Body composition-mediated and drug-related metabolic dysregulation during long-term antipsychotic treatment in youth – Nature Mental Health

1. Giron, N. C., Oh, H., Rehmet, E. & Shireman, T. I. Descriptive trends in Medicaid antipsychotic prescription claims and expenditures, 2016–2021. J. Behav. Health Serv. Res. 51, 516–528 (2024).

   Article  PubMed  PubMed Central  Google Scholar 

2. Olfson, M., King, M. & Schoenbaum, M. Treatment of young people with antipsychotic medications in the United States. JAMA Psychiatry 72, 867–874 (2015).

   Article  PubMed  Google Scholar 

3. Alexander, G. C., Gallagher, S. A., Mascola, A., Moloney, R. M. & Stafford, R. S. Increasing off-label use of antipsychotic medications in the United States, 1995–2008. Pharmacoepidemiol. Drug Saf. 20, 177–184 (2011).

   Article  PubMed  PubMed Central  Google Scholar 

4. Libowitz, M. R. & Nurmi, E. L. The burden of antipsychotic-induced weight gain and metabolic syndrome in children. Front. Psychiatry 12, 623681 (2021).

   Article  PubMed  PubMed Central  Google Scholar 

5. Speyer, H. et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front. Endocrinol. 12, 577919 (2021).

   Article  Google Scholar 

6. Højlund, M. et al. Excess cardiometabolic risk in children and adolescents initiating antipsychotic treatment compared to young adults: results from a nationwide cohort study. World Psychiatry 24, 103–112 (2025).

   Article  PubMed  PubMed Central  Google Scholar 

7. Carnovale, C. et al. Umbrella review: association between antipsychotic drugs and metabolic syndrome hallmarks in children and adolescents. J. Am. Acad. Child Adolesc. Psychiatry 63, 313–335 (2024).

   Article  PubMed  Google Scholar 

8. Collares, S. F. et al. Systematic review and meta-analysis of weight gain and metabolic changes in children and adolescents using second-generation antipsychotics. Pharmacol. Biochem. Behav. 251, 174012 (2025).

   Article  PubMed  Google Scholar 

9. Galling, B. et al. Type 2 diabetes mellitus in youth exposed to antipsychotics: a systematic review and meta-analysis. JAMA Psychiatry 73, 247–254 (2016).

   Article  PubMed  Google Scholar 

10. Rogdaki, M. et al. Comparative physiological effects of antipsychotic drugs in children and young people: a network meta-analysis. Lancet Child Adolesc. Health 8, 510–521 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

11. Radha Krishnan, R. P. et al. Cardiometabolic adverse effects of long-term antipsychotic treatment in children and adolescents with non-psychotic disorders: a systematic review of available evidence. Eur. Child Adolesc. Psychiatry 34, 3331–3343 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

12. Burschinski, A. 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 22, 116–128 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

13. Cohen, D., Bonnot, O., Bodeau, N., Consoli, A. & Laurent, C. Adverse effects of second-generation antipsychotics in children and adolescents: a Bayesian meta-analysis. J. Clin. Psychopharmacol. 32, 309–316 (2012).

    Article  PubMed  Google Scholar 

14. Coughlin, M. et al. Enhancing metabolic monitoring for children and adolescents using second-generation antipsychotics. Int. J. Ment. Health Nurs. 27, 1188–1198 (2018).

    Article  PubMed  Google Scholar 

15. Merino, D. et al. Cardiac and metabolic safety profile of antipsychotics in youths: a WHO safety database analysis. Psychiatry Res. 334, 115786 (2024).

    Article  PubMed  Google Scholar 

16. Cernea, S., Dima, L., Correll, C. U. & Manu, P. Pharmacological management of glucose dysregulation in patients treated with second-generation antipsychotics. Drugs 80, 1763–1781 (2020).

    Article  PubMed  Google Scholar 

17. Siafis, S., Tzachanis, D., Samara, M. & Papazisis, G. Antipsychotic drugs: from receptor-binding profiles to metabolic side effects. Curr. Neuropharmacol. 16, 1210–1223 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

18. Nicol, G. E. et al. Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths: a randomized clinical trial. JAMA Psychiatry 75, 788–796 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

19. Tirosh, A. et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N. Engl. J. Med. 364, 1315–1325 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

20. Bays, H. E. et al. Obesity, dyslipidemia, and cardiovascular disease: a joint expert review from the Obesity Medicine Association and the National Lipid Association 2024. J. Clin. Lipidol. 18, e320–e350 (2024).

    Article  PubMed  Google Scholar 

21. Lister, N. B. et al. Child and adolescent obesity. Nat. Rev. Dis. Primers 9, 24 (2023).

    Article  PubMed  Google Scholar 

22. González-Muniesa, P. et al. Obesity. Nat. Rev. Dis. Primers 3, 17034 (2017).

    Article  PubMed  Google Scholar 

23. Carli, M. et al. Atypical antipsychotics and metabolic syndrome: from molecular mechanisms to clinical differences. Pharmaceuticals 14, 238 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

24. Newcomer, J. W. et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch. Gen. Psychiatry 59, 337–345 (2002).

    Article  PubMed  Google Scholar 

25. Au, E. et al. Antipsychotic-induced dysregulation of glucose metabolism through the central nervous system: a scoping review of animal models. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 10, 244–257 (2025).

    PubMed  Google Scholar 

26. Cai, H. L. et al. A potential mechanism underlying atypical antipsychotics-induced lipid disturbances. Transl. Psychiatry 5, e661 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

27. Kang, S. H. et al. Metabolic disturbances independent of body mass in patients with schizophrenia taking atypical antipsychotics. Psychiatry Investig. 12, 242–248 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

28. Yang, Y. & Wu, R. Atypical antipsychotic drugs cause abnormal glucose and lipid metabolism independent of weight gain. Eur. Arch. Psychiatry Clin. Neurosci. 275, 619–627 (2025).

    Article  PubMed  Google Scholar 

29. Arango, C. et al. Second-generation antipsychotic use in children and adolescents: a six-month prospective cohort study in drug-naive patients. J. Am. Acad. Child Adolesc. Psychiatry 53, 1179–1190 (2014).

    Article  PubMed  Google Scholar 

30. Vancampfort, D. 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 19, 116–128 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

31. Avan, R. et al. Update on statin treatment in patients with neuropsychiatric disorders. Life 11, 1365 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

32. Correll, C. U. 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 19, 69–80 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

33. Mead, L., Ayres, A., Blake, J. A. & Scott, J. G. Monitoring of metabolic side-effects in children and adolescents prescribed antipsychotic medication: a systematic review. Aust. N. Z. J. Psychiatry 55, 763–771 (2021).

    Article  PubMed  Google Scholar 

34. Little, R. J. Pattern-mixture models for missing data. J. Am. Med. Assoc. 334, 2126–2127 (2025).

    Article  Google Scholar 

35. Burghardt, K. J. et al. Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies. Prog. Neuropsychopharmacol. Biol. Psychiatry 83, 55–63 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

36. De Hert, M., Detraux, J., Van Winkel, R., Yu, W. & Correll, C. U. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat. Rev. Endocrinol. 8, 114–126 (2012).

    Article  Google Scholar 

37. James, D. E., Stöckli, J. & Birnbaum, M. J. The aetiology and molecular landscape of insulin resistance. Nat. Rev. Mol. Cell Biol. 22, 751–771 (2021).

    Article  PubMed  Google Scholar 

38. Correll, C. U., 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 14, 119–136 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

39. Correll, C. U. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J. Am. Acad. Child Adolesc. Psychiatry 46, 687–700 (2007).

    Article  PubMed  Google Scholar 

40. Penzner, J. B. et al. Lack of effect of stimulant combination with second-generation antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in youth with clinically relevant aggression or oppositionality. J. Child Adolesc. Psychopharmacol. 19, 563–573 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

41. McCutcheon, R. A. et al. INTEGRATE: international guidelines for the algorithmic treatment of schizophrenia. Lancet Psychiatry 12, 384–394 (2025).

    Article  PubMed  Google Scholar 

42. Carolan, A. et al. Metformin for the prevention of antipsychotic-induced weight gain: guideline development and consensus validation. Schizophr. Bull. 51, 1193–1205 (2024).

    Article  Google Scholar 

43. Correll, C. U. et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. J. Am. Med. Assoc. 302, 1765–1773 (2009).

    Article  Google Scholar 

44. Marshall, W. A. & Tanner, J. M. Variations in the pattern of pubertal changes in boys. Arch. Dis. Child. 45, 13–23 (1970).

    Article  PubMed  PubMed Central  Google Scholar 

45. Marshall, W. A. & Tanner, J. M. Variations in pattern of pubertal changes in girls. Arch. Dis. Child. 44, 291–303 (1969).

    Article  PubMed  PubMed Central  Google Scholar 

46. Hollingshead, A. B. Four Factor Index of Social Status (Yale Univ., 1975).

47. R Core Team R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2024).

48. Bates, D., Mächler, M., Bolker, B. & Walker, S. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1–48 (2015).

    Article  Google Scholar 

49. Leucht, S., Samara, M., Heres, S. & Davis, J. M. Dose equivalents for antipsychotic drugs: the DDD method. Schizophr. Bull. 42, S90–S94 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Authors and Affiliations

1. Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and Psychotherapy, Charité Universitätsmedizin–Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

   Till J. Adam, Marco Solmi & Christoph U. Correll

2. Einstein Center Population Diversity, Berlin, Germany

   Till J. Adam & Christoph U. Correll

3. Einstein Center for Youth Mental Health, Berlin, Germany

   Till J. Adam & Christoph U. Correll

4. Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark

   Mikkel Højlund

5. Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark

   Mikkel Højlund

6. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

   Toby Pillinger & Robert A. McCutcheon

7. South London and Maudsley NHS Foundation Trust, London, UK

   Toby Pillinger

8. Department of Psychiatry, University of Oxford, Oxford, UK

   Robert A. McCutcheon

9. Metro South Addiction and Mental Health Service, Brisbane, Queensland, Australia

   Dan Siskind

10. Faculty of Health, Medicine and Behavioural Sciences, University of Queensland, Brisbane, Queensland, Australia

    Dan Siskind

11. Queensland Centre for Mental Health Research, Brisbane, Queensland, Australia

    Dan Siskind

12. Department of Psychiatry and Behavioral Neuroscience, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Melissa P. DelBello & Jeffrey A. Welge

13. Department of Environmental and Public Health Sciences, Division of Biostatistics and Bioinformatics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Jeffrey A. Welge

14. Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland

    Heidi Taipale & Jari Tiihonen

15. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Heidi Taipale & Jari Tiihonen

16. Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden

    Heidi Taipale & Jari Tiihonen

17. Neuroscience Center, University of Helsinki, Helsinki, Finland

    Jari Tiihonen

18. Department of Psychiatry, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China

    Wing Chung Chang

19. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Roger S. McIntyre

20. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Roger S. McIntyre

21. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Rene E. Nielsen

22. Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark

    Rene E. Nielsen

23. Psychiatric Centre Copenhagen, Mental Health Services in the Capital Region of Copenhagen, Copenhagen, Denmark

    Anders Fink-Jensen

24. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Anders Fink-Jensen

25. Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada

    Marco Solmi

26. Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada

    Marco Solmi

27. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    Marco Solmi

28. German Center for Mental Health (DZPG), partner site Berlin, Berlin, Germany

    Christoph U. Correll

29. German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany

    Christoph U. Correll

30. The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, New York, NY, USA

    Christoph U. Correll

31. Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Christoph U. Correll

32. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

    Christoph U. Correll

Contributions

Conceptualization: T.J.A. and C.U.C. Data curation: T.J.A. and C.U.C. Formal analysis: T.J.A. Funding acquisition: C.U.C. Investigation: C.U.C. Methodology: T.J.A. and C.U.C. Project administration: C.U.C. Resources: C.U.C. Supervision: C.U.C. Validation: T.J.A. and C.U.C. Visualization: T.J.A. Writing—original draft: T.J.A. Writing—review and editing: M.H., T.P., R.A.M., D.S., M.P.D., J.A.W., H.T., J.T., W.C.C., R.S.M., R.E.N., A.F.-J., M.S. and C.U.C.

Corresponding author

Correspondence to Till J. Adam.

Competing interests

T.J.A. has been a consultant and/or advisor to: MedLink Global. C.U.C. has been a consultant and/or advisor to or has received honoraria from: AbbVie, Alkermes, Allergan, Angelini, Aristo, Autobahn, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Draig, Eli Lilly, Eumentis Therapeutics, Gedeon Richter, GH Research, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedInCell, MedLink Global, Merck, Mindpax, Mitsubishi Tanabe Pharmaceuticals, Maplight, Mylan, Neumora Therapeutics, Neuraxpharm, Neurocrine, Neurelis, Neurosterix, NeuShen, Neusignal Therapeutics, Newron, Noven, Novo Nordisk, Orion Pharma, Otsuka, PPD Biotech, Recognify Life Science, Recordati, Relmada, Response Pharmaeutical, Reviva, Rovi, Saladax, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Terran, Tolmar, Vertex, Viatris and Xenon Pharmaceuticals. C.U.C. provided expert testimony for Janssen, Lundbeck, Neurocrine and Otsuka. C.U.C. served on a Data Safety Monitoring Board for Compass Pathways, IntraCellular Therapies, Relmada, Reviva, Rovi. C.U.C. has received grant support from Boehringer-Ingelheim, Janssen and Takeda. C.U.C. received royalties from UpToDate and is also a stock option or stock holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharmaceuticals, MedLink Global, Mindpax, Quantic, Terran. D.S. has served on the Viatris Quality Assurance Committee and received honorarium for independent educational talks from Servier, Viatris and Lundbeck. M.H. has been a consultant to or has received honoraria from Lundbeck and Otsuka. H.T. has participated in research projects funded by grants from Janssen-Cilag to her employing institution and has received honoraria from Gedeon Richter, Janssen, Lundbeck and Otsuka. J.T. has participated in research projects funded by grants from Janssen-Cilag to his employing institution. J.T. has served as a consultant to HealthCare Global Village, Janssen, Lundbeck, Orion Pharma, Teva and WebMD Global; given an expert testimony to Janssen; and has received honoraria from Janssen, Lundbeck, Orion Pharma, Otsuka and Teva; and received support for attending meetings and/or travel from Teva; all outside the submitted work. R.E.N. has, within the past 3 years, been an investigator for Compass Pharmaceuticals and Boehringer-Ingelheim for clinical trials and has received speaking fees from Lundbeck, Teva Pharmaceuticals, Janssen-Cilag and Boehringer-Ingelheim. M.S. has received honoraria/has been a consultant for AbbVie, Angelini, Bausch Health, Boehringer Ingelheim, Lundbeck, Otsuka and Teva. T.P. has received speaker/consultancy fees from Boehringer Ingelheim, Recordati, Lundbeck, Otsuka, Janssen, CNX Therapeutics, Sunovion, ROVI Biotech, Schwabe Pharma and Lecturing Minds Stockholm AB. T.P. receives book royalties from Wiley Blackwell and co-directs a company that designs digital resources to support treatment of mental illness. M.P.D. has received research support from Johnson and Johnson. Janssen, Shire/Takeda, Otsuka, Eli Lilly, IntraCellular, Vanda, Collegium, Ironshore, Sage, Alkermes, Myriad, Oui, Lundbeck and has received consulting/advisory board/honoraria from Myriad, Otsuka, Johnson and Johnson, Sage, Sunovion, Lundbeck, Alkermes and AGB Pharma. A.F.-J. has received an unrestricted research grant from Novo Nordisk A/S and is an unpaid member of a Novo Nordisk A/S advisory board. R.S.M. has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Johnson and Johnson, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Sage, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, MindMed, Neurocrine, Neurawell, Supernus, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, IntraCellular, NewBridge Pharmaceuticals, Viatris, Abbvie and Atai Life Sciences. The other authors declare no competing interests.

Peer review information

Nature Mental Health thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions