The Onset of Glucose Dysregulation Among Adults Treated with Antipsychotics: A Systematic Review of Cohort Studies

Authors

  • Riri Erwina Putri Department of Emergency, Datu Beru General Hospital, Aceh, Indonesia
  • Hedya Nadhrati Surura RSUD Kota Subulussalam

DOI:

https://doi.org/10.29103/jkkmm.v5i1.24735

Abstract

Antipsychotic pharmacotherapy, particularly second-generation agents, is widely recognized for its efficacy in psychotic disorders but is strongly associated with adverse metabolic consequences, including disturbances in glucose homeostasis in addition to weight gain and dyslipidemia, though the precise time-to-onset of glucose dysregulation under real-world conditions remains insufficiently characterized. This systematic review aimed to synthesize cohort evidence on the incidence and timing of glucose dysregulation in adults treated with antipsychotics. Following PRISMA guidelines, systematic searches were conducted in PubMed, Scopus, and ScienceDirect for cohort studies published in the past five years, focusing on adult patients with outcomes including fasting plasma glucose, HbA1c, oral glucose tolerance test results, or incidence of diabetes mellitus, with methodological quality appraised using the Cochrane Risk of Bias 2 tool. Eight cohort studies with more than 60,000 participants and follow-up durations ranging from one to twenty years were included, showing that glucose dysregulation often emerged within 6–12 months of initiating high-risk agents such as clozapine and olanzapine, with cumulative risk increasing over prolonged exposure. Baseline factors such as elevated BMI, dyslipidemia, and family history of diabetes were consistently associated with earlier onset, while structured inpatient environments with diet and exercise interventions appeared to mitigate metabolic deterioration despite long-term clozapine use. Overall, antipsychotic treatment in adults is consistently linked to an increased risk of glucose dysregulation, typically arising within the first months to years of therapy, highlighting the importance of proactive monitoring from treatment initiation and the implementation of preventive strategies to reduce long-term cardiometabolic burden.

Keywords : Antipsychotics, Glucose dysregulation, Diabetes mellitus, Cohort studies

Author Biographies

Riri Erwina Putri, Department of Emergency, Datu Beru General Hospital, Aceh, Indonesia

Department of Emergency, Datu Beru General Hospital, Aceh, Indonesia

Hedya Nadhrati Surura, RSUD Kota Subulussalam

Departemen IGD

References

1. 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 Jan 1;7(1):64–77.

2. Holt RIG. Association Between Antipsychotic Medication Use and Diabetes. Curr Diab Rep. 2019 Oct 1;19(10).

3. Fang YJ, Lee WY, Lin CL, Cheah YC, Hsieh HH, Chen CH, et al. Association of antipsychotic drugs on type 2 diabetes mellitus risk in patients with schizophrenia: a population-based cohort and in vitro glucose homeostasis-related gene expression study. BMC Psychiatry. 2024 Dec 1;24(1).

4. Bae H, Lee JH, Je S, Lee SH, Choi H. Diabetic Ketoacidosis Associated With Second Generation Antipsychotics: A Case Study and Review of Literature. Psychiatry Investig. 2024 Feb 1;21(2):111–22.

5. Madsen NM, Sørensen MA, Danielsen AA, Højlund M, Rohde C, Köhler-Forsberg O. The risk of diabetes and HbA1c deterioration during antipsychotic drug treatment: A Danish two-cohort study among patients with first-episode schizophrenia. Acta Psychiatr Scand. 2025 Jan 1;151(1):69–80.

6. Ishibashi M, Matsui K, Kawano M, Oshibuchi H, Ishigooka J, Nishimura K, et al. Clinical factors associated with new-onset glucose intolerance among patients with schizophrenia during clozapine treatment: All-case surveillance in Japan. Tohoku Journal of Experimental Medicine. 2020;252(2):177–83.

7. Garrido-Torres N, Ruiz-Veguilla M, Olivé Mas J, Rodríguez Gangoso A, Canal-Rivero M, Juncal-Ruiz M, et al. Metabolic syndrome and related factors in a large sample of antipsychotic naïve patients with first-episode psychosis: 3 years follow-up results from the PAFIP cohort. Spanish Journal of Psychiatry and Mental Health. 2023 Jul 1;16(3):175–83.

8. de Filippis R, Gaetano R, Schoretsanitis G, Verde G, Oliveti CA, Kane JM, et al. Clozapine management in schizophrenia inpatients: A 5-year prospective observational study of its safety and tolerability profile. Neuropsychiatr Dis Treat. 2021;17:2141–50.

9. Garcia-Rizo C, Cabrera B, Bioque M, Mezquida G, Lobo A, Gonzalez-Pinto A, et al. The effect of early life events on glucose levels in first-episode psychosis. Front Endocrinol (Lausanne). 2022 Dec 5;13.

10. Miyakoshi T, Ishikawa S, Okubo R, Hashimoto N, Sato N, Kusumi I, et al. Risk factors for abnormal glucose metabolism during antipsychotic treatment: A prospective cohort study. J Psychiatr Res. 2023 Dec 1;168:149–56.

11. Zhuo C, Xu Y, Wang H, Zhou C, Liu J, Yu X, et al. Clozapine induces metformin-resistant prediabetes/diabetes that is associated with poor clinical efficacy in patients with early treatment-resistant schizophrenia. J Affect Disord. 2021 Dec 1;295:163–72.

12. Miyakoshi T, Ishikawa S, Okubo R, Hashimoto N, Sato N, Kusumi I, et al. Risk factors for abnormal glucose metabolism during antipsychotic treatment: A prospective cohort study. J Psychiatr Res. 2023 Dec 1;168:149–56.

13. Hirsch L, Patten SB, Bresee L, Jette N, Pringsheim T. Second-generation antipsychotics and metabolic side-effects: Canadian population-based study. BJPsych Open. 2018 Jul;4(4):256–61.

14. Dong K, Wang S, Qu C, Zheng K, Sun P. Schizophrenia and type 2 diabetes risk: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2024;15.

15. Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, et al. Atypical antipsychotics and metabolic syndrome: From molecular mechanisms to clinical differences. Pharmaceuticals. 2021 Mar 1;14(3).

16. Castellani LN, Pereira S, Kowalchuk C, Asgariroozbehani R, Singh R, Wu S, et al. Antipsychotics impair regulation of glucose metabolism by central glucose. Mol Psychiatry. 2022 Nov 1;27(11):4741–53.

17. Mortimer KRH, Katshu MZUH, Chakrabarti L. Second-generation antipsychotics and metabolic syndrome: a role for mitochondria. Front Psychiatry. 2023;14.

18. Mortimer KRH, Katshu MZUH, Chakrabarti L. Second-generation antipsychotics and metabolic syndrome: a role for mitochondria. Vol. 14, Frontiers in Psychiatry. Frontiers Media SA; 2023.

19. Makary S, Abd El Moez K, Elsayed M, Hassan H. Second-generation antipsychotic medications and metabolic disturbance in children and adolescents. Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 2023 Dec 1;59(1).

20. Grajales D, Ferreira V, Valverde ÁM. Second-generation antipsychotics and dysregulation of glucose metabolism: Beyond weight gain. Vol. 8, Cells. MDPI; 2019.

21. Vasiliu O. Therapeutic management of atypical antipsychotic related metabolic dysfunctions using GLP 1 receptor agonists: A systematic review. Exp Ther Med. 2023 Jun 1;26(1).

Downloads

Published

2026-02-28