Pooled analysis finds sex differences in response to intranasal esketamine for TRD
A pooled analysis of five randomized trials found intranasal esketamine improved MADRS scores in adults with TRD in both sexes. Females showed greater improvement and higher odds of treatment-response toward trial end.
Esketamine improved total Montgomery–Åsberg Depression Rating Scale (MADRS) scores in both sexes in a pooled analysis of five randomized, double-blind, placebo-controlled trials in adults with treatment-resistant depression (TRD). 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. Males showed a significant reduction in sadness symptoms after esketamine on day 2.
The analysis included adults with TRD who received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. The study evaluated the effects of sex-assigned-at-birth on overall depression severity, measured via total MADRS scores, across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms, and rates of clinical response and remission.
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. The findings state that sex-assigned-at-birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement.
The paper states that esketamine was approved by the US Food and Drug Administration and in Europe in 2019, and by Health Canada in 2020 for the treatment of TRD, in combination with an oral antidepressant, and as a monotherapy by the FDA in 2025. The 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.