Antipsychotic Drugs and Dysregulated Glucose Homeostasis: A Systematic Review and Meta-Analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 40864439 · doi:10.1001/jamapsychiatry.2025.2240
What was done
The authors conducted a systematic review and random-effects meta-analysis of blinded randomized clinical trials (RCTs) searched across MEDLINE, Embase, PsychINFO, CINAHL, CENTRAL, and Web of Science through February 3, 2025. Studies evaluated patients with severe mental illness or healthy volunteers assigned to antipsychotics (APs) versus control (placebo or no intervention) and reported glucose metabolism parameters. Of 163 eligible RCTs (35,952 AP-treated and 19,010 placebo-treated patients), 127 RCTs (28,975 AP-treated and 15,101 placebo-treated patients) were quantitatively meta-analyzed. Primary outcomes included changes in fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c); secondary outcomes included hyperglycemia incidence and insulin resistance. Subgroup analyses and metaregressions evaluated the effects of diagnosis, AP type, age, duration, dose, concomitant medication, and prior AP exposure.
What was found
Compared with placebo, AP treatment was associated with significant increases across all primary glucose markers: - Fasting glucose: mean difference (MD) 0.72 mg/dL (95% CI, 0.54–1.08; P < .001) - Fasting insulin: MD 1.94 µIU/mL (95% CI, 1.28–2.61; P < .001) - HbA1c: MD 0.04% (95% CI, 0.02%–0.05%; P < .001) - Hyperglycemia incidence: odds ratio 1.29 (95% CI, 1.04–1.59; P = .02) Findings were consistent in healthy volunteers. Metaregression and subgroup analyses showed dysglycemia risk was independent of exposure time, AP dose, AP type, diagnosis, age, concomitant medications, previous AP exposure, and weight gain propensity.
Why it matters
This study provides high-level evidence that antipsychotics directly impair glucose homeostasis independently of weight gain, drug type, or dosage. It establishes that metabolic monitoring is necessary for all patients receiving antipsychotics, rather than only those who gain weight.
Limits
The review was restricted to English-language publications. While statistically significant, the mean continuous changes across trials were small in absolute terms (e.g., 0.72 mg/dL for glucose, 0.04% for HbA1c), and the abstract does not report long-term rates of progression to clinical diabetes, specific treatment durations, or statistical heterogeneity metrics (such as I²).
Cited by
- supports Antipsychotic drugs used to treat bipolar and schizophrenia cause patients to overeat and develop diabetes or insulin resistance.