Glucose dysregulation signals in weight-neutral atypical antipsychotics: A pharmacovigilance-pharmacodynamic...

Glucose dysregulation is a known adverse effect of antipsychotics, particularly with agents like olanzapine and clozapine. Paradoxically, even weight-neutral atypical antipsychotics may pose similar concerns, but the specific agents involved, and the underlying receptor mechanisms have not been clarified.

We extracted reports for 11 atypical antipsychotics from the FDA Adverse Event Reporting System (FAERS) database covering January 2020 to March 2025, with sensitivity analysis extending back to September 2015. To detect safety signals for glucose dysregulation, logistic regression-based disproportionality analyses were conducted. Signal strength was assessed using the adjusted reporting odds ratio (aROR), with significance defined as a 95 % confidence interval (CI) excluding 1. Linear regression analyses examined the associations between aROR and receptor occupancy estimated from in vitro binding profiles.

Ziprasidone (aROR: 4.83, 95 % CI: 1.97-12.15) and asenapine (aROR: 4.77, 95 % CI: 1.44-14.10) exhibited stronger safety signals than olanzapine (aROR: 3.37, 95 % CI: 1.78-7.25), while lurasidone (aROR: 2.58, 95 % CI: 1.23-5.92) and aripiprazole (aROR: 2.41, 95 % CI: 1.27-5.17) showed signal strengths comparable to quetiapine (aROR: 2.55, 95 % CI: 1.34-5.50). Sensitivity analyses revealed slight instability in asenapine's signal. Linear regression revealed a significant positive association between aROR and 5-HT2C receptor occupancy (β = 0.031, p = 0.002).

Weight-neutral drugs such as ziprasidone, asenapine, lurasidone, and aripiprazole may be associated with glucose dysregulation, underscoring the need for vigilance when switching antipsychotics. This phenomenon might be attributable to their antagonistic effects on 5-HT2C receptors. However, given the exploratory nature of this study, these findings warrant further validation.