Major Depressive Disorder (MDD)Treatment-Resistant Depression (TRD)Depressive DisordersKetamineEsketaminePlacebo

Rapidity of Symptom Improvement With Intranasal Esketamine for Major Depressive Disorder: A Systematic Review and Meta-Analysis

This meta-analysis (s=8, n=1437) compared the effect of intranasal esketamine to placebo (both in combination with standard antidepressants) as a treatment for major depressive disorder (MDD). It was found that intranasal esketamine, in combination with the standard treatment, did effectively reduce depression severity when compared to the placebo, with higher doses having a longer-lasting effect.

Authors

  • Sanjay Mathew
  • James Murrough
  • Daniel Iosifescu

Published

Journal of Clinical Psychiatry
meta Study

Abstract

Objective

Rapid-acting treatment options are needed for major depressive disorder (MDD). The objective of this systematic review and meta-analysis was to estimate the magnitude of the treatment effect for intranasal esketamine over placebo at 24 hours after the first dose and at endpoint.

Data Sources

PubMed, abstracts of major psychiatric meetings, and ClinicalTrials.gov were searched up to November 2020 with no language constraints, cross-referencing the term intranasal with esketamine and randomized.

Study Selection

Of 27 studies reviewed, 8 articles, with a total of 1,437 patients with MDD, met study criteria and were included in the meta-analysis.

Data Extraction

Randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with intranasal esketamine for MDD, using intranasal placebo augmentation as a comparator, were selected.

Results

Estimates of the standardized mean difference (SMD) in change scores were pooled after examining for homogeneity using the test statistic proposed by DerSimonian and Laird. Findings of the random effects model were presented. Augmentation of standard antidepressants with intranasal esketamine resulted in greater Montgomery-Asberg Depression Rating Scale (MADRS) score reduction than adjunctive intranasal placebo at 24 hours. Across the trials, the SMD was 0.34 (95% CI = 0.11 to 0.46, P < .0001) with a 2.9-point greater mean MADRS score reduction following intranasal esketamine versus active control plus intranasal saline. A similar finding was evident at endpoint.

Conclusions

This updated systematic review and meta-analysis found that augmentation of antidepressants with intranasal esketamine was statistically and clinically more effective in reducing depression severity than augmentation with placebo, at both 24 hours and study endpoint. Future studies are needed to evaluate dose-response relationship for esketamine.

Available with Blossom Pro

Research Summary of 'Rapidity of Symptom Improvement With Intranasal Esketamine for Major Depressive Disorder: A Systematic Review and Meta-Analysis'

Introduction

Major depressive disorder (MDD) is a leading cause of disability worldwide and clinicians lack rapid-acting pharmacological options because conventional oral antidepressants typically require weeks to months for full effect. Over the past decade, intravenous (IV) ketamine and its S-enantiomer, esketamine, have shown fast-acting antidepressant effects in controlled trials, and intranasal (IN) esketamine is now approved in the US and EU as an adjunctive treatment for treatment-resistant depression (TRD). However, individual Phase III IN esketamine trials failed to demonstrate a statistically significant excess of sustained responders at day 2 (24 hours) for esketamine versus control, a key secondary endpoint agreed with regulators for demonstrating rapidity of action. Hock and colleagues therefore undertook an updated systematic review and meta-analysis to quantify the magnitude of the treatment effect of adjunctive IN esketamine versus intranasal placebo at 24 hours after the first dose, and as a secondary objective to estimate the magnitude of effect at study endpoint. The analysis also planned exploratory subgroup and dose-related analyses to examine potential moderators of response.

Expert Research Summaries

Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.

See Pro PlansAlready have an account? Sign in

Study Details

References (1)

Papers cited by this study that are also in Blossom

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)

Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)

174 cited

Cited By (1)

Papers in Blossom that reference this study

Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis

Fountoulakis, K. N., Saitis, A., Schatzberg, A. F. · American Journal of Psychiatry (2025)

Your Personal Research Library

Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.

See Pro PlansSign in
Rapidity of Symptom Improvement With Intranasal... — Research Summary & Context | Blossom