Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis
This systematic review and meta-analysis (s=87; 2025) finds esketamine's efficacy as an adjunctive therapy for treatment-resistant depression (TRD) to be modest (effect size 0.15-0.23) and comparable to atypical antipsychotics, with no significant effect on suicidality. The review raises concerns about esketamine's abuse potential and unknown long-term effects. It also highlights regulatory issues, including deaths and emerging suicidality during clinical trials.
Authors
- Alan Schatzberg
Published
Abstract
Objective
Intranasal esketamine has been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior. The authors conducted a systematic review and meta-analysis of the available data on its efficacy against depression and suicidality as well as its side effects.
Methods
MEDLINE was searched with the keyword “esketamine” on March 24, 2024, using the PRISMA method. Data processing and statistical analysis were performed with R, version 4.3.3, and the meta-analysis was performed with the METAFOR package.
Results
Of 1,115 articles initially identified, 87 were included for analysis and discussion. At weeks 2-4, randomized controlled trials were mostly negative or failed; however, the meta-analysis returned a weak but significant positive effect for depression (effect size range, 0.15-0.23 at weeks 2-4), similar to augmentation strategies with atypical antipsychotics for treatment-resistant depression. The effect size concerning suicidality was not significant at any time point. The sensitivity analysis produced the same results.
Conclusions
The study findings suggest that esketamine’s efficacy as an add-on to antidepressants is modest in treatment-resistant depression (similar to augmentation strategies with atypical antipsychotics) and is absent against suicidality itself. These findings need to be considered in light of esketamine’s abuse potential and the fact that long-term effects are still not fully known. Some alarming signs concerning deaths and emerging suicidality during the testing phase are discussed, along with other regulatory issues.
Research Summary of 'Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis'
Introduction
Earlier research establishes that conventional antidepressants have proven efficacy but a substantial proportion of patients fail to achieve sustained remission, with treatment-resistant depression (TRD) commonly defined as nonresponse to two adequate antidepressant trials. Interest in rapid-acting agents has grown because of this unmet need; ketamine and its enantiomers are central to that work. Esketamine, the S-enantiomer of ketamine, has higher affinity for NMDA (and to some extent mu-opioid) receptors and was approved by the U.S. Food and Drug Administration in 2019 as an intranasal adjunctive therapy for TRD, with a subsequent indication for major depression with acute suicidal ideation and behaviour. Despite many publications, uncertainty remains about the durability of esketamine’s antidepressant effect, its true antisuicidal efficacy, and how its benefit compares with other augmentation strategies. Fountoulakis and colleagues set out to synthesise the entire esketamine literature to clarify these questions. Using a PICO framework focused on adults with depression receiving esketamine versus placebo, the investigators aimed to assess effects on depressive symptoms and suicidality, and to examine safety signals and longer-term outcomes. The study therefore undertook a broad systematic review and meta-analysis of randomized controlled trials (RCTs) and related literature to evaluate efficacy at multiple clinically relevant time points and to explore sensitivity analyses by TRD status and dose arms.
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Study Details
- Study Typemeta
- Journal
- Compounds
- Topics
- Author
- APA Citation
Fountoulakis, K. N., Saitis, A., & Schatzberg, A. F. (2025). Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry, 182(3), 259-275. https://doi.org/10.1176/appi.ajp.20240515
References (11)
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Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
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