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Meta-Analysis
. 2025 Oct 1;82(10):977-991.
doi: 10.1001/jamapsychiatry.2025.2240.

Antipsychotic Drugs and Dysregulated Glucose Homeostasis: A Systematic Review and Meta-Analysis

Emily C C Smith  1   2 , Sri Mahavir Agarwal  1   2   3   4 , Kristoffer J Panganiban  1   2 , Kateryna Maksyutynska  1   2 , Jonathan Monteiro  5 , Jiwon Lee  1   2 , Femin Prasad  2 , Andrew Ji  2 , Divia Shah  6 , Samantha Cavalier  6 , Reva U Prabhune  6 , Emril Radoncic  6 , Zilu Yang  6 , Kaitlin Fuller  7 , Michael J McCarthy  8   9 , Tyler R Prestwood  10 , Jacob S Ballon  10 , Christoph U Correll  11   12   13   14 , Margaret K Hahn  1   2   3   4   15   16 , Zachary Freyberg  6   17
Affiliations
Meta-Analysis

Antipsychotic Drugs and Dysregulated Glucose Homeostasis: A Systematic Review and Meta-Analysis

Emily C C Smith et al. JAMA Psychiatry. .

Abstract

Importance: Antipsychotic drug (AP)-induced glucose homeostasis changes are often attributed to AP-induced weight gain. Nevertheless, dysregulated glucose control can occur independently of weight gain.

Objective: To examine the association between AP use and glucose homeostasis while considering weight gain propensity, medication type, and treatment duration.

Data sources: MEDLINE, Embase, PsychINFO, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through February 3, 2025.

Study selection: Blinded randomized clinical trials (RCTs) comparing changes in glucose homeostasis-related parameters between patients with severe mental illness or healthy volunteers assigned to AP or control (placebo or no intervention) groups were included. Studies were limited to English-language human studies without restrictions on study length, AP type, or previous AP exposure. Of 22 773 unique citations, 163 RCTs met inclusion criteria, with 127 studies included in the meta-analysis.

Data extraction and synthesis: Each article was screened independently by 2 authors using predefined inclusion and exclusion criteria. Data extraction and risk of bias assessment were completed using a standardized spreadsheet. Data were analyzed via random-effects meta-analysis, with subgroup analyses for diagnosis, study length, AP type, age, concomitant medication use, and previous AP exposure. Metaregressions identified covariate effects. Data analysis was completed from October 2023 to February 2025.

Main outcomes and measures: Primary study outcomes were changes in fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c) following AP treatment. Secondary outcomes included any other glucose metabolism-related parameters including, but not limited to, insulin resistance and hyperglycemia.

Results: A total of 35 952 AP-treated patients and 19 010 placebo-treated patients were included in the qualitative synthesis, while 28 975 AP-treated and 15 101 placebo-treated patients were included in the meta-analysis. AP use was associated with significantly increased fasting glucose (mean difference [MD], 0.72 mg/dL; 95% CI, 0.54-1.08 [to convert to millimoles per liter, multiply by 0.0555]; P < .001), fasting insulin (MD, 1.94 μIU/mL; 95% CI, 1.28-2.61 [to convert to picomoles per liter, multiply by 6]; P < .001), glycated hemoglobin (MD, 0.04%; 95% CI, 0.02%-0.05% [to convert to proportion of total hemoglobin, multiply by 0.01]; P < .001), and hyperglycemia (odds ratio, 1.29; 95% CI, 1.04-1.59; P = .02) vs placebo. Findings were corroborated in healthy volunteers. Subgroup analyses suggested that AP type, diagnosis, age, concomitant medication use, and previous AP exposure do not consistently affect dysglycemia risk. In metaregression analyses, AP-associated dysregulations in glucose homeostasis were independent of study length and AP dose.

Conclusions and relevance: In this systematic review and meta-analysis, results indicate that AP exposure significantly disrupts glucose homeostasis independent of exposure time, dose, diagnosis, and weight gain propensity. Increased awareness of AP-induced dysregulations in glucose homeostasis alongside ongoing metabolic monitoring and potential treatment is warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Agarwal reported personal fees from Boehringer Ingelheim and HLS Therapeutics outside the submitted work. Dr McCarthy reported personal fees from Alkermes outside the submitted work. Dr Ballon reported grants from Alkermes, Boehringer Inglemeim, Bristol Myers Squibb (Karuna Therapeutics), Corcept Therapeutics, Janssen, Neurocrine, Roche, and Teva; consultant or advisory fees from Alkermes, Aluco BioSciences, Corcept Therapeutics, Indivior, Lundbeck, and Teva outside the submitted work; holding stock options in Aluco BioSciences; and receiving royalties from American Psychiatric Association Publishing. Dr Correll reported consultant or advisor fees or honoraria from AbbVie, Alkermes, Allergan, Angelini, Aristo Pharma, Autobahn Therapeutics, Boehringer Ingelheim, Bristol Meyers Squibb, Cardio Diagnostics, Cerevel Therapeutics, CNX Therapeutics, Compass Pathways, Darnytsia, Delpor, Denovo Biopharma, Draig Therapeutics, Eli Lilly, EuMentis Therapeutics, Gedeon Richter, Hikma Pharmaceuticals, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/Johnson & Johnson, Karuna Therapeutics, LB Pharmaceuticals, Lundbeck, MapLight, MedinCell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neumora Therapeutics, Neuraxpharm, Neurelis, Neurocrine Biosciences, Newron Pharmaceuticals, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada Therapeutics, Response Pharmaceuticals, Reviva Pharmaceuticals, Rovi, Saladax Biomedical, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion Pharmaceuticals, Sun Pharma, Supernus Pharmaceuticals, Tabuk Pharmaceuticals, Takeda Pharmaceuticals, Teva Pharmaceuticals, Terran Biosciences, Tolmar, Vertex Pharmaceuticals, Viatris, and Xenon Pharmaceuticals; providing expert testimony for Janssen, Lundbeck, and Otsuka; serving on a data safety monitoring board for Compass Pathways, Intra-Cellular Therapies, Relmada Therapeutics, Reviva Pharmaceuticals, and Rovi; receiving grant support from Boehringer Ingelheim, Janssen, and Takeda Pharmaceuticals; receiving royalties from UpToDate; and holding stock options in Cardio Diagnostics, Küleon Bioscience, LB Pharmaceuticals, Medlink, Mindpax, The Quantic Group, and Terran Biosciences. Dr Hahn reported grants from Merck and personal fees from Alkermes and Eli Lilly outside the submitted work. Dr Freyberg reported grants from UPMC Enterprises outside the submitted work. No other disclosures were reported.

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