A Systematic Review and Meta-Analysis of the Efficacy and Safety of Intranasal Esketamine for Rapid Symptom Relief in Treatment-resistant Depression.
Ritika Saun, Aakriti Garg, Mohd Ashif Khan
Reviews on recent clinical trials April 7, 2026 DOI: 10.2174/0115748871407261251215071206 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Peer reviewed |
|---|---|
| Population | Adults aged 18 or older with treatment-resistant depression |
| Intervention | Intranasal esketamine |
| Topics | Depression Esketamine |
| Keywords | Severe depression Systematic review Treatment-resistant depression. |
| Key findings | Intranasal esketamine plus an antidepressant produced a significant improvement in MADRS scores within 24 hours but was associated with higher rates of elevated blood pressure and dissociation. |
Abstract
Most of the Major Depressive Disorder (MDD) patients experience Treatment-Resistant Depression (TRD), wherein standard pharmaceutical and psychological interventions fail to provide adequate symptom relief. This systematic review and meta-analysis investigated the efficacy and safety of intranasal esketamine for rapid symptom relief in adults with TRD. The search strategy adhered to PRISMA guidelines and included PubMed, Science Direct, and Google Scholar up to January 2024. The study focused on adults aged 18 or older with TRD. Exclusions were non-RCTs, participants under 18 years, those with recent (past 6 months) suicidal or homicidal ideation, and non-English articles. Quality assessment was done using the Risk of Bias Tool 2 (ROB2). Nine RCTs were included. Esketamine plus an antidepressant produced a significant improvement in MADRS scores within 24 hours (mean difference -3.44; 95% CI -5.51 to -1.38). However, esketamine was associated with a higher incidence of adverse events, including elevated blood pressure (RR 3.10; 95% CI 2.24-4.29) and dissociation (RR 5.90; 95% CI 4.32-8.05). These findings support intranasal esketamine as a rapidly acting intervention for TRD, consistent with emerging evidence on glutamatergic modulation. Nonetheless, short follow-up periods, heterogeneity in dosing protocols, and a notable adverse event profile limit broader generalization. Long-term safety, durability of response, and real-world tolerability remain insufficiently explored. Esketamine demonstrates efficacy in achieving rapid relief of depressive symptoms in TRD, but findings must be interpreted with caution, given the heterogeneity and adverse event profile. Further high-quality, long-term studies are warranted to establish sustained 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 |