Sex differences in placebo and antidepressant response to intranasal esketamine for treatment-resistant depression
Marie Huc, Sara Siddiqi, Mysa Myers, Ian Colman, Natalina Salmaso, Natalia Jaworska, Argel Aguilar-Valles
Molecular Psychiatry February 18, 2026 DOI: 10.1038/s41380-026-03493-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pooled analysis of randomized, double-blind, placebo-controlled trials Peer reviewed |
|---|---|
| Population | Adults with treatment-resistant depression |
| Interventions | Intranasal esketamine placebo |
| Duration | Four weeks |
| Topics | Depression Esketamine |
| Citations | 1 |
| Post-publication review | 1 comment on PubPeer (opens in new tab) · last active February 2026 |
| Key findings | Females showed greater overall improvement and higher odds of treatment response than males toward the end of the trials, while males showed a significant reduction in sadness symptoms after esketamine on day 2. |
Abstract
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.
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.
Citations in the library
Cites 20
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. American Journal of Psychiatry March 29, 2019
and 15 more in the library