Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistance Depression and Major Depression with Suicide Ideation: A Meta-Analysis

This meta-analysis (s=7; n=1488) of double-blind placebo-controlled studies with those suffering from depression (MDD; TRD) and suicidal ideation (SI) found that esketamine (24-84mg) significantly improved scores on a measure of depression (MADRS) over the placebo up to 28 days alter, the SI scores were only significant within the first 24 hours.


Objective: We performed a meta-analysis of randomized double-blinded placebo controlled trials (DB-RCTs) to investigate efficacy and safety of intranasal esketamine in treating major depressive disorder (MDD) including treatment resistant depression (TRD) and major depression with suicide ideation (MDSI).

Methods: Mean change in total scores on Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to different time-points were our primary outcome measure. Secondary efficacy measures included rate of remission of depression and resolution of suicidality.

Results: Eight DB-RCTs (seven published and one un-published) covering 1,488 patients with MDD were included. Esketamine more significantly improved MADRS total scores than placebo starting from 2-4 hours after the first administration (standardized mean difference, -0.41 [95% CI, -0.58 to -0.25], p < 0.00001), and this superiority maintained until end of double-blinded period (28 days). Sub-group analysis showed that superior antidepressant effects of esketamine over placebo in TRD and MDSI was observed from 2-4 hours, which was maintained until 28 days. Resolution of suicide in MDSI was also greater for esketamine than for placebo at 2-4 hours (OR of 2.04, 95% CIs, 1.37 to 3.05, p = 0.0005), but two groups did not statistically differ at 24 hours and day 28. Total adverse events (AEs), and other common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence were more frequent in esketamine than in placebo group.

Conclusion: Esketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI.”

Authors: Sheng-Min Wang, Nak-Young Kim, Hae-Ran Na, Hyun Kook Lim, Young Sup Woo, Chi-Un Pae & Won-Myong Bahk


This is one of the many papers reviewing (es)ketamine in recent months. For a more critical view on esketamine, see Gastaldon and colleagues (2021).

This study is the largest meta-analysis to date (2021) of placebo-controlled double-blind trials (RCTs).

This meta-analysis showed esketamine to be statistically significantly better than placebo on a measure of depression (MADRS). The resolution of suicide was not significant beyond the first 2-4 hours. Esketamine did, expectedly, produce more side-effects (e.g. dissociation) than placebo.

Although very favorable, lowering depression scores, the study didn’t find significant reductions in suicidal ideation (which Spravato, the brand name of esketamine, is approved for). See the supplementary data for the graphs on this.

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