Citalopram serum concentrations in men and women of pre- and post-menopausal age

Abstract

Background: Sex and reproductive life-stage are currently not considered in (es)citalopram prescription guidelines, despite evidence of sex-related differences in its pharmacokinetics, tolerability, and therapeutic response. Research design and methods: This study investigated the influence of sex and estimated reproductive life-stage (pre- versus post-menopause; using an age cut at 51 years) on citalopram serum concentrations and the norcitalopram:citalopram ratio. In total, 1,729 citalopram serum concentration measurements and 1,541 norcitalopram:citalopram ratios were analyzed using linear mixed-effects models and predefined pairwise contrasts. Results: Women showed on average 38% higher citalopram serum concentrations (p < 0.001) and 9% lower norcitalopram:citalopram ratios (p < 0.001) than men. Sex differences were most pronounced in the premenopausal stage (ages ≤51 years) with 56% higher citalopram serum concentrations (p < 0.001) and a 17% lower norcitalopram:citalopram ratio (p < 0.001) compared to men aged ≤51 years. After age 51, differences decreased to 23% higher citalopram serum concentrations (p = 0.009) in women than men and no significant sex differences in the norcitalopram:citalopram ratio (p = 0.622). Conclusions: These findings suggest a reproductive life-stage-specific sex difference, likely attributable to estrogen-associated reduction in CYP2C19 and CYP1A2 activity in premenopausal women. Our results indicate that sex and reproductive life-stage substantially influence (es)citalopram pharmacokinetics, potentially affecting tolerability, safety, and therapeutic response.