Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis.
Konstantinos N Fountoulakis, Athanasios Saitis, Alan F. Schatzberg
American Journal of Psychiatry March 1, 2025 DOI: 10.1176/appi.ajp.20240515 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Randomized Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant major depressive disorder |
| Intervention | Intranasal esketamine |
| Topics | Depression Esketamine |
| Keywords | Depressive disorders Ketamine/esketamine Meta-analysis Suicidality Clinical efficacy Mental health treatment |
| Citations | 78 |
| Key findings | Esketamine as an add-on to antidepressants has a modest effect on depression but no significant effect on suicidality. |
Abstract
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. 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. 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. 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.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
Citations in the library
Cited by 48
- Pharmacological Monotherapy for Depressive Disorders: Current and Future-A Narrative Review. Medicina (Kaunas, Lithuania) March 21, 2025
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
- 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. BMC Medicine November 28, 2025
- Lessons learned from the regulatory alignment in ketamine, esketamine and arketamine clinical trials: A cross-sectional analysis of protocols from ClinicalTrials.gov. Psychiatry Research August 1, 2025
and 43 more in the library
Cites 54
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
and 49 more in the library