Abstract

Treatment-resistant depression (TRD) represents a significant therapeutic challenge in psychiatry. While both intravenous (IV) ketamine and intranasal (IN) esketamine have been raised as promising medical treatments for TRD, their comparative efficacy and safety profiles remain unclear. This meta-analysis aimed to evaluate the relative effectiveness and pharmacovigilance outcomes of both treatments in TRD. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines, a well-defined literature search strategy was conducted across major databases for randomized controlled trials investigating IV ketamine or IN esketamine in adults with TRD. Treatment response was analyzed using standardized mean change differences (SMCD), and adverse events were evaluated through safety profiling assessments. Twelve studies (N = 993) were included. IV ketamine demonstrated a larger effect size (SMCD = -2.62, 95% CI: -3.45 to -1.79) compared to IN esketamine (SMCD = -1.53, 95% CI: -2.31 to -0.75), with significant subgroup differences (p-value = 0.015). Safety analysis revealed higher rates of central nervous system symptoms (34.4% vs. 13.4%) and dissociative effects (21.9% vs. 10.1%) with IN esketamine. Significant heterogeneity was observed in IV ketamine studies (I² = 78.9%) compared to IN esketamine (I² = 68.4%). While both IV ketamine and IN esketamine have shown significant efficacy in TRD, IV ketamine showed larger treatment effects but with more heterogeneous outcomes based on the current included studies in the analysis. Esketamine demonstrated more consistent but moderate effects, with a higher incidence of certain adverse events. The results highlighted the need for individualized treatment selection based on efficacy expectations, safety considerations, and practical factors, including accessibility and monitoring requirements for each patient.

Key words: Treatment-resistant depression, major depressive disorder, depression, ketamine, esketamine, meta-analysis