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

Background: Antidepressants are among the most widely prescribed drugs worldwide, with 13.2% of U.S. adults using antidepressants and women doing so more than twice as often than men (17.7% vs. 8.4%). Evidence suggests that sex influences antidepressant pharmacokinetics, potentially leading to sex differences in antidepressant tolerability, safety and therapeutic response. However, current prescription guidelines do not incorporate sex as a biological factor influencing antidepressant exposure or treatment outcome. This study investigated sex-related differences in serum levels of 11 commonly prescribed antidepressants, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, and norepinephrine and serotonin selective antagonists.

Aims & Objectives: To determine whether sex is associated with systematic differences in antidepressant serum levels in a real-world clinical population, and to evaluate whether such differences warrant consideration in future sex-informed dosing recommendations.

Method: Serum levels of amitriptyline, nortriptyline, citalopram, clomipramine, fluoxetine, fluvoxamine, imipramine, mirtazapine, paroxetine, sertraline, and venlafaxine, along with their active metabolites, were collected from the laboratory information system (GLIMS) database of the University Medical Centre Groningen (UMCG) between January 2016 and October 2024. When metabolites exhibited comparable pharmacological potency, parent and metabolite concentrations were summed. Linear mixed-effects models were applied with antidepressant serum level as dependent variable, random intercepts for participants and fixed effects for sex and age. The dataset comprised 38,298 samples from 10,500 unique adult men and women. To assess whether dosing differences contributed to the sex differences in serum levels, subgroup analysis using dosing data from the MOnitoring psychoPHARmacology (MOPHAR) program was performed.

Results: Women exhibited significantly higher serum levels than men for citalopram (+38%, p<0.001), fluoxetine (+20%, p=0.002), fluvoxamine (+85%, p<0.001), paroxetine (+51%, p<0.001), sertraline (+13%, p=0.048), clomipramine (+10%, p <0.001), imipramine (+20%, p=0.001 ), nortriptyline (+9%, p<0.001), and venlafaxine (+25%, p<0.001). Trend level higher serum levels were observed in women for amitriptyline (p=0.058). Dosing did not significantly differ between sexes, except for higher doses in men than in women for clomipramine (p=0.016) and nortriptyline (p<0.001).

Discussion & Conclusions: Under current treatment guidelines, women are exposed to significantly higher antidepressant serum levels than men for citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, clomipramine, imipramine, nortriptyline, and venlafaxine. Subgroup analyses confirmed that the observed sex differences are unlikely to result from dosing practices but instead reflect sex differences in underlying mechanisms such as pharmacokinetic variations or sex-specific epigenetic regulation of hepatic drug-metabolizing enzymes. Whereas most antidepressants investigated are prescribed using standardized dosing regimens, dosing of amitriptyline, clomipramine, imipramine and nortriptyline is guided by therapeutic drug monitoring (TDM). The smaller, though persisting, sex differences observed for these antidepressants suggest that TDM partially mitigates but does not fully eliminate sex-related pharmacokinetic variability. These findings highlight the need to consider sex in antidepressant dosing strategies to improve treatment tolerability, and safety for women. Further research is warranted to inform the development of sex-specific dosing guidelines.