Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials.
Zhibin Wang, Lili Jiang, Wenzhuang Ma, Xingyue Li, Qiushi Gao, Siyu Lian, Weiwei Yu
Clinical Pharmacology & Therapeutics June 1, 2025 DOI: 10.1002/cpt.3555 (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 major depressive disorder or treatment-resistant depression |
| Intervention | Esketamine nasal spray |
| Topics | Depression Esketamine |
| Keywords | Mental health Depression treatment Medical breakthrough Antidepressants Psychiatric medicine |
| Citations | 8 |
| Key findings | Esketamine nasal spray plus an antidepressant reduced depressive symptoms more than placebo in the short term and lowered long-term relapse rates by 40%. |
Abstract
Despite being approved by the US FDA and the EU European Medicines Agency, the performance of esketamine nasal spray as an adjunctive therapy with an antidepressant in major depressive disorder is still controversial. Comprehensive retrieval in Embase, Pubmed, and Web of Science was conducted to identify randomized controlled trials comparing esketamine nasal spray versus control in major depressive disorder or treatment-resistant depression. The primary efficacy outcome was a reduction of the Montgomery-Asberg Depression Rating Scale, from baseline to Day 2 or Day 28 for patients with or without suicidal ideation, respectively. The long-term efficacy outcome was the relapse rate of patients who achieved stable remission. The certainty of evidence was assessed according to the Cochrane recommendation. Esketamine nasal spray was superior to placebo in reduction of Montgomery-Asberg Depression Rating Scale from baseline to Day 28 in patients without suicidal ideation (standardized mean difference: -0.24, 95% confidence interval: -0.38, -0.09, P = 0.001, I2 = 24%), and on Day 2 in patients with suicidal ideation (standardized mean difference: -0.30, 95% confidence interval: -0.47, -0.12, P = 0.0008, I2 = 0%). The long-term relapse rate was significantly lower in the esketamine nasal spray group than in the placebo/quetiapine group (risk ratio: RR: 0.60, 95% confidence interval: 0.45-0.80, I2 = 0%). The rate of suicidal ideation was similar between the two groups. The certainty of evidence was graded as "moderate" or "high" in the abovementioned results. Esketamine nasal spray in conjunction with an antidepressant effectively controls short-term and long-term depressive symptoms in major depressive disorder and treatment-resistant depression, with a manageable trade-off between efficacy and safety.
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 |
Citations in the library
Cited by 6
- Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries: An EudraVigilance Database Analysis. Pharmaceuticals May 9, 2025
- Intranasal esketamine for treatment-resistant depression: real-world effectiveness in electroconvulsive therapy non-responders The European Journal of Psychiatry March 7, 2026
- Appetite measures as correlates of clinical response in mood disorders treated with ketamine: systematic review Frontiers in Nutrition August 21, 2025
- Real-world clinical practice, effectiveness and safety of esketamine nasal spray in major depressive disorder patients: a French prospective cohort (ELLIPSE study) Therapeutic Advances in Psychopharmacology August 1, 2026
- Comparison of rTMS and esketamine for treatment-resistant depression: A target trial emulation. Journal of Affective Disorders April 15, 2026
and 1 more in the library
Cites 21
- 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
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis American Journal of Psychiatry October 3, 2017
and 16 more in the library