Risk of Diabetes Mellitus Associated with Newer vs. Traditional Atypical Antipsychotics in Patients with Psychiatric Disorders: A Pharmacovigilance Analysis of FAERS Data

Background Antipsychotic-induced diabetes mellitus (DM) is a major metabolic complication of schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. 1– 3 Despite efforts since 2006 to improve metabolic tolerability, contemporary pharmacovigilance data have not assessed comparative diabetes risks of atypical antipsychotics across these populations. Objective This study compares diabetes disproportionality signals across 13 antipsychotics in patients with psychiatric disorders, using crude and adjusted analyses of 198,336 FAERS reports through Q3 2024. Methods Retrospective FAERS analysis. Reporting odds ratios (RORs) were calculated with 2×2 tables and within-class comparators; age- and sex-adjusted RORs (aRORs) used multivariable logistic regression. Signals required a lower 95% confidence interval (CI) >1.0; strong signals also required an estimate >2.0. Results Among 198,336 reports, 1,651 diabetes mellitus events involved 13 antipsychotics. Of post-2006 agents, only paliperidone showed a strong signal. Lurasidone showed a sensitive signal, reaching the robust threshold only after demographic adjustment. Brexpiprazole (aROR = 0.33), lumateperone (aROR = 0.61), and cariprazine (aROR = 0.69) had low, nonsignificant signals. Traditional agents asenapine and ziprasidone had the strongest adjusted signals. Olanzapine and aripiprazole had significant but sub-threshold signals. Clozapine (crude ROR = 0.50), quetiapine (aROR = 0.67), and risperidone (aROR = 0.61) showed protective-direction signals, reflecting reporting bias rather than metabolic safety. Conclusions Paliperidone and lurasidone show diabetes signals, warranting metabolic monitoring like high-risk agents. Among traditional agents, asenapine and ziprasidone have the strongest adjusted signals, likely due to H1 antagonism and channeling bias, respectively. Clozapine and olanzapine’s protective signals may reflect Weber-effect masking, not metabolic safety.