Efficacy and Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
B Gowthami, Ishita Mehta, Sneha Baiju, Ashish Appani, Tilak Suvarna, Kinza Randhawa, Anuj Manish Kakkad, Syed Azeemuddin, Vaishnavi Kumar, Harshawardhan Dhanraj Ramteke, Rakhshanda Khan
medRxiv September 25, 2025 preprint DOI: 10.1101/2025.09.22.25336317 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized |
|---|---|
| Sample size | 10,073 |
| Population | Patients with treatment-resistant depression |
| Intervention | Esketamine nasal spray plus oral antidepressant |
| Topics | Depression Ketamine Esketamine |
| Keywords | Randomized controlled trial Meta-analysis Odds ratio Placebo Confidence interval Adverse effect Depression economics Anesthesia Nasal spray Subgroup analysis Clinical trial Antidepressant |
| Citations | 1 |
| Key findings | Esketamine nasal spray plus an oral antidepressant significantly improves response, remission, and functional outcomes in treatment-resistant depression but increases the risk of dissociation and hypertension. |
Abstract
Abstract Introduction Treatment-resistant depression (TRD) affects up to one-third of patients with major depressive disorder, leading to poor outcomes and increased suicide risk. Esketamine nasal spray, a novel glutamatergic modulator, has emerged as an adjunctive option with rapid onset of action. However, the efficacy and safety of esketamine across randomized controlled trials (RCTs) remain variably reported, necessitating a systematic synthesis.
Methods: We systematically searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov from inception to September 2025. Seventeen RCTs comprising 10,073 patients were included, of whom 5,707 received esketamine plus oral antidepressant and 4,622 received placebo plus oral antidepressant. Primary efficacy outcomes included change in depressive symptoms, response (≥50% reduction), and remission rates. Secondary outcomes were functional improvement (Sheehan Disability Scale, SDS) and safety events (dissociation, sedation, hypertension, nausea). Random-effects models were used to pool mean differences (MD), odds ratios (OR), and risk ratios (RR) with 95% confidence intervals (CI).
Results: Esketamine significantly improved response (OR = 0.51; 95% CI: 0.30–0.73; p < 0.001; 14 RCTs) and remission (OR = 0.35; 95% CI: 0.11–0.58; p < 0.01; 13 RCTs). Functional outcomes also favored esketamine (SDS MD = –2.27; 95% CI: –3.50 to –1.04; p < 0.01; 4 RCTs). Pooled analysis of continuous MADRS and CGI-S change showed non-significant differences (MADRS MD = –1.47; 95% CI: –3.01 to 0.07; CGI-S MD = –0.30; 95% CI: –0.75 to 0.14). Safety analysis revealed increased risk of dissociation (RR = 1.98; 95% CI: 1.68–2.28; 9 RCTs) and hypertension (RR = 1.42; 95% CI: 1.04–1.80; 9 RCTs), with non-significant elevations for sedation (RR = 1.23; 95% CI: 0.80–1.66) and nausea (RR = 1.10; 95% CI: 0.82–1.37).
Conclusion: Esketamine nasal spray plus oral antidepressant significantly improves treatment response, remission, and functioning in TRD patients but is associated with increased risk of dissociation and hypertension. While efficacy is robust, safety monitoring and structured clinical delivery remain essential. Further long-term and comparative effectiveness studies are warranted to define esketamine’s role in TRD management.