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Antipsychotic-Induced Weight Gain in Severe Mental Illness: Risk Factors and Special Considerations

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Abstract

Purpose of Review

Weight gain is a disconcerting issue experienced by patients treated with antipsychotics (APs). This review summarizes current knowledge on the prevalence, etiology, and risk factors for antipsychotic-induced weight gain (AIWG), and evidence for interventions, including special considerations.

Recent Findings

Predisposing risk factors for AIWG include lack of prior AP exposure, sex, and age. AP dose and duration of exposure are additional treatment-related factors that may contribute to this issue. Among current approaches to target AIWG, metformin has the most evidence to support its use, and this is increasingly reflected in clinical guidelines. While lifestyle approaches are recommended, cost-effectiveness and scalability represent limitations.

Summary

More research is needed to identify newer treatment options and inform clinical recommendations for AIWG. Concerns around scope of practice in psychiatry to address AIWG and related comorbidities will require enhanced training opportunities and interdisciplinary collaborations, as well as updated position statements/practice guidelines emphasizing prevention.

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References

Papers of particular interest, published recently, have been highlighted as: •  Of importance •• Of major importance

  1. Westman J, Eriksson SV, Gissler M, Hällgren J, Prieto ML, Bobo WV, et al. Increased cardiovascular mortality in people with schizophrenia: a 24-year national register study. Epidemiol Psychiatr Sci. 2018;27(5):519–27.

    Article  CAS  PubMed  Google Scholar 

  2. Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry. 2015;14(3):339–47.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rajkumar AP, Horsdal HT, Wimberley T, Cohen D, Mors O, Borglum AD, et al. Endogenous and antipsychotic-related risks for diabetes mellitus in young people with schizophrenia: a Danish population-based cohort study. Am J Psychiatry. 2017;174(7):686–94.

    Article  PubMed  Google Scholar 

  4. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005;150(6):1115–21.

    Article  PubMed  Google Scholar 

  5. Laursen TM, Munk-Olsen T, Vestergaard M. Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry. 2012;25(2):83–8.

    Article  PubMed  Google Scholar 

  6. Correll CU, Solmi M, Veronese N, Bortolato B, Rosson S, Santonastaso P, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017;16(2):163–80.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Nasrallah HA, Meyer JM, Goff DC, McEvoy JP, Davis SM, Stroup TS, et al. Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res. 2006;86(1–3):15–22.

    Article  PubMed  Google Scholar 

  8. Amini M, Zayeri F, Salehi M. Trend analysis of cardiovascular disease mortality, incidence, and mortality-to-incidence ratio: results from global burden of disease study 2017. BMC Public Health. 2021;21(1):401.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present, and future. Schizophr Res. 2010;122(1–3):1–23.

    Article  PubMed  Google Scholar 

  10. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012;379(9831):2063–71.

    Article  CAS  PubMed  Google Scholar 

  11. Pringsheim T, Gardner DM. Dispensed prescriptions for quetiapine and other second-generation antipsychotics in Canada from 2005 to 2012: a descriptive study. CMAJ Open. 2014;2(4):E225–32.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Radojčić MR, Pierce M, Hope H, Senior M, Taxiarchi VP, Trefan L, et al. Trends in antipsychotic prescribing to children and adolescents in England: cohort study using 2000–19 primary care data. Lancet Psychiatry. 2023;10(2):119–28.

    Article  PubMed  Google Scholar 

  13. Pringsheim T, Gorman D, Pringsheim T, Gorman D. Second-generation antipsychotics for the treatment of disruptive behaviour disorders in children: a systematic review. Can J Psychiat. 2012;57(12):722–7.

    Article  Google Scholar 

  14. Pringsheim T, Lam D, Patten SB. The pharmacoepidemiology of antipsychotic medications for Canadian children and adolescents: 2005–2009. J Child Adolesc Psychopharmacol. 2011;21(6):537–43.

    Article  PubMed  Google Scholar 

  15. Correll CU, Detraux J, De Lepeleire J, De Hert M. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry. 2015;14(2):119–36.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Musil R, Obermeier M, Russ P, Hamerle M. Weight gain and antipsychotics: a drug safety review. Expert Opin Drug Saf. 2015;14(1):73–96.

    Article  CAS  PubMed  Google Scholar 

  17. Kowalchuk C, Castellani LN, Chintoh A, Remington G, Giacca A, Hahn MK. Antipsychotics and glucose metabolism: how brain and body collide. Am J Physiol Endocrinol Metab. 2019;316(1):E1–15.

    Article  CAS  PubMed  Google Scholar 

  18. Werner FM, Coveñas R. Safety of antipsychotic drugs: focus on therapeutic and adverse effects. Expert Opin Drug Saf. 2014;13(8):1031–42.

    Article  CAS  PubMed  Google Scholar 

  19. Vrbová K, Kamarádová D, Látalová K, Ocisková M, Praško J, Mainerová B, et al. Self-stigma and adherence to medication in patients with psychotic disorders–cross-sectional study. Neuro Endocrinol Lett. 2014;35(7):645–52.

    PubMed  Google Scholar 

  20. Bora E, Akdede BB, Alptekin K. The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis. Psychol Med. 2017;47(6):1030–40.

    Article  CAS  PubMed  Google Scholar 

  21. Cooper SJ, Reynolds GP, Barnes T, England E, Haddad P, Heald A, 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):717–48.

    Article  CAS  PubMed  Google Scholar 

  22. Simon J, Wienand D, Park AL, Wippel C, Mayer S, Heilig D, et al. Excess resource use and costs of physical comorbidities in individuals with mental health disorders: a systematic literature review and meta-analysis. Eur Neuropsychopharmacol. 2023;66:14–27.

    Article  CAS  PubMed  Google Scholar 

  23. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–96.

    Article  CAS  PubMed  Google Scholar 

  24. • Barton BB, Segger F, Fischer K, Obermeier M, Musil R. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf. 2020;19(3):295–314. A large meta-analysis demonstrating that all antipsychotics, including first-generation agents, induce significant weight gain; most also cause clinically significant weight gain ≥7%.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tarricone I, Ferrari Gozzi B, Serretti A, Grieco D, Berardi D. Weight gain in antipsychotic-naive patients: a review and meta-analysis. Psychol Med. 2010;40(2):187–200.

    Article  CAS  PubMed  Google Scholar 

  27. •• Campforts B, Drukker M, Crins J, Van Amelsvoort T, Bak M. Association between antipsychotic medication and clinically relevant weight change: meta-analysis. BJPsych Open. 2023;9(1). This study conducted large meta-analyses and meta-regressions to better understand risk factors and moderators of clinically significant AIWG. AIWG was more pronounced in first-episode patients, individuals with schizophrenia, and longer duration of AP use.

  28. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085–97.

    Article  CAS  PubMed  Google Scholar 

  29. Chang S-C, Goh KK, Lu M-L. Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: state-of-the-art and future perspectives. World J Psychiatry. 2021;11(10):696–710.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Benarroch L, Kowalchuk C, Wilson V, Teo C, Guenette M, Chintoh A, et al. Atypical antipsychotics and effects on feeding: from mice to men. Psychopharmacology. 2016;233(14):2629–53.

    Article  CAS  PubMed  Google Scholar 

  31. Dayabandara M, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera C, de Silva VA. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat. 2017;13:2231–41.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Roerig JL, Steffen KJ, Mitchell JE. Atypical antipsychotic-induced weight gain. CNS Drugs. 2011;25(12):1035–59.

    Article  CAS  PubMed  Google Scholar 

  33. Carlsson A. Antipsychotic drugs, neurotransmitters, and schizophrenia. Am J Psychiatry. 1978;135(2):165–73.

    Article  CAS  PubMed  Google Scholar 

  34. Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160(1):13–23.

    Article  PubMed  Google Scholar 

  35. Nicol GE, Kolko R, Lenze EJ, Yingling MD, Miller JP, Ricchio AR, et al. Adiposity, hepatic triglyceride, and carotid intima media thickness during behavioral weight loss treatment in antipsychotic-treated youth: a randomized pilot study. J Child Adolesc Psychopharmacol. 2019;29(6):439–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555(7698):623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singh R, Stogios N, Smith E, Lee J, Maksyutynsk K, Au E, et al. Gut microbiome in schizophrenia and antipsychotic-induced metabolic alterations: a scoping review. Ther Adv Psychopharmacol. 2022;12:204512532210965.

    Article  Google Scholar 

  38. Singh R, Bansal Y, Medhi B, Kuhad A. Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives. Eur J Pharmacol. 2019;844:231–40.

    Article  CAS  PubMed  Google Scholar 

  39. Mu C, Yang Y, Zhu W. Gut microbiota: the brain peacekeeper. Front Microbiol. 2016;7:345.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Fonseka TM, Müller DJ, Kennedy SH. Inflammatory cytokines and antipsychotic-induced weight gain: review and clinical implications. Mol Neuropsychiatry. 2016;2(1):1–14.

    PubMed  PubMed Central  Google Scholar 

  41. Jin H, Meyer JM, Mudaliar S, Jeste DV. Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin. Schizophr Res. 2008;100(1):70–85.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Stubbs B, Wang AK, Vancampfort D, Miller BJ. Are leptin levels increased among people with schizophrenia versus controls? A systematic review and comparative meta-analysis. Psychoneuroendocrinology. 2016;63:144–54.

    Article  CAS  PubMed  Google Scholar 

  43. Ragguett RM, Hahn M, Messina G, Chieffi S, Monda M, De Luca V. Association between antipsychotic treatment and leptin levels across multiple psychiatric populations: an updated meta-analysis. Hum Psychopharmacol. 2017;32(6).

  44. Bartoli F, Lax A, Crocamo C, Clerici M, Carrà G. Plasma adiponectin levels in schizophrenia and role of second-generation antipsychotics: a meta-analysis. Psychoneuroendocrinology. 2015;56:179–89.

    Article  CAS  PubMed  Google Scholar 

  45. Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, et al. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology. 2008;33(7):1633–41.

    Article  CAS  PubMed  Google Scholar 

  46. Teff KL, Rickels MR, Grudziak J, Fuller C, Nguyen H-L, Rickels K. Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes. 2013;62(9):3232–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Agarwal SM, Caravaggio F, Costa-Dookhan KA, Castellani L, Kowalchuk C, Asgariroozbehani R, et al. Brain insulin action in schizophrenia: something borrowed and something new. Neuropharmacology. 2020;163:107633.

    Article  CAS  PubMed  Google Scholar 

  48. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, et al. Brain dopamine and obesity. Lancet. 2001;357(9253):354–7.

    Article  CAS  PubMed  Google Scholar 

  49. Stogios N, Smith E, Asgariroozbehani R, Hamel L, Gdanski A, Selby P, et al. Exploring patterns of disturbed eating in psychosis: a scoping review. Nutrients. 2020;12(12).

  50. Shams TA, Müller DJ. Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep. 2014;16(10).

  51. Ye W, Xing J, Yu Z, Hu X, Zhao Y. Mechanism and treatments of antipsychotic-induced weight gain. Int J Obesity. 2023.

  52. Castellani LN, Costa-Dookhan KA, McIntyre WB, Wright DC, Flowers SA, Hahn MK, et al. Preclinical and clinical sex differences in antipsychotic-induced metabolic disturbances: a narrative review of adiposity and glucose metabolism. J Psychiatr Brain Sci. 2019;4.

  53. Lee S-Y, Park M-H, Patkar AA, Pae C-U. A retrospective comparison of BMI changes and the potential risk factors among schizophrenic inpatients treated with aripiprazole, olanzapine, quetiapine or risperidone. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):490–6.

    Article  CAS  PubMed  Google Scholar 

  54. Lau SL, Muir C, Assur Y, Beach R, Tran B, Bartrop R, et al. Predicting weight gain in patients treated with clozapine: the role of sex, body mass index, and smoking. J Clin Psychopharmacol. 2016;36(2):120–4.

    Article  CAS  PubMed  Google Scholar 

  55. Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Remschmidt H, Krieg JC, et al. Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res. 2009;43(6):620–6.

    Article  PubMed  Google Scholar 

  56. Konarzewska B, Stefańska E, Wendołowicz A, Cwalina U, Golonko A, Małus A, et al. Visceral obesity in normal-weight patients suffering from chronic schizophrenia. BMC Psychiatry. 2014;14(1):35.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sugawara N, Yasui-Furukori N, Tsuchimine S, Fujii A, Sato Y, Saito M, et al. Body composition in patients with schizophrenia: comparison with healthy controls. Ann Gen Psychiatry. 2012;11(1):11.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zhang ZJ, Yao ZJ, Liu W, Fang Q, Reynolds GP. Effects of antipsychotics on fat deposition and changes in leptin and insulin levels: magnetic resonance imaging study of previously untreated people with schizophrenia. Br J Psychiatry. 2004;184(JAN.):58–62.

    Article  PubMed  Google Scholar 

  59. Grajales D, Ferreira V, Valverde ÁM. Second-generation antipsychotics and dysregulation of glucose metabolism: beyond weight gain. Cells. 2019;8(11):1336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. •• Stogios N, Smith E, Bowden S, Tran V, Asgariroozbehani R, McIntyre WB, et al. Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis. Neuropsychopharmacology. 2022;47(3):664–72. Systematic review and meta-analysis demonstrating that APs induce significant weight gain in individuals treated with APs for off-label indications (i.e. non-psychotic spectrum disorders).

    Article  PubMed  Google Scholar 

  61. • Smith E, Stogios N, Au E, Maksyutynska K, De R, Ji A, et al. The metabolic adverse effects of antipsychotic use in individuals with intellectual and/or developmental disability: a systematic review and meta-analysis. Acta Psychiatr Scand. 2022;146(3):201–14. APs induce signficiant weight gain in individuals with intellectual and/or developmental disabilities, an already vulnerable population with intrinsic risk of metabolic dysregulation.

    Article  PubMed  Google Scholar 

  62. 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):1765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. • Bak M, Drukker M, Cortenraad S, Vandenberk E, Guloksuz S. Antipsychotics result in more weight gain in antipsychotic naive patients than in patients after antipsychotic switch and weight gain is irrespective of psychiatric diagnosis: a meta-analysis. PLoS ONE. 2021;16:e0244944. Meta-analysis of 404 studies, 58 of which were in AP naive patients. All APs resulted in body weight gain in the AP-naïve group; most APs resulted in body weight gain, with exception of amisulpride, aripiprazole, and ziprasidone that showed no body weight gain or even some weight loss after switching APs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Marteene W, Hollingworth S, Winckel K, Kisely S, Gallagher E, Siskind D, et al. Strategies to counter antipsychotic-associated weight gain in patients with schizophrenia. Expert Opin Drug Saf. 2019;18(12):1149–60.

    Article  CAS  PubMed  Google Scholar 

  65. Foley DL, Morley KI. Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis. Arch Gen Psychiatry. 2011;68(6):609–16.

    Article  PubMed  Google Scholar 

  66. • Van Der Esch CCL, Kloosterboer SM, Van Der Ende J, Reichart CG, Kouijzer MEJ, De Kroon MMJ, et al. Risk factors and pattern of weight gain in youths using antipsychotic drugs. Eur Child Adolesc Psychiatry. 2021;30(8):1263–71. AIWG is most pronounced during the first 15 weeks of use in youth and adolescents treated with APs.

    Article  PubMed  Google Scholar 

  67. Libowitz MR, Nurmi EL. The burden of antipsychotic-induced weight gain and metabolic syndrome in children. Front Psych. 2021;12(101545006):623681.

    Article  Google Scholar 

  68. • Schoemakers RJ, van Kesteren C, van Rosmalen J, Eussen MLJM, Dieleman HG, Beex-Oosterhuis MM. No differences in weight gain between risperidone and aripiprazole in children and adolescents after 12 months. J Child Adolesc Psychopharmacol. 2019;29(3):192–6. Aripiprazole does not appear to be metabolically neutral in youth and adolescents and shows no difference in terms of weight gain in comparison to risperidone.

    Article  CAS  PubMed  Google Scholar 

  69. Pozzi M, Pisano S, Marano G, Carnovale C, Bravaccio C, Rafaniello C, et al. Weight-change trajectories of pediatric outpatients treated with risperidone or aripiprazole in a naturalistic setting. J Child Adolesc Psychopharmacol. 2018;29(2):133–40.

    Article  PubMed  Google Scholar 

  70. Guber KM, Cortes ND, Duan L. Risk of obesity among children prescribed atypical antipsychotics for six months or more. J Child Adolesc Psychopharmacol. 2021;32(1):52–60.

    Article  PubMed  Google Scholar 

  71. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, 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):225–33.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Vandenberghe F, Gholam-Rezaee M, Saigí-Morgui N, Delacrétaz A, Choong E, Solida-Tozzi A, et al. Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. J Clin Psychiatry. 2015;76(11):e1417–23.

    Article  PubMed  Google Scholar 

  73. •• Burschinski A, Schneider-Thoma J, Chiocchia V, Schestag K, Wang D, Siafis S, et al. Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials. World Psychiatry. 2023;22(1):116–28. Large network meta-analysis of 137 eligible trials (with 35,007 participants) on 31 antipsychotics that demonstrates the differing propensity of antipsychotic drugs to induce metabolic side effects in mid- to long-term treatment. Given that schizophrenia is often a chronic disorder, these findings should be given more consideration than short-term data in drug choice.

    Article  PubMed  PubMed Central  Google Scholar 

  74. •• Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, 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. Large network meta-analysis of 100 trials and 25,952 patients that demonstrated olanzapine and clozapine have the worst metabolic profiles while aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone have the most benign profiles.

    Article  PubMed  PubMed Central  Google Scholar 

  75. • Wu H, Siafis S, Hamza T, Schneider-Thoma J, Davis JM, Salanti G, et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr Bull. 2022;48(3):643–54. Large-scale meta-analysis demonstrating different dose-response curves of APs in terms of weight gain; this information is important for dosing decisions in clinical practice.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Piras M, Chahma J, Ranjbar S, Laaboub N, Grosu C, Plessen KJ, et al. Is clozapine-induced weight gain dose-dependent? Results from a prospective cohort study. Schizophr Bull. 2023:sbad009.

  77. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596–601. https://doi.org/10.2337/diacare.27.2.596. PMID: 14747245.

  78. Wharton S, Lau DCW, Vallis M, Sharma AM, Biertho L, Campbell-Scherer D, et al. Obesity in adults: a clinical practice guideline. Can Med Assoc J. 2020;192(31):E875–91.

    Article  Google Scholar 

  79. De Hert M, Dekker JM, Wood D, Kahl KG, Holt RIG, Möller HJ. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry. 2009;24(6):412–24.

    Article  PubMed  Google Scholar 

  80. • Vancampfort D, Firth J, Correll CU, Solmi M, Siskind D, De Hert M, et al. The impact of pharmacological and non-pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta-review of meta-analyses of randomized controlled trials. Focus. 2021;19(1):116–28. Systematic review and meta-analysis of pharmacological and non-pharmacological interventions for treating AIWG; the current evidence for these interventions is still limited and larger trials are urgently needed.

    Article  PubMed  PubMed Central  Google Scholar 

  81. • Holt RIG, Gossage-Worrall R, Hind D, Bradburn MJ, McCrone P, Morris T, et al. Structured lifestyle education for people with schizophrenia, schizoaffective disorder and first-episode psychosis (STEPWISE): randomised controlled trial. Br J Psychiatry. 2019;214(2):63–73. STEPWISE is the largest randomized controlled trial to date of a theory-based, group-structured lifestyle education programme in patients with schizophrenia spectrum disorder. The STEPWISE intervention was neither clinically nor cost-effective, emphasizing the need for further research to determine how to manage overweight and obesity in people with schizophrenia.

    Article  PubMed  PubMed Central  Google Scholar 

  82. •• Speyer H, Jakobsen AS, Westergaard C, Nørgaard HCB, Jørgensen KB, Pisinger 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):350–62. Meta-analysis of 41 trials showing that individualized lifestyle treatments have a statistically significant, but not clinically significant mean effect for weight reduction in people with severe mental illness.

    Article  PubMed  Google Scholar 

  83. Firth J, Cotter J, Elliott R, French P, Yung AR. A systematic review and meta-analysis of exercise interventions in schizophrenia patients. Psychol Med. 2015;45(7):1343–61.

    Article  CAS  PubMed  Google Scholar 

  84. Speyer H, Christian Brix Nørgaard H, Birk M, Karlsen M, Storch Jakobsen A, Pedersen K, et al. The CHANGE trial: no superiority of lifestyle coaching plus care coordination plus treatment as usual compared to treatment as usual alone in reducing risk of cardiovascular disease in adults with schizophrenia spectrum disorders and abdominal obesity. World Psychiatry. 2016;15(2):155–65.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Firth J, Rosenbaum S, Stubbs B, Gorczynski P, Yung AR, Vancampfort D. Motivating factors and barriers towards exercise in severe mental illness: a systematic review and meta-analysis. Psychol Med. 2016;46(14):2869–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Detke HC, DelBello MP, Landry J, Hoffmann VP, Heinloth A, Dittmann RW. A 52-week study of olanzapine with a randomized behavioral weight counseling intervention in adolescents with schizophrenia or bipolar I disorder. J Child Adolesc Psychopharmacol. 2016;26(10):922–34.

    Article  PubMed  Google Scholar 

  87. Mizuno Y, Suzuki T, Nakagawa A, Yoshida K, Mimura M, Fleischhacker WW, 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):1385–403.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Agarwal SM, Stogios N, Ahsan Z, Lockwood J, Duncan M, Takeuchi H, et al. S90. A systematic review and meta-analysis of pharmacological interventions for reduction of weight gain in people with schizophrenia: 2019 update. Schizophr Bull. 2020;46(Suppl 1):S68–S68.

    Article  PubMed Central  Google Scholar 

  89. Lyu X, Du J, Zhan G, Wu Y, Su H, Zhu Y, et al. Naltrexone and bupropion combination treatment for smoking cessation and weight loss in patients with schizophrenia. Front Pharmacol. 2018;9:181.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Joffe G, Takala P, Tchoukhine E, Hakko H, Raidma M, Putkonen H, et al. Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69(5):706–11.

    Article  CAS  PubMed  Google Scholar 

  91. Taveira TH, Wu WC, Tschibelu E, Borsook D, Simonson DC, Yamamoto R, et al. The effect of naltrexone on body fat mass in olanzapine-treated schizophrenic or schizoaffective patients: a randomized double-blind placebo-controlled pilot study. J Psychopharmacol. 2014;28(4):395–400.

    Article  PubMed  Google Scholar 

  92. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960–70.

    Article  PubMed  Google Scholar 

  93. Lee K, Abraham S, Cleaver R. A systematic review of licensed weight-loss medications in treating antipsychotic-induced weight gain and obesity in schizophrenia and psychosis. Gen Hosp Psychiatry. 2022;78:58–67.

    Article  PubMed  Google Scholar 

  94. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–39.

    Article  CAS  PubMed  Google Scholar 

  95. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971–84.

    Article  CAS  PubMed  Google Scholar 

  96. Garvey WT, Batterham RL, Bhatta M, Buscemi S, Christensen LN, Frias JP, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325(14):1414–25.

    Article  CAS  PubMed  Google Scholar 

  98. Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021;325(14):1403–13.

    Article  CAS  PubMed  Google Scholar 

  99. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002.

    Article  CAS  PubMed  Google Scholar 

  100. Singh G, Krauthamer M, Bjalme-Evans M. Wegovy (semaglutide): a new weight loss drug for chronic weight management. J Investig Med. 2022;70(1):5–13.

    Article  PubMed  Google Scholar 

  101. Patoulias D, Michailidis T, Dimosiari A, Fragakis N, Tse G, Rizzo M. Effect of glucagon-like peptide-1 receptor agonists on cardio-metabolic risk factors among obese/overweight individuals treated with antipsychotic drug classes: an updated systematic review and meta-analysis of randomized controlled trials. Biomedicines. 2023. https://doi.org/10.3390/biomedicines11030669.

    Article  PubMed  PubMed Central  Google Scholar 

  102. de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.

    Article  PubMed  PubMed Central  Google Scholar 

  103. • Siskind D, Hahn M, Correll CU, Fink-Jensen A, Russell AW, Bak N, 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. Meta-analysis synthesizing the available evidence for the use of GLP-1RAs for the treatment of AIWG; GLP-1RAs appear to be effective and tolerable for this use, particularly clozapine/olanzapine-treated patients.

    Article  CAS  PubMed  Google Scholar 

  104. Nordisk N. Rybelsus (semaglutide) tablets [prescribing information]. Plainsboro, NJ, Novo Nordisk. 2019.

  105. Siskind D, Russell AW, Gamble C, Winckel K, Mayfield K, Hollingworth S, et al. Treatment of clozapine‐associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: a randomised controlled trial. Diabetes Obes Metab. 2017.

  106. Sass MR, Danielsen AA, Köhler-Forsberg O, Storgaard H, Knop FK, Nielsen M, et al. Effect of the GLP-1 receptor agonist semaglutide on metabolic disturbances in clozapine-treated or olanzapine-treated patients with a schizophrenia spectrum disorder: study protocol of a placebo-controlled, randomised clinical trial (SemaPsychiatry). BMJ Open. 2023;13(1):e068652.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Prasad F, De R, Korann V, Chintoh AF, Remington G, Ebdrup BH, et al. Semaglutide for the treatment of antipsychotic-associated weight gain in patients not responding to metformin - a case series. Ther Adv Psychopharmacol. 2023;13:20451253231165170.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Hahn MK, Cohn T, Teo C, Remington G. Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters. Clin Schizophr Relat Psychoses. 2013;6(4):186–96.

    Article  PubMed  Google Scholar 

  109. Idrees Z, Cancarevic I, Huang L. FDA-approved pharmacotherapy for weight loss over the last decade. Cureus. 2022;14(9):e29262–362.

    PubMed  PubMed Central  Google Scholar 

  110. • 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. Meta-analysis of 10 trials showing that topiramate is superior to the control group in mitigating weight gain in antipsychotic-treated patients with schizophrenia.

    Article  CAS  PubMed  Google Scholar 

  111. Zheng W, Xiang YT, Xiang YQ, Li XB, Ungvari G, Chiu H, et al. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2016;134(5):385–98.

    Article  CAS  PubMed  Google Scholar 

  112. Agarwal SM, Stogios N. Cardiovascular health in severe mental illness. J Clin Psychiatry. 2022;83(2).

  113. Agarwal SM, Panda R, Costa-Dookhan KA, Mackenzie NE, Treen QC, Caravaggio F, et al. Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial. Transl Psychiatry. 2021;11(1).

  114. Ying MA, Maruschak N, Mansur R, Carvalho AF, Cha DS, McIntyre RS. Metformin: repurposing opportunities for cognitive and mood dysfunction. CNS Neurol Disord Drug Targets. 2014;13(10):1836–45.

    Article  PubMed  Google Scholar 

  115. Chen Q, Cao T, Li N, Zeng C, Zhang S, Wu X, et al. Repurposing of anti-diabetic agents as a new opportunity to alleviate cognitive impairment in neurodegenerative and neuropsychiatric disorders. Front Pharmacol. 2021;12.

  116. World Health Organisation. Guidelines for the management of physical health conditions in adults with severe mental disorders. World Health Organization. 2018(Licence: CC BY-NC-SA 3.0 IGO).

  117. •• Siskind D, Gallagher E, Winckel K, Hollingworth S, Kisely S, Firth J, et al. Does switching antipsychotics ameliorate weight gain in patients with severe mental illness? A systematic review and meta-analysis. Schizophr Bull. 2021;47(4):948–58. Meta-analysis of 59 studies demonstrating that switching APs to agents with lower weight gain potential can improve weight profiles and other cardiometabolic outcomes; however, the risk of psychiatric relapse in stabe patients must be considered.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Correll CU, Sikich L, Reeves G, Johnson J, Keeton C, Spanos M, et al. Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry. 2020;19(1):69–80.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Keks N, Schwartz D, Hope J. Stopping and switching antipsychotic drugs. Aust Prescr. 2019;42(5):152–7.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Flanagan RJ, Lally J, Gee S, Lyon R, Every-Palmer S. Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals. Br Med Bull. 2020;135(1):73–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Speyer H, Westergaard C, Albert N, Karlsen M, Stürup AE, Nordentoft M, et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front Endocrinol. 2021;12.

  122. Caroff SN, Mu F, Ayyagari R, Schilling T, Abler V, Carroll B. Hospital utilization rates following antipsychotic dose reductions: implications for tardive dyskinesia. BMC Psychiatry. 2018;18(1):306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA. 2020;324(9):879–87.

    Article  PubMed  Google Scholar 

  124. Flores CA. Psychological assessment for bariatric surgery: current practices. Arq Bras Cir Dig. 2014;27(Suppl 1):59–62.

    Article  PubMed  PubMed Central  Google Scholar 

  125. • Kouidrat Y, Amad A, Stubbs B, Moore S, Gaughran F. Surgical management of obesity among people with schizophrenia and bipolar disorder: a systematic review of outcomes and recommendations for future research. Obes Surg. 2017;27(7):1889–95. Narrative review to summarize the available knowledge on bariatric surgery in people with schizophrenia or bipolar disorder; growing evidence suggests that bariatric surgery may improve short-term weight status in these populations.

    Article  PubMed  Google Scholar 

  126. Hamoui N, Kingsbury S, Anthone GJ, Crookes PF. Surgical treatment of morbid obesity in schizophrenic patients. Obes Surg. 2004;14(3):349–52.

    Article  PubMed  Google Scholar 

  127. Ahmed AT, Warton EM, Schaefer CA, Shen L, McIntyre RS. The effect of bariatric surgery on psychiatric course among patients with bipolar disorder. Bipolar Disord. 2013;15(7):753–63.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Shelby SR, Labott S, Stout RA. Bariatric surgery: a viable treatment option for patients with severe mental illness. Surg Obes Relat Dis. 2015;11(6):1342–8.

    Article  PubMed  Google Scholar 

  129. •• Agarwal SM, Stogios N, Ahsan ZA, Lockwood JT, Duncan MJ, Takeuchi H, et al. Pharmacological interventions for prevention of weight gain in people with schizophrenia. Cochrane Database Syst Rev. 2022(10). Cochrane systematic review of all available adjunctive pharmacological interventions for the prevention of AIWG; metformin is presently the best researched drug with the most evidence for this purpose.

  130. Hakami AY, Felemban R, Ahmad RG, Al-Samadani AH, Salamatullah HK, Baljoon JM, et al. The association between antipsychotics and weight gain and the potential role of metformin concomitant use: a retrospective cohort study. Front Psychiatry. 2022;13.

  131. •• Stogios N, Maksyutynska K, Navagnanavel J, Sanches M, Powell V, Gerretsen P, et al. Metformin for the prevention of clozapine-induced weight gain: a retrospective naturalistic cohort study. Acta Psychiatr Scand. 2022;146(3):190–200. Largest natrualistic retrospective cohort study to date demonstrating the effectiveness of cocomitant metformin in preventing clozapine-induced weight gain.

    Article  CAS  PubMed  Google Scholar 

  132. Rehan ST, Siddiqui AH, Khan Z, Imran L, Syed AA, Tahir MJ, et al. Samidorphan/olanzapine combination therapy for schizophrenia: efficacy, tolerance and adverse outcomes of regimen, evidence-based review of clinical trials. Ann Med Surg. 2022;79:104115.

    Article  Google Scholar 

  133. Correll CU, Newcomer JW, Silverman B, DiPetrillo L, Graham C, Jiang Y, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177(12):1168–78.

    Article  PubMed  Google Scholar 

  134. Correll CU, Stein E, Graham C, DiPetrillo L, Akerman S, Stanford AD, et al. Reduction in multiple cardiometabolic risk factors with combined olanzapine/samidorphan compared with olanzapine: post hoc analyses from a 24-week phase 3 study. Schizophr Bull. 2023;49(2):454–63.

    Article  PubMed  Google Scholar 

  135. Galderisi S, De Hert M, Del Prato S, Fagiolini A, Gorwood P, Leucht S, et al. Identification and management of cardiometabolic risk in subjects with schizophrenia spectrum disorders: a Delphi expert consensus study. Eur Psychiatry. 2021;64(1):e7.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: aneEndocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Figures were created using BioRenders.com. NS is supported by the Novo Nordisk Banting and Best Diabetes Centre (BBDC) Graduate Studentship and the Ontario Graduate Studentship. SMA is supported by an Academic Scholars Award from the Department of Psychiatry, University of Toronto, and has grant support from the CIHR, PSI Foundation, and the CAMH Discovery Fund. MH is supported by an Academic Scholars Award from the Department of Psychiatry, University of Toronto, and has grant support from the BBDC, the Canadian Institutes of Health Research (CIHR) (PJT-153262), and the PSI Foundation. She holds the Kelly and Michael Meighen Chair in Psychosis Prevention and the Cardy Schizophrenia Research Chair.

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  1. Sri Mahavir Agarwal and Margaret Hahn share senior authorship.

Authors and Affiliations

  1. Schizophrenia Division, Centre for Addiction and Mental Health (CAMH), 1051 Queen Street West, Toronto, ON, M6J 1H3, Canada

    Nicolette Stogios, Bailey Humber, Sri Mahavir Agarwal & Margaret Hahn

  2. Institute of Medical Science, University of Toronto, Toronto, Canada

    Nicolette Stogios, Bailey Humber, Sri Mahavir Agarwal & Margaret Hahn

  3. Department of Psychiatry, University of Toronto, Toronto, Canada

    Sri Mahavir Agarwal & Margaret Hahn

  4. Banting and Best Diabetes Centre (BBDC), University of Toronto, Toronto, Canada

    Sri Mahavir Agarwal & Margaret Hahn

  5. Department of Pharmacology, University of Toronto, Toronto, Canada

    Margaret Hahn

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Correspondence to Margaret Hahn.

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Stogios, N., Humber, B., Agarwal, S.M. et al. Antipsychotic-Induced Weight Gain in Severe Mental Illness: Risk Factors and Special Considerations. Curr Psychiatry Rep 25, 707–721 (2023). https://doi.org/10.1007/s11920-023-01458-0

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