Do sex and gender matter in the pharmacological treatment of depression?

Depression shows significant differences in prevalence, symptomology and treatment outcomes in men and women. Women have a twofold higher risk of depression than men and often present with different depression subtypes. These differences are at least partly mediated by gender roles as well as biological differences, especially regarding the effects sex hormones, which may also impact the efficacy and tolerability of antidepressant drugs (ADDs). This narrative review examines how both biological sex and gender affect the occurrence and presentation of depression as well as the pharmacodynamics and pharmacokinetics of ADDs, focusing on hormonal modulation, treatment efficacy, adverse drug reactions (ADRs), placebo response and sex-/gender-specific symptom presentation of depression. Relevant research pertaining to the objective of this narrative review was extracted in a non-systematic manner. Although many interactions between sex hormones and serotonergic and noradrengic neurotransmission have been described, they rarely translate into robust clinical implications that allow for sex-specific treatment recommendations. The neurosteroid allopregnanolone, however, has been exclusively approved for postpartum depression. Sex hormones, especially estrogen, also impact drug metabolism, which is relevant particularly during pregnancy. Regarding ADRs, women are less willing to tolerate weight gain, whereas men suffer more from sexual dysfunction. Whether or not placebo- and nocebo-response to ADDs is subject to sex/gender differences is currently unknown. Current research does not allow any conclusive recommendations in the treatment of depression according to sex and gender. Future research should prioritize sex-stratified analyses to better comprehend and address these biological differences.