Sex differences in adverse event reporting for psychotropic medicines: a disproportionality analysis of benzodiazepines, atypical antipsychotics and antiepileptic agents in 1,231,335 reports

Abstract

Sex differences in psychotropic drug safety are clinically important but have been studied drug by drug, without a common comparator. Whether reported differences reflect class-specific pharmacology or a general asymmetry in how adverse events are reported for women and men has not been established. Case/non-case disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) via openFDA database. All reports listing a benzodiazepine, atypical antipsychotic or antiepileptic agent with a recorded patient sex were included. Comparisons were made within each class, holding drug exposure constant. Reporting odds ratios (RORs) for women versus men were calculated for 32 pre-specified Preferred Terms, with Benjamini-Hochberg control of the false discovery rate across all comparisons. 1,231,335 reports were analysed. Male reports were more often serious in every class (79.8% vs 70.9%, 80.8% vs 78.5%, 80.2% vs 73.4%; all p < 0.001), and the ROR for death was near-invariant (0.60, 0.66, 0.65). Against this baseline, women disproportionately reported memory impairment (ROR 1.46, 95% CI 1.40-1.52) and falls (1.38) with benzodiazepines; QT prolongation (1.44, 1.36-1.52) and tardive dyskinesia (1.40) with antipsychotics; and cutaneous reactions with antiepileptics, including Stevens-Johnson syndrome (1.17, 1.08-1.25). Men disproportionately reported drug abuse (0.42, 0.41-0.44) and dependence (0.51), and hyperprolactinaemia (0.44) and galactorrhoea (0.48). A general severity asymmetry underlies sex-stratified FAERS analyses and must be accounted for before class-specific signals are interpreted. Once it is, benzodiazepine harms separate into therapeutic-use effects in women and misuse-related outcomes in men, and two recognised sex effects in antipsychotic safety are reproduced.