Sex Differences in Placebo and Antidepressant Response to Intranasal Esketamine for Treatment-Resistant Depression

Esketamine has emerged as a fast-acting antidepressant option for individuals with treatment-resistant depression (TRD). Yet, little is known about how sex-assigned-at-birth shapes symptom-specific responses to these interventions, a critical gap in the move toward precision psychiatry. To address this gap, we conducted a pooled analysis of five randomized, double-blind, placebo-controlled trials in which adults with TRD received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. We evaluated the effects of sex-assigned-at-birth on overall depression severity, measured via total Montgomery-Åsberg Depression Rating Scale (MADRS) scores, across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms, and rates of clinical response and remission. Esketamine treatment improved total MADRS scores in both sexes. However, females showed greater improvement in total MADRS scores and higher odds of treatment-response than males towards the end of the trials, in both the placebo and esketamine arms. Females also showed more pronounced reductions in the sadness and detachment factors at the end of the trials, as well as in the neurovegetative factor on day 15, regardless of treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2. These findings reveal that sex-assigned-at-birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement. Our findings emphasize the importance of incorporating sex-assigned-at-birth as a key variable to consider for optimizing TRD treatment strategies and advancing precision mental care.