cross-Sectional Studies; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Male; Middle Aged; Obesity; Outpatients; Triglycerides

Topics: Adult; Antipsychotic Agents; Bulimia; Clozapine; Diseases in Twins; Humans; Male; Obesity; Schizophrenia, Paranoid; Twins, Monozygotic; Weight Gain

Topics: Adrenal Gland Neoplasms; Adult; Antipsychotic Agents; Catecholamines; Clozapine; Female; Humans; Hypertension; Male; Obesity; Pheochromocytoma; Schizophrenia; Sweating; Syndrome; Tachycardia; Time Factors

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Cognitive Behavioral Therapy; Counseling; Exercise; Female; Humans; Male; Obesity; Olanzapine; Pirenzepine; Relaxation Therapy; Schizophrenia; Treatment Outcome; Weight Gain

We performed a retrospective analysis of data involving 121 inpatients to examine the rate of weight gain during antipsychotic-free periods and during treatment with various antipsychotic drugs.. Data were analyzed to determine differences in weekly weight change during antipsychotic-free (N = 65), typical antipsychotic (N = 51), or atypical antipsychotic (N = 130) treatment periods. Atypical antipsychotic treatment periods were further subdivided into olanzapine (N = 45), clozapine (N = 47), or risperidone (N = 36) treatment periods. A paired comparison was conducted on 65 patients who had an antipsychotic-free treatment period preceding or following a neuroleptic drug treatment period. In addition, patients were classified as either non-obese (with a body mass index [BMI] < or = 29.9 kg/ml) or obese (BMI > or = 30.0 kg/m2) to test whether the rate of weight gain during treatment periods was related to initial BMI.. Across all treatment periods, weekly weight gain was as follows: 0.89 lb/wk (0.40 kg/wk) on atypical antipsychotic medication, 0.61 lb/wk (0.27 kg/wk) on typical antipsychotic medication, and 0.21 lb/wk (0.09 kg/wk) on no antipsychotic medications. The atypical antipsychotic versus antipsychotic-free comparison was significant (F = 3.51; df = 2,231; p = .031), while the typical antipsychotic versus antipsychotic-free comparison was not. Among the individual atypical antipsychotic medications, significantly more weight gain occurred during olanzapine treatment (1.70 lb/wk) (0.76 kg/wk) than with either clozapine (0.50 lb/wk) (0.22 kg/wk) or risperidone (0.34 lb/wk) (0.15 kg/wk) treatments (F = 7.77; df = 2,117; p = .001). In the paired analysis with patients serving as their own controls, the difference between weekly weight gain during atypical antipsychotic treatment and antipsychotic-free treatment was significant (t = -3.91; df = 44; p = .001), while the difference between weight gain during typical antipsychotic treatment and antipsychotic-free treatment was not significant. With the individual drugs. treatment with both olanzapine and clozapine caused significantly higher weekly weight gain than antipsychotic-free treatment (p = .001 and p = .036, respectively). while treatment with risperidone did not. Non-obese patients (BMI < 29.9 kg/m2) and obese patients (BMI > 30.0 kg/m2) did not differ significantly in their weight gain during typical or atypical antipsychotic treatment.. Treatment with atypical antipsychotics was associated with more weight gain than treatment with typical antipsychotics. Among the atypical drugs, olanzapine was associated with more weight gain than either clozapine or risperidone. The patient's admission BMI was not associated with the amount of weight gained during subsequent antipsychotic treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Drug Administration Schedule; Female; Hospitalization; Humans; Male; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Regression Analysis; Research Design; Retrospective Studies; Risperidone; Schizophrenia; Weight Gain

Overweight is a considerable clinical problem in patients treated with antipsychotic agents. Recent results suggest that insulin resistance with increased insulin levels is also associated with treatment with the atypical antipsychotic agent clozapine. Leptin is important for the control of body weight and has been proposed to be a link between obesity and the insulin resistance syndrome. This study examined if clozapine-treated subjects and subjects treated with conventional antipsychotics had increased leptin levels compared with the general population and whether there was a gender difference in this respect.. Clozapine-treated patients (N = 41), patients treated with conventional antipsychotic drugs (N = 62), and healthy subjects from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project (N = 189) were investigated with a cross-sectional study design. Weight, body mass index (BMI), and plasma leptin concentrations were measured, and all study subjects were investigated for the presence of diabetes mellitus. Drug treatment, health status, and smoking habits were registered.. After adjustment for gender, BMI, smoking habits, age, and diabetes, hyperleptinemia was independently (p < .001) associated with clozapine treatment and with treatment with conventional antipsychotics (p < .005) within a multiple regression analysis. In separate multiple regression analyses, leptin levels were significantly associated with clozapine treatment in men (p = .002) and women (p =.023) and with conventional antipsychotic treatment in men (p = .027) but not in women.. Treatment with clozapine as well as with conventional antipsychotics is associated with increased levels of circulating leptin. Hyperleptinemia can be an important link in the development of overweight and the insulin resistance syndrome in subjects receiving antipsychotic drugs, especially atypical agents like clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Clozapine; Cross-Sectional Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Humans; Hyperinsulinism; Leptin; Male; Middle Aged; Obesity; Psychotic Disorders; Radioimmunoassay

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

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Obesity; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Weight Gain

Weight gain has been reported with nearly every antipsychotic drug on the market (molindone is an exception). Weight gain occurs no matter what the patient's age, sex, or race and is seen with both oral and depot drug formulations. Numerous studies have found that patients gain weight when treated with a conventional antipsychotic, such as chlorpromazine, fluphenazine, and haloperidol. The newer, novel antipsychotics offer advantages over conventional antipsychotics, especially a relative lack of extrapyramidal symptoms, but some still have the disadvantage of causing weight gain. Clozapine and olanzapine in particular appear to cause substantial weight gain, much more so than do most conventional neuroleptics and novel agents such as risperidone. Given the risks to health and treatment compliance associated with weight gain and obesity, clinicians should monitor weight during the course of antipsychotic therapy and consider switching agents if excessive weight gain occurs.

Topics: Administration, Oral; Antipsychotic Agents; Benzodiazepines; Clozapine; Delayed-Action Preparations; Humans; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Weight Gain

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Obesity; Olanzapine; Pirenzepine; Risperidone; Weight Gain

Topics: Adult; Age Factors; Ambulatory Care; Arkansas; Cause of Death; Clozapine; Comorbidity; Humans; Middle Aged; Obesity; Retrospective Studies; Risk Factors; Schizophrenia

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

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

The aim of this study was to determine the prevalence and clinical relevance of weight gain during clozapine treatment. Previous reports indicated clinically significant weight gain in 13% to 85% of patients and an average gain of 9.0 to 24.7 lb.. Twenty-one state hospital patients with treatment-resistant schizophrenia or schizoaffective disorder were weighed weekly for 12 weeks before clozapine treatment and during the first 16 weeks of treatment. Psychiatric symptoms were rated with a modified version of the Brief Psychiatric Rating Scale (BPRS).. The mean weight gain for the entire group was 13.9 lb, or 8.9% of body weight. During the 16 weeks of clozapine treatment, 38% of the patients experienced marked weight gains and 29% had moderate weight gains. The improvements in BPRS total score and composite negative symptom score were significantly greater for the eight patients with marked weight gains than for the other 13 patients.. Clozapine's propensity to induce weight gain may relate to the drug's efficacy and/or its unique neuropharmacologic effects. Increased attention to this phenomenon is important because of the morbidity associated with obesity.

Topics: Adult; Clozapine; Female; Humans; Male; Middle Aged; Obesity; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Weight Gain

Topics: Adolescent; Clozapine; Humans; Obesity; Psychotic Disorders; Schizophrenia; Weight Gain

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