Antipsychotic-associated weight gain: management strategies and impact on treatment adherence

Madhubhashinee Dayabandara, Raveen Hanwella, Suhashini Ratnatunga, Sudarshi Seneviratne, Chathurie Suraweera, Varuni A de Silva, Madhubhashinee Dayabandara, Raveen Hanwella, Suhashini Ratnatunga, Sudarshi Seneviratne, Chathurie Suraweera, Varuni A de Silva

Abstract

Antipsychotic-induced weight gain is a major management problem for clinicians. It has been shown that weight gain and obesity lead to increased cardiovascular and cerebrovascular morbidity and mortality, reduced quality of life and poor drug compliance. This narrative review discusses the propensity of various antipsychotics to cause weight gain, the pharmacologic and nonpharmacologic interventions available to counteract this effect and its impact on adherence. Most antipsychotics cause weight gain. The risk appears to be highest with olanzapine and clozapine. Weight increases rapidly in the initial period after starting antipsychotics. Patients continue to gain weight in the long term. Children appear to be particularly vulnerable to antipsychotic-induced weight gain. Tailoring antipsychotics according to the needs of the individual and close monitoring of weight and other metabolic parameters are the best preventive strategies at the outset. Switching to an agent with lesser tendency to cause weight gain is an option, but carries the risk of relapse of the illness. Nonpharmacologic interventions of dietary counseling, exercise programs and cognitive and behavioral strategies appear to be equally effective in individual and group therapy formats. Both nonpharmacologic prevention and intervention strategies have shown modest effects on weight. Multiple compounds have been investigated as add-on medications to cause weight loss. Metformin has the best evidence in this respect. Burden of side effects needs to be considered when prescribing weight loss medications. There is no strong evidence to recommend routine prescription of add-on medication for weight reduction. Heterogeneity of study methodologies and other confounders such as lifestyle, genetic and illness factors make interpretation of data difficult.

Keywords: antipsychotics; metabolic; treatment adherence; weight gain; weight-reducing agents.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

References

    1. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114–126.
    1. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007;49(4):403–414.
    1. Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M. Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizoph Bull. 2013;39(2):295–305.
    1. Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders–a systematic review and meta-analysis. Schizophr Bull. 2013;39(2):306–318.
    1. Olfson M, Gerhard T, Huang C, Crystal S, Stroup TS. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry. 2015;72(12):1172–1181.
    1. Fan Z, Wu Y, Shen J, Ji T, Zhan R. Schizophrenia and the risk of cardiovascular diseases: a meta-analysis of thirteen cohort studies. J Psychiatr Res. 2013;47(11):1549–1556.
    1. Cotes RO, de Nesnera A, Kelly M, et al. Antipsychotic cardiometabolic side effect monitoring in a state community mental health system. Community Ment Health J. 2015;51(6):685–694.
    1. Weissman E, Jackson C, Schooler N, Goetz R, Essock S. Monitoring metabolic side effects when initiating treatment with second-generation antipsychotic medication. Clin Schizophr Relat Psychoses. 2012;5(4):201–207.
    1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–1696.
    1. 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.
    1. Rummel-Kluge C, Komossa K, Schwarz S, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123(2–3):225–233.
    1. De Hert M, Yu W, Detraux J, Sweers K, van Winkel R, Correll CU. 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.
    1. Bak M, Fransen A, Janssen J, van Os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One. 2014;9(4):e94112.
    1. Tek C, Kucukgoncu S, Guloksuz S, Woods SW, Srihari VH, Annamalai A. 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.
    1. Fleischhacker WW, Heikkinen ME, Olie JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol. 2010;13(8):1115–1125.
    1. Henderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM. Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry. 2015;2(5):452–464.
    1. Roerig JL, Steffen KJ, Mitchell JE. Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs. 2011;25(12):1035–1059.
    1. Ak M, Sezlev D, Sutcigil L, Akarsu S, Ozgen F, Yanik T. The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: olanzapine monotherapy. Psychoneuroendocrinology. 2013;38(3):341–347.
    1. 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.
    1. Lu ML, Wang TN, Lin TY, et al. Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin. Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:47–50.
    1. Goncalves P, Araujo JR, Martel F. Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms. Eur Neuropsychopharmacol. 2015;25(1):1–16.
    1. Kristiana I, Sharpe LJ, Catts VS, Lutze-Mann LH, Brown AJ. Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol. Pharmacogenomics J. 2010;10(5):396–407.
    1. Zhang JP, Lencz T, Zhang RX, et al. Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophr Bull. 2016;42(6):1418–1437.
    1. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302(16):1765–1773.
    1. Vandenberghe F, Gholam-Rezaee M, Saigi-Morgui N, et al. Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. J Clin Psychiatry. 2015;76(11):e1417–e1423.
    1. Patel NC, Crismon ML, Hoagwood K, et al. Trends in the use of typical and atypical antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2005;44(6):548–556.
    1. Pathak P, West D, Martin BC, Helm ME, Henderson C. Evidence-based use of second-generation antipsychotics in a state Medicaid pediatric population, 2001–2005. Psychiatr Ser. 2010;61(2):123–129.
    1. Pringsheim T, Panagiotopoulos C, Davidson J, Ho J, CAMESA guideline group Evidence-based recommendations for monitoring safety of second generation antipsychotics in children and youth. J Can Acad Child Adolesc Psychiatry. 2011;20(3):218–233.
    1. Ratzoni G, Gothelf D, Brand-Gothelf A, et al. Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry. 2002;41(3):337–343.
    1. De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry. 2011;26(3):144–158.
    1. McCracken JT, McGough J, Shah B, et al. Research Units on Pediatric Psychopharmacology Autism Networks Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347(5):314–321.
    1. Eapen V, John G. Weight gain and metabolic syndrome among young patients on antipsychotic medication: what do we know and where do we ssgo? Australas Psychiatry. 2011;19(3):232–235.
    1. Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res. 2004;66(1):51–57.
    1. Manschreck TC, Boshes RA. The CATIE schizophrenia trial: results, impact, controversy. Harv Rev Psychiatry. 2007;15(5):245–258.
    1. Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223.
    1. Kinon BJ, Basson BR, Gilmore JA, Tollefson GD. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry. 2001;62(2):92–100.
    1. Jonsdottir H, Opjordsmoen S, Birkenaes AB, et al. Predictors of medication adherence in patients with schizophrenia and bipolar disorder. Acta Psychiatr Scand. 2013;127(1):23–33.
    1. Velligan DI, Weiden PJ, Sajatovic M, et al. Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(Suppl 4):1–46. quiz 47–48.
    1. Faulkner G, Cohn T, Remington G. Interventions to reduce weight gain in schizophrenia. Schizophr Bull. 2007;33(3):654–656.
    1. Fakhoury WK, Wright D, Wallace M. Prevalence and extent of distress of adverse effects of antipsychotics among callers to a United Kingdom National Mental Health Helpline. Int Clin Psychopharmacol. 2001;16(3):153–162.
    1. Lester H, Marshall M, Jones P, et al. Views of young people in early intervention services for first-episode psychosis in England. Psychiatr Serv. 2011;62(8):882–887.
    1. Angermeyer MC, Matschinger H. Neuroleptika und Lebensqualitat. Ergebnisse einer Patientenbefragung. [Neuroleptics and quality of life. A patient survey] Psychiatr Prax. 2000;27(2):64–68. German.
    1. Perkins DO. Adherence to antipsychotic medications. J Clin Psychiatry. 1999;60(Suppl 21):25–30.
    1. Keller WR, Fischer BA, McMahon R, Meyer W, Blake M, Buchanan RW. Community adherence to schizophrenia treatment and safety monitoring guidelines. J Nerv Ment Dis. 2014;202(1):6–12.
    1. Lasikiewicz N, Myrissa K, Hoyland A, Lawton CL. Psychological benefits of weight loss following behavioural and/or dietary weight loss interventions. A systematic research review. Appetite. 2014;72:123–137.
    1. Warkentin LM, Das D, Majumdar SR, Johnson JA, Padwal RS. The effect of weight loss on health-related quality of life: systematic review and meta-analysis of randomized trials. Obes Rev. 2014;15(3):169–182.
    1. Evans S, Newton R, Higgins S. Nutritional intervention to prevent weight gain in patients commenced on olanzapine: a randomized controlled trial. Aust N Z J Psychiatry. 2005;39(6):479–486.
    1. Grandy S, Fox KM, Hardy E, SHIELD Study Group Association of weight loss and medication adherence among adults with type 2 diabetes mellitus: SHIELD (Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes) Curr Ther Res Clin Exp. 2013;75:77–82.
    1. 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.
    1. 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 pii: 898013. Epub 2010 Aug 25.
    1. 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.
    1. Stahl SM, Cucchiaro J, Simonelli D, Hsu J, Pikalov A, Loebel A. Effectiveness of lurasidone for patients with schizophrenia following 6 weeks of acute treatment with lurasidone, olanzapine, or placebo: a 6-month, open-label, extension study. J Clin Psychiatry. 2013;74(5):507–515.
    1. Cooper SJ, Reynolds GP, Barnes T, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol. 2016;30(8):717–748.
    1. Alvarez-Jimenez M, Hetrick SE, Gonzalez-Blanch C, Gleeson JF, McGorry PD. 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.
    1. Bruins J, Jorg F, Bruggeman R, Slooff C, Corpeleijn E, Pijnenborg M. 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.
    1. Alvarez-Jimenez M, Gonzalez-Blanch C, Vazquez-Barquero JL, et al. Attenuation of antipsychotic-induced weight gain with early behavioral intervention in drug-naive first-episode psychosis patients: a randomized controlled trial. J Clin Psychiatry. 2006;67(8):1253–1260.
    1. 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.
    1. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174.
    1. Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256(1):1–14.
    1. Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6(1):47–53.
    1. 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.
    1. Generali JA, Cada DJ. Topiramate: antipsychotic-induced weight gain. Hosp Pharm. 2014;49(4):345–347.
    1. Evers SS, van Vliet A, van Vugt B, Scheurink AJ, van Dijk G. A low TSH profile predicts olanzapine-induced weight gain and relief by adjunctive topiramate in healthy male volunteers. Psychoneuroendocrinology. 2016;66:101–110.
    1. 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.
    1. Ko YH, Joe SH, Jung IK, Kim SH. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol. 2005;28(4):169–175.
    1. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol. 2009;23(2):157–162.
    1. 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.
    1. 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):441–448.
    1. Ball MP, Warren KR, Feldman S, McMahon RP, Kelly DL, Buchanan RW. Placebo-controlled trial of atomoxetine for weight reduction in people with schizophrenia treated with clozapine or olanzapine. Clin Schizophr Relat Psychoses. 2011;5(1):17–25.
    1. Henderson DC, Copeland PM, Daley TB, et al. A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain. Am J Psychiatry. 2005;162(5):954–962.
    1. Henderson DC, Fan X, Copeland PM, et al. A double-blind, placebo-controlled trial of sibutramine for clozapine-associated weight gain. Acta Psychiatr Scand. 2007;115(2):101–105.
    1. Baptista T, Uzcategui E, Rangel N, et al. Metformin plus sibutramine for olanzapine-associated weight gain and metabolic dysfunction in schizophrenia: a 12-week double-blind, placebo-controlled pilot study. Psychiatry Res. 2008;159(1–2):250–253.
    1. Goodall E, Oxtoby C, Richards R, Watkinson G, Brown D, Silverstone T. A clinical trial of the efficacy and acceptability of D-fenfluramine in the treatment of neuroleptic-induced obesity. Br J Psychiatry. 1988;153:208–213.
    1. 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.
    1. Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci. 2005;25(13):3312–3322.
    1. Graham KA, Gu H, Lieberman JA, Harp JB, Perkins DO. Double-blind, placebo-controlled investigation of amantadine for weight loss in subjects who gained weight with olanzapine. The American Journal of Psychiatry. 2005;162(9):1744–1746.
    1. Deberdt W, Winokur A, Cavazzoni PA, et al. Amantadine for weight gain associated with olanzapine treatment. Eur Neuropsychopharmacol. 2005;15(1):13–21.
    1. Assuncao SS, Ruschel SI, Rosa Lde C, et al. Weight gain management in patients with schizophrenia during treatment with olanzapine in association with nizatidine. Rev Bras Psiquiatr. 2006;28(4):270–276.
    1. Cavazzoni P, Tanaka Y, Roychowdhury SM, Breier A, Allison DB. Nizatidine for prevention of weight gain with olanzapine: a double-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(2):81–85.
    1. Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Nizatidine treatment and its relationship with leptin levels in patients with olanzapine-induced weight gain. Human Psychopharmacol. 2003;18(6):457–461.
    1. Poyurovsky M, Fuchs C, Pashinian A, Levi A, Weizman R, Weizman A. Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination. Psychopharmacology (Berl) 2013;226(3):615–622.
    1. Gross C, Blasey CM, Roe RL, Allen K, Block TS, Belanoff JK. Mifepristone treatment of olanzapine-induced weight gain in healthy men. Adv Ther. 2009;26(10):959–969.
    1. Roerig JL, Steffen KJ, Mitchell JE, Crosby RD, Gosnell BA. An exploration of the effect of modafinil on olanzapine associated weight gain in normal human subjects. Biol Psychiatry. 2009;65(7):607–613.
    1. Henderson DC, Freudenreich O, Borba CP, et al. Effects of modafinil on weight, glucose and lipid metabolism in clozapine-treated patients with schizophrenia. Schizophr Res. 2011;130(1–3):53–56.
    1. Lian J, Huang XF, Pai N, Deng C. Preventing olanzapine-induced weight gain using betahistine: a study in a rat model with chronic olanzapine treatment. PLoS One. 2014;9(8):e104160.
    1. 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.
    1. Barak N, Beck Y, Albeck JH. Betahistine decreases olanzapine-induced weight gain and somnolence in humans. J Psychopharmacol. 2016;30(3):237–241.
    1. Barak N, Beck Y, Albeck JH. A randomized, double-blind, placebo-controlled pilot study of betahistine to counteract olanzapine-associated weight gain. J Clin Psychopharmacol. 2016;36(3):253–256.
    1. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.
    1. Lykkegaard K, Larsen PJ, Vrang N, Bock C, Bock T, Knudsen LB. The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance. Schizophr Res. 2008;103(1–3):94–103.
    1. Fiedorowicz JG, Miller DD, Bishop JR, Calarge CA, Ellingrod VL, Haynes WG. Systematic review and meta-analysis of pharmacological interventions for weight gain from antipsychotics and mood stabilizers. Curr Psychiatry Rev. 2012;8(1):25–36.
    1. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, Group RI-NAS Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295(7):761–775.
    1. Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA. 2008;299(2):185–193.

Source: PubMed

3
구독하다