Seizures associated with clozapine augmentation by other antipsychotics: a pharmacovigilance-pharmacodynamic analysis using VigiBase.

BACKGROUND

Clozapine is associated with a high risk of central nervous system abnormalities. However, seizure risk related to interactions between clozapine and other antipsychotics remains poorly characterized, and the pharmacological mechanisms underlying these seizures are unclear.

OBJECTIVES

We aimed to evaluate safety signals for seizures associated with clozapine augmentation by other antipsychotics and analyze the relationship between these signals and neurotransmitter receptor occupancy profiles.

DESIGN

A pharmacovigilance-pharmacodynamic analysis using a spontaneous reporting system.

METHODS

This pharmacovigilance study used VigiBase, an adverse drug reaction database maintained by the World Health Organization. Drug-drug interactions (DDIs) between clozapine and other antipsychotics were assessed using the Ω shrinkage measure model. The association between DDI signals and neurotransmitter receptor occupancy was evaluated using linear regression. Robustness was tested using four frequency statistical models: additive, multiplicative, combination risk ratio, and chi-square statistic models.

RESULTS

Of 38,758,077 reports in VigiBase between 1990 and 2024, 230,371 involved clozapine. Among antipsychotics classified under ATC code N05A, DDIs with clozapine were detected for amisulpride, chlorpromazine, haloperidol, lurasidone, olanzapine, penfluridol, risperidone, sulpiride, zotepine, and zuclopenthixol. A significant association between dopamine D4 receptor occupancy and the point estimates of signal values was observed in the Ω shrinkage measure model (β = 0.295, 95% confidence interval: 0.119-0.471, p = 0.002) and replicated across all frequency statistical models.

CONCLUSIONS

These findings suggest a potential role of dopamine D4 receptor occupancy in seizures associated with clozapine augmentation by other antipsychotics. Further large-scale epidemiological studies are needed to validate these findings.