Efficacy and Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

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.