First generation antipsychotic-associated serious adverse events in women: a retrospective analysis of a pharmacovigilance database

Women have been under-represented in trials of antipsychotic medications.

Our primary objective was to evaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to men through an analysis of the FDA Adverse Event Reporting System (FAERS).

We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men.

A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71–0.87) for NMS, 0.83 (0.68–1.01) for TD, 1.21 (0.94–1.53) for TdP, 0.71 (0.51–0.98) for AG, and 0.91 (0.68–1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29–2.94) and death associated with reports of AG (ROR = 2.46, 1.15–5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26–2.21) for women relative to men for TdP.

The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.