Abstract
The introduction of second-generation antipsychotic drugs (SGAs) has contributed to a more effective treatment of mental diseases and patients’ improved quality of life. Their particular superiority to first-generation antipsychotics (FGAs) includes better outcomes in treating "negative" symptoms, impact on mood and lower risk of motor side effects (1). Their increasing use, going beyond psychotic disorders, has highlighted the problem of medication-induced weight gain and obesity in patients. Obesity leads to increased cardiovascular morbidity and mortality, decreased quality of life, and poor adherence. This narrative review discusses the impact of various SGA on weight gain and related adherence to medication, as well as available pharmacological and non-pharmacological interventions to counteract these effects. Most SGA commonly cause weight gain but the risk appears to be highest with olanzapine and clozapine. The best preventative strategies are tailored antipsychotic drugs and close monitoring of body weight and other metabolic parameters. Switching from one SGA to another less likely to cause metabolic disturbances is an option but carries a risk of relapse. Non-pharmacological interventions in the form of dietary counseling, exercise programs, cognitive and behavioral strategies appear to be equally effective in both individual and group forms. Both non-pharmacological prophylaxis and intervention strategies showed little effect on weight. Of the additional weight loss medications, metformin appears to be the compound with the best documented efficacy. There is no evidence of benefit from the routine prescription of additional weight loss medications. Drawing conclusions is hampered by the high heterogeneity of research methodology, as well as the participation of other factors such as lifestyle, genetic and disease-related factors.
References
(1) Hasan A, Falkai P, Wobrock T et al. WFSBP Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia – a short version for primary care. Int J Psychiatry Clin Pract 2017; 21(2):82-90.
(2) de Hert M, Correll CU, Bobes J, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 2011; 10(1):52-77.
(3) Strassnig M, Brar JS, Ganguli R. Dietary intake in patients with schizophrenia. Psychiatry 2005; 31-35.
(4) Pearsall R, Praveen KT, Pelosi A, et al. Dietary advice for people with schizophrenia. Cochrane Database of Syst Rev 2016; 3:CD009547. DOI:10.1002/14651858.CD009547.pub2.
(5) Olfson M, Gerhard T, Huang C, et al. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry 2015; 72(12):1172-1181.
(6) Lahti M, Tiihonen J, Wildgust H, et al. Cardiovascular morbidity, mortality and pharmacotherapy in patients with schizophrenia. Psychol Med 2012; 42:2275-2285.
(7) Seeman M. Men and women respond differently to antipsychotic drugs. Neuropharmacology 2020; 163:107631. DOI: 10.1016/j.neuropharm.2019.05.008.
(8) Jauhar S, Young AH. Controversies in bipolar disorder; role of second-generation antipsychotic for maintenance therapy. Int J Bipolar Disord 2019; 7(1):10. DOI:10.1186/s40345-019-0145-0.
(9) Calsolaro V, Antognoli R, Okoye Ch, et al. The Use of Antipsychotic Drugs for Treating Behavioral Symptoms in Alzheimer’s Disease. Front Pharmacol 2019; 10:1465. DOI: 10.3389/fphar.2019.01465.
(10) Barton B, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf 2020; 19(3):295-314. DOI:10.1080 /14740338.2020.1713091.
(11) Koga M. Clinical factors related to gains in body mass index (BMI) among patients under long-term antipsychotic treatment. Seishin Shinkeigaku Zasshi 2003; 105(4):473-88.
(12) Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res 2004; 66(1):51-57.
(13) Manschreck TC, Boshes RA. The CATIE schizophrenia trial: results, impact, controversy. Harv Rev Psychiatry 2007; 15(5):245-258.
(14) Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156(11):1686-1696.
(15) Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382(9896):951-962.
(16) De Hert M, Yu W, Detraux J, et al. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs 2012; 26(9):733-759.
(17) Tek C, Kucukgoncu S, Guloksuz S, et al. Antipsychotic-induced weight gain in first-episode psychosis patients: a meta-analysis of differential effects of antipsychotic medications. Early Interv Psychiatry 2016; 10(3):193-202.
(18) Kahn RS, Fleischhacker WW, Boter H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371(9618):1085-1097.
(19) McEvoy JP, Lieberman JA, Perkins DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 2007; 164(7):1050-1060.
(20) Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394(10202):939-951.
(21) Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7(1):64-77.
DOI:10.1016/S2215-0366(19)30416-X.
(22) Bazo-Alvarez J, Morris T, Carpenter J, et al. Effects of long-term antipsychotics treatment on body weight: A population-based cohort study. J Psychopharmacol 2020; 34(1):79-85. DOI: 10.1177/0269881119885918.
(23) Domecq JP, Prutsky G, Leppin A, et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100(2): 363-370. DOI: 10.1210/jc.2014-3421.
(24) Smith GC, Vickers MH, Cognard E, et al. Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behaviour. Schizophr Res 2009; 115(1):30-40.
(25) Smith GC, Vickers MH, Shepherd PR. Olanzapine effects on body composition, food preference, glucose metabolism and insulin sensitivity in the rat. Arch Physiol Biochem 2011; 117(4):241-249.
(26) Potvin S, Zhornitsky S, Stip E. Antipsychotic-induced changes in blood levels of leptin in schizophrenia: a meta-analysis. Can J Psychiatry 2015; 60(3):26-34.
(27) Ak M, Sezlev D, Sutcigil L, et al. The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: olanzapine monotherapy. Psychoneuroendocrinology 2013; 38(3):341-347.
(28) Hosojima H, Togo T, Odawara T, et al. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol 2006; 20(1):75-79.
(29) Goncalves P, Araujo JR, Martel F. Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms. Eur Neuropsychopharmacol 2015; 25(1):1-16.
(30) Misiak B, Bartoli F, Stramecki F. Appetite regulating hormones in first-episode psychosis: a systematic review and meta-analysis. Neurosci Biobehav Rev 2019; 102:362-370. DOI:10.1016/j.neubiorev.2019.05.018.
(31) Shin YK, Martin B, Golden E, et al. Modulation of taste sensitivity by GLP-1 signaling. J Neurochem 2008; 106(1):455-463.
(32) van Galen KA, Ter Horst KW, Booij J, et al. The role of central dopamine and serotonin in human obesity: lessons learned from molecular neuroimaging studies. Metabolism 2018; 85:325-339.
(33) Singh R, Bansal Y, Medhi B, et al. Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives. Eur J Pharmacol 2019; 844:231-240.
(34) Nielsen MO, Rostrup E, Wulff S, et al. Striatal Reward Activity and Antipsychotic-Associated Weight Change in Patients With Schizophrenia Undergoing Initial Treatment. JAMA Psychiatry 2016; 73(2):121-128.
(35) Lord CC, Wyler SC, Wan R, et al. The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Invest 2017; 127(9):3402-3406.
(36) Rasmussen H, Ebdrup BH, Oranje B, et al. Neocortical serotonin2A receptor binding predicts quetiapine associated weight gain in antipsychotic-naÏve first-episode schizophrenia patients. Int J Neuropsychopharmacol 2014; 17(11):1729-1736.
(37) Kim SF, Huang AS, Snowman AM, et al. From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci USA 2007; 104(9):3456-3459.
(38) Malhotra AK, Robinson DG, Lencz T, et al. Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. Schizophrenia Bulletin 2016; 42(6):1418-1437.
(39) Zhang JP, Malhotra AK. Recent Progress in Pharmacogenomics of Antipsychotic Drug Response. Curr Psychiatry Rep 2018; 20(4):24.
(40) Suetani RJ, Siskind D, Reichhold H, et al. Genetic variants impacting metabolic outcomes among people on clozapine: a systematic review and meta-analysis. Psychopharmacology 2017; 234(20):2989-3008.
(41) Kanji S, Fonseka TM, Marshe VS, et al. The microbiome -gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain. Eur Arch Psychiatry Clin Neurosci 2018; 268(1):3-15.
(42) Davey KJ, O'Mahony SM, Schellekens H, et al. Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology 2012; 221(1):155-169.
(43) Bahra SM, Weidemann BJ, Castro AN, et al. Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure. EBioMedicine 2015; 2(11):1725-1734.
(44) Davey KJ, Cotter PD, O'Sullivan O, et al. Antipsychotics and the gut microbiome: olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat. Transl Psychiatry 2013; 3(10):e309.
(45) Bahr SM, Tyler BC, Wooldridge N, et al. Use of the second-generation antipsychotic, risperidone, and secondary weight gain are associated with an altered gut microbiota in children. Transl Psychiatry 2015; 5(10):e652.
(46) Faulkner G, Cohn T, Remington G. Interventions to reduce
weight gain in schizophrenia. Schizophr Bull 2007; 33(3): 654-656.
(47) Nyboe L, Lemcke S, Møller AV, Stubbs B. Non-pharmacological interventions for preventing weight gain in patients with first episode schizophrenia or bipolar disorder: A systematic review. Psychiatry Res 2019; 281:112556. DOI:10.1016/j.psychres.2019.112556.
(48) Alvarez-Jimenez M, Hetrick SE, Gonzalez-Blanch C, et al. Non-pharmacological management of antipsychotic-induced weight gain: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry 2008; 193(2):101-107.
(49) Bonfioli E, Berti L, Goss C, et al. Health promotion lifestyle interventions for weight management in psychosis: a systematic review and meta-analysis of randomised controlled trials. BMC Psychiatry 2012; 12(1):78-89.
(50) Bruins J, Jorg F, Bruggeman R, et al. The effects of lifestyle interventions on (long-term) weight management, cardiometabolic risk and depressive symptoms in people with psychotic disorders: a meta-analysis. PLoS One 2014; 9(12):e112276.
(51) Tumiel E, Wichniak A, Jarema M, Lew-Starowicz M. Nonpharmacological Interventions for the Treatment of Cardiometabolic Risk Factors in People With Schizophrenia – A Systematic Review Front Psychiatry 2019; 10:566. DOI:10.3389/fpsyt. 2019.00566.
(52) Speyer H, Storch Jakobsen A, Westergaard C, et al. Lifestyle Interventions for Weight Management in People with Serious Mental Illness: A Systematic Review with Meta-Analysis, Trial Sequential Analysis, and Meta-Regression Analysis Exploring the Mediators and Moderators of Treatment Effects. Psychother Psychosom 2019; 88(6):350-362. DOI: 10.1159/000502293.
(53) Caemmerer J, Correll CU, Maayan L. Acute and maintenance effects of non-pharmacologic interventions for antipsychotic associated weight gain and metabolic abnormalities: A meta-analytic comparison of randomized controlled trials. Schizophr Res 2012; 140(1):159-168.
(54) Firth J, Rosenbaum S, Stubbs B, et al. Motivating factors and barriers towards exercise in severe mental illness: a systematic review and meta-analysis. Psychol Med 2016; 46(14):2869-2881.
(55) Mizuno Y, Suzuki T, Nakagawa A, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 2014; 40(6):1385-1403.
(56) Mukundan A, Faulkner G, Cohn T, Remington G. Antipsychotic switching for people with schizophrenia who have neuroleptic-induced weight or metabolic problems. Cochrane Database Syst Rev 2010; (12):CD006629. DOI:10.1002/14651858.CD006629.pub2.
(57) Barak Y, Aizenberg D. Switching to aripiprazole as a strategy for weight reduction: a meta-analysis in patients suffering from schizophrenia. J Obes 2011; 2011:898013. DOI: 10.1155 /2011/898013.
(58) Stroup TS, McEvoy JP, Ring KD, et al. Schizophrenia Trials Network. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry 2011; 168(9):947-956.
(59) Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review. J Clin Psychiatry 2009; 70(7):1041-1050.
(60) de Silva VA, Dayabandara M, Wijesundara H, et al. Metformin for treatment of antipsychotic-induced weight gain in a South Asian population with schizophrenia or schizoaffective disorder: a double blind, randomized, placebo controlled study. J Psychopharmacol 2015; 29(12):1255-1261.
(61) Zheng W, Yang XH, Cai DB, et al. Adjunctive metformin for antipsychotic-related hyperprolactinemia: A meta-analysis of randomized controlled trials J Psychopharmacol 2017; 31(5):625-631. DOI:10.1177/0269881117699630.
(62) Generali JA, Cada DJ. Topiramate: antipsychotic-induced weight gain. Hosp Pharm 2014; 49(4):345-347.
(63) Nickel MK, Nickel C, Muehlbacher M, et al. Influence of topiramate on olanzapine-related adiposity in women: a random, double-blind, placebo-controlled study. J Clin Psychopharmacol 2005; 25(3):211-217.
(64) Goh KK, Chen CH, Lu ML. Topiramate mitigates weight gain in antipsychotic-treated patients with schizophrenia: meta-analysis of randomised controlled trials. Int J Psychiatry Clin Pract 2019; 23(1):14-32.
(65) Poyurovsky M, Isaacs I, Fuchs C, et al. Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study. Am J Psychiatry 2003; 160(2):297-302.
(66) Poyurovsky M, Fuchs C, Pashinian A, et al. Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: a double-blind placebo-controlled study. Psychopharmacology 2007; 192(3):441-444.
(67) Ghanizadeh A, Nikseresht MS, Sahraian A. The effect of zonisamide on antipsychotic-associated weight gain in patients with schizophrenia: a randomized, double-blind, placebo-controlled clinical trial. Schizophr Res 2013; 147(1):110-115.
(68) Lian J, Huang XF, Pai N, Deng C. Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications. Pharmacol Res 2016; 106:51-63.
(69) Barak N, Beck Y, Albeck JH. Betahistine decreases olanzapine-induced weight gain and somnolence in humans. J Psychopharmacol 2016; 30(3):237-241.
(70) Ishøy PL, Knop FK, Broberg BV, et al. Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial. Diabetes Obes Metab 2017; 19(2):162-171.
(71) Siskind DJ, Russell AW, Gamble C, et al. Treatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CO-DEX). Diabetes Obes Metab 2018; 20(4):1050-1055.
(72) Larsen JR, Vedtofte L, Jakobsen MS, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine – or olanzapine – treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2017; 74(7):719-728.
(73) Siskind D, Hahn M, Correll CU, et al. Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: A systematic review and individual participant data meta-analysis. Diabetes Obes Metab 2019; 21(2):293-302.
(74) Wichniak A, Dudek D, Heitzman J, et al. Metabolic risk reduction in patients with schizophrenia treated with antipsychotics: recommendations of the Polish Psychiatric Association. Psychiatr Pol 2019; 53(6):1191-1218. DOI:10.12740/PP/113222.