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

Why It Matters

Recognizing sex‑specific efficacy patterns can refine esketamine prescribing and improve outcomes for treatment‑resistant depression.

Key Takeaways

• Esketamine outperforms placebo across all time points
• Females show greater MADRS reduction at weeks 3‑4
• Males exhibit stronger acute response on day 1
• Female placebo responders higher, indicating expectancy effects
• No sex difference observed in remission rates

Pulse Analysis

Treatment‑resistant depression (TRD) remains a major clinical challenge, prompting the FDA and Health Canada to approve intranasal esketamine as a rapid‑acting option. While its overall efficacy is well documented, prior studies rarely examined whether biological sex influences therapeutic outcomes, leaving a critical gap for clinicians seeking personalized strategies. By aggregating data from five rigorously designed trials, researchers now provide a robust evidence base to assess sex‑based response patterns, an essential step toward more nuanced psychiatric care.

The analysis revealed that esketamine consistently lowered MADRS scores compared with placebo, confirming its antidepressant potency. Notably, women experienced larger symptom reductions at later visits (days 22‑28), especially in sadness, detachment, and neurovegetative domains, suggesting heightened sensitivity to sustained treatment effects. Men, conversely, displayed a pronounced acute benefit on the first day and a specific early advantage in alleviating sadness. These divergent trajectories underscore the importance of timing and symptom focus when evaluating treatment response, and they hint at underlying pharmacokinetic or neurobiological mechanisms that differ by sex.

For the industry and prescribers, these findings signal a move toward sex‑aware dosing algorithms and trial designs that stratify participants by biological sex. Incorporating such variables could enhance response rates, reduce unnecessary exposure, and inform labeling updates. Future research should expand to gender identity, adverse‑effect profiling, and metabolic studies to fully capture the spectrum of patient experiences. As the market for rapid‑acting antidepressants grows, integrating sex‑specific insights will be key to delivering equitable, effective care for individuals battling TRD.