Atypical Antipsychotic-induced Weight Gain Research Articles

Histaminergic regulation of food intake.

Histamine is a biogenic amine that acts as a neuromodulator within the brain. In the hypothalamus, histaminergic signaling contributes to the regulation of numerous physiological and homeostatic processes, including the regulation of energy balance. Histaminergic neurons project extensively throughout the hypothalamus and two histamine receptors (H1R, H3R) are strongly expressed in key hypothalamic nuclei known to regulate energy homeostasis, including the paraventricular (PVH), ventromedial (VMH), dorsomedial (DMH), and arcuate (ARC) nuclei. The activation of different histamine receptors is associated with differential effects on neuronal activity, mediated by their different G protein-coupling. Consequently, activation of H1R has opposing effects on food intake to that of H3R: H1R activation suppresses food intake, while H3R activation mediates an orexigenic response. The central histaminergic system has been implicated in atypical antipsychotic-induced weight gain and has been proposed as a potential therapeutic target for the treatment of obesity. It has also been demonstrated to interact with other major regulators of energy homeostasis, including the central melanocortin system and the adipose-derived hormone leptin. However, the exact mechanisms by which the histaminergic system contributes to the modification of these satiety signals remain underexplored. The present review focuses on recent advances in our understanding of the central histaminergic system's role in regulating feeding and highlights unanswered questions remaining in our knowledge of the functionality of this system.

Adjunctive use of metformin in the treatment of atypical antipsychotic-induced weight gain

Introduction. Atypical antipsychotics are the gold standard in the treatment of psychotic and other mental disorders due to their efficacy and tolerability. However, the relatively frequent occurrence of antipsychotic-induced metabolic syndrome has encouraged research into possible solutions to this problem, including the adjunctive use of metformin. The aim of this review article is to present a concise, comprehensive and critical overview of the aforementioned issue based on the analysis of available experimental research. Material and Methods. PubMed and Google Scholar databases were searched for relevant literature published in a fifteen-year period between 2008 and 2022. The following terms were used in the search: atypical antipsychotics, metformin, and weight gain. Only double-blind, placebo-controlled, randomized, and cohort studies were taken into consideration. Results. A total of 145 papers were analyzed, of which 10 papers with 852 subjects met the inclusion criteria. All the reviewed studies concluded that the adjunctive administration of metformin at a daily dose of 500 mg to 2,000 mg has significantly reduced atypical antipsychotic-induced weight gain, with a favorable effect on other metabolic parameters that were examined in the analyzed papers. Conclusion. Taking into account the increased cardiovascular morbidity and the consequent mortality among those who have been using atypical antipsychotics in the long term, it is necessary to assess the risks and benefits of introducing adjunctive metformin in every patient who is at risk of developing metabolic syndrome. In order to recommend the routine use of metformin in such indications, studies that would include a larger sample and a longer period of treatment are needed.

Atypical Antipsychotic Induced Weight Gain in Schizophrenic Patients

Atypical antipsychotics are widely prescribed and have the potential to cause weight gain, which may result in the development of metabolic syndrome. Also, it is important to monitor the use of atypical antipsychotic for metabolic disturbance. The purpose of this study is to determine the side effects of atypical antipsychotics in increasing body weight in schizophrenia patients after 4 weeks of use. Furthermore, a retrospective design was conducted and data were collected based on consecutive sampling in 80 adult psychiatric inpatients (20 women and 60 men) with initial diagnoses of schizophrenia and with the same daily nutrition. The patients were hospitalized from January to March 2019, within the term (over 4 weeks) of initiation atypical antipsychotic. The patient body weight was collected before and 4 weeks after the treatment of atypical antipsychotic. The results showed that patients (20 women and 60 men) receiving atypical antipsychotic had a mean age of 35.6 years and a percentage of 70% women and 56% men had a weight gain of 1–5 kg over 4 weeks. The mean weight observed among our subjects increased from 57.55±10.743 kg to 59.83±12.205 kg after initiating treatment (p=0.001). However, the dual combination of atypical antipsychotics risperidone and clozapine are the most widely atypical antipsychotic used with a percentage equal to 91.25%, 3.75% clozapine, and 5% risperidone. Furthermore, it can be concluded that atypical antipsychotics use for at least 4 weeks can cause weight gain in schizophrenic patients. Pharmacist and doctors are recommended to monitor the metabolic side effects due to the atypical antipsychotic use. Keywords: Atypical antipsycotic, schizophrenia, weight gain Antipsikotik Atipikal Menginduksi Peningkatan Berat Badan pada Pasien Skizofrenia AbstrakAntipsikotik atipikal banyak diresepkan dan berpotensi menyebabkan kenaikan berat badan yang dapat menyebabkan sindrom metabolik. Ada kebutuhan klinis yang mendesak untuk memantau penggunaan antipsikotik atipikal terhadap gangguan metabolisme. Penelitian ini bertujuan untuk mengetahui efek samping antipsikotik atipikal dalam meningkatkan berat badan pada pasien skizofrenia setelah pemakaian 4 minggu. Melalui desain retrospektif, data dikumpulkan dengan consecutive sampling pada 80 pasien rawat inap psikiatri dewasa (20 wanita dan 60 pria) dengan diagnosis awal skizofrenia dan dengan pengaturan nutrisi harian yang sama. Pasien dirawat di rumah sakit sejak Januari 2019 sampai dengan Maret 2019, dalam jangka menengah (lebih dari 4 minggu) pemberian antipsikotik atipikal. Data berat badan pasien dicatat sebelum dan 4 minggu sesudah pemakaian antipsikotik atipikal. Pasien (20 wanita dan 60 pria) yang menerima antipsikotik atipikal memiliki usia rata-rata 35,6 tahun, semua pasien dengan persentase 70% wanita dan 56% pria memiliki kenaikan berat badan 1–5 kg selama periode 4 minggu. Berat rata-rata yang diamati di antara subyek meningkat dari 57,55±10,743 kg menjadi 59,83±12,205 kg setelah memulai pengobatan (p=0,001). Antipsikotik atipikal yang paling banyak digunakan adalah kombinasi antipsikotik atipikal risperidon clozapin dengan persentase sebesar 91,25%, clozapin 3,75%, risperidon 5%. Kami menyimpulkan bahwa penggunaan antipsikotik atipikal selama setidaknya 4 minggu dapat menyebabkan penambahan berat badan pada pasien skizofrenia. Apoteker dan dokter direkomendasikan untuk memantau efek samping metabolik akibat penggunaan antipsikotik atipikal.Kata kunci: Antipsikotik atipikal, peningkatan berat badan, skizofrenia

Protein Kinase C β: a New Target Therapy to Prevent the Long-Term Atypical Antipsychotic-Induced 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.

Effects of Topiramate for atypical antipsychotic-induced body weight gain and metabolic adversities: a systematic review and meta-analysis

To systematically determine the effectiveness of Topiramate to counteract atypical antipsychotic-induced body weight gain and metabolic adversities in patients with psychiatric disorders. A literature search using MEDLINE, EMBASE, PsycINFO, The Cochrane Library, CNKI, CBM and WanFang Data for randomized, open and double-blind, placebo-controlled trials of Topiramate targeting atypical antipsychotic-induced weight gain was performed.Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, and assessed methodological quality of included studies.Then meta-analysis was performed using RevMan 5.2 software. A total of 10 RCTs was included, consisting of 453 subjects. The results of meta-analysis showed that: compared with placebo, Topiramate was moderate effective in reducing antipsychotics-related weight gain (WMD=-1.82 kg (95%CI: -2.65--0.99), P<0.000 1), BMI increase (WMD=-1.31 kg/m(2) (95%CI: -1.69--0.93), P<0.000 01) and fasting glucose increase (SMD=-1.15 (95%CI: -1.50--0.79), P<0.000 01); but can not regulate the lipid metabolic disorders (Cholesterol: SMD=-0.23 (95%CI: -0.81-0.35), P=0.44); Triglycerides: SMD=-0.28 (95%CI: -0.75-0.19), P=0.24; HDL: SMD= 0.01 (95%CI: -0.52-0.53), P=0.98); LDL: SMD=-0.39 (95%CI: -0.89-0.11), P=0.13). Meanwhile, when compared with placebo, Positive and Negative Syndrome Scale (PANSS) in patients with schizophrenia did not show obviously clinical improvement in concomitant Topiramate group. Topiramate can prevent and/or treat atypical antipsychotic induced weight gain and glucose disorder, but current evidence does not support the effect of Topiramate in lipid metabolic regulation and the clinical symptoms improvement assessed by PANSS.

Cost-utility Analysis of Lurasidone Versus Aripiprazole in Adults with Schizophrenia in Scotland

Introduction Atypical antipsychotic induced weight gain and metabolic side effects are a key contributor to discontinuations and relapses among schizophrenia patients. Current treatment guidelines in Scotland recommend aripiprazole for adults with schizophrenia 'who are particularly concerned about weight gain, or who may be at the greatest risk of weight gain”. Lurasidone, recently approved in Europe for schizophrenia, is effective in treating acute symptoms and preventing long-term relapse, and demonstrates minimal effects on weight and metabolic parameters. Objectives To conduct a cost-utility analysis of lurasidone versus aripiprazole in adults with schizophrenia. Methods A 10-year Scotland-specific Markov model, incorporating a 6-week acute phase and a maintenance phase across three health states (discontinuation, relapse, death) was constructed. Six-week probabilities of discontinuation and adverse events (weight gain, extrapyramidal side effects, long-term diabetes) were based on a published independent mixed treatment comparison; long-term risks of relapse and discontinuation were from an internal indirect comparison. Costs (discounted at 3.5%) included drug therapy, relapse, outpatient, primary and residential care. Literature based utility estimates were expressed as Quality Adjusted Life Years (QALYs). Results Lurasidone yielded a cost saving of £3,863 and a small QALY improvement compared with aripiprazole. Deterministic sensitivity analysis demonstrated that results were sensitive to relapse rates. Probabilistic sensitivity analysis suggested that lurasidone had the highest expected net benefit at willingness-to-pay thresholds of £20-30,000 per quality-adjusted life-year. Conclusions This analysis suggests lurasidone could be a valuable and less costly treatment option than aripiprazole among adults with schizophrenia at risk of weight gain and metabolic adverse effects.

Atypical Antipsychotic-Induced Weight Gain

Prescriptions for second-generation antipsychotics (SGAs) have surpassed those for first-generation agents in the treatment of schizophrenia and bipolar disorder. While SGAs have the benefit of a much reduced risk of causing movement disorders, they have been associated with weight gain and metabolic effects. These adverse reactions are not uncommon, and threaten to have a significant impact on the patient's health over the long-term treatment that the patient requires. Currently, the aetiology of these effects is not known. This article reviews the data exploring the weight gain phenomenon. The literature was reviewed from searches of PubMed and the references of major articles in the field. The SGAs present a heterogeneous risk for weight gain. In addition, different individuals receiving the same drug can exhibit substantially different weight changes. This pattern suggests that a group of factors are associated with the weight gain phenomenon rather than a single mechanism. Coupled with the genetic profile that the patient brings to the treatment, the risk for SGA-induced weight gain will be different for different drugs and different individuals. Targets for exploration of the weight gain phenomenon include receptor interactions involving serotonin, histamine, dopamine, adrenergic, cannabinoid and muscarinic receptors. The association of SGA-induced weight gain and the role of orexigenic and anorexigenic peptides are reviewed. Also, a brief discussion of genetic factors associated with SGA-induced weight gain is presented, including that of the serotonin 5-HT(2C) receptor gene (HTR2C) and the cannabinoid 1 receptor gene (CNR1). The most promising data associated with SGA-induced weight gain include investigations of the histamine H(1), 5-HT(2A), 5-HT(2C), muscarinic M(3) and adrenergic receptors. In addition, work in the genetic area promises to result in a better understanding of the variation in risk associated with different individuals.

Why Research On the Pharmacogenetics of Atypical Antipsychotic-Induced Weight Gain in Individuals With Intellectual Disabilities Is Warranted

Weight gain is an often-observed side effect of atypical antipsychotics (AAPs) and is particularly significant in individuals with intellectual disabilities (ID). The majority of individuals treated with AAPs will gain at least 10% of their initial body weight over the course of therapy (Umbricht & Kane, 1996). One's genetic constitution is an important factor that influences the variability of weight gain observed among patients taking AAPs. This article reviews the existing literature on psychopharmacogenetics of AAP-induced weight gain and the importance of this research for individuals with ID.

The Adjunctive Use of Metformin to Treat or Prevent Atypical Antipsychotic-Induced Weight Gain: A Review

Patients with schizophrenia have a greater incidence of being overweight or obese compared with the general population. Such individuals are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidemia, and other metabolic derangements. As a result, frequent monitoring of weight and other metabolic parameters is recommended. In addition, several pharmacologic strategies to help prevent or reduce SGA-induced weight gain have been proposed. Despite this, clinicians often struggle to manage obesity and metabolic issues in such patients. Metformin has attracted attention as a potential treatment option because it is thought to result in weight reduction and improved glycemic control in obese patients with and without type 2 diabetes mellitus. This article focuses on relevant pharmacologic aspects of metformin and reviews currently available evidence on the use of metformin as an augmentation agent for the treatment or prevention of SGA-induced weight gain.

Metformin for Atypical Antipsychotic-Induced Weight Gain and Glucose Metabolism Dysregulation

Individuals receiving certain atypical antipsychotic medications are at risk of gaining weight and developing metabolic problems. There are no established drug treatments to prevent or counter these problems. However, the antihyperglycaemic agent metformin appears promising in some recent studies and we review the literature that evaluates metformin for limiting or reversing atypical antipsychotic drug-induced weight gain and glucose metabolism dysregulation. These studies suggest that metformin is beneficial if started early in antipsychotic drug treatment. Metformin has also been shown to prevent or delay the onset of type 2 diabetes mellitus in high-risk individuals from the general population. Based on these findings, we identify antipsychotic drug-treated patients who might benefit from metformin therapy and offer clinical guidelines for its use. Further long-term studies are needed to extend our observations and improve this strategy.

The role of histaminergic H1 and H3 receptors in food intake: A mechanism for atypical antipsychotic-induced weight gain?

Atypical antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a low risk of extra-pyramidal side-effects. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding the weight gain problem. In addition, atypical antipsychotics may affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor.

Weight effects associated with antipsychotics: A comprehensive database analysis

Background Available data on atypical antipsychotic-induced weight gain are limited by a number of methodological factors. The objective of this report is to evaluate short-term ( N = 1742) and long-term ( N = 1649) weight effects in patients receiving standard doses of amisulpride, haloperidol, olanzapine, risperidone, ziprasidone, and placebo based on 21 randomized, placebo-controlled, parallel-group studies from an integrated clinical trial database. Method Analyses of the integrated ziprasidone schizophrenia trials database were performed to estimate the weighted average of weight change and the percentage of subjects experiencing weight gain (or weight loss) across studies for each agent studied, based on fixed- and random-effects models. Durations of treatment exposure in long-term trials were controlled by well-defined time windows (6 month: 150 to 210 days; 1 year: 330 to 390 days). Weight gain or loss was defined using a 7% change from baseline threshold. Results During long-term therapy with 1-year treatment duration, incidence of weight gain for subjects treated with ziprasidone (17%) was not significantly different from the placebo (13%) or haloperidol (41%) groups based on 95% confidence interval. In contrast, significantly greater weight gain incidence was observed for the olanzapine (57%) and risperidone (39%) groups compared to placebo. Median weight change of + 0.49, − 0.18, + 1.50 and + 0.55 lb/month was observed for haloperidol, ziprasidone, olanzapine and risperidone subjects, respectively, indicating differential weight change patterns compared to placebo (− 0.32). Similar results were observed for the short-term (4–12 weeks) and 6-month treatment exposure cohorts. Conclusions Our results confirm significant differences in long-term weight effects among atypical antipsychotics, consistent with findings from prior meta-analysis of antipsychotic-induced weight gain [Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Capelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156, 1686–1696] and the CATIE schizophrenia study [Lieberman, J.A., Stroup, T.S., McEvoy, J.P., et al., 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353, 1209–1223].

Atypical antipsychotic induced weight gain and metabolic disorders

The advent of new antipsychotic drugs has improved the treatment of schizophrenic patients as well as those suffering from other severe psychiatric disorders. Its widespread use, however, has been associated to the development of obesity and metabolic disturbances such as diabetes mellitus, dyslipidemia and increased coronary risk. This has caused a serious concern, due to the high cardiovascular mortality that prematurely affects these patients. The etiology of these abnormalities is still a matter of debate, although it is generally believed that the new antipsychotic drugs have a control stimulating effect on appetite, and their use is associated to an increased level of cortisol and to an insulin-resistance state. In addition, there is an increase in inflammatory mediator and cytokine production, induced by the pathophysiology of the schizophrenic process itself and also caused by the direct action of the antipsychotic drugs. In spite of the mounting evidence, the metabolic management of these patients is still deficient. A close follow-up in the initial stages of the antipsychotic treatment is recommended, as well as giving advice about diet and physical exercise. Finally, when obesity or other conditions associated to metabolic syndrome appear, the recommendation is to switch to drugs with less secondary effects or to add adjuvant medications to improve the overall evolution of these patients.

Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine

Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia. In a putative model of antipsychotic drug-induced weight gain, we investigated the effects of sub-chronic olanzapine on body weight, meal patterns, the expression of genes encoding for hypothalamic feeding-related neuropeptides and the contribution of hyperphagia to olanzapine-induced weight gain in rats. In experiment 1, female rats received either olanzapine (1 mg/kg, p.o.) or vehicle, twice daily for 7 days, while meal patterns were recorded. At the end of the treatment regimen, we measured the levels of hypothalamic messenger RNAs (mRNAs) encoding neuropeptide-Y (NPY), hypocretin/orexin (HCRT), melanin concentrating hormone and pro-opiomelanocortin. NPY and HCRT mRNA levels were also assessed in a separate cohort of female rats treated acutely with olanzapine (1 mg/kg, p.o.). In experiment 2, we investigated the effect of a pair-feeding paradigm on sub-chronic (1 mg/kg, p.o.) olanzapine-induced weight gain. In experiment 1, sub-chronic olanzapine increased body weight, food intake and meal size. Hypothalamic neuropeptide mRNA levels were unchanged after both acute and sub-chronic olanzapine treatment. In experiment 2, the restriction of food intake to the level of vehicle-treated controls abolished the sub-chronic olanzapine-induced increase in body weight. Hyperphagia mediated by drug-induced impairments in satiety (as evidenced by increased meal size) is a key requirement for olanzapine-induced weight gain in this paradigm. However, olanzapine-induced hyperphagia and weight gain may not be mediated via alterations in the expression of the feeding-related hypothalamic neuropeptides examined in this study.

Pharmacological Management of Atypical Antipsychotic-Induced Weight Gain

Excessive bodyweight gain was reported during the 1950s as an adverse effect of typical antipsychotic drug treatment, but the magnitude of bodyweight gain was found to be higher with the atypical antipsychotic drugs that were introduced after 1990. Clozapine and olanzapine produce the greatest bodyweight gain, ziprasidone and aripiprazole have a neutral influence, and quetiapine and risperidone cause an intermediate effect. In the CATIE study, the percentage of patients with bodyweight gain of >7% compared with baseline differed significantly between the antipsychotic drugs, i.e. 30%, 16%, 14%, 12% and 7% for olanzapine, quetiapine, risperidone, perphenazine (a typical antipsychotic) and ziprasidone, respectively (p<0.001). Appetite stimulation is probably a key cause of bodyweight gain, but genetic polymorphisms modify the bodyweight response during treatment with atypical antipsychotics. In addition to nutritional advice, programmed physical activity, cognitive-behavioural training and atypical antipsychotic switching, pharmacological adjunctive treatments have been assessed to counteract excessive bodyweight gain. In some clinical trials, nizatidine, amantadine, reboxetine, topiramate, sibutramine and metformin proved effective in preventing or reversing atypical antipsychotic-induced bodyweight gain; however, the results are inconclusive since few randomized, placebo-controlled clinical trials have been conducted. Indeed, most studies were short-term trials without adequate statistical power and, in the case of metformin, nizatidine and sibutramine, the results are contradictory. The tolerability profile of these agents is adequate. More studies are needed before formal recommendations on the use of these drugs can be made. Meanwhile, clinicians are advised to use any of these adjunctive treatments according to their individual pharmacological and tolerability profiles, and the patient's personal and family history of bodyweight gain and metabolic dysfunction.

C.06.02 Predictors of individual response and long-term compliance in schizophrenia treatment

Available data on atypical antipsychotic-induced weight gain are limited by a number of methodological factors. The objective of this report is to evaluate short-term (N = 1742) and long-term (N = 1649) weight effects in patients receiving standard doses of amisulpride, haloperidol, olanzapine, risperidone, ziprasidone, and placebo based on 21 randomized, placebo-controlled, parallel-group studies from an integrated clinical trial database.Analyses of the integrated ziprasidone schizophrenia trials database were performed to estimate the weighted average of weight change and the percentage of subjects experiencing weight gain (or weight loss) across studies for each agent studied, based on fixed- and random-effects models. Durations of treatment exposure in long-term trials were controlled by well-defined time windows (6 month: 150 to 210 days; 1 year: 330 to 390 days). Weight gain or loss was defined using a 7% change from baseline threshold.During long-term therapy with 1-year treatment duration, incidence of weight gain for subjects treated with ziprasidone (17%) was not significantly different from the placebo (13%) or haloperidol (41%) groups based on 95% confidence interval. In contrast, significantly greater weight gain incidence was observed for the olanzapine (57%) and risperidone (39%) groups compared to placebo. Median weight change of + 0.49, − 0.18, + 1.50 and + 0.55 lb/month was observed for haloperidol, ziprasidone, olanzapine and risperidone subjects, respectively, indicating differential weight change patterns compared to placebo (− 0.32). Similar results were observed for the short-term (4–12 weeks) and 6-month treatment exposure cohorts.Our results confirm significant differences in long-term weight effects among atypical antipsychotics, consistent with findings from prior meta-analysis of antipsychotic-induced weight gain [Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Capelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156, 1686–1696] and the CATIE schizophrenia study [Lieberman, J.A., Stroup, T.S., McEvoy, J.P., et al., 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353, 1209–1223].

Energy Expenditure and Physical Activity in Clozapine use: Implications for Weight Management

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.

Energy expenditure and physical activity in clozapine use: implications for weight management

Objective: 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. Method: 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. Results: 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. Conclusions: 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.

Atypical antipsychotic induced weight gain: pathophysiology and management.

There is compelling evidence that patients with schizophrenia are prone to gain weight. In addition, atypical antipsychotic (AAP) drugs also induce weight gain. All antipsychotic drugs produce weight gain but the potential varies. Many studies overwhelmingly confirm that AAP drugs produce substantially more weight gain in comparison to conventional antipsychotic drugs. Clozapine and olanzapine have the most weight inducing potential. Even ziprasidone, which is considered to be weight neutral, and aripiprazole a dopamine modulator produce weight gain in some. The pathophysiology of weight gain is complicated. Many neurohormones, neuropeptides, gut hormones, as well as adipose tissue and hair root derived hormones interact with environmental factors to produce weight gain. Management of weight gain is a difficult problem. Basic to treatment is an understanding of the etiology. Drug induced obesity provides a unique opportunity to psychiatrists to understand this clinically important problem. In the absence of this knowledge, prevention is the best hope. Education, diet control and simple behavioral measures may prevent excessive weight gain. In those with weight gain, treatment can be attempted with pharmacotherapy with careful monitoring of the side effects.