clozapine and Weight-Gain

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

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

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

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

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

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

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

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

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

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

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

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

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

Clozapine (CLZ) is the prototype atypical antipsychotic and it has many advantages over other antipsychotic drugs. Several data suggest that both CLZ response and induced weight gain are strongly determined by genetic variability. However, results remain mainly inconclusive. We aim to review the literature data about pharmacogenetics studies on CLZ efficacy, focusing on pharmacodynamic genes. Further, we performed meta-analyses on response when at least three studies for each polymorphism were available. Sensitivity analyses were conducted on Caucasian population when feasible. Electronic literature search was performed to identify pertinent studies published until May 2014 using PubMed, ISI Web of Knowledge and PsycINFO databases. For meta-analyses, data were entered and analyzed through RevMan version 5.2 using a random-effect model. Our literature search yielded 9266 articles on CLZ; among these, we identified 59 pertinent pharmacogenetic studies. Genotype data were retrieved for 14 polymorphisms in 9 genes. Among these, we had available data from at least three independent samples for 8 SNPs in 6 genes to perform meta-analyses: DRD2 rs1799732, DRD3 rs6280, HTR2A rs6313, rs6311, rs6314, HTR2C rs6318, HTR3A rs1062613, TNFa rs1800629. Although literature review provided conflicting results, in meta-analyses three genetic variants within serotonin genes resulted associated to CLZ response: rs6313 and rs6314 within HTR2A gene and rs1062613 within HT3A gene. On the other hand, no clear finding emerged for CLZ-induced weight gain. Our results suggest a possible serotonergic modulation of CLZ clinical response.

Topics: Antipsychotic Agents; Clozapine; Databases, Factual; Humans; Mental Disorders; Pharmacogenetics; Weight Gain

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

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

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

Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Electroencephalography; Humans; Leptin; Metabolic Syndrome; Paraproteinemias; Receptor, Serotonin, 5-HT2C; Seizures; Weight Gain

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Numerous publications have provided evidence for clinically important metabolic adverse effects of antipsychotics, but there is no systematic evaluation as to whether weight gain and other metabolic changes are dose dependent.. This review of the available literature aimed to explore a possible relationship between dosage of second-generation antipsychotics (SGAs) and the degree of metabolic side effects.. A literature review was conducted in 3 steps: (1) Articles published between 1975 and 2004 were identified on the basis of the bibliography of an extensive review of the metabolic effects of SGAs. (2) Articles published between 2004 and 2008 were identified by a PubMed search with the keywords weight gain, metabolic, glucose, insulin, and lipid AND dose combined with amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, and ziprasidone. (3) A hand search was conducted based on the bibliography of the identified articles.. All studies that provided information on metabolic side-effects in different dose ranges were selected. Data extraction was carried out independently by 2 observers.. Preliminary evidence suggests a dose-response relationship between clozapine and olanzapine serum concentrations and metabolic outcomes, although the association between administered daily dose and metabolic outcomes is not clear. Data are controversial with regard to risperidone, and no study has as yet assessed risperidone serum concentrations in association with metabolic outcomes. For the other SGAs, there was little evidence to suggest a dose-response relationship, although, in these agents also, no assessment of serum concentrations was conducted.. The finding that metabolic complications may be associated with clozapine and olanzapine plasma concentrations provides further evidence for a causal contribution to the metabolic disturbances observed with these agents. Further well-designed, prospective studies investigating a possible association between SGA serum concentrations and metabolic outcomes are needed.

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Clozapine; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Insulin; Male; Metabolic Syndrome; Risperidone; Treatment Outcome; Triglycerides; Weight Gain

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Brain; Cardiomyopathies; Child; Clozapine; Dyskinesia, Drug-Induced; Energy Metabolism; Feeding Behavior; Female; Gene Expression; Genetic Association Studies; Humans; Male; Myocarditis; Olanzapine; Pericarditis; Risperidone; Tourette Syndrome; Twin Studies as Topic; Weight Gain

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D(2) receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and "high-dose" olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Disorders of Excessive Somnolence; Haloperidol; Humans; Olanzapine; Prolactin; Schizophrenia, Childhood; Treatment Outcome; Weight Gain

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

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

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

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

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

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

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

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

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

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

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

Five new antipsychotic drugs introduced in the United States in the last decade offer physicians the ability to treat patients with schizophrenia and bipolar mania without the adverse effects of the first-generation antipsychotics. In this article, the authors discuss the advantages and side effects of these agents and present a guide to help physicians choose the optimal drug in the most favorable formulation for each patient.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Drug Administration Schedule; Humans; Hyperprolactinemia; Mental Disorders; Olanzapine; Patient Compliance; Piperazines; Practice Guidelines as Topic; Prescription Fees; Quetiapine Fumarate; Quinolones; Risk Assessment; Risperidone; Thiazoles; Torsades de Pointes; Treatment Outcome; 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

Topics: Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyskinesias; Haloperidol; Humans; Hyperglycemia; Hyperprolactinemia; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Thioridazine; Weight Gain

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

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

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

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

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

Antidepressants and antipsychotics are frequently used as mood stabilizers in the treatment of bipolar disorder. As common as these agents appear to be in bipolar treatment, the literature contains little research on their efficacy and safety in the long term. Most of the available literature on long-term antidepressant treatment focuses on tricyclic antidepressants, which have been shown to induce mania or hypomania. Rapid cycling is another side effect that is associated with antidepressant treatment in bipolar disorder. Antidepressants do not appear to be any more effective than mood stabilizers in treating bipolar depression. Conventional antipsychotics in depot formulations have been shown to be an effective treatment, but conventional antipsychotics may cause tardive dyskinesia. The novel antipsychotics clozapine, risperidone, and olanzapine appear to be efficacious; however, their side effect profiles include agranulocytosis and weight gain. Given the frequency with which antidepressants and antipsychotics are used in bipolar disorder and that bipolar disorder is a chronic disease requiring maintenance treatment, more research on the use of these types of agents in long-term treatment is needed. Until more evidence is available on the long-term treatment outcomes, clinicians should be aware that the adverse events associated with antidepressants and antipsychotics may outweigh the benefit, if any, of the use of these agents in bipolar disorder.

Topics: Agranulocytosis; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Humans; Long-Term Care; Treatment Outcome; Weight Gain

The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs. In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000. Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight. The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics. Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Histamine H1; Receptors, Serotonin; Risk Factors; Smoking Cessation; Weight Gain

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

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

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

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

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

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

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

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

Hormonally related side effects of antipsychotic drugs, e.g. weight gain, hyperlipidemia and diabetes have come to the forefront in that the use of clozapine and new antipsychotics have increased. Hormones involved are prolactin, growth hormone (GH), insulin-like growth factor I (IGF-I), insulin and leptin. Patients treated with clozapine had lower levels of GH-dependent IGF-I than patients receiving classical antipsychotics. Patients treated with olanzapine had higher serum insulin levels than those receiving classical antipsychotics, indicating a probable influence of olanzapine on insulin secretion. In clozapine-treated patients the insulin levels correlated to the clozapine serum concentration, indicating a likely influence also of clozapine on insulin secretion. The gender difference, i.e. that women normally have higher leptin levels than men, was found in patients receiving classical antipsychotics, but not in patients treated with clozapine or olanzapine.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus; Female; Human Growth Hormone; Humans; Hyperlipidemias; Hyperprolactinemia; Insulin; Insulin-Like Growth Factor I; Lipids; Male; Prolactin; Weight Gain

Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment-resistant schizophrenic patients; unlike other antipsychotics, it causes minimal extrapyramidal side effects (EPS) and has little effect on serum prolactin. Despite these benefits, the use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. The occurrence of seizures appears to be dose-related and can generally be managed by reduction in clozapine dosage. Less serious and more common side effects of clozapine including sedation, hypersalivation, tachycardia, hypotension, hypertension, weight gain, constipation, urinary incontinence, and fever can often be managed medically and are generally tolerated by the patient. Appropriate management of clozapine side effects facilitates a maximization of the benefits of clozapine treatment, and physicians and patients alike should be aware that there is a range of benefits to clozapine use that is wider than its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Drug Monitoring; Humans; Respiration Disorders; Seizures; Sialorrhea; Weight Gain

To review systematically data relating to weight changes with atypical antipsychotics.. We conducted a Medline search on October 29 1999 and covered the period 1980-99. All recovered papers were examined for further relevant reports. In addition, we wrote to pharmaceutical manufacturers and 10 practising clinicians to ask them to provide other relevant reports known to them.. Eighty reports mentioning change in body weight were retrieved. Data relating to weight changes were of variable quality. Weight changes were indicated by a variety of measures. The majority of reports related to short-term changes.. All atypical drugs, with the exception of ziprasidone, have been associated with weight increases. Clozapine seems to have the highest risk of weight gain, followed by olanzapine and quetiapine. There is probably a lower risk with risperidone, sertindole and zotepine and a still lower risk with amisulpride. Ziprasidone appears not to be associated with weight gain. In the absence of more compelling data, these rankings must be considered approximate and preliminary. Longer, more robust trials are needed.

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

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

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

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

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

Since its introduction to the United States in 1990, the benefits of clozapine use have been repeatedly validated. Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia. Because clozapine has been part of the psychiatric pharmacopeia for considerably less time than neuroleptics, which have dominated the field for over 4 decades, its underutilization may be partly attributed to a lack of experience in managing associated side effects. Most side effects associated with clozapine are typical of antipsychotics in general, and with clozapine, these side effects are typically benign, tolerable, and manageable. It is conceivable that there remains a concern over the risk of agranulocytosis. However, the mandatory blood monitoring carried out through the Clozaril National Registry has considerably reduced the incidence of fully developed cases of agranulocytosis from premarketing values of approximately 1% to 2% to current values of 0.38% and virtually prevented mortalities. These values are likely to decrease further with the application of cytokine augmentation therapy among patients developing blood dyscrasias. Many side effects of clozapine are observed early after treatment onset and are greatly reduced by dose adjustments. Appropriate management of side effects will facilitate a maximization of the benefits of clozapine treatment. Clearly, the benefits of clozapine therapy far outweigh its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Drug Administration Schedule; Drug Monitoring; Humans; Incidence; Risk Factors; Schizophrenia; Sleep Wake Disorders; Tachycardia; Urinary Incontinence; Weight Gain

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

Most traditional neuroleptics have a narrow therapeutic-to-toxic index, and thus, the novel antipsychotics are the result of a search to substantially widen the distance between the dose that treats psychosis and the one that produces adverse effects. In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole. These profiles, which were compared with that of the typical neuroleptic haloperidol, provide guidance for predicting the adverse effects produced by these drugs. Most conventional antipsychotics have central nervous system effects, particularly extrapyramidal symptoms (EPS) and tardive dyskinesia, sedation, and dulling of cognition. Other adverse effects of the typical antipsychotics include the neuroleptic malignant syndrome, orthostatic hypotension, changes in liver function, anticholinergic and antiadrenergic side effects, sexual dysfunction, and weight gain. The newer agents have a lower incidence of EPS and tardive dyskinesia, while weight gain and changes in blood pressure and liver function tests are adverse effects that have been associated with the use of the newer agents. The favorable side effect profile of these new antipsychotics is likely to make patients more willing to continue treatment, and thus these agents represent a step forward in the treatment of patients with severe, chronic mental illness.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Receptors, Neurotransmitter; Seizures; Sleep; Weight Gain

Although neuroleptic drugs have become the mainstay of treating acute and chronic psychosis, they are substantially limited by troublesome side effects. The traditional neuroleptic drugs have a wide array of central nervous system and peripheral system side effects that often lead to problems in management or patient noncompliance. Of particular difficulty are the extrapyramidal symptoms and tardive dyskinesia. However, other side effects of seizures, sedation, neuroleptic malignant syndrome and cardiovascular, hematologic, endocrinological, and weight gain problems remain as clinical management challenges posed by existing antipsychotic drug therapy. Considerable progress has been made in improving the motor side effect profile with the advent of clozapine and risperidone. However, each of these drugs has its own dose-limiting side effect profile. Two new drugs, olanzapine and sertindole, are now added to the pharmacopeia for treating psychosis. They further improve the benefit/ risk ratio because they have even fewer EPS and other side effects. Overall, these new antipsychotic agents greatly improve the treatment of psychosis by reducing drug-induced morbidity and improving the quality of life for patients.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Imidazoles; Indoles; Neuroleptic Malignant Syndrome; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Schizophrenia; Seizures; Sleep; Weight Gain

Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans.. Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics.. Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

Topics: Adult; Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Humans; Male; Mice; Prospective Studies; Schizophrenia; Weight Gain

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

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

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

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

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

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

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

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

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genotype; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; Prospective Studies; Risperidone; Schizophrenia; Single-Blind Method; Tumor Necrosis Factor-alpha; Weight Gain

Glutamate antagonists such as topiramate have been proposed based on the glutamate hypothesis of schizophrenia because its properties encourage its exploration and possible development as a medication for the treatment of schizophrenia. A randomised, double-blind, placebo-controlled clinical trial was performed on 18- to 45-year-old patients with schizophrenia. Baseline information including vital signs, height, weight, smoking status, demographic characteristics, (past) psychiatric history, medication history and medication-related adverse effects were collected. Patients were randomly assigned to a topiramate or placebo group. Efficacy of medication was measured by administering Positive and Negative Syndrome Scale (PANSS), and tolerability of treatment was recorded on day 0 (baseline), day 28 and day 56. PANSS values (95% confidence interval) at baseline, day 28 and day 56 in the topiramate group were 96.87 (85.37-108.37), 85.68 (74.67-96.70) and 76.87 (66.06-87.69), respectively; compared with 101.87 (90.37-113.37), 100.31 (89.29-111.32) and 100.56 (89.74-111.37) in the placebo group. General linear model for repeated measures analysis showed that topiramate has lowered PANSS values significantly compared with the placebo group. Similar significant decline patterns were found in all three subscales (negative, positive and psychopathology sign). Clinical response (more than 20% reduction in PANSS) was significantly higher in topiramate-treated subjects than controls (50% vs 12.5%). Topiramate can be an effective medication in controlling schizophrenic symptoms, considering its effect on negative symptoms and controlling antipsychotic-associated weight gain.

Topics: Adolescent; Adult; Anti-Obesity Agents; Anticonvulsants; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology; Topiramate; Weight Gain

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapine's and olanzapine's similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapine's differential effects on interleukin-6.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cytokines; Double-Blind Method; Female; Fever; Humans; Leptin; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Weight Gain

Clozapine is associated with significant weight gain. However, it is still debatable whether the majority of weight gain occurs in the early phase of treatment or if weight gain is a persistent side effect. The inconsistent results in previous outpatient studies may be due to many confounding factors, such as variations in drug adherence, diet content, activity level and environmental factors. The objective of this study was to investigate long-term weight changes in hospitalized Chinese schizophrenic patients treated with clozapine.. Patients were admitted at the largest mental hospital in Taiwan and had routine monthly body weight monitoring during the study period. Retrospective chart reviews were conducted to obtain demographic data, age at which clozapine treatment was initiated, and weight changes after the initiation of clozapine treatment.. The study sample consisted of 349 hospitalized schizophrenic patients, including 204 males (58.8%), with an average age at clozapine initiation of 38.6+/-9.3 and an average clozapine dosage of 318+/-9.3 mg/day. Body weight increased over time, and reached a plateau at month 42. Younger age at clozapine initiation (P=0.0038) and lower baseline body mass index (BBMI) (P<0.0001) were associated with more weight gain. The patients with BBMI<25 gained significantly more weight (10.98+/-8.48 kg) compared to patients with BBMI>or=25 (1.17+/-13.29 kg) (P=0.004).. Similar to reports on Caucasians, clozapine-associated weight gain in Chinese patients reached a plateau at month 42. Younger patients with normal BBMI were associated with higher risk of weight gain.

Topics: Adult; Antipsychotic Agents; Asian People; Body Mass Index; Clozapine; Cohort Studies; Female; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Schizophrenia; Weight Gain

The second-generation antipsychotic agents clozapine and olanzapine have been associated with weight gain and increased lipid and glucose blood levels. Since some of the neurotransmitters that are impaired in aggressive patients are involved in lipid/glucose metabolism, aggressive patients may represent a subgroup with a differential profile of adverse metabolic reactions to these medications. The goal of this study was to assess the effects of clozapine and olanzapine in comparison to the first-generation agent haloperidol on these metabolic parameters in aggressive patients with schizophrenia.. 110 inpatients with schizophrenia and a history of physical assaults were included in a randomized double-blind 12-week study. Fasting glucose, cholesterol and triglycerides were collected at baseline and at the end of the study. Ninety-three patients provided blood samples at baseline and at least at one point after randomization to clozapine (N=34), olanzapine (N=31) or haloperidol (N=28).. There were significant differences among the three medication groups in weight gain and in increases in blood lipids and glucose. Patients on haloperidol showed no increase on any of these parameters. Patients on olanzapine gained the most weight, but patients on clozapine had the greatest increases in cholesterol, triglyceride, and glucose. An effect of ethnicity was observed, as African-American patients were more likely to develop metabolic abnormalities than other ethnic groups, especially on clozapine.. In this prospective randomized trial, clozapine and olanzapine were associated with weight gain. Clozapine was associated with increases in both lipids and glucose. This effect was most prominent in the African-American patients.

Topics: Adult; Aggression; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Clozapine; Double-Blind Method; Ethnicity; Female; Haloperidol; Humans; Inpatients; Lipid Metabolism; Male; Middle Aged; Olanzapine; Prospective Studies; Schizophrenia; Weight Gain; Young Adult

Clozapine, despite its side-effect burden, has been considered to be the drug of choice for patients with schizophrenia whose psychotic symptoms fail to respond adequately to other anti-psychotic drugs. There are conflicting data concerning the potential utility of olanzapine in treatment-resistant schizophrenia at doses beyond the 10- to 20-mg/day range that has proven to be effective for most nonrefractory patients with schizophrenia.. The main objective of this study was to compare the efficacy and tolerability of high-dose olanzapine (target dose, 25-45 mg/day) and clozapine (300-900 mg/day) in patients with schizophrenia or schizoaffective disorder who had failed to respond adequately to prior treatment with other antipsychotic drugs.. This 6-month, randomized, double-blind, parallel-group study compared the efficacy and tolerability of olanzapine (mean dose, 34 mg/day; N = 19) or clozapine (mean dose, 564 mg/day; N = 21) in patients with treatment-resistant schizophrenia or schizoaffective disorder, diagnosed according to DSM-IV criteria. Outcome measures included psychopathology, cognitive performance (as assessed with a comprehensive neuropsychological test battery), and tolerability. The study was conducted between May 2000 and December 2003.. Robust and significant (mostly p < .001) improvement in multiple measures of psychopathology, mainly between 6 weeks and 6 months of treatment, was found in both treatment groups, with no significant difference between the 2 treatments except for the Global Assessment of Functioning score, which favored clozapine (p = .01). Improvement in some domains of cognition was significant-and equivalent for both drugs, as well. Nonsignificantly different improvement in Verbal List Learning-Immediate Recall (p < .05), Controlled Word Association Test (p < .05), and Digit Symbol Substitution Test (p < .001) was found. There were no significant differences in extrapyramidal symptoms. Weight gain was significantly (p = .01) greater with olanzapine.. Olanzapine, at higher than customary doses, demonstrated similar efficacy to clozapine in treatment-resistant schizophrenia and schizoaffective disorder in this study. However, the small sample size precludes definitively concluding that the 2 treatments are equivalent, at these doses, in treatment-resistant schizophrenia. The metabolic side effects of olanzapine are a limitation in its use.. ClinicalTrials.gov identifier NCT00179231.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Time Factors; Treatment Outcome; Weight Gain

Possible variables associated with weight gain during clozapine treatment include dosing, treatment duration, baseline body mass index (BMI), sex, and plasma norclozapine concentrations. Weight gains during a double-blind, randomized clozapine study using 100-, 300-, and 600-mg/d doses were analyzed. It was hypothesized that weight gain was associated with baseline BMI, clozapine dosing, and demographic factors. The possible contribution of plasma clozapine and norclozapine concentrations was explored. Fifty treatment-refractory schizophrenia patients were randomized to 100-, 300-, or 600-mg/d doses of clozapine for a 16-week, double-blind treatment in a research ward. Nonresponsive patients went onto a second and/or a third 16-week, double-blind treatment at the other doses. Weights of patients were measured every week. During the first clozapine treatment, weight gain varied across 3 baseline BMI categories (normal-weight patients [4.1 kg, P < 0.001], overweight patients [2.6 kg, P = 0.05], and obese patients [0.36 kg, not significant]) and according to dosing (600 mg/d [4.4 kg], 300 mg/d [2.6 kg], and 100 mg/d [1.3 kg]). Sex had no effect after controlling for baseline BMI and dose, but the African-American race had a strong significant effect despite the small number of African Americans (n = 6). At the end of the first clozapine treatment, plasma norclozapine concentration was not significantly correlated with weight gain in the total sample (r = 0.16, P = 0.32, n = 43), but seems to be strongly correlated in nonsmokers. Despite its limitations, this study indicates that baseline BMI, dosing, and, possibly, the African-American race may be major determinants of clozapine-induced weight gain.

Topics: Antipsychotic Agents; Body Mass Index; Clozapine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Risk Factors; Smoking; Weight Gain

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

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

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

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

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

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale 0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale 0-6: clozapine, 36.6 +/- 8.8 to 15.9 +/- 13.7; olanzapine, 36.7 +/- 9.9 to 19.1 +/- 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 +/- 0.6 to 2.5 +/- 1.5; olanzapine, 4.5 +/- 0.6 to 2.3 +/- 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Appetite; Benzodiazepines; Blood Pressure; Body Mass Index; Bulimia; Clozapine; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Fatigue; Female; Heart Rate; Humans; Male; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia; Sialorrhea; Treatment Outcome; Weight Gain

We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m2) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Clozapine; Female; Ghrelin; Humans; Leptin; Longitudinal Studies; Male; Peptide Hormones; Prospective Studies; Schizophrenia; Schizophrenia, Catatonic; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Weight Gain

Weight gain, a common adverse effect of clozapine, may impair health and affect patient compliance during treatment with this agent. The aim of this study was to investigate the relationship between genetic variants of the adrenergic beta3 receptor (ADRB3) and the G-protein beta3 subunit (GNB3) and clozapine-induced body weight change (BWC). Eighty-seven treatment-resistant schizophrenic patients were weighed before and after 4 months of clozapine treatment, with the subjects gaining an average of 2.6 kg in body weight. No statistically significant relationship was demonstrated for the investigated ADRB3 Trp64Arg and the GNB3 C825T polymorphisms in terms of BWC post-treatment, suggesting these two polymorphisms do not play a significant role in clozapine-induced BWC. Further exploration of other genetic variants implicated in clozapine-induced BWC is important, however, in order to predict and reduce clozapine-associated weight gain.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Female; GTP-Binding Proteins; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Adrenergic, beta-3; Schizophrenia; Weight Gain

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

Adjunctive fluvoxamine inhibits clozapine metabolism and decreases plasma norclozapine (a toxic metabolite of clozapine) to clozapine ratios. This study aimed to demonstrate the effects of fluvoxamine on clozapine-related weight gain, hyperglycemia, and lipid abnormalities.. Sixty-eight treatment-resistant inpatients with a DSM-IV diagnosis of schizophrenia were randomly assigned to 2 treatment groups for 12 weeks. The monotherapy group (N = 34) received clozapine (< or = 600 mg/day). The coadministration group (N = 34) received fluvoxamine (50 mg/day) plus low-dose clozapine (< or = 250 mg/day). The study was conducted from August 1999 to October 2002.. The 2 groups were similar in demographic data; baseline body weight and body mass index (BMI); baseline serum glucose, triglyceride, and cholesterol levels; and steady-state plasma clozapine concentration. The monotherapy patients (but not the coadministration patients) had significantly higher (p < .05) body weight, BMI, and serum glucose and triglyceride levels after treatment than at baseline. At week 12, the monotherapy patients also had significantly higher glucose (p = .035), triglyceride (p = .041), and norclozapine (p = .009) (and numerically higher cholesterol) levels than the cotreatment patients. The changes in weight and serum glucose and triglyceride levels were significantly correlated (p = .026, p = .005, and p = .028, respectively) with the plasma concentration of norclozapine but not with plasma levels of clozapine.. These results suggest that fluvoxamine cotreatment can attenuate weight gain and metabolic disturbances in clozapine-treated patients. Plasma levels of norclozapine, but not clozapine, are associated with increases in weight and serum glucose and triglyceride levels. Of note, coadministration of fluvoxamine could increase plasma clozapine levels markedly and carry the risk of adverse events. If this combined treatment is applied, conservative introduction with reduced clozapine dosage and careful therapeutic drug monitoring of clozapine concentration is recommended.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Cholesterol; Clozapine; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Hyperglycemia; Hyperlipidemias; Male; Middle Aged; Selective Serotonin Reuptake Inhibitors; Triglycerides; Weight Gain

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

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

We examined the effects of long-term clozapine treatment, concurrent treatment with beta-adrenergic antagonists, and clozapine-induced weight gain on serum glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for schizophrenia or schizoaffective disorder, participated in a 10-week, double-blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine trial, and had available serum glucose and lipid levels. Weight and glucose, and lipid laboratory values were measured at the baseline and throughout the double-blind and year-long study. There were significant increases in serum triglyceride, total cholesterol, and glucose levels during the course of clozapine treatment. There were no significant changes in high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had additive effects on changes in the total cholesterol and triglycerides, with propranolol having the most pronounced effects. Propranolol and atenolol had no significant effect on the serum glucose levels. There were significant correlations between the triglyceride and HDL level changes and clozapine-associated weight gain during the study. There were no significant correlations between the change in serum total cholesterol, LDL, or glucose and weight gain. Clozapine therapy has adverse effects on glucose and lipid homeostasis, with clozapine-induced changes in serum glucose likely due to the inherent pharmacological properties of clozapine. Concurrent beta-adrenergic receptor antagonist treatment may have an additive effect on serum lipids, and clozapine-associated weight gain also plays a modest role in triglyceride increases.

Topics: Adrenergic beta-Antagonists; Adult; Analysis of Variance; Antipsychotic Agents; Atenolol; Blood Glucose; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Haloperidol; Humans; Lipids; Male; Propranolol; Psychotic Disorders; Schizophrenia; Statistics, Nonparametric; Weight Gain

The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors' goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial.. One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period.. One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22).. In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Hospitalization; Humans; Hypercholesterolemia; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Prospective Studies; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperazines; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome; Weight Gain

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

This study compares medication continuation and regimen compliance with the atypical antipsychotic medication clozapine versus the conventional antipsychotic haloperidol.. Data from a 15-site double-blind, randomized clinical trial (N = 423) were used to compare patients with DSM-III-R schizophrenia assigned to clozapine or haloperidol in terms of duration of participation while taking the randomly assigned study drug (continuation) and the proportion of prescribed pills that were taken (compliance). Multiple regression analysis was used to determine the relationship of baseline characteristics and measures of clinical change to continuation for the entire sample and for patients assigned to each medication.. Patients assigned to clozapine continued taking the study drug for a mean of 35.5 weeks as compared with only 27.2 among patients assigned to haloperidol (F = 4.45, df = 1,422; p = .0001). No differences were found between the groups in the proportion of prescribed pills that were returned at any timepoint. Among patients assigned to haloperidol, poorer continuation was associated with being older and greater continuation with receiving public support. Among patients on clozapine treatment, continuation was poorer among African American patients and greater among patients who showed reduced clinical symptoms and akathisia. Continuation with clozapine was greater even after adjusting for these factors.. Continuation with medication is greater with clozapine than haloperidol and is partly explained by greater symptom improvement and reduced side effects. No differences were found in regimen compliance.

Topics: Adult; Antipsychotic Agents; Black or African American; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Haloperidol; Humans; Male; Patient Compliance; Patient Dropouts; Regression Analysis; Schizophrenia; Treatment Outcome; Treatment Refusal; Weight Gain

There has been an absence of controlled studies focusing specifically on neuroleptic treatment in the elderly schizophrenic population. Therefore, we conducted a 12-week double-blind comparison study to assess the efficacy and tolerability of clozapine and chlorpromazine in a group of elderly inpatients with chronic schizophrenia.. Forty-two elderly DSM-IV schizophrenic veterans were randomly assigned to clozapine or chlorpromazine and assessed for efficacy at baseline and at termination with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions scale (CGI). Side effects were also monitored. Medications were titrated, on the basis of clinical response and side effects, to a maximum dose of 300 mg/day of clozapine or 600 mg/day of chlorpromazine.. The results suggest that both the chlorpromazine and clozapine groups improved their PANSS scores at termination compared with baseline, but the difference between the 2 groups was not statistically significant. The mean CGI scores reflecting severity of illness also demonstrated improvement in both groups over time. Both groups had similar incidences of side effects. One patient in each group had a life-threatening side effect. More patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients noted sedation.. We concluded that both clozapine and chlorpromazine are effective treatments for psychosis and behavioral disturbances in geriatric schizophrenia. Both agents had similar incidences of side effects. With careful monitoring and titration of dosage, both clozapine and chlorpromazine were fairly well tolerated in this population.

Topics: Age Factors; Aged; Agranulocytosis; Antipsychotic Agents; Chlorpromazine; Clozapine; Double-Blind Method; Humans; Intestinal Pseudo-Obstruction; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

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

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

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

The aim of this study was to assess the prevalence and magnitude of weight changes pre- and post-clozapine and to explore the ability of demographic and clinical factors to predict weight gain at 12 months post-clozapine.. Weight changes in a sample of 51 patients were assessed at 3 months pre-clozapine, at baseline, and at 3 and 12 months post-clozapine. In addition, demographic data and information concerning changes in appetite and activity level at 3 months was gathered and used to predict weight gain at 12 months.. Seventy percent of patients gained an average of 7.5 kg (10.6% increase in baseline body weight) over the 12-month period. Although post-clozapine weight gain for the total group was significant at 12 months, weight gain for the female subsample (n = 16) did not reach significance at either the 3 or 12 month assessments. The only factors associated with marked weight gain (> 15% increase) at 12 months were increased food intake early in treatment and having gained weight at 3 months.. Clozapine treatment was found to be associated with significant weight gain in patients prescribed clozapine, especially male patients. Considering the long-term health risks associated with excess weight gain, health professionals can play an important role in educating clients about the potential for weight gain with clozapine treatment.

Topics: Adult; Aged; Antipsychotic Agents; Behavioral Symptoms; Clozapine; Eating; Female; Humans; Logistic Models; Male; Middle Aged; Prospective Studies; Risk Factors; Schizophrenia; Weight Gain

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

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

This study examined whether clozapine induces more weight gain than haloperidol and whether weight gain is related to clinical improvement.. The weight and symptoms of 39 outpatients with schizophrenia who were randomly assigned to double-blind treatment with either clozapine or haloperidol were assessed. The weight and symptoms of 33 of the patients who chose to take clozapine during a 1-year follow-up after the study ended were also assessed.. The patients treated with clozapine gained significantly more weight over baseline (7%) than the haloperidol-treated patients (1%). Weight gain was not significantly correlated with improvements in either positive or negative symptoms. Fifty-eight percent of the patients followed for 1 year gained at least 10% over their baseline weight.. Weight gain is an important side effect of clozapine and is unrelated to the drug's differential antipsychotic efficacy.

Topics: Ambulatory Care; Clozapine; Double-Blind Method; Follow-Up Studies; Haloperidol; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

Patients were investigated to gain more insight into the incidence and time course of clozapine induced weight gain (n = 81) and to compare weight gain in patients treated with clozapine (n = 31) with that of patients treated with standard antipsychotics (haloperidol, n = 11). 35.7% of the patients treated with clozapine gained weight according to our definition. If patients gained weight on clozapine this side effect was apparent within the first 12 weeks of treatment. Deviation from normal body weight at the beginning of treatment showed a significant influence on weight gain. Sex, severity of illness, comedication, mean clozapine dose and degree of improvement did not show an influence on this side effect. Weight increase was significantly higher in patients treated with clozapine than in patients treated with haloperidol.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Haloperidol; Humans; Male; Schizophrenia; Weight Gain

Periodontitis is a highly prevalent disease in psychiatric patients, including those undergoing symptomatic treatment with second-generation antipsychotics. Some of these drugs, such as clozapine (CLO) and olanzapine (OLA), have prominent metabolic effects such as weight gain, hyperglycemia, and dyslipidemia, which are risk factors for periodontitis. In addition to the metabolic effects, there are reports of changes in salivary flow, gingival bleeding, and caries. In this context, we aimed to evaluate if the metabolic effects of OLA and CLO alter periodontal parameters in an animal model of periodontitis without the environmental and psychosocial biases inherent to human diseases.. In the first set of experiments, male and female adult Wistar rats received oral administration of CLO, OLA, or vehicle for 45 days. They were evaluated for body mass composition and weight gain, blood glucose parameters (fasting and glucose tolerance and insulin resistance tests), and lipid profile (HDL, total cholesterol, and triglycerides). In a second set of experiments, the same measurements were performed in female rats exposed to the antipsychotics for 45 days and ligature-induced periodontitis on the 30th day of treatment. Macroscopic measurements of exposed roots, microtomography in the furcation region of the first molar, and histological evaluation of the region between the first and second molars were evaluated to assess bone loss. Additionally, gingival measurements of myeloperoxidase activity and pro-inflammatory cytokine TNF-α were made.. Only females exposed to OLA had more significant weight gain than controls. They also exhibited differences in glucose metabolism. Ligature-induced periodontitis produced intense bone retraction without changing the density of the remaining structures. The bone loss was even higher in rats with periodontitis treated with OLA or CLO and was accompanied by a local increase in TNF-α caused by CLO. These animals, however, did not exhibit the same metabolic impairments observed for animals without periodontitis.. The use of clozapine and olanzapine may be a risk factor for periodontal disease, independent of systemic metabolic alterations.

Topics: Adult; Animals; Antipsychotic Agents; Bone Diseases, Metabolic; Clozapine; Female; Humans; Male; Olanzapine; Periodontitis; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Weight Gain

Antipsychotic-induced metabolic adverse effects are risk factors for cardiometabolic comorbidities. Whether dose lowering could mitigate such effects remains unclear. The present study aims to investigate the associations between clozapine doses and modifications of weight, blood pressure, blood glucose, and lipid levels.. Linear mixed-effects models of weight changes over 1 year and of variations of other metabolic parameters over 4 months were applied to a prospective cohort of 115 patients. Age- and sex-stratified analyses of weight changes were also performed.. Each 100 mg dose increment of clozapine was associated on average with a +0.48% weight increase (P = .004) over 1 year of treatment. Weight increase was greater for treatment duration ≤3 vs >3 months (+0.84% and +0.47% per month, respectively, P < .001), with a significant association with the dose for durations >3 months (+0.54%, P = .004) and a trend for durations ≤3 months (+0.33%, P = .075). Dose increments of 100 mg were also associated with weight increases of +0.71% among adults (P = .001), +1.91% among the elderly (P < .001) and +1.32% among men (P < .001) with no associations among women (P = .62). Among young adults, weight change was positively associated with doses ≤300 mg/day (+2.19% per 100 mg, P = .001), whereas no association was found with doses >300 mg/day (P = .60). No significant effect of clozapine dose on other metabolic parameters was found.. This study reports a modest effect of clozapine dose increases on weight gain over 1 year with differences among age categories and sexes and no dose effect on other metabolic parameters over 4 months.

Topics: Aged; Antipsychotic Agents; Clozapine; Female; Humans; Infant; Male; Prospective Studies; Risk Factors; Weight Gain; Young Adult

Patients diagnosed with schizophrenia are characterized by early mortality compared to the general population. The main cause of this premature death reflects medical complications linked to metabolic syndrome (MetS). The use of antipsychotics such as clozapine is associated with weight gain and metabolic disturbances in certain predisposed individuals. Non-pharmacological interventions for weight control have become a key element for secondary prevention in the health of patients diagnosed with schizophrenia. Here, we aim to evaluate the physical health effects of a nurse-led non-pharmacological intervention program in patients with a diagnosis of schizophrenia treated with clozapine. Thirty-one outpatients from the outpatient clinical facility of Hospital Clinic in Barcelona, Spain diagnosed with schizophrenia and other psychotic disorders receiving clozapine treatment were enrolled in a prospective interventional study, comprising an 8-week group program of therapeutic education in a healthy lifestyle. MetS factors, physical activity, diet, and lifestyle were evaluated at baseline, post-intervention (8 weeks), and 3 months after the program. Weight, body mass index, high-density lipoprotein cholesterol, and diet patterns displayed significant differences post-intervention and after 3 months, while only waist, hip perimeter, and lifestyle improved post-intervention. Our results suggest the effectiveness of the lifestyle intervention in patients under clozapine treatment despite its long-time differential effect. Strategies to prevent weight gain and metabolic decline will help prevent premature cardiometabolic disease in this vulnerable population.

Topics: Antipsychotic Agents; Clozapine; Humans; Life Style; Metabolic Syndrome; Nurse's Role; Prospective Studies; Schizophrenia; Weight Gain

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapine-associated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n = 698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4 % of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6 %), weight gain (69.3 %), and increased sleep necessity (65.9 %), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10 %). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Prevalence; Sex Characteristics; Weight Gain

Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain.. We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes.. Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only.. In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Humans; Male; Metformin; Retrospective Studies; Schizophrenia; Weight Gain

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

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

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Cytochrome P-450 CYP1A2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Retrospective Studies; Serotonin; Weight Gain

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

Schizophrenia is one of the major neuropsychiatric disorders affecting people worldwide. Unfortunately, currently available antipsychotic medications possess several side effects. Among them, clozapine is one of the atypical antipsychotics prescribed in schizophrenia wing to its blocking effect on dopamine (D2) and serotonin (5-HT

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Clozapine; Flavanones; Humans; Rats; Weight Gain

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms.. This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia.. In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed.. Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels.. The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.

Topics: Animals; Antipsychotic Agents; Clozapine; Female; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hypoglycemic Agents; Liraglutide; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT. We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT. These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT

Topics: Animals; Antipsychotic Agents; Clozapine; Eating; Feeding Behavior; Male; Motivation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT1; Reinforcement Schedule; Serotonin Antagonists; Weight Gain

Mining the data contained within Electronic Health Records (EHRs) can potentially generate a greater understanding of medication effects in the real world, complementing what we know from Randomised control trials (RCTs). We Propose a text mining approach to detect adverse events and medication episodes from the clinical text to enhance our understanding of adverse effects related to Clozapine, the most effective antipsychotic drug for the management of treatment-resistant schizophrenia, but underutilised due to concerns over its side effects.. We used data from de-identified EHRs of three mental health trusts in the UK (>50 million documents, over 500,000 patients, 2835 of which were prescribed Clozapine). We explored the prevalence of 33 adverse effects by age, gender, ethnicity, smoking status and admission type three months before and after the patients started Clozapine treatment. Where possible, we compared the prevalence of adverse effects with those reported in the Side Effects Resource (SIDER).. Sedation, fatigue, agitation, dizziness, hypersalivation, weight gain, tachycardia, headache, constipation and confusion were amongst the highest recorded Clozapine adverse effect in the three months following the start of treatment. Higher percentages of all adverse effects were found in the first month of Clozapine therapy. Using a significance level of (p< 0.05) our chi-square tests show a significant association between most of the ADRs and smoking status and hospital admission, and some in gender, ethnicity and age groups in all trusts hospitals. Later we combined the data from the three trusts hospitals to estimate the average effect of ADRs in each monthly interval. In gender and ethnicity, the results show significant association in 7 out of 33 ADRs, smoking status shows significant association in 21 out of 33 ADRs and hospital admission shows the significant association in 30 out of 33 ADRs.. A better understanding of how drugs work in the real world can complement clinical trials.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Databases, Factual; Female; Hospitals, Psychiatric; Humans; Infant; Male; Middle Aged; Olanzapine; Piperazines; Risperidone; Schizophrenia; Thiazoles; Weight Gain

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

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

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

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

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

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

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

Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the hypothalamus and an important regulator of energy homeostasis; however, the specific contributions of different CART neuronal populations to this process are not known. Here, we show that depolarization of mouse arcuate nucleus (Arc) CART neurons via DREADD technology decreases energy expenditure and physical activity, while it exerts the opposite effects in CART neurons in the lateral hypothalamus (LHA). Importantly, when stimulating these neuronal populations in the absence of CART, the effects were attenuated. In contrast, while activation of CART neurons in the LHA stimulated feeding in the presence of CART, endogenous CART inhibited food intake in response to Arc CART neuron activation. Taken together, these results demonstrate anorexigenic but anabolic effects of CART upon Arc neuron activation, and orexigenic but catabolic effects upon LHA-neuron activation, highlighting the complex and nuclei-specific functions of CART in controlling feeding and energy homeostasis.

Topics: Adipose Tissue, Brown; Animals; Arcuate Nucleus of Hypothalamus; Behavior, Animal; Body Temperature; Clozapine; Dependovirus; Eating; Energy Metabolism; Hypothalamic Area, Lateral; Injections; Integrases; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Neurotransmitter Agents; Physical Conditioning, Animal; Reproducibility of Results; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Schizophrenia; Weight Gain

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

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

Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.

Topics: Adipose Tissue, White; Animals; Antipsychotic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Clozapine; Disease Models, Animal; Glucose; Glucose Metabolism Disorders; Humans; Lipid Metabolism; Lipid Metabolism Disorders; Liver; Metabolic Networks and Pathways; Olanzapine; Rats; Sterol Regulatory Element Binding Proteins; Weight Gain

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

Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Among them, clozapine is the most effective medication for treatment-resistant schizophrenia and is most helpful in controlling aggression and the suicidal behavior in schizophrenia and schizoaffective disorder. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, it is well known for the weight gain and metabolic side effects, which expose the patient to a greater risk of cardiovascular disorders and premature death, as well as psychosocial issues, leading to non-adherence to therapy. The mechanisms underlying these iatrogenic metabolic disorders are still controversial. We have therefore investigated the in vivo effects of the selective PKCβ inhibitor, ruboxistaurin (LY-333531), in a preclinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry, and behavioral tests have been performed in wild-type and PKCβ knockout mice to investigate the contribution of endogenous PKCβ and its pharmacological inhibition to the psychomotor effects of clozapine. Finally, we also shed light on a novel aspect of the mechanism underlying the clozapine-induced weight gain, demonstrating that the clozapine-dependent PKCβ activation promotes the inhibition of the lipid droplet-selective autophagy process. This paves the way to new therapeutic approaches to this serious complication of clozapine therapy.

Topics: Animals; Antipsychotic Agents; Cells, Cultured; Clozapine; Drug Delivery Systems; Enzyme Inhibitors; Indoles; Male; Maleimides; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Kinase C beta; Time Factors; Weight Gain

Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.

Topics: Adult; Animals; Antidepressive Agents; Antipsychotic Agents; Body Mass Index; Cholestadienols; Clozapine; Dehydrocholesterols; Female; Haloperidol; Humans; Lipid Metabolism; Male; Mental Disorders; Psychiatric Status Rating Scales; Random Allocation; Rats, Sprague-Dawley; Weight Gain

Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG.. Schizophrenia or schizoaffective disorder subjects (n = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates.. Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (P<0.05). In the replication analysis two SNPs rs3134701 (P = 0.043) and rs12662510 (P = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG.. This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genetic Association Studies; Humans; Male; Middle Aged; Olanzapine; Orexin Receptors; Polymorphism, Single Nucleotide; Risperidone; Schizophrenia; United States; Weight Gain; White People; Young Adult

Weight gain on clozapine is highly variable and poorly predictable. Its mechanisms are not well understood. This study explores the factors that predict weight gain between 3 and 12 months of clozapine therapy in community-dwelling patients.. We conducted a retrospective audit of patients attending an outpatient clozapine clinic. Weight change from 3 to 12 months of therapy was recorded, expressed as a percentage of the 3-month weight. Univariate analyses compared percent weight change according to sex, smoking status, country of birth, and baseline body mass index. Correlations between weight gain, age, and clozapine dose were explored. A general linear model identified independent predictors of weight gain.. The mean weight change from 3 to 12 months in 117 patients was +3.1% (range, -17% to +30%). Females gained more weight than males (+5.5% vs +1.3%, P = 0.01), smokers gained more than nonsmokers (+5.1% vs +1.2%, P = 0.02), and obese patients gained less than normal or overweight individuals (0.15% vs 4.6% and 5.2%, respectively, P = 0.01). Age and clozapine dose had no relation to weight change. On multivariate analysis, baseline BMI and smoking status remained independent predictors of percent weight change in females. These 2 predictors explained 25% of weight change in females in the first 3 to 12 months of therapy. These associations were not observed in males.. We hypothesize that smoking affects weight change by promoting clozapine metabolism to norclozapine via cytochrome P450 enzymes. Verifying this hypothesis and exploring the mechanisms underpinning the sex dichotomy are areas for further research.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Clozapine; Cohort Studies; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Schizophrenia; Sex Characteristics; Smoking; Treatment Outcome; Weight Gain; Young Adult

Topics: Adolescent; Antipsychotic Agents; Clozapine; Disease Management; Humans; Male; Metformin; Pancreatitis; Schizophrenia; Weight Gain

Receptors for antipsychotics in the hypothalamus contribute to antipsychotics-induced weight gain; however, many of these receptors are also expressed in the intestine. The role of these intestinally-expressed receptors, and their potential modulation of nutrient absorption, have not been investigated in the context of antipsychotics-induced weight gain. Here we tested the effect of dietary fructose and intestinal fructose uptake on clozapine-induced weight gain in mice. Weight gain was determined in wild type mice and mice lacking the GLUT5 fructose transporter that were "orally-administered" 20mg/kg clozapine for 28 days. To assess the role of dietary fructose, clozapine-treated mice were fed controlled diets with different levels of fructose. Effect of clozapine treatment on intestinal fructose transport activity and expression levels of various receptors that bind clozapine, as well as several genes involved in gluconeogenesis and lipogenesis were measured using real-time RT-PCR and western blotting. Oral administration of clozapine significantly increased body weight in wild type C57BL/6 mice but not in GLUT5 null mice. The clozapine-induced weight gain was proportional to the percentage of fructose in the diet. Clozapine-treated mice increased intestinal fructose uptake without changing the intestinal expression level of GLUT5. Clozapine-treated mice expressed significantly higher levels of intestinal H1 histamine receptor in the wild type but not GLUT5 null mice. Clozapine also increased the intestinal expression of fructokinase and several genes involved in gluconeogenesis and lipogenesis. Our results suggest that increased intestinal absorption and metabolism of fructose contributes to clozapine-induced weight gain. Eliminating dietary fructose might prevent antipsychotics-induced weight gain.

Topics: Animals; Antipsychotic Agents; Clozapine; Dietary Carbohydrates; Disease Models, Animal; Fructokinases; Fructose; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 5; Intestinal Absorption; Mice; Mice, Inbred C57BL; Mice, Knockout; Weight Gain

To investigate INSIG2's association with obesity, weight change and serum lipid profile during clozapine treatment.. Subjects with schizophrenia (n = 190) were genotyped, identifying seven SNPs. Genetic risk scores (GRSs) were calculated to adiponectin, high-density lipoprotein cholesterol, triglycerides and weight gain.. In the model for weight gain, SNPs rs12151787, rs17047733 and rs10490626 were selected. Explanatory variables were BMI (p = 5.05 × 10. INSIG2 plays a role in weight gain and obesity during clozapine treatment.

Topics: Adiponectin; Adult; Antipsychotic Agents; Cholesterol, HDL; Clozapine; Dyslipidemias; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Schizophrenia; Weight Gain

Administration of second-generation antipsychotic drugs (SGAs) often leads to weight gain and consequent cardio-metabolic side effects. We observed that clozapine but not six other antipsychotic drugs reprogrammed the gene expression pattern of differentiating human adipocytes ex vivo, leading to an elevated expression of the browning marker gene UCP1, more and smaller lipid droplets and more mitochondrial DNA than in the untreated white adipocytes. Laser scanning cytometry showed that up to 40% of the differentiating single primary and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes had the characteristic morphological features of browning cells. Furthermore, clozapine significantly upregulated ELOVL3, CIDEA, CYC1, PGC1A and TBX1 genes but not ZIC1 suggesting induction of the beige-like and not the classical brown phenotype. When we tested whether browning induced by clozapine can be explained by its known pharmacological effect of antagonizing serotonin (5HT) receptors, it was found that browning cells expressed 5HT receptors 2A, 1D, 7 and the upregulation of browning markers was diminished in the presence of exogenous 5HT. Undifferentiated progenitors or completely differentiated beige or white adipocytes did not respond to clozapine administration. The clozapine-induced beige cells displayed increased basal and oligomycin-inhibited (proton leak) oxygen consumption, but these cells showed a lower response to cAMP stimulus as compared with control beige adipocytes indicating that they are less capable to respond to natural thermogenic anti-obesity cues. Our data altogether suggest that novel pharmacological stimulation of these masked beige adipocytes can be a future therapeutic target for the treatment of SGA-induced weight gain.

Topics: Adipocytes, Beige; Adipocytes, Brown; Adipocytes, White; Adult; Aged; Antipsychotic Agents; Arrhythmias, Cardiac; Cell Differentiation; Cells, Cultured; Clozapine; Cyclic AMP; DNA, Mitochondrial; Female; Gene Expression; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Intellectual Disability; Lipid Droplets; Male; Middle Aged; Oxygen Consumption; Phenotype; Receptors, Serotonin; Thermogenesis; Uncoupling Protein 1; Up-Regulation; Weight Gain; Young Adult

Metabolic disturbances are major adverse side effects in the treatment of schizophrenia patients with antipsychotics. A substantial proportion of patients discontinue treatment with second-generation antipsychotics due to weight gain. The objective of this study was to investigate molecular factors predisposing patients to the development of such metabolic disturbances.. We investigated whether serum molecules measured before treatment initiation were associated with subsequent weight gain following a 6-week treatment with antipsychotics. The concentrations of 191 molecules were measured longitudinally in serum from 77 schizophrenia patients using multiplex immunoassays.. This showed that the levels of 10 serum molecules at T0 were significantly associated with ΔBMI, which included interleukin-6 receptor, epidermal growth factor and thyroid stimulating hormone.. Our results suggest that patients who experience antipsychotic-induced weight gain have specific molecular alterations already prior to treatment. Further studies are required to validate and evaluate current findings in the context of response and side-effect development. This may ultimately lead to molecular tests that can aid in the selection of antipsychotic treatments.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Clozapine; Disease Susceptibility; ErbB Receptors; Female; Humans; Male; Middle Aged; Receptors, Interleukin-6; Receptors, Thyrotropin; Risperidone; Schizophrenia; Weight Gain; Young Adult

Clozapine treatment is associated with weight gain and cardio-metabolic consequences among patients with schizophrenia. Polymorphisms of leptin, serotonin receptor HTR2C and adiponectin genes have been associated with antipsychotic-induced weight gain and metabolic comorbidity. However, the results of the studies so far are inconclusive. The aim of the present study was first to test for a possible role of serum leptin and adiponectin levels as a marker of weight gain in association with inflammatory cytokines/adipokines (IL-6, IL-1Ra, hs-CRP and adipsin), and second to study associations between SNPs LEP rs7799039 (-2548 A/G), ADIPOQ rs1501299 and HTR2C rs1414334 and weight gain and levels of leptin and adiponectin, in 190 patients with schizophrenia on clozapine treatment, with retrospectively assessed weight change and cross-sectionally measured cytokine levels. A strong association was found between serum levels of leptin and weight gain and cytokines/adipokines related to metabolic comorbidity, especially among female patients (in women leptin vs. weight gain, IL-6 and IL-1Ra, P<0.001; in men leptin vs. weight gain, P=0.026, leptin vs. IL-1Ra, P<0.001). In male patients low adiponectin level was a more specific marker of clozapine-induced weight gain (P=0.037). The results of the present study do not support a major role of SNPs LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of weight gain or association of serum levels of leptin and adiponectin and corresponding studied SNPs in patients with schizophrenia on clozapine treatment.

Topics: Adiponectin; Adult; Antipsychotic Agents; Biomarkers; C-Reactive Protein; Clozapine; Complement Factor D; Cross-Sectional Studies; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Retrospective Studies; Schizophrenia; Weight Gain

Second-generation antipsychotics (SGAP) and mood stabilizers (MS) are prescribed widely for the treatment of bipolar disorder, but they are associated with the risk of relevant side-effects, among which is weight gain. The identification of genes that predispose to weight gain would represent a useful tool to evaluate the risk-benefit ratio of treatment.. This study investigated the genetic factors associated with weight gain in bipolar patients treated with SGAP, MS and their combinations (n=486). Single-nucleotide polymorphisms belonging to 16 candidate genes supported by the literature were investigated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) genome-wide dataset. Linear regression models were constructed including age, sex, initial weight and prescription of SGAP at high risk for inducing weight gain (olanzapine or clozapine) as covariates. Genes harbouring single-nucleotide polymorphisms associated with phenotypes were investigated by a pathway analysis.. No association was found between phenotypes and individual polymorphisms or pathways after multiple-test correction. HTR2C, LEP, FTO and TBC1D1 represented the top genes for weight gain during treatment with a SGAP and/or MS. A genome-wide signal (FTO rs9930506) associated previously with obesity was associated with psychotropic-induced weight gain. The genes that influenced both SGAP and MS weight gain were FTO, TBC1D1, MTHFR and HRH1. ADCY9, ADCY5 and PRKAG2 were interesting candidate genes that emerged from the pathway analysis.. This study was the first to compare the genes involved in SGAP-induced and MS-induced weight gain. Individual genes probably play a limited role in psychotropic-induced weight gain; further studies should focus on the extension from known candidate genes to wider groups of molecular pathways.

Topics: Adipose Tissue; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeostasis; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Psychotropic Drugs; Weight Gain

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

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

GLP-1 plays a key role in glucose metabolism and influences antipsychotic-induced weight gain (AIWG). Our study is the first to investigate the encoding gene, GCG, and the GLP-1 receptor gene, GLP1R, and association with AIWG.. In 216 schizophrenic patients treated with antipsychotics for up to 14 weeks, we investigated four GCG and 33 GLP1R polymorphisms. Statistical analyses were conducted using SPSS, Haploview 4.2, UNPHASED 3.1.4 and the R-package mbmdr.. We observed association of rs13429709 near GCG with AIWG (p(corr) = 0.044) in patients of European ancestry receiving olanzapine or clozapine (n = 87). We also found significant gene-gene interaction between rs13429709 and rs2268639 in GLP1R. Only nonsignificant trends were observed for GLP1R polymorphisms with AIWG.. We found significant association of rs13429709 with AIWG. Although there was no significant finding for GLP1R, the observed trends and interaction suggest this to be an interesting gene for further examination.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Genetic Association Studies; Genotype; Glucagon-Like Peptide-1 Receptor; Humans; Male; Olanzapine; Polymorphism, Single Nucleotide; Receptors, Glucagon; Schizophrenia; Weight Gain; White People

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

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

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

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

Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment.. The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined.. PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46 ± 1.06 U/ml, p < 0.001; risperidone 50.57 ± 1.54 U/ml, p < 0.01; control 52.27 ± 1.34 U/ml). A similar pattern was observed for the PON(DHC)/HDL-cholesterol (HDLC) ratio. On the contrary, PON(PO) and PON(PA) were increased in the treated group, but the corresponding paraoxonase/HDLC ratios were not significantly different from controls, except for PON/HDLC in the clozapine group. TEAC and GAP were only decreased in the clozapine-treated group.. In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP.

Topics: Adult; Antipsychotic Agents; Aryldialkylphosphatase; Cardiovascular Diseases; Clozapine; Female; Humans; Lipids; Male; Middle Aged; Risk Factors; Risperidone; Schizophrenia; Weight Gain

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

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

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

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

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

Although many patients with schizophrenia fail to respond adequately to trials of 2 or more antipsychotics, utilization of clozapine for these patients remains low, despite recommendations for its use by accepted treatment guidelines. Some experts estimate that 5-10 times more patients could benefit from clozapine than who are now receiving it. Learning how to manage the unique side effect profile of clozapine can potentially remove barriers to prescribing this agent and thus unlock its unique therapeutic efficacy for more patients.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus; Eosinophilia; Humans; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Sialorrhea; Tachycardia; Weight Gain

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

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

The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Biological Availability; Coumarins; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; In Vitro Techniques; Isoxazoles; Lethal Dose 50; Mice; Motor Activity; Prolactin; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Dopamine D3; Structure-Activity Relationship; Weight Gain

Clozapine increases meal size and meal duration, effects similar to the pharmacological blockade or congenital deficiency of CCK-1 receptor. We aimed to investigate the role of CCK-1 receptor in clozapine-induced weight gain and insulin sensitivity in CCK-1 receptor deficient, male Otsuka Long Evans Tokushima Fatty rats (OLETF). Long Evans Tokushima Otsuka (LETO) rats served as healthy control. Animals were orally treated with either clozapine (10mg/kg) or its vehicle over 25 days. Daily metabolic parameters were measured by metabolic cages. The insulin sensitivity was determined by hyperinsulinaemic euglycaemic glucose clamping (HEGC). Adiposity was determined by measuring the perirenal, intraabdominal and epididymal white adipose tissue fat pads. Hypothalamic mRNA expression of CCK-1 and CCK-2 receptor was measured by real-time PCR, plasma insulin by radioimmunoassay. Clozapine failed to increase weight gain or daily food intake, but it increased adiposity, 1st meal size and duration and decreased insulin sensitivity both in OLETF or LETO rats. The glucose infusion rate during the steady state of the HEGC was unaltered, but the metabolic clearance rate of insulin was reduced by the clozapine treatment. Hypothalamic mRNA of CCK-1 and CCK-2 receptor was elevated in LETO rats, but the mRNA of CCK-2 receptor was reduced by clozapine in OLETF rats. Our results suggest that the CCK-1 receptor has no direct role in the clozapine-induced adiposity and insulin resistance. We also demonstrated that atypical antipsychotic treatment can induce insulin resistance in the absence of manifest obesity in male rats.

Topics: Animals; Body Composition; Clozapine; Feeding Behavior; Gene Expression Regulation; Glucose; Insulin Resistance; Male; Rats; Rats, Inbred OLETF; Receptors, Cholecystokinin; RNA, Messenger; Time Factors; Weight Gain

Antipsychotic-induced weight gain (AIWG) may result in the metabolic syndrome in schizophrenia (SCZ) patients. Downstream variants of the melanocortin-4 receptor (MC4R) gene have been associated with obesity in various populations. Thus, we examined single-nucleotide polymorphisms (SNPs) in the MC4R region for association with AIWG in SCZ patients. Four SNPs (rs2229616, rs17782313, rs11872992 and rs8087522) were genotyped in 224 patients who underwent treatment for SCZ and were evaluated for AIWG for up to 14 weeks. We compared weight change (%) across genotypic groups using analysis of covariance for three SNPs (r²≤0.8). European-ancestry patients who were rs8087522 A-allele carriers (AG+AA) on clozapine gained significantly more weight than non-carriers (P=0.027, n=69). These observations were marginal after correction for multiple testing. We performed in vitro electrophoretic mobility-shift assay that suggested that the presence of the A-allele may create a transcription factor-binding site. Further investigation is warranted for both these exploratory findings.

Topics: Adult; Alleles; Antipsychotic Agents; Clozapine; Electrophoretic Mobility Shift Assay; Female; Genetic Association Studies; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Melanocortin, Type 4; Schizophrenia; Weight Gain

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

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

Significant body weight gain (BWG) is a serious adverse effect of a number of antipsychotic drugs. Previous studies have demonstrated an influence of clozapine, but not haloperidol, on neuropeptide Y (NPY) expression in the hypothalamus. Because NPY is a potent orexigenic peptide stimulating food intake, and genetic variation of the gene has been shown to influence development of obesity, we investigated the impact of NPY polymorphisms on antipsychotic-induced BWG.We analyzed 5 polymorphisms in the NPY gene (rs10551063, rs16147, rs5573, rs5574, and rs16475) in schizophrenia subjects (n = 226), treated mostly with clozapine and olanzapine for up to 14 weeks. Association was tested using analysis of covariance with change (%) from baseline weight as the dependent variable and duration of treatment and baseline body weight as covariates.In patients of European ancestry who received either clozapine or olanzapine, significant genotypic and allelic association of rs16147 with weight change was observed (P(corrected) = 0.012 and 0.018, respectively). Carriers of the C allele gained significantly more weight compared with individuals with TT genotype (CC + CT vs TT; 5.82% ± 5.6% vs 2.25% ± 4.8%; P= 0.001). Similarly, 2 other polymorphisms (rs5573 and rs5574) were also significantly associated with weight change (P(corrected) = 0.018 and 0.03). In addition, we observed a significant gene-gene interaction between the rs16147 in NPY and rs806378 in cannabinoid receptor 1 (P(corrected) = 0.011).Our observation of association of NPY polymorphisms gives further evidence for a genetic influence on antipsychotic-induced BWG and suggests a role of NPY gene in influencing this complex adverse effect.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Black or African American; Chi-Square Distribution; Clozapine; Female; Gene Frequency; Genotype; Germany; Humans; Male; Middle Aged; Neuropeptide Y; New York; Ohio; Olanzapine; Phenotype; Polymorphism, Single Nucleotide; Receptor, Cannabinoid, CB1; Risk Assessment; Risk Factors; Schizophrenia; Weight Gain; White People; Young Adult

Early and effective treatment in first-episode schizophrenia is associated with better outcomes. Evidence suggests that response is generally robust in a first antipsychotic trial, but a marked reduction in response rate is observed among patients for whom a second trial is warranted, and even further reductions are seen in subsequent trials. Clozapine, the treatment of choice in refractory schizophrenia, is routinely employed only as a third-line treatment, and it has been shown to markedly enhance the rate of response, even when compared with other atypical antipsychotics. This raises the question of whether clozapine would be more effectively positioned as a first-line treatment. Current evidence addressing this question does not support this position, although the limited data available and methodological issues preclude a firm conclusion. Practical issues related to clozapine use, in combination with the robust response reported for other agents when used as first-line treatment, certainly call into question the likelihood that clozapine would be chosen if it were an option at this stage. In contrast, the notable reduction in response rate to second-line treatments, coupled with clozapine's substantial response rate in refractory schizophrenia and evidence indicating better outcomes with early, effective treatment, makes a compelling argument for research examining clinical and functional outcomes with clozapine positioned as a second-line treatment.

Topics: Age of Onset; Agranulocytosis; Algorithms; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Resistance; Drug Tolerance; Episode of Care; Humans; Medication Therapy Management; Outcome and Process Assessment, Health Care; Pharmacovigilance; Schizophrenia; Treatment Outcome; Weight Gain

This study aims to investigate whether orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain.. In the current study, we examined whether a single intraperitoneal injection of clozapine or olanzapine induced metabolic disturbances in adult female outbred Sprague-Dawley rats. Serum glucose and lipid parameters were measured during time-course experiments up to 48 h. Real-time quantitative PCR was used to measure specific transcriptional alterations in lipid and carbohydrate metabolism in adipose tissue depots or in the liver.. Our results demonstrated that acute administration of clozapine or olanzapine induced a rapid, robust elevation of free fatty acids and glucose in serum, followed by hepatic accumulation of lipids evident after 12-24 h. These metabolic disturbances were associated with biphasic patterns of gluconeogenic and lipid-related gene expression in the liver and in white adipose tissue depots.. Our results support that clozapine and olanzapine are associated with primary effects on carbohydrate and lipid metabolism associated with transcriptional changes in metabolically active peripheral tissues prior to the development of drug-induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Carbohydrate Metabolism; Clozapine; Fatty Acids, Nonesterified; Female; Lipid Metabolism; Olanzapine; Rats; Rats, Sprague-Dawley; Time Factors; Weight Gain

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

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

Weight gain is a common problem of treatment with atypical antipsychotics. However, the dimension of body weight change differs interindividually, and various genetic factors are considered to be associated with this effect. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism and its reported relationship to type 2 diabetes susceptibility and body mass accumulation prompted us to investigate the impact of this single nucleotide polymorphism (SNP) on antipsychotic-induced changes of body weight and body mass index (BMI) in a naturalistic study design.. Included were 138 olanzapine- and 32 clozapine-treated psychiatric inpatients whose demographic data, medical anamnesis, and drug treatment were assessed at admission to hospital and 4 weeks thereafter. The PPARG Pro12Ala SNP was determined with a validated real-time PCR assay.. In contrast to previous investigations, we did not detect significant variations of weight gain among the different PPARG Pro12Ala genotypes.. Our results suggest that the examined polymorphism appears to play a minor or no role in clinical practice concerning antipsychotic drug-induced weight gain.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Female; Genetic Association Studies; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; PPAR gamma; Weight Gain; Young Adult

Brown adipose tissue is specialized to burn lipids for thermogenesis and energy expenditure. Second-generation antipsychotics (SGA) are the most commonly used drugs for schizophrenia with several advantages over first-line drugs, however, it can cause clinically-significant weight gain. To reveal the involvement of brown adipocytes in SGA-induced weight gain, we compared the effect of clozapine, quetiapine, and ziprasidone, SGA with different propensities to induce weight gain, on the differentiation and the expression of brown fat-specific markers, lipogenic genes and adipokines in a mouse brown preadipocyte cell line. On Oil Red-O staining, the differentiation was inhibited almost completely by clozapine (40 μM) and partially by quetiapine (30 μM). Clozapine significantly down-regulated the brown adipogenesis markers PRDM16, C/EBPβ, PPARγ2, UCP-1, PGC-1α, and Cidea in dose- and time-dependent manners, whereas quetiapine suppressed PRDM16, PPARγ 2, and UCP-1 much weakly than clozapine. Clozapine also significantly inhibited the mRNA expressions of lipogenic genes ACC, SCD1, GLUT4, aP2, and CD36 as well as adipokines such as resistin, leptin, and adiponectin. In contrast, quetiapine suppressed only resistin and leptin but not those of lipogenic genes and adiponectin. Ziprasidone (10 μM) did not alter the differentiation as well as the gene expression patterns. Our results suggest for the first time that the inhibition of brown adipogenesis may be a possible mechanism to explain weight gain induced by clozapine and quetiapine.

Topics: Adipocytes, Brown; Adipogenesis; Adipokines; Animals; Antipsychotic Agents; Cell Differentiation; Cell Line; Cell Survival; Clozapine; Dibenzothiazepines; Gene Expression Regulation; Humans; Mice; Piperazines; Quetiapine Fumarate; Schizophrenia; Thiazoles; Weight Gain

Metabolic syndrome is an important side effect associated with clozapine. It has been hypothesized that weight gain contributes to the development of metabolic syndrome, but a direct diabetogenic effect has also been suggested. We conducted an 8-year cohort study to determine the association between weight gain and metabolic parameters among schizophrenic patients taking clozapine.. This study is a retrospective cohort study combining a cross-sectional survey of metabolic syndrome and retrospective chart review. The subjects were hospitalized schizophrenic patients (DSM-IV) who began to receive clozapine at least 3 months before the survey (March to September 2005) and subsequently had monthly body weight monitoring. Anthropometric and biochemical measurements were performed to determine the presence of metabolic syndrome. The chart reviews were conducted to obtain gender, age at initiation of clozapine treatment, baseline body mass index (BMI), BMI changes after the initiation of clozapine treatment, treatment duration with clozapine, and concomitant psychotropic medications.. One hundred eighty-nine patients were maintained on clozapine for a mean ± SD treatment duration of 57.6 ± 27.3 months (range, 5-96). The prevalence of metabolic syndrome was 28.4%. The cohort regression models showed that baseline BMI (P < .01) and BMI change after clozapine treatment (P < .01) were significant factors for metabolic syndrome and 4 metabolic parameters except hyperglycemia, which was related to treatment duration (P < .05).. For patients treated with clozapine, metabolic syndrome and most metabolic parameters were related to weight gain; however, glucose dysregulation was associated with treatment duration independent of weight gain. The results confirm that monitoring body weight is important, but periodic monitoring of blood sugar may also be required for clozapine patients who do not have significant weight gain.

Topics: Adult; Age Factors; Antipsychotic Agents; Body Mass Index; Clozapine; Cross-Sectional Studies; Female; Humans; Logistic Models; Male; Metabolic Syndrome; Regression Analysis; Retrospective Studies; Schizophrenia; Sex Factors; Weight Gain

Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Brain; Clozapine; Eating; Energy Metabolism; Feeding Behavior; Female; Male; Mice; Mice, Transgenic; Neurons; Weight Gain

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.

Topics: Agouti-Related Protein; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Arcuate Nucleus of Hypothalamus; Benzodiazepines; Clozapine; Feeding Behavior; Female; Gene Expression Regulation; Hyperphagia; Hypothalamus; Injections, Intraventricular; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Neuropeptides; Olanzapine; Orexins; Phosphorylation; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Ribonucleotides; Signal Transduction; Weight Gain

Weight gain and metabolic abnormalities are serious side effects associated with the use of several second generation antipsychotics (SGA). The adipose tissue has been considered a direct SGA target involved in the development of these adverse effects. Recent studies, mainly using murine cells, have suggested that SGA increase both adipogenesis of preadipocytes and lipid accumulation in mature adipocytes. However, to date there has been little research comparing the effects of antipsychotics with different propensities to induce weight gain on human in vitro models of white adipose tissue neoformation and metabolism. The present study aimed to investigate the effects of antipsychotics either strongly associated with weight gain, such as the SGA clozapine and olanzapine, or not, such as the SGA ziprasidone and the classical antipsychotic haloperidol, on proliferation and adipocyte differentiation of human adipose-derived stem cells (ADSCs) and lipogenesis in human mature adipocytes. Whereas ziprasidone induced elevated levels of cell death during adipogenesis and could not be investigated further, we observed that clozapine, olanzapine and haloperidol had slight stimulatory effects on the transcriptional program of ADSCs adipogenesis. However, the observed changes in adipocyte-specific genes were not accompanied by a significant increase in triglyceride accumulation within differentiated adipocytes. Our data also showed that these three antipsychotics displayed inhibitory effects on the proliferation rates of undifferentiated ADSCs. Regarding mature adipocyte metabolism, we observed that olanzapine slightly inhibited insulin-stimulated lipogenesis at the highest concentration used, and haloperidol exerted the strongest inhibitory effects on both basal and insulin-stimulated lipogenesis. Taken together, our results suggest that a direct and potent effect of clozapine and olanzapine on adipose tissue biology is not an important mechanism by which these SGA induce metabolic disturbances in humans. On the other hand, the haloperidol-mediated downregulation of the lipogenic capacity of human adipose tissue may be a possible mechanism contributing to its lower propensity to induce serious metabolic side effects.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Haloperidol; Humans; Olanzapine; Piperazines; Thiazoles; Weight Gain

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain-Derived Neurotrophic Factor; Clozapine; Female; Genetic Association Studies; Haplotypes; Humans; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risperidone; Schizophrenia; Weight Gain; Young Adult

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

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

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

The aim of our study was to investigate the impact of typical and atypical antipsychotic drugs on leptin concentration in blood and changes in the receptor expression in the hypothalamus of male Wistar rats.. From the age of 13 to 18 weeks, three groups of 20 animals were fed an average dose of 3.5 + 0.03 mg/ kg body weight (BW) haloperidol; 30.6 + 0.22 mg/kg BW clozapine; or 14.9 + 0.13 mg/kg BW ziprasidone in ground food pellets containing 15% fat. Twenty control animals received no drugs. Blood samples were taken at week 14, 16, and 19. Locomotor activity and exploratory behavior were measured using the alcove test at weeks 15 and 17. The expression of the hypothalamic leptin receptor in rat brains was determined by using a Western blot.. Rats medicated with haloperidol and ziprasidone showed a significantly decreased percentage weight gain and food consumption. We observed no differences in the alcove test, but locomotor activity was significantly reduced in the haloperidol group. Except for rats in the clozapine and ziprasidone groups, after 2 weeks of drug application, we found no changes in the leptin blood concentrations among the four groups or animals within each group. Moreover, we did not find specific differences in hypothalamic leptin receptor expression among the groups.. We concluded that in male Wistar rats during this treatment period, the tested drugs did not act directly on the leptin regulatory system. We recommend further studies using long-term treatment of different rat strains.

Topics: Animals; Antipsychotic Agents; Blotting, Western; Clozapine; Eating; Exploratory Behavior; Haloperidol; Hypothalamus; Leptin; Male; Motor Activity; Piperazines; Rats; Rats, Wistar; Receptors, Leptin; Thiazoles; Time Factors; Weight Gain

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

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

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1 and INSIG2) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (P=0.0003-0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.

Topics: Adolescent; Adult; Antipsychotic Agents; Chi-Square Distribution; Child; Clozapine; Female; Genetic Linkage; Genetic Predisposition to Disease; Haplotypes; Humans; Intracellular Signaling Peptides and Proteins; Lipogenesis; Male; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Retrospective Studies; Schizophrenia; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Sterol Regulatory Element Binding Proteins; Weight Gain; Young Adult

Clozapine is an atypical antipsychotic indicated for the treatment of refractory schizophrenia. Clozapine treatment is associated with the metabolic side effects. Weight gain, hyperlipidemia and hyperglycemia are the risk factors for onset of diabetes and cardiovascular disorders. We report a case vignette of a patient in whom the decrease in negative and general psychopathology after adjunctive aripiprazole appeared simultaneously with a reduction of clozapine-induced increase in weight and metabolic measures. Combined application of clozapine and aripiprazole is in accordance with a neurobiological rationale and appears to be a safe and well tolerated.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Drug Therapy, Combination; Humans; Male; Piperazines; Quinolones; Schizophrenia, Paranoid; Weight Gain

The aim of this study was to evaluate long-term weight gain associated with clozapine, olanzapine, and risperidone treatment and its clinical risk factors in children and adolescents. At four child and adolescent psychiatric departments, the weight and body mass index of initially hospitalized patients (aged 9.0-21.3 years) treated with clozapine (n = 15), olanzapine (n = 8), and risperidone (n = 10) were prospectively monitored for 45 weeks. Clinical risk factors (age, gender, baseline weight, dosage, drug-naivety) were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint. The absolute and percentage average weight gains were significantly higher for the olanzapine group (16.2 +/- 8.8 kg; 30.1 +/- 18.9%) than for the clozapine (9.5 +/- 10.4 kg; 14.8 +/- 15.8%) and the risperidone (7.2 +/- 5.3 kg; 11.5 +/- 6.0%) groups. Olanzapine is associated with extreme long-term weight gain in children and adolescents that, in addition, is much higher than that expected in adults. Clozapine and risperidone are associated with a less marked weight gain in children and adolescents but also much higher than that expected in adults. These differences may affect compliance with medication and health risk.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Child; Clozapine; Female; Hospitals, Psychiatric; Humans; Inpatients; Male; Olanzapine; Patch-Clamp Techniques; Risk Factors; Risperidone; Weight Gain; Young Adult

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

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

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

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

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

The atypical antipsychotic drugs (AAPDs) have markedly enhanced the treatment of schizophrenias but their use has been hindered by the major weight gain elicited by some AAPDs. We report that orexigenic AAPDs potently and selectively activate hypothalamic AMP-kinase, an action abolished in mice with deletion of histamine H1 receptors. These findings may afford a means of developing more effective therapeutic agents and provide insight into the hypothalamic regulation of food intake.

Topics: Adenylate Kinase; Animals; Antipsychotic Agents; Enzyme Activation; Hypothalamus; Immunohistochemistry; Mice; Phosphorylation; Receptors, Histamine H1; Weight Gain

The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzoxazines; Biogenic Monoamines; Humans; Hyperprolactinemia; Indoles; Metabolic Diseases; Phthalimides; Piperazines; Principal Component Analysis; Pyridines; Radioligand Assay; Receptors, Biogenic Amine; Weight Gain

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

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

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

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

Significant weight gain is a serious side effect of many antipsychotic medications, yet successful strategies for significant weight loss are lacking. The transtheoretical model for weight management can be used to identify people who are ready to change (contemplation-preparation group) their eating habits and physical activity. This study compared characteristics of patients in Canada who had a psychotic disorder and were ready to make lifestyle changes with characteristics of patients who were not considering lifestyle changes.. Participants were surveyed to determine their stages of change for eating habits and physical activity, and various characteristics were measured, including body mass index, body image, nutritional intake, and level of physical activity.. A total of 101 participants (64 men) (mean+/-SD age 35+/-11 years) were taking antipsychotic medications. Seventy-one percent had schizophrenia spectrum disorders, and 15% had affective psychosis. The prevalence of patients identified as being ready for change was higher than expected: 68% for eating habits and 54% for physical activity. Participants who were ready to change eating habits were also ready to change physical activity habits (p<.04). Stages of change for eating habits were associated with body mass index (p<.004), whereas stages of change for physical activity were associated with self-reported vigorous (p<.001) and moderate (p<.005) physical activity but not mild physical activity.. Clinicians may help patients develop healthier eating and physical activity habits by using the transtheoretical model, because it identifies patients who are ready to change to healthier lifestyle strategies and may help patients with antipsychotic-induced weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise; Feeding Behavior; Female; Health Knowledge, Attitudes, Practice; Humans; Life Style; Male; Middle Aged; Nutrition Surveys; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Weight Gain

Cyproheptadine is a cheap, widely available anti-allergy drug with a broad receptor binding profile which resembles that of clozapine. In rats discriminating clozapine from vehicle cyproheptadine mimicked clozapine very closely. Acutely it induced full generalization in the absence of response suppression, as observed with clozapine. Chronic administration of clozapine and cyproheptadine induced tolerance and cross-tolerance respectively to the clozapine stimulus. This was characterized by circa 3.5-fold parallel shifts to the right in the clozapine generalization curves. Such tolerance and cross-tolerance was spontaneously reversible, suggesting that it was pharmacodynamic, and that clozapine and cyproheptadine induce similar neuroadaptations when administered chronically. Administration of chlordiazepoxide at a very high dose induced no cross-tolerance to the clozapine stimulus showing the pharmacological specificity of tolerance. The clozapine stimulus is a compound cue involving actions at various receptors, and various clozapine-like antipsychotic (APD) drugs generalize fully to it. These data demonstrate that in vivo cyproheptadine resembles clozapine both acutely and chronically. Our findings, in conjunction with other actions of cyproheptadine -- induction of weight gain, alleviation of clozapine withdrawal, anxiolytic actions, alleviation of 'typical' APD-induced motoric side effects, and some preliminary clinical findings -- suggest that further study of cyproheptadine in conjunction with a 'typical' APD for the possible treatment of schizophrenia is merited at both pre-clinical and clinical levels.

Topics: Animals; Anti-Allergic Agents; Antipsychotic Agents; Clozapine; Conditioning, Operant; Cyproheptadine; Discrimination Learning; Discrimination, Psychological; Dose-Response Relationship, Drug; Drug Tolerance; Dyskinesia, Drug-Induced; Female; Generalization, Psychological; Pharmaceutical Vehicles; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Weight Gain

The structurally related neuropeptides, substance P, neurokinin A, and neurokinin B, belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems. These peptides mediate their effects through three G protein coupled receptor subtypes, the neurokinin-1, neurokinin-2 and neurokinin-3 receptors, respectively.. To study the physiological functions of NK3, a line of NK3 knockout mice were generated and characterized in a broad spectrum of well-established behavioral tests.. In several tests, including spontaneous locomotor activity, elevated plus maze, forced swim, and hot plate, wild-type and knockout mice performed similarly. However, in several cognition tests, including passive avoidance, acquisition of conditioned avoidance responding (CAR), and the Morris water maze, NK3 knockout mice displayed deficits compared to wild-type mice. Although NK3 wild-type and knockout mice performed similarly in the training phase of the passive avoidance test, knockout mice had shorter latencies to enter the dark compartment on days 3 and 4, suggesting impaired retention. In the acquisition phase of the conditioned avoidance responding assay, NK3 knockout mice acquired the CAR task at a slower rate than wild-type mice. Once the CAR test was acquired, both NK3 wild-type and knockout mice responded similarly to clozapine and risperidone, drugs which suppress responding in this test. In the Morris water maze, NK3 knockout mice showed increased latencies to find the escape platform on day 3 of training, suggesting a modest, but significant delay in acquisition compared to wild-type mice.. These studies suggest a role for NK3 in learning and memory in mice.

Topics: Age Factors; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Clozapine; Cognition Disorders; Conditioning, Operant; Dose-Response Relationship, Drug; Electric Stimulation; Gene Expression; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Receptors, Neurokinin-3; Reverse Transcriptase Polymerase Chain Reaction; Risperidone; Swimming; Time Factors; Weight Gain

The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10-12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20-40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D(2) receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed "the Youdim factor", directing a DA-NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Brain Chemistry; Catecholamines; Clozapine; Denervation; Dopamine; Dopamine Agents; Female; Haloperidol; Iron; Iron Overload; Levodopa; Male; Mice; Mice, Inbred C57BL; Motor Activity; Movement Disorders; MPTP Poisoning; Norepinephrine; Pregnancy; Psychotic Disorders; Signal Transduction; Weight Gain

The 5HT2C receptor (HTR2C) has been hypothesized to represent an important modulator in feeding behavior. Evidence was based on the observation that knock-out mice for the HTR2C receptor gene develop obesity and that many antipsychotics (AP) with potent HTR2C antagonism may induce weight gain in susceptible individuals. Pharmacogenetic studies focusing either on the Cys23Ser polymorphism or on the -759C/T promoter polymorphism of the X-linked HTR2C receptor gene revealed significant findings for the -759C/T polymorphism, however, no study has performed haplotype analyses for both polymorphisms.. We analyzed three functional polymorphisms (Cys23Ser, -759C/T, and (GT)12-18/(CT) 4-5) of the HTR2C in 139 schizophrenic patients mainly treated with clozapine. Weight gain was assessed over a time course of 6-14 weeks (mean 8.2 weeks).. Single marker and haplotype analysis revealed no significant associations with AP-induced weight gain. The haplotype Long-C-Ser was protective against weight gain, but the number of subjects available for that analysis was small.. Our pilot study did not detect any significant haplotype conferring risk for antipsychotic-induced weight gain although the statistical model took into account the X-linked heterogeneity and did correct for confounding factors (i.e., ethnicity, medications, clinical response, time of assessment).

Topics: Antipsychotic Agents; Clozapine; Female; Genes, X-Linked; Haplotypes; Humans; Male; Pilot Projects; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Schizophrenia; Time Factors; Weight Gain

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Eating; Female; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Weight Gain

A panel of academic psychiatrists and pharmacists, clinicians from the Texas public mental health system, advocates, and consumers met in June 2006 in Dallas, Tex., to review recent evidence in the pharmacologic treatment of schizophrenia. The goal of the consensus conference was to update and revise the Texas Medication Algorithm Project (TMAP) algorithm for schizophrenia used in the Texas Implementation of Medication Algorithms, a statewide quality assurance program for treatment of major psychiatric illness.. Four questions were identified via premeeting teleconferences. (1) Should antipsychotic treatment of first-episode schizophrenia be different from that of multiepisode schizophrenia? (2) In which algorithm stages should first-generation antipsychotics (FGAs) be an option? (3) How many antipsychotic trials should precede a clozapine trial? (4) What is the status of augmentation strategies for clozapine? Subgroups reviewed the evidence in each area and presented their findings at the conference.. The algorithm was updated to incorporate the following recommendations. (1) Persons with first-episode schizophrenia typically require lower antipsychotic doses and are more sensitive to side effects such as weight gain and extrapyramidal symptoms (group consensus). Second-generation antipsychotics (SGAs) are preferred for treatment of first-episode schizophrenia (majority opinion). (2) FGAs should be included in algorithm stages after first episode that include SGAs other than clozapine as options (group consensus). (3) The recommended number of trials of other antipsychotics that should precede a clozapine trial is 2, but earlier use of clozapine should be considered in the presence of persistent problems such as suicidality, comorbid violence, and substance abuse (group consensus). (4) Augmentation is reasonable for persons with inadequate response to clozapine, but published results on augmenting agents have not identified replicable positive results (group consensus).. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.

Topics: Algorithms; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Drug Therapy; Humans; Mental Health Services; Schizophrenia; Substance-Related Disorders; Suicide, Attempted; Texas; Violence; Weight Gain

This retrospective study examined adjunct divalproex (N = 15) or lithium (N = 9) in treatment-resistant schizophrenia patients added to clozapine and compared to clozapine monotherapy (N = 25). Six month total BPRS scores were similarly improved in all treatment groups, however significantly greater improvements occurred in the first month for those on divalproex (-9) or lithium (-8) vs. clozapine alone (-4.5) (F = 3.32, df = 10.43, p = 0.0003). Rates of sedation, tachycardia, orthostasis, GI disturbances, confusion and dizziness were similar among groups. Mean weight gain was 8.7 pounds for clozapine monotherapy, 3.0 pounds in the adjunct divalproex group and 13.3 pounds in the adjunct lithium group (P = NS). A trend was noted for greater increases in blood glucose levels for those treated with adjunct lithium (F = 2.62, df = 2.28, p = 0.09). The addition of divalproex was significantly more effective in reducing global symptoms (driven by hostility and anxiety) in the first month of adjunct treatment as compared to clozapine monotherapy and to previous clozapine treatment.

Topics: Adult; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Anxiety; Blood Glucose; Brief Psychiatric Rating Scale; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; Hostility; Humans; Lithium Carbonate; Male; Middle Aged; Prospective Studies; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Valproic Acid; Weight Gain

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

The management of atypical antipsychotic-induced weight gain is a significant challenge for people with mental illness. Fundamental research into energy metabolism in people taking atypical antipsychotic medication has been neglected. The current study of men with schizophrenia taking clozapine aimed to measure total energy expenditure (TEE) and energy expended on physical activity--activity energy expenditure (AEE) and to consider the clinical implications of the findings.. The well-established reference method of doubly labelled water (DLW) was used to measure TEE and AEE in men with schizophrenia who had been taking clozapine for more than 6 months. Resting energy expenditure was determined using indirect calorimetry.. The TEE was 2511+/-606 kcal day-1 which was significantly different to World Health Organization recommendations (more than 20% lower). The Physical activity level (PAL) was 1.39+/-0.27 confirming the sedentary nature of people with schizophrenia who take clozapine.. The findings support the need for weight management strategies for people with schizophrenia who take clozapine to focus on the enhancement of energy expenditure by increasing physical activity and reducing inactivity or sedentary behaviours, rather than relying primarily on strategies to reduce energy intake.

Topics: Adult; Antipsychotic Agents; Calorimetry, Indirect; Clozapine; Energy Metabolism; Humans; Male; Motor Activity; Schizophrenia; Weight Gain

Topics: Abdominal Fat; Adipocytes; Antipsychotic Agents; Body Composition; Cell Differentiation; Cells, Cultured; Clozapine; Stem Cells; Weight Gain

To assess the perceptions of clinicians in the psychiatric community about pharmacotherapy and its impact on weight gain and adverse metabolic effects in patients with bipolar disorder.. In November 2005, self-administered questionnaires were sent to 7000 psychiatrists who treat bipolar disorder in their clinical practice. An additional mailing of these questionnaires was sent in January 2006 to a different group of 7000 psychiatrists who treat bipolar disorder in their clinical practice. The first 298 completed surveys were analyzed.. Almost half of the respondents (48%) were psychiatrists in individual private practice and 32% were in community mental health centers. About two-thirds of respondents reported that 30-60% of their bipolar patients were overweight. Thirty-eight percent of respondents reported metabolic syndrome present in 20-40% of their patients. Almost all respondents (96%) reported a 20 lb increase in patients' weight as a troublesome potential adverse event associated with the use of some agents. After initiating a new medication, more than 80% of respondents monitored their patients' weight, fasting plasma glucose level, and fasting lipid profile at regular intervals. However, 80% did not monitor waist circumference. Overall, respondents viewed several agents (aripiprazole, ziprasidone, carbamazepine, and lamotrigine) as not (or minimally) problematic in terms of weight gain and adverse metabolic concerns. Clozapine and olanzapine were viewed as highly problematic due to their propensity to induce weight gain and negatively influence lipid and glucose metabolism. Other agents considered to be minimally to moderately problematic in terms of weight gain and metabolic issues were quetiapine, risperidone, lithium, and valproate. Respondents reported that the profile of a bipolar agent in terms of weight gain and adverse metabolic effects was an important consideration in the management of bipolar disorder.. Although the study is limited by a low response rate and self-selection of respondents, clinicians who did respond were concerned about the risks of weight gain and metabolic disturbances in their patients treated with bipolar agents. For most parameters, such concerns were being integrated into clinical care. However, it appears that there is a need to increase clinicians' appreciation of the importance of abdominal obesity and the need to monitor waist circumference. A growing recognition of the differences in weight-gain potential and adverse metabolic effects among agents appears to have had a definite impact on prescribing patterns in the management of bipolar disorder.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Clozapine; Female; Humans; Lipids; Male; Metabolic Syndrome; Olanzapine; Overweight; Perception; Practice Patterns, Physicians'; Weight Gain

Weight gain has been documented as a significant adverse effect associated with many of the atypical antipsychotic medications. Several recent reports have linked a -759C/T polymorphism of the 5HT2C receptor gene and obesity as well as chlorpromazine, risperidone, and clozapine induced to weight gain. This aim was to determine the association between changes in body mass index (BMI) during clozapine treatment and the -759C/T polymorphism of the 5HT2C receptor gene. This study included 41 patients with treatment-refractory schizophrenia (DSM-IV) who were followed prospectively during treatment with clozapine. Weight and height measurements were obtained prior to starting clozapine and after 6-months of treatment. Genomic DNA was isolated from a whole blood sample and analyzed for the -759C/T polymorphism of the 5HT2C receptor gene. A chi(2) analysis comparing whether or not the subjects carried a -759T allele in subjects grouped as having an increase of more or less than 7% of their baseline BMI during treatment with clozapine found that the presence of the -759T allele was significantly higher in subjects with less than or equal to a 7% increase in baseline BMI compared to those with a greater than 7% increase in BMI. A multiple linear regression analysis showed that both baseline BMI and the presence or absence of the -759T allele had significant effects on 6-month BMI. The T allele may have a protective function in preventing significant weight gain from clozapine. Subjects without the -759T variant allele were at a greater risk for weight gain from clozapine over 6-months compared to those with the -759T allele.

Topics: Adult; Alleles; Antipsychotic Agents; Body Mass Index; Clozapine; Female; Gene Frequency; Genotype; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Schizophrenia; Weight Gain

Clozapine is an atypical antipsychotic known to cause considerable weight gain. The extent to which genetic factors determine weight gain is unknown. Here we report on a pair of female monozygotic twins concordant for schizophrenia and mild mental retardation who were treated with clozapine over 5.5 years. One twin gained a total of 53.1 kg and had a weight of 107.5 kg (BMI=38.1 kg/m2) at the end of the observation period. The other twin gained a total of 48.2 kg and finally had a weight of 100.4 kg (BMI=33.8 kg/m2). Because both patients experienced considerable weight gain during treatment, our observation suggests that the antipsychotic-induced weight gain is under strong genetic control.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Intellectual Disability; Psychotic Disorders; Schizophrenia; Twins, Monozygotic; Weight Gain

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

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

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

Weight gain is a serious side effect of atypical antipsychotics, especially in childhood. In this study, the authors examined six weight gain-related hormones in patients with childhood-onset schizophrenia (COS) after 6 weeks of clozapine treatment.. Fasting serum samples for 24 patients with COS and 21 matched healthy controls (HC) were obtained. Levels of leptin, insulin, adiponectin, amylin, ghrelin, and tumor necrosis factor alpha were measured and compared between the groups. For 23 patients with COS, hormonal levels were measured at background and week 6 of clozapine treatment. Change in body mass index was correlated with levels of clozapine and changes in hormonal levels and clinical ratings.. At baseline, COS did not differ significantly from HC on any hormonal measure. Clozapine treatment was associated with significant (7.9% +/- 8.5%) increase in mean body mass index. Only leptin levels increased significantly from baseline to week 6 on clozapine (p = .003). Body mass index increase was significantly correlated with decrease in ghrelin and adiponectin and was positively correlated with clinical improvement.. This is the first study of weight gain-related hormones in children on clozapine. Hormonal changes are correlated with weight gain. How effectiveness of clozapine is linked to weight gain remains uncertain.

Topics: Adolescent; Antipsychotic Agents; Body Mass Index; Child; Clozapine; Female; Hormones; Humans; Male; Schizophrenia; Schizophrenic Psychology; Weight Gain

Weight gain, leading to further morbidity and poor treatment compliance, is a common adverse effect of treatment with clozapine. The C825T polymorphism in the human G protein beta3 subunit gene has been noted to be associated with obesity, hypertension and coronary artery disease. Clozapine increases the level of G protein beta3 subunit in the rat striatum. The aim of the present study was to investigate the relationship between G protein beta3 polymorphisms and clozapine-induced body weight change in a Chinese population during long-term treatment. One hundred and thirty-four schizophrenic patients, who were treated with clozapine continuously (13.4+/-0.5 months), were genotyped for G protein beta3 subunit C825T polymorphism. None of these patients received second-generation antipsychotics before clozapine treatment. Body weight was monitored at baseline before clozapine treatment and at the endpoint after clozapine treatment. Patients with the TT type experienced significantly more weight gain (16.2+/-2.5%) compared to those with CT (9.3+/-1.2%) or CC types (5.5+/-2.4%) after long-term clozapine treatment (P = 0.003). Further stratification by gender demonstrated that the effect of C825T polymorphism on weight gain remained significant both in males and females. These findings confirm the importance of genetic factors in body weight change induced by long-term clozapine treatment in patients with schizophrenia, and indicate a role for the G protein beta3 subunit in body weight regulation during long-term clozapine treatment.

Topics: Adult; Antipsychotic Agents; China; Clozapine; Female; Heterotrimeric GTP-Binding Proteins; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Schizophrenia; Weight Gain

The present cross-sectional study examined the relationships of psychopathology, side effects, and sociodemographic factors with treatment outcomes in terms of patients' quality of life (QOL), functioning, and needs for care.. Sixty outpatients with chronic schizophrenia who had been treated with either clozapine or olanzapine for at least 6 months were investigated.. Most psychopathological symptoms as well as psychic side effects, weight gain, and female sex were associated with lower QOL, while cognitive symptoms correlated with better QOL. Female sex, cognitive symptoms, and parkinsonism negatively influenced occupational functioning, and negative symptoms determined a lesser likelihood of living independently. Age, education, depression/anxiety, negative symptoms, and psychic side effects were predictors of patients' needs for care.. Our results highlight the complex nature of patient outcomes in schizophrenia. They reemphasize the need of targeting effectiveness, i.e. both symptomatic improvement as well as drug safety, in such patients.

Topics: Adult; Age Factors; Antipsychotic Agents; Anxiety Disorders; Benzodiazepines; Clozapine; Cognition; Comorbidity; Cross-Sectional Studies; Depressive Disorder; Educational Status; Female; Humans; Male; Olanzapine; Parkinsonian Disorders; Quality of Life; Schizophrenia; Schizophrenic Psychology; Sex Factors; Socioeconomic Factors; Treatment Outcome; Weight Gain

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

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

Treatment-emergent weight gain may be a general marker of therapeutic improvement, even when improvements occur in the absence of active antipsychotic treatment. To investigate the association between treatment-emergent weight gain and therapeutic improvement across placebo and active treatments, and to examine the association between reported treatment-emergent weight changes and the treatments' reported efficacy. Data from a randomized, double-blind trial comparing treatment of schizophrenia with placebo and olanzapine were used to correlate weight change and change in psychopathology. Additionally, we correlated effect sizes of the efficacy of clozapine, olanzapine, risperidone, haloperidol and placebo (reported in meta-analytical reviews), with their reported weight changes. Weight gain significantly correlated with clinical improvements for placebo and olanzapine. The correlation between treatments' efficacy and corresponding weight changes was high (r 0.88, p 0.05). Treatment-emergent weight gain appears to be an important marker of symptom reduction, and may not be exclusively attributable to pharmacological perturbations.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Female; Haloperidol; Humans; Linear Models; Male; Meta-Analysis as Topic; Middle Aged; Olanzapine; Placebo Effect; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome; Weight Gain

To assess the relative contribution of genetic factors in antipsychotic-induced weight gain, we explored the similarity in body mass index (BMI) (kg/m(2)) change under clozapine only (clozapine DeltaBMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total DeltaBMI) of five monozygotic twins in comparison with seven same-sex sibs. Twin and sib pairs were identified by a telephone screening of 786 office-based psychiatrists. Measured data on weight and other clinical variables were obtained cross-sectionally and retrospectively from medical records. We found greater similarity in total DeltaBMI in monozygotic twins (intrapair difference 2.78+/-3.41 kg/m(2)) than in same-sex sibs (5.55+/-4.35 kg/m(2)), resulting in heritability estimates of h(2)=0.8 and A=0.45 (ACE twin model). However, intrapair differences in clozapine DeltaBMI were similar between twins (4.18+/-4.27 kg/m(2)) and sibs (4.68+/-4.88 kg/m(2)). We hypothesize that the weight plateau achieved under clozapine is influenced by genetic factors. The weight gain achieved during pretreatment with other antipsychotics seems to limit clozapine-induced weight gain, thus presumably explaining why heritability/similarity in monozygotic twins in comparison with same-sex sibs is greater for total DeltaBMI than for clozapine DeltaBMI. An important caveat is that, owing to the sample size, the heritability estimates have a large standard error and thus have to be interpreted with caution.

Topics: Adolescent; Adult; Body Mass Index; Clozapine; Cross-Sectional Studies; Female; Humans; Male; Retrospective Studies; Sex Characteristics; Siblings; Twins, Monozygotic; Weight Gain

We describe the case of a 39-year-old patient with schizophrenia who developed worsening of glucose metabolism during treatment with two different atypical antipsychotics, clozapine and quetiapine. Diabetes mellitus was recognized during clozapine treatment. During quetiapine treatment, while patient was taking diabetic diet, fasting and 1-hour glucose levels and body mass index, decreased, but 2-hour glucose levels increased. This suggests that, in some patients, monitoring of only fasting glucose level and body mass index may be insufficient for detecting the glucose metabolism abnormalities. In those patients oral glucose tolerance test may be recommended. Recommendations about when and how often clinicians should administer the test do not exist in current guidelines. Further studies are needed for the elucidation of this question.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Fluphenazine; Glucose Tolerance Test; Humans; Male; Schizophrenia; Weight Gain

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

Schizophrenia is a heterogeneous syndrome both at the etiological and clinical levels. In particular, patients with schizophrenia exhibit important variability in their therapeutic and metabolic responses to clozapine, an antipsychotic medication.. Here, we determine whether two mouse strains show differing clozapine responses with respect to weight gain, enhancement of prepulse inhibition of acoustic startle, and reversal of amphetamine-induced locomotion. Observed between-strain differences may be partly due to genetic factors that can be subsequently mapped using quantitative genetic approaches.. We treated the A/J and C57BL/6J inbred mouse strains with clozapine for 22 days. Prepulse inhibition and amphetamine-induced locomotion were measured after 3-4 days of clozapine treatment and again after 21-22 days of treatment. Weight gain was also monitored during treatment. RESULTS. Three-day treatment with clozapine increased prepulse inhibition in both strains. Four-day clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain. Long-term (21-22 days) clozapine treatment did not affect these behaviors in either strain. After an initial weight loss during the first 5 days, clozapine (4 mg/kg) induced a significant weight gain in both strains.. The reversal of schizophrenia-related behaviors after short-term, but not long-term, clozapine treatment is consistent with other rodent studies. Although short-term clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain, strain differences in amphetamine responses confound the interpretation of these results; therefore, quantitative genetic approaches may be difficult to carry out with this trait. In contrast, enhancement of prepulse inhibition after three days of clozapine treatment and weight gain induced by clozapine are relatively straightforward to quantify, making these trait more amenable to quantitative genetic approaches.

Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Drug Administration Schedule; Genetics, Behavioral; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Motor Activity; Reflex, Startle; Schizophrenia; Species Specificity; Time Factors; Weight Gain

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Interactions; Drug Therapy, Combination; Fructose; Humans; Leukopenia; Male; Topiramate; United Kingdom; Weight Gain

There are limited data in the literature regarding clozapine use in adolescents with diagnoses other than schizophrenia. This report describes the use of clozapine in adolescents with diagnoses of bipolar disorder, intermittent explosive disorder (IED), and posttraumatic stress disorder (PTSD).. A chart review of 39 adolescents treated with clozapine at two residential facilities was undertaken. Data extraction included demography, illness variables, medication information, and clinical outcomes. Categorical outcomes were analyzed using contingency statistics, and continuous variables were analyzed using a paired t test.. The cohort included 26 females and 13 males with a mean age of 14 years. Clozapine was titrated slowly, and the mean daily dose was 102 mg. The diagnoses included bipolar disorder (n = 7), IED (n = 9), and PTSD (n = 19). There were significant reductions in polypharmacy once the clozapine dosage was stabilized. Prior to clozapine treatment, nearly 70% of the subjects were receiving either mood-stabilizing or antidepressant agents in combination with the previous antipsychotic drug. Once the clozapine dosage was stabilized, only 24% of the subjects required concomitant mood stabilizers (p < 0.001), and only 21% of the subjects required concomitant antidepressants (p < 0.001). Anxiolytic medication use was also significantly reduced during clozapine treatment. Most patients were discharged to a less restrictive setting. Eight subjects discontinued clozapine due to agranulocytosis (n = 1), neutropenia (n = 2), excessive weight gain (n = 2), or not requiring it long term (n = 1), and data were unavailable in 2 subjects. Significant weight gain (5% or greater change from baseline) was noted in 20 subjects.. Clozapine, in relatively modest doses, appears to have clinical benefits for adolescent with bipolar disorder, IED, and PTSD. There is no labeled indication for clozapine use in these disorders. Clozapine is also associated with serious side effects in subsets of individuals. Therefore, a very careful evaluation of the risk-to-benefit ratio in each individual subject being considered for clozapine is highly recommended.

Topics: Adolescent; Bipolar Disorder; Chi-Square Distribution; Child; Clozapine; Disruptive, Impulse Control, and Conduct Disorders; Female; Humans; Male; Retrospective Studies; Stress Disorders, Post-Traumatic; Weight Gain

Weight gain is a major side effect of treatment with clozapine and other antipsychotics. Recent studies suggest an important role of the serotonin type 2C receptor gene (5-HT2CR) in antipsychotic-induced weight gain. However, investigations pertaining to a possible association between a -759C/T polymorphism (C allele) of the 5-HT2CR and weight gain induced by clozapine and/or other antipsychotics have yielded inconsistent results. We investigated the -759C/T polymorphism of the 5-HT2CR in relation to clozapine-induced change in body mass index (BMI) (kg/m) in 97 German patients with schizophrenia and found no association between the -759C allele and weight gain after 12 weeks of clozapine treatment. In addition, confounding effects of initial BMI, age, sex and duration of illness on change in BMI could not be detected by multiple linear regression analysis. Our data do not support an involvement of the -759C/T polymorphism of the 5-HT2CR in clozapine-induced weight gain in German patients with schizophrenia. Further pharmacogenetic studies pertaining to antipsychotic-induced weight gain are warranted.

Topics: Adolescent; Adult; Antipsychotic Agents; Body Mass Index; Clozapine; Female; Genotype; Germany; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2C; Schizophrenia; Weight Gain; Weil Disease

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

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus; Dyskinesia, Drug-Induced; Humans; Patient Compliance; Schizophrenia; Weight Gain

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT(2A) and 5-HT(2C) serotonin receptors, H(1)-histamine receptors, alpha(1)- and alpha(2)-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H(1)-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman rho=-0.72; p<0.01), as were affinities for alpha(1A) adrenergic (rho=-0.54; p<0.05), 5-HT(2C) (rho=-0.49; p<0.05) and 5-HT(6) receptors (rho=-0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H(1), alpha(2A), alpha(2B), 5-HT(2A), 5-HT(2C), and 5-HT(6) receptors were most highly correlated with the first principal component, and affinities for the D(2), 5-HT(1A), and 5-HT(7) receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H(1) and alpha(1A) receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H(1)-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H(1)-histamine receptor antagonists are known to induce weight gain with chronic use, and because H(1)-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H(1)-histamine receptors.

Topics: Animals; Antipsychotic Agents; Discriminant Analysis; Drug Evaluation, Preclinical; Forecasting; Humans; Protein Binding; Receptors, Histamine H1; Statistics, Nonparametric; Weight Gain

The authors explored the binge eating symptomatology in 74 patients receiving clozapine (N = 57) or olanzapine (N = 17), and compared body mass index (BMI, kg/m(2)) and weight gain in patients with and without binge eating symptomatology. Subjects who screened positively for binge eating were interviewed using a modified version of the Questionnaire on Eating and Weight Patterns (QEWP). Current BMIs were assessed cross-sectionally, BMIs at initiation of clozapine/olanzapine treatment retrospectively. Thirty-seven subjects (50%) screened positively. Taking clozapine and olanzapine together, 6/27 (22.2%) females and 3/47 (6.4%) males fulfilled criteria for binge eating disorder, 3/27 (11.1%) females and 2/47 (4.3%) males for bulimia nervosa. Patients who screened positively showed higher current BMIs (26.8 +/- 3.9 vs. 24.7 +/- 3.7 kg/m(2)) and higher BMI increments during clozapine/olanzapine treatment (3.9 +/- 3.1 vs. 2.6 +/- 3.4 kg/m(2)) than patients who screened negatively. We conclude that clozapine/olanzapine may induce binge eating and full blown eating disorders which may have predictive value for weight gain. For future research in this field we suggest a novel DSM-IV research classification "Medication-induced eating disorders".

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Bulimia; Clozapine; Female; Humans; Hyperphagia; Male; Olanzapine; Pirenzepine; Risk Factors; Surveys and Questionnaires; Weight Gain

Weight gain with atypical antipsychotics such as clozapine has been hypothesized to have a multifactorial genesis. Beside changes in neurotransmitter systems caused by antipsychotic-induced receptor blockade, hormonal changes and other neuroleptic side-effects (sedation, reduced activity, reduced basal metabolic rate, dry mouth) are also discussed. Our unique case report of a patient with comorbid galactosemia and schizophrenia is an interesting example of weight gain being a positive side-effect of clozapine, not necessarily associated with increased appetite and higher caloric intake.

Topics: Adult; Antipsychotic Agents; Clozapine; Galactosemias; Humans; Male; Schizophrenia; Weight Gain

Topics: Adipose Tissue; Antipsychotic Agents; Clozapine; Humans; Leptin; Weight Gain

Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. A recent study showed that a polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene is associated with antipsychotic-induced weight gain. The authors determined whether this association held true for weight gain after clozapine treatment.. Thirty-two Chinese Han patients with first-episode schizophrenia were genotyped for the -759C/T polymorphism and had weight changes monitored after 6 weeks of clozapine treatment.. The authors found that the 10 patients with the -759T variant allele showed significantly less weight gain than those without this allele. The effect was strongest in the male patients and not apparent in the female patients.. These findings identify an important genetic factor associated with clozapine-induced weight increases in schizophrenia.

Topics: Antipsychotic Agents; Body Mass Index; China; Clozapine; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Receptors, Serotonin; Schizophrenia; Sex Factors; 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: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Female; Humans; Long-Term Care; Male; Middle Aged; Olanzapine; Pirenzepine; Quetiapine Fumarate; Retrospective Studies; Risk; Risperidone; Schizophrenia; Triglycerides; Weight Gain

Topics: Antipsychotic Agents; Choice Behavior; Clozapine; Humans; Neuroleptic Malignant Syndrome; Psychotic Disorders; Weight Gain

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

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

Weight gain is a widely reported side effect of clozapine, but no predictive factor has been identified so far. We investigated whether pretreatment values of circulating leptin or its early changes during clozapine administration could predict the long-term weight gain induced by the drug. Body weight and plasma levels of leptin were prospectively measured in 22 patients (13 men and 9 women) with drug-resistant schizophrenia undergoing a long-term treatment with clozapine. At the end of the second week of clozapine administration, circulating leptin increased much more than weight gain, and this increase was inversely correlated to body weight increase observed after 6 and 8 months of treatment. These findings suggest that early changes in leptin secretion may predict long-term weight gain in the course of clozapine administration.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Female; Humans; Leptin; Male; Middle Aged; Prospective Studies; Schizophrenia; Statistics, Nonparametric; Weight Gain

Issues to consider when evaluating maintenance drug therapy for patients with schizophrenia are discussed; these include potential adverse effects of antipsychotic therapy, such as weight gain, diabetes mellitus, extrapyramidal symptoms, sexual dysfunction, cognitive dysfunction, and cardiac effects, as well as quality of life. Patients with schizophrenia are more likely to be overweight than the general population. Olanzapine and clozapine have been associated with the greatest weight gain of the newer antipsychotics. While patients with schizophrenia are at increased risk of developing diabetes mellitus independent of antipsychotic therapy, diabetes may be more prevalent in patients taking the newer agents. Acute extrapyramidal symptoms occur in 75-90% of patients receiving first-generation antipsychotics like thioridazine and haloperidol. The probability of tardive dyskinesia (TD) occurring with second- and third-generation agents is less than 1% per year, compared with about 5% per year for the traditional antipsychotics. When patients are switched from a traditional antipsychotic to clozapine or olanzapine, TDs usually abate somewhat. Thioridazine causes a pronounced prolongation of the QTc interval, which can lead to ventricular arrhythmias. The slight increase in QTc interval caused by ziprasidone most likely will not be a problem in healthy individuals. Newer antipsychotics are associated with improved neurocognitive functioning and most cause less prolactin elevation, compared with traditional agents. The newer antipsychotic agents are not devoid of adverse effects, but those that do occur can be managed. Once issues related to adherence are resolved, rehabilitation of patients with schizophrenia will be a high priority.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Continuity of Patient Care; Diabetes Mellitus; Electrocardiography; Humans; Movement Disorders; Olanzapine; Pirenzepine; Quality of Life; Schizophrenia; Weight Gain

The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels.. The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses.. Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations.. It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Haloperidol; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Triglycerides; Weight Gain

Topics: Adult; Antipsychotic Agents; China; Clozapine; Female; Humans; Male; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Weight Gain

Topics: Animals; Antipsychotic Agents; Clozapine; Female; Genotype; Humans; Male; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Schizophrenia; Weight Gain

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

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

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

Controversy persists about links between psychotropic drug use, obesity, and consequent menstrual irregularities. Although these interrelationships have been suggested to possibly explain polycystic ovarian syndrome among women taking valproate, less is known about menstrual irregularities associated with weight gain caused by other psychotropics. Clozapine, sparing of prolactin-related menstrual effects yet often associated with weight gain, offers a model psychotropic from which to test such hypotheses. We studied outpatient premenopausal women from a clozapine clinic to preliminarily assess the association between menstrual cycle patterns and body mass index (BMI). Records were reviewed for 13 female premenopausal schizophrenic, bipolar, or schizoaffective outpatients who took clozapine with no conventional antipsychotics for >6 months. Mean 6-month menstrual cycle lengths were compared with BMIs and relative weight changes since starting clozapine. Subjects took clozapine (mean +/- SD dose 392.2 +/- 195.7 mg/day) for a mean +/- SD of 4.4 +/- 3.2 years, with a mean preclozapine weight increase of 27%. Twenty-three percent had menstrual irregularities in the preceding 6 months (mean +/- SD cycle length = 36.4 +/- 18.1 days), although no significant associations were observed between cycle length and (a) mean +/- SD BMI (32.0 +/- 8.4) (r = -0.09, p = 0.78) or (b) weight change since starting clozapine (r = -0.10, p = 0.75). The observed lack of association between clozapine-induced weight gain and menstrual disturbances would provisionally suggest that iatrogenic weight gain does not robustly explain the emergence of irregular menses among premenopausal women taking clozapine.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Data Collection; Female; Humans; Medical Records; Menstruation Disturbances; Middle Aged; Pilot Projects; Psychotic Disorders; Schizophrenia; Weight Gain

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

Conventional as well as newer antipsychotics cause weight gain, and, in the regulation of body weight, both insulin and leptin are hormones involved.. The aim of the present study was to compare these hormonal levels in patients on treatment with different antipsychotics.. Nineteen patients receiving conventional antipsychotics, 14 patients receiving clozapine and 14 patients receiving olanzapine, were studied. Fasting blood samples for insulin, leptin, glucose, and drug serum concentrations were analyzed. In addition, body mass index (BMI) was calculated.. The median insulin level was significantly higher in the patients receiving olanzapine than in those receiving conventional agents, whereas there was no significant difference in insulin between the clozapine and the other two groups. However, in the clozapine group, insulin levels were positively correlated to the drug serum concentration. BMI was elevated in about half of the patients, with no difference being found between the groups. The leptin level was significantly higher in the women than in the men in the conventional agent group, but not in the olanzapine or clozapine groups.. The higher insulin level in the patients receiving olanzapine than in those receiving conventional antipsychotics, despite similar BMI, points to a probable influence of olanzapine on insulin secretion. The correlation between the insulin levels and the clozapine concentration indicates, in addition, an influence of clozapine on insulin secretion. The gender difference in leptin, i.e. females normally having higher leptin levels than males, was found in the conventional agent group, but not in the olanzapine or clozapine groups, suggesting that also leptin regulation is altered during olanzapine or clozapine treatments. Moreover, it was mainly due to an increase of leptin in the males that leptin levels were equalized between sexes in the olanzapine group. We conclude that the influence of olanzapine and clozapine on both insulin and leptin levels might be associated with their weight-gain-inducing ability, while other mechanisms may be involved in the weight gain caused by conventional antipsychotics.

Topics: Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Clozapine; Female; Humans; Insulin; Leptin; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia; Statistics, Nonparametric; Weight Gain

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

Clozapine-induced weight gain may impair health and affect patient compliance. The aim of this study is to investigate the relationship between the genetic variants of the serotonin system and clozapine-induced body weight change (BWC). Ninety-three treatment-resistant schizophrenic patients were weighed monthly for 4 months during clozapine treatment. At the conclusion of treatment, patients had gained an average of 2.4 kg body weight, with BWC ranging from -17.5 to +12.9 kg. The levels of the serotonin transporter variants, serotonin 2A, serotonin 2C and serotonin 6, demonstrated no statistically significant relationship to BWC. Patients with a lower initial body mass index demonstrated a greater weight gain associated with clozapine treatment. Further exploration of the neurotransmitters implicated in the antipsychotic-induced BWC is important in order to reduce the morbidity and noncompliance associated with weight gain.

Topics: Adolescent; Adult; Aged; Alleles; Antipsychotic Agents; Body Mass Index; Carrier Proteins; Clozapine; Female; Genetic Variation; Genotype; Humans; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Receptors, Serotonin; Risk Factors; Schizophrenia; Serotonin Plasma Membrane Transport Proteins; Weight Gain

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

To evaluate the impact of clozapine on aggressive behaviour and clinical outcomes in children and adolescents with schizophrenia or schizoaffective disorder.. We reviewed the charts of 6 children and adolescents who were admitted consecutively to a long-term care facility for clinical outcomes, including seclusion and restraints incidents prior to and during clozapine treatment. We also present a representative case history.. We noted clinically significant improvements in social interaction and decreases in the number of violent episodes and homicidal or suicidal thoughts. The global assessment of functioning (GAF) scores improved significantly. Weight gain was significant.. These cases illustrate the benefits of clozapine treatment in refractory childhood-onset schizophrenia. Outcomes are similar to those described in adults. Even though open data limit conclusions from this study, it is pertinent that there was a clinically significant improvement in aggressive behaviours. This may be particularly important for improved morale of patients, their families, and treating staff. It may also be helpful in discharge to a less restrictive environment.

Topics: Adolescent; Aggression; Clozapine; Female; Humans; Long-Term Care; Male; Patient Admission; Psychiatric Status Rating Scales; Schizophrenia, Childhood; Treatment Outcome; Weight Gain

Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial.. The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics.. Forty-five patients, 35 males and ten females, aged 19-65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less.. Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472+/-220 versus 328+/-128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%).. These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations.

Topics: Adult; Aged; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Conscious Sedation; Constipation; Dizziness; Dose-Response Relationship, Drug; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Sialorrhea; Tachycardia; Treatment Outcome; Weight Gain

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

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

The present study evaluated chronic oral treatment of rats with haloperidol or clozapine. Drugs were given in the drinking water for a 23-day period. Rat behavior was analyzed once a week in an open field. Rats ingested either 1.7 mg/kg haloperidol or 40 mg/kg clozapine daily. Blood serum analysis revealed concentrations of 6 ng/ml for haloperidol and 22 ng/ml for clozapine at the end of the treatment. Haloperidol decreased overall activity from the onset of treatment. Clozapine showed similar effects only on the last test day. Control animals showed a slight habituation in exploration-related parameters. In conclusion, these results indicate that oral drug administration through the drinking water is a suitable mode of noninvasive chronic treatment that led to sufficiently high drug levels to induce specific pharmacological effects in rats.

Topics: Administration, Oral; Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Dyskinesia, Drug-Induced; Exploratory Behavior; Female; Habituation, Psychophysiologic; Haloperidol; Locomotion; Rats; Rats, Sprague-Dawley; Time Factors; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Male; Prospective Studies; Schizophrenia; Sex Factors; Treatment Outcome; Weight Gain

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

During clinical experience with the "atypical" neuroleptic drugs clozapine, risperidone, and zotepine, some patients have shown a marked weight gain. To prove whether weight gain is a relevant side effect of atypical neuroleptics, the charts of all patients admitted with DSM-III-R diagnoses of schizophrenia, schizoaffective disorder, or delusional disorder in the years 1991 to 1995 were evaluated. A retrospective chart review was performed, which included all patients who were treated longer than 2 weeks with a single neuroleptic. The data analysis showed that weight gain must be considered as a common side effect of atypical neuroleptics (clozapine, risperidone, sulpiride, or zotepine). The mean weight gain (3.1, 1.5, 1.9, or 4.3 kg, respectively) was significantly higher than that of patients treated with "classic" neuroleptics (mean, 0.0-0.5 kg) (Kruskal-Wallis, p = 0.01). Young and not obese patients show the highest weight increase. Because weight gain occurs in the first weeks of treatment, particularly in previously untreated subjects, this side effect has to be considered in view of compliance with long-term neuroleptic medication.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Body Mass Index; Clozapine; Delusions; Dibenzothiepins; Female; Humans; Long-Term Care; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Risperidone; Schizophrenia; Sulpiride; Weight Gain

Subjective evaluations by schizophrenic patients of clozapine treatment were assessed as part of an exploratory study.. A problem-centred interview was carried out with 80 patients at discharge from in-patient or day hospital treatment.. In addition to expected effects (improvement or stabilisation of one's state of mental health, antipsychotic effects), patients surprisingly often highlighted clozapine's calming and relaxing effect as well as improved sleep as particularly positive. While more than half of the respondents expected a worsening of their condition in case they stopped taking their medication, only every fifth patient feared a relapse. Among the negative effects, fatigue and sedation were cited by far the most often. The absence of extrapyramidal side effects was clearly noted as an advantage of clozapine. Only every tenth of those questioned was aware of the risks for the haemotopoietic system associated with the drug. With regard to the obligatory blood tests, a surprisingly large number of patients was indifferent or stated that they had no opinion on the matter.. Possible implications for patient information and compliance will be discussed.

Topics: Adolescent; Adult; Antipsychotic Agents; Attitude to Health; Clozapine; Female; Humans; Male; Middle Aged; Patient Discharge; Patient Education as Topic; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; 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

The aim of this study was to investigate the influence of classical antipsychotics and the atypical antipsychotic agent clozapine on glucose-insulin homeostasis to explain possible mechanisms behind weight gain associated with antipsychotic treatment.. Twenty-eight patients on therapy with classical antipsychotics and 13 patients treated with clozapine (all meeting DSM-III-R criteria for schizophrenia or related psychoses) were studied. Fasting blood samples for glucose and insulin, as well as for 2 markers of the glucose-insulin homeostasis, i.e., the growth hormone (GH)-dependent insulin-like growth factor I (IGF-I) and the insulin-dependent insulin-like growth factor binding protein-1, were analyzed. Body mass index (BMI) was calculated and serum concentrations of the different antipsychotic drugs were measured. In addition, the relationship between the endocrine parameters and drug serum concentrations was examined.. The insulin levels were positively correlated to the serum concentration of clozapine, whereas no correlations were found between insulin and the serum concentrations of perphenazine (N = 12) or zuclopenthixol (N = 9). Insulin elevation was seen in the patients receiving clozapine more frequently than in the patients receiving classical antipsychotics. In addition, the median level of IGF-I was significantly lower in the patients receiving clozapine than in the patients receiving classical antipsychotics. No significant difference in BMI was found between the 2 patient groups, and all patients but 1 were normoglycemic.. The correlation between insulin and the clozapine concentration indicates a probable influence of clozapine on insulin secretion. The normal blood glucose levels in the clozapine group support the theory that clozapine induces concentration-dependent insulin resistance with secondary increased insulin secretion. In addition, lower median level of IGF-I in patients receiving clozapine compared with patients receiving classical antipsychotics points to a lower GH secretion in the clozapine group. This impaired GH secretion together with the clozapine-induced insulin resistance might be mechanisms behind weight gain during clozapine therapy.

Topics: Adult; Aged; Ambulatory Care; Antipsychotic Agents; Blood Glucose; Body Mass Index; Clozapine; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Male; Middle Aged; Schizophrenia; Weight Gain

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

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

Recent case reports indicate that clozapine treatment diminishes excessive diurnal weight gain and alleviates hyponatremia observed in some chronically psychotic patients. We examined the influence of clozapine on sodium metabolism and water regulation across a group of patients with the syndrome of polydipsia and intermittent hyponatremia.. Eleven patients with treatment-resistant DSM-III-R schizophrenia or schizoaffective disorder were studied. Each had a history of repeated diurnal weight gains of greater than 10% with at least one documented bout of hyponatremia in the 6 months before clozapine treatment. We utilized a target weight protocol and serial laboratory measures to compare changes in sodium metabolism and water regulation during 26 weeks of standard antipsychotic medication and 26 weeks of clozapine treatment.. Across patients, we found significant improvement in routinely monitored 6 a.m. and 4 p.m. serum sodium, reflecting normalization of sodium metabolism. We also found that the frequency (as reflected by diurnal weight gain), severity (lowest serum sodium), and estimated quantity (calculated urine volume) of polydipsia improved across patients. Improvement in polydipsia and hyponatremia was associated with decreased necessity for monitoring and restrictive interventions, and tended to be associated with psychiatric improvement.. We found a corrective and stabilizing effect of clozapine on polydipsia and intermittent hyponatremia. Future studies need to examine the relationship of psychiatric improvement and alterations in the regulation of sodium and water physiology to our findings.

Topics: Adult; Circadian Rhythm; Clozapine; Drinking; Female; Humans; Hyponatremia; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Sodium; Thirst; Water Intoxication; Water-Electrolyte Balance; Weight Gain

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

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

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

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

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

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

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Eating; Female; Humans; Male; Weight Gain

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

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

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