Sex differences in placebo and antidepressant response to intranasal esketamine for treatment-resistant depression: a pooled participant analysis of randomized controlled trials
Bibliographic record
Abstract
Summary Background Racemic ketamine and its enantiomer, esketamine, have emerged as fast-acting antidepressant options for individuals with treatment-resistant depression (TRD). Yet, despite growing clinical use, little is known about how sex assigned at birth shapes symptom-specific responses to these interventions, a critical gap in the move toward personalized psychiatry. Methods 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, and across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms. Rates of clinical response and remission were also analyzed by sex assigned at birth. Findings Overall, esketamine treatment improved total MADRS scores in both sexes; however, significant sex-specific patterns emerged. Females showed greater improvement in total MADRS scores 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 the treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2 of the treatment. Females had higher odds of responding, regardless of treatment arm, during later time points. Interpretation 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 critical importance of incorporating sex assigned at birth as a key variable, essential for optimizing TRD treatment strategies and advancing individualized mental healthcare. Funding Canadian Institutes for Health Research.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.044 | 0.055 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.015 | 0.030 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".