Clozapine-induced Weight Gain Research Articles

Genetic association between TNF‐α −308 G>A polymorphism and longitudinal weight change during clozapine treatment

The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-alpha) gene and longitudinal weight change during long-term clozapine treatment. Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and -308 G > A polymorphism in the human TNF-alpha gene were analyzed using generalized estimating equations. In addition to having a lower baseline BMI (p = 0.0013) and a longer treatment time (p = 0.050), the -308 GG carriers gained significantly more weight than the -308 A allele carriers (p = 0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. The -308 G > A genetic variant of the TNF-alpha gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain.

Chronic clozapine treatment in female rats does not induce weight gain or metabolic abnormalities but enhances adiposity: Implications for animal models of antipsychotic-induced 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 antipsychotics to enhance adiposity.

Acute administration of clozapine concurrently increases blood glucose and circulating plasma ghrelin levels in rats

Among antipsychotics, clozapine ranks highest in terms of the risk for weight gain and developing diabetes. However, the mechanism by which clozapine induces weight gain and diabetes remains unclear. The aim of this study was to determine the mechanism of clozapine-induced weight gain and hyperglycemia, and to clarify whether clozapine-induced hyperglycemia results from impairment of the system regulating appetite. Circulatory glucose, insulin, leptin and ghrelin levels were analyzed after acute administration of clozapine in rats. Clozapine (10 mg/kg) or a vehicle was injected intraperitoneally and blood samples were collected at 0, 15, 30, and 60 min after the injection. Clozapine (5, 10 or 20 mg/kg) or the vehicle was given, and blood samples were collected at 30 min after the injection. Since clozapine has receptor affinity for multiple neurotransmitters, selective antagonists of it, including dopamine, serotonin, alpha-adrenergic, muscarine and histamine were administered to clarify the pathway of clozapine-induced blood glucose and changes in plasma ghrelin. Clozapine administration increased the blood glucose level at all time points (p<0.05) compared to controls. Plasma ghrelin was elevated at 30 min (p=0.0124) and 60 min (p=0.00152). Blood glucose was increased in rats given 5 (p=0.0344), 10 (p<0.0001), or 20 mg/kg (p<0.0001) clozapine, while plasma ghrelin was increased in rats treated with 10 mg/kg (p=0.0009) or 20 mg/kg (p=0.0059) clozapine. Blood glucose was increased in rats treated with a selective alpha1-adrenergic receptor antagonist (p<0.0001), while plasma ghrelin was significantly increased in rats given a selective alpha1- (p=0.025) or alpha2-adrenergic receptor antagonist (p=0.0003). Clozapine impairs glucose metabolism and the appetite-regulation system. Clozapine increases blood glucose independent of insulin. The antagonistic action of alpha-adrenergic receptors is one of the mechanisms that induces both hyperglycemia and elevation of ghrelin.

Memantine-associated Reversal of Clozapine-induced Weight Gain

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

Association of Clozapine-Induced Weight Gain With a Polymorphism in the Leptin Promoter Region in Patients With Chronic Schizophrenia in a Chinese Population

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.

Weight Gain During a Double-Blind Multidosage Clozapine Study

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.

Clozapine enhances differentiation of adipocyte progenitor cells

A common side effect of antipsychotic treatment with atypical neuroleptics is a significant weight gain. This stabilizes in the short to medium term but with clozapine often continues beyond the first year leading to weight gains of up to 20–30 kg.1 This increase in weight is significantly correlated with clinical improvements, but the causes of treatment-emergent weight gain in schizophrenic patients are currently unknown. It is assumed that the perception of satiety is impaired, as patients experience a lower suppression of appetite after meals when consuming atypical neuroleptics.1 Supporting this hypothesis, clozapine has been found to increase serum leptin levels within days after starting treatment.2 Unfortunately, strict food reduction shows little success indicating that central pathways rather than peripheral actions of atypical neuroleptics or their mediators are involved in weight gain. Evaluation of the body composition revealed an increase in body fat under antipsychotic treatment with atypical antipsychotic drugs,3 and blockade of serotonin and histamine receptors by these drugs was previously shown to be associated with weight gain.4 In addition to enhanced lipid accumulation in adipocytes, enhanced differentiation of preadipocytes can increase body fat. Our study addresses the question of whether clozapine-induced weight gain is based on neo-formation of adipose tissue from precursor cells. All experiments had been approved by the Ethical Committee of the Aachen University of Technology.

Clozapine-induced weight gain: a study in monozygotic twins and same-sex sib pairs

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.

Genetic polymorphisms of the beta2-adrenoceptor gene might influence metabolic disturbances during antipsychotic treatment

Novel antipsychotics are increasingly associated with metabolic disturbances and recent studies have shown a relation between a SNP in the 5-HT2C receptor gene and clozapine induced weight gain thus confirming that genetic factors might have an impact on this side effect.

Hormonal Correlates of Clozapine-Induced Weight Gain in Psychotic Children: An Exploratory Study

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.

Poster sessions: Apolipoprotein D is associated with Clozapine-induced weight gain

Poster sessions: Apolipoprotein D is associated with Clozapine-induced weight gain

Polymorphism of the adrenergic receptor alpha 2a −1291C&gt;G genetic variation and clozapine-induced 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.

P.3.003 Association between clozapine-induced weight gain and serotonin 5-HT2C receptor gene polymorphism in Korean schizophrenic patients

P.3.003 Association between clozapine-induced weight gain and serotonin 5-HT2C receptor gene polymorphism in Korean schizophrenic patients

Table of Contents

The Brown University Child & Adolescent Psychopharmacology UpdateVolume 7, Issue 11 p. 1-8 Table of Contents First published: 28 October 2005 https://doi.org/10.1002/cpu.20007AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract CATIE Compares Old and New Medications for Schizophrenia Treatment Careful Monitoring Required in Clozapine-Treated Children and Adolescents Risperidone for Aggression in Male Youth with Low IQ and DBDs Hormonal Correlates of Clozapine-Induced Weight Gain AACAP Responds to FDA's Strattera Advisory The Cost of Aggression Treating Autism with Dextromethorphan Suicidal Risk with Strattera Topamax Confused with Toprol-XL Volume7, Issue11November 2005Pages 1-8 RelatedInformation

Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals.

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.

Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia

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

Clozapine-induced weight gain predicts improvement in psychopathology

Background: 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. Methods: 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). Results: 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. Conclusions: 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.

Pharmacogenomics in schizophrenia: the quest for individualized therapy.

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 replicated, the field of psychiatry will move closer to clinically meaningful tests that will be useful in deciding the best drug for each individual patient.

A Preliminary Study of the Relationship Between Clozapine-Induced Weight Gain and Menstrual Irregularities in Schizophrenic, Schizoaffective, and Bipolar Women

A Preliminary Study of the Relationship Between Clozapine-Induced Weight Gain and Menstrual Irregularities in Schizophrenic, Schizoaffective, and Bipolar Women

Serum glucose and lipid changes during the course of clozapine treatment: the effect of concurrent β-adrenergic antagonist treatment

We examined the effects of long-term clozapine treatment, concurrent treatment with β-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 β-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.