Seizures Risk Related to Atypical Antipsychotics: A Disproportionality Analysis Based on the FDA Adverse Event...

This pharmacovigilance study aimed to characterize the spectrum of seizure-related adverse events (AEs) associated with eight commonly used atypical antipsychotics (AAPs)-clozapine, quetiapine, olanzapine, aripiprazole, ziprasidone, risperidone, lurasidone, and paliperidone-based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, and to explore potential receptor mechanisms underlying AAP-related seizures.

Disproportionality analysis was performed using FAERS data from the first quarter of 2004 to the second quarter of 2025. Signal values were assessed using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms. Spearman correlation analysis was performed to examine associations between ROR values and receptor binding affinity (Ki) data for D1, D2, D3, 5-HT_1A, 5-HT_2A, 5-HT_2C receptors and 5-HT_1A/D2, 5-HT_2A/D2, and 5-HT_2C/D2 receptor ratios.

The final analysis included 9057 reports of AAPs-seizures pairs (N ≥3), and 8540 cases demonstrating significant seizures-related signals detected by ROR analysis at the preferred term (PT) level. The eight AAPs demonstrated distinct seizures AE profiles, with quetiapine associated with the broadest spectrum (15 PTs). At the High-Level Group Term (HLGT) level, ziprasidone showing the strongest association (ROR₀₂₅ = 3.21), followed by quetiapine (ROR₀₂₅ = 2.62), clozapine (ROR₀₂₅ = 2.58), olanzapine (ROR₀₂₅ = 2.53) and aripiprazole (ROR₀₂₅ = 2.05). Risperidone, paliperidone, and lurasidone exhibited comparatively lower signals. Spearman correlation analysis revealed a significant negative correlation between the 5-HT_1A/D2 receptor affinity ratio and ROR values (rs = -0.79, p = 0.036).

This large-scale real-world analysis suggests that clozapine, quetiapine, olanzapine, aripiprazole, and particularly ziprasidone are associated with higher reporting signals for seizures compared with risperidone, paliperidone, and lurasidone. The inverse correlation with the 5-HT_1A/D2 ratio suggests a potential pharmacodynamic mechanism. Clinicians should consider these differential risks, especially when prescribing for patients with predisposing factors, and maintain vigilance for specific seizures types. These findings warrant further validation through prospective studies and clinical causality assessments.