Esketamine for depression: pooled results from 67 randomized trials

The question

Does esketamine help treat major depression and treatment-resistant depression, and does it help prevent depression after childbirth or after surgery? And does the way it is given matter?

What they did

Researchers searched five research databases up to July 24, 2025 for randomized controlled trials comparing esketamine with a control group for depression. Out of 12,285 records screened, they included 67 trials with 11,553 participants: 19 on major depressive disorder or treatment-resistant depression, 18 on postpartum depression, and 30 on depression after surgery. They pooled depression scale scores, remission and response rates, and rates of new depression, and also compared different routes of administration. Side effects reported in more than two comparisons were pooled as well.

What they found

Compared with control groups, esketamine was linked to lower depression scores in major or treatment-resistant depression (standardized mean difference -0.36, 95% confidence interval -0.49 to -0.24), a small-to-moderate effect. For postpartum depression at six weeks the pooled effect was -0.40 (95% CI -0.78 to -0.02), and for depression three months after surgery it was -0.82 (95% CI -1.46 to -0.18) — both statistically significant but with wide ranges of uncertainty. Intravenous administration ranked highest for treating major or treatment-resistant depression and for preventing postpartum depression, across the different outcome measures used. Esketamine was associated with more dizziness than control in both the treatment and prevention trials.

The fine print

The analysis combines trials in very different groups of people — people seeking treatment for depression, new mothers, and surgical patients — so a single pooled number can hide important differences. The confidence intervals for the postpartum and postoperative results are wide and come close to no effect, meaning the true size of the benefit is uncertain. The abstract does not describe how well the individual trials were blinded or their overall quality, and blinding is difficult with a drug that produces noticeable effects. This summary is based on the abstract only.

What it means

Across many randomized trials, esketamine was associated with modest reductions in depression scores and fewer new cases of depression after childbirth or surgery, with dizziness as a common side effect; the route of administration appeared to matter, but the pooled estimates carry real uncertainty.

Evidence grade: Moderate. A large meta-analysis of randomized trials, but it pools very different populations and treatment settings, and some pooled estimates have wide confidence intervals.

This summary is based on the study’s published abstract.