A New Era for Esketamine in Managing Treatment-Resistant Depression: A Systematic Review of Its Use From Adjunct to First-Line Therapy.
Srijan Shetty, Balakrishnan Sadasivam
Cureus September 2025 DOI: 10.7759/cureus.91829 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Peer reviewed |
|---|---|
| Intervention | Esketamine |
| Topics | Esketamine Depression Ketamine |
| Keywords | Esketamine monotherapy Nasal spray Treatment-resistant depression trd |
| Key findings | The review identified only one qualifying clinical trial of esketamine monotherapy for treatment-resistant depression, preventing a meta-analysis and underscoring scarce direct evidence. The authors conclude that intranasal esketamine shows potential as a rapid-acting standalone therapy, but that larger randomized controlled trials are needed to confirm its benefit and establish optimal dosing. |
Abstract
Treatment-resistant depression (TRD) remains a major clinical challenge, affecting nearly one-third of individuals with major depressive disorder (MDD) who fail to respond to standard antidepressant therapies. Esketamine, the S-enantiomer of ketamine, has emerged as a novel therapeutic option. Esketamine, initially introduced as an add-on therapy, has more recently also received recognition for use as a standalone treatment. This review aims to synthesize current clinical evidence on the efficacy and safety of esketamine monotherapy while exploring its molecular mechanisms and identifying research gaps. A systematic literature search was conducted across PubMed, Google Scholar, MedRxiv, and BioRxiv up to March 2025. Although designed as a systematic review, only one qualifying clinical trial was identified, limiting the feasibility of a meta-analysis and underscoring the scarcity of direct evidence. Despite this limitation, molecular insights suggest that TRD is associated with glutamatergic system dysfunction, impaired neuroplasticity, hypothalamic-pituitary-adrenal (HPA) axis abnormalities, and neuroinflammatory processes. Intranasal esketamine demonstrates potential as a rapid-acting and effective standalone therapy for TRD; nevertheless, further robust, large-scale randomized controlled trials are essential to confirm its therapeutic benefit, establish optimal dosing strategies, and overcome current research limitations.
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
Cites 9
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
- Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. Journal of Psychiatric Research May 1, 2022
- Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys European Archives of Psychiatry and Clinical Neuroscience April 18, 2016
- Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry March 1, 2025
and 4 more in the library