A Systematic Review and Meta-Analysis of the Efficacy and Safety of Intranasal Esketamine for Rapid Symptom Relief in Treatment-resistant Depression.

In adults with treatment-resistant depression, intranasal esketamine plus an antidepressant improved depressive symptoms within 24 hours, as measured by the MADRS scale (average 3.44 points greater reduction than placebo). However, esketamine raised the risk of elevated blood pressure threefold and dissociation nearly sixfold. The analysis of nine randomized controlled trials supports esketamine as a fast-acting option, but short follow-up periods, varying dosing protocols, and the notable side-effect profile limit broader conclusions. Long-term safety and durability of response remain insufficiently studied.

Study at a glance

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.