The Impact of Sex and Age on Antipsychotic Serum Concentrations

Background and Hypothesis Estrogen affects drug metabolism for specific antipsychotics, which may produce sex differences in serum levels, especially over the menopausal transition. Here, we explore sex differences in concentrations of four commonly used antipsychotics: clozapine, olanzapine, aripiprazole, and quetiapine and examined how these vary across age groups, including postmenopause (>55). Study Design Antipsychotic concentrations of 44 378 serum samples drawn between January 2016 and October 2024 were analyzed. Samples were provided by 6147 unique adult men and women for clozapine (n = 34 761 samples, 26% female), olanzapine (n = 5114, 27% female), aripiprazole (n = 3171, 37% female), and quetiapine (n = 1332, 50% female). To investigate the effect of sex and age on antipsychotic concentrations, we employed linear mixed-effects models and pairwise contrasts by dividing the samples in 6 groups according to sex and age (<45, 45-55, and >55 years). Study Results We found higher concentrations in women compared to men for clozapine (P < .001), and olanzapine (P < .001), but not for quetiapine or aripiprazole. Young women (<45) showed higher levels of clozapine (P = .004) and olanzapine (P < .001) than men, but older women did not. Clozapine levels were higher in women <45 and 45-55 compared to women >55 years (all P < .05). For olanzapine, aripiprazole, and quetiapine concentrations differences between female age groups were absent. Conclusions We found sex differences in olanzapine and clozapine concentrations, which were most pronounced until 45 years of age. Our findings suggest that monitoring antipsychotic levels may add clinical value and underscore the need for sex-specific prescription guidelines for olanzapine and clozapine.