Efficacy and safety of esketamine for "treatment resistant depression": registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials.
Florian Naudet, Claude Pellen, Liviu A Fodor, Chiara Gastaldon, Corrado Barbui, Erick H Turner, Estelle Le Pabic, Ioana A. Cristea
BMC Medicine November 28, 2025 DOI: 10.1186/s12916-025-04435-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and individual patient data meta-analysis Randomized Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 1,505 |
| Population | Patients with treatment-resistant depression |
| Intervention | intranasal esketamine |
| Duration | At least 4 weeks for initiation trials; continuation trial assessed relapse |
| Topics | Depression Esketamine |
| Keywords | Re-analysis |
| Citations | 5 |
| Key findings | Esketamine plus an antidepressant showed a statistically significant but small reduction in depression scores at 4 weeks, with unclear clinical relevance and increased adverse events. |
Abstract
In 2019, the FDA and EMA approved intranasal esketamine for treatment-resistant depression (TRD). The current study re-evaluated its efficacy and safety. This registered report presents a systematic review and individual patient data (IPD) meta-analysis of double-blind, randomised, placebo-controlled trials (RCTs) assessing intranasal esketamine for TRD. Two reviewers independently screened studies from multiple databases and obtained IPD via the Yale Open Data Access Project. Two independent researchers selected studies and assessed risk of bias. The primary outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) score at ≥ 4 weeks in initiation trials, benchmarked against the 6.5-point clinical significance threshold used in the design of pivotal trials. Evidence certainty was rated using GRADE. Secondary outcomes included additional efficacy and safety endpoints. A two-step IPD meta-analysis was conducted, with separate analyses by trial phase (initiation vs. continuation) and treatment type (combination vs. monotherapy). A one-stage meta-analysis explored moderators (e.g. age and resistance level). We re-analysed IPD from 7 RCTs including 1505 patients. In five initiation trials of esketamine plus an antidepressant, esketamine reduced MADRS scores at 4 weeks (mean difference (MD) = - 2.94, 95% CI [- 5.39 to - 0.48]; GRADE: moderate certainty). A continuation trial showed reduced relapse risk (HR = 0.38 [0.26-0.57]), though FDA concerns about one centre could not be addressed due to data privacy restrictions. A monotherapy trial (aggregate data only) showed a larger effect (MD = - 6.32 [- 8.62 to - 4.03]), but there were concerns over selection bias and unblinding. Esketamine increased sedation (RR = 3.70 [2.02-6.78]), dissociation (RR = 2.36 [2.10-2.65]), and adverse events (IRR = 3.91 [2.37-6.45]), with no increase in serious adverse events (IRR = 1.35 [0.54-3.40]). No treatment effect moderation was found by age or resistance level, with most patients displaying low-stage TRD. Based on the IPD used for approval, esketamine in combination with an antidepressant showed an advantage over placebo that was statistically significant but small. The clinical relevance of this benefit is unclear, particularly given the risks of adverse events. PROSPERO: CRD42021290721.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |