¹UMCG, Department of Clinical Neuroscience and Cognition, Groningen, Netherlands, ²UMCG, Department of Clinical Pharmacy and Pharmacology, Groningen, Netherlands

Background: Citalopram, a selective serotonin reuptake inhibitor, is among the most prescribed antidepressants. Currently, sex and reproductive life-stage are not considered in citalopram prescription guidelines, despite evidence of sex-related differences in its pharmacokinetics, tolerability, and therapeutic response. This study investigated the influence of sex and estimated menopausal status on citalopram serum levels and the norcitalopram:citalopram ratio.

Aims & Objectives: To investigate whether sex and estimated menopausal status impact citalopram serum levels and norcitalopram:citalopram ratios, and to support the development of sex- and reproductive-life-stage-specific dosing strategies to optimize drug safety, tolerability, and efficacy in pre- and post-menopausal women.

Method: Serum levels of citalopram and its active metabolite norcitalopram were collected from the laboratory information system (GLIMS) database of the University Medical Centre Groningen (UMCG) between January 2016 and October 2024. Samples were grouped by sex and age (≤51 years, >51 years) into four categories using 51 years of age as a proxy for menopause. Linear mixed-effects models and predefined pairwise contrasts were applied with citalopram serum level or norcitalopram:citalopram ratio as dependent variable, random intercepts for participants, and fixed effects for sex, menopausal age group, and age. In total, 1,729 citalopram serum level measurements from 1,387 unique adult patients (63% women) and 1,541 norcitalopram:citalopram ratios from 1,227 (65% women) unique adult patients were included. To assess whether dosing differences contributed to the sex differences in citalopram serum levels, subgroup analysis using dosing data from the MOnitoring psychoPHARmacology (MOPHAR) program was performed.

Results: Women showed on average 38% higher citalopram serum levels (estimate=24.59, CI=12.89 to 36.29, p<0.001) and 9% lower norcitalopram:citalopram ratios (estimate=-6.83, CI=-0.10 to -0.034, p<0.001) than men. Sex differences were most pronounced in the premenopausal stage (ages ≤51 years): +56% for citalopram serum levels (estimate=24.590, CI=9.180 to 40.000, p<0.001) and -17% for the norcitalopram:citalopram ratio (estimate=-0.068, CI=-0.114 to -0.023, p<0.001). In the postmenopausal stage (>51 years), citalopram serum levels were 23% higher in women than in men (estimate=18.869, CI=1.441 to 36.296, p=0.009) and norcitalopram:citalopram ratios were similar between sexes (estimate=-0.010, CI=-0.060 to 0.040, p=0.622). Citalopram dosing did not differ between sexes (estimate=1.23, CI=-1.64 to 4.10, p=0.404) nor between menopausal age groups (p=0.977).

Discussion & Conclusions: Citalopram serum levels were significantly higher in women than in men, with the difference most pronounced in the premenopausal age group (≤51 years). The similar sex- and estimated menopausal status-dependent pattern observed for both citalopram serum levels and norcitalopram:citalopram ratios suggest a shared underlying mechanism, likely estrogen-induced downregulation of the activity of CYP2C19 and/or CYP1A2 in assumed premenopausal women. The involvement of estrogen is further supported by the attenuation of the sex difference in citalopram serum levels and ratios after average menopausal age. Differences in dosing practices are unlikely to explain these findings, as no significant sex differences in citalopram prescribing were observed. Consideration of sex and women’s reproductive life-stage when prescribing citalopram can improve treatment tolerability, safety and efficacy in women. Especially premenopausal women may reach high serum levels with standard dosing and consequently become vulnerable for adverse effects.