Comparative Efficacy of Esketamine Versus Standard Antidepressants for Rapid Reduction of Suicidal Ideation in Treatment-Resistant Depression: A Meta-Analysis

Abstract

Background: Acute suicidal ideation in treatment-resistant depression (TRD) requires timely intervention, but rapid improvement in depressive symptoms does not necessarily establish a suicide-specific treatment benefit. Objective: To systematically review and quantitatively synthesize the effects of adjunctive intranasal esketamine versus standard antidepressant-based care on early and short-term suicidal ideation in adults with TRD. Methods: PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science were searched for publications from January 2010 through mid-2026, supplemented by trial registries and gray literature. Eligible designs comprised randomized controlled trials and prospective comparative cohorts. Risk of bias was assessed using RoB 2 and the Newcastle–Ottawa Scale. Standardized mean differences (SMDs) were pooled using DerSimonian–Laird random-effects models; heterogeneity was assessed using I². Results: Ten studies, comprising eight randomized trials and two prospective cohorts, were reported to include 1,642 participants: 838 receiving adjunctive esketamine and 804 receiving comparator care. Reported effects favored esketamine at 24 hours (SMD −0.58; 95% CI −0.74 to −0.42; I²=58.4%), 48 hours (SMD −0.52; 95% CI −0.67 to −0.37), and day 28 (SMD −0.34; 95% CI −0.48 to −0.20; all p<0.001). However, unresolved study identities, TRD eligibility, outcome classification, and missing study-level data prevented independent verification. Conclusion: The reported estimates suggest an early benefit for suicidal ideation, but methodological and source-verification concerns preclude a firm TRD-specific efficacy conclusion. These findings do not establish prevention of suicidal behavior or mortality. Verification and reproducible reanalysis are required before clinical recommendations can be supported.