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.

Abstract

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

Notes

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.

Summary

Esketamine is a nonselective, noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, which modulates glutamatergic transmission. It was approved by the US Food and Drug Administration for the treatment of TRD in 2019.

Intranasal esketamine showed rapid onset of action in patients with TRD, but mixed findings in subsequent DB-RCTs. Its anti-suicidal effects are still obscure, however. A meta-analysis of intranasal esketamine in the treatment of patients with MDD found that it was significantly more effective than placebo for Montgomery-sberg Depression Rating Scale (MADRS) score change, response, and remission. However, the study did not address whether or not esketamine had rapid antidepressive effects.

Sources of Data

Three investigators searched for published articles on esketamine and depression using PubMed, Embase, PubMed, PsycINFO, CINAHL, and Web of Science, and manually searched reference lists from identified articles and reviews to find additional studies.

Study Criteria and Data Extraction

We included all double-blinded RCTs (DB-RCTs) comparing intranasal esketamine with standard antidepressants for MDD that had placebo as a comparator, were exclusively focused on patients with MDD, and clearly described all inclusion and exclusion criteria.

Study Outcomes

The primary outcome measures were change in MADRS total score and rate of study-defined remission and resolution of suicidality. The secondary efficacy measures were rate of adverse events and common AEs.

Statistical Analysis

We used Review Manager version 5.4 software to undertake statistical analysis and used Cohen’s classification to assess effect size. We used I2 statistic to evaluate heterogeneity and used a threshold of 50% or more in I2 value and p 0.10.

Study Characteristics

Initially, 804 abstracts were identified with use of Embase, PubMed, Psychinfo, and Web of Science. Of the remaining 50 full-text articles, seven published DB-RCTs were included in the meta-analysis.

Table 1 presents main characteristics of eight DB-RCTs. Five studies involved TRD, three studies involved MDSI, four studies used flexible doses, and four studies used fixed doses of intranasal esketamine.

Primary endpoint: mean change of MADRS

Esketamine significantly improved MADRS total scores more than placebo for treating MDD starting from 2 4 hours after the first injection, and the significant superiority maintained at 24 hours, week 1, and end of double-blinded period.

We conducted sub-group analysis for patients with TRD and MDSI. Esketamine significantly improved MADRS from 2 4 hours to 24 hours, week 1 and week 34, and showed similar trends for patients with MDSI.

Resolution of suicide

Esketamine showed superior efficacy over placebo in resolution of suicide at 2 4 hours, but not at 24 hours or week 34.

Rate of remission

Intranasal esketamine showed superior remission rate than placebo at week 34, and superior efficacy was noted at 24 hours and 2 days after initial nasal esketamine infusion.

Safety and Tolerability

Esketamine showed higher incidence of total adverse effects, dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence compared with placebo. However, headache was numerically more common in esketamine group than in placebo group, but the two groups did not differ statistically.

DISCUSSION

This meta-analysis of eight DB-RCTs with 1,488 subjects showed that intranasal esketamine was significantly more effective than placebo for MADRS score change and depression remission in patients with MDD. In addition, the superior treatment response and remission of intranasal esketamine were noticeable as early as 24 hours after the first injection.

Intranasal esketamine showed small to medium effect size in MADRS across different time, and the efficacy was greatest at 24 hours or 24 hours after the 1st administration of intranasal esketamine. It may be useful to overcome the efficacy gap observed between drug administration and onset of action for conventional antidepressants.

Intranasal esketamine has been shown to cause dissociation and blood pressure increment, but these effects are transient, asymptomatic, and not associated with serious cardiovascular complications.

Our study contained several limitations, such as combining all doses of intranasal esketamine, not conducting meta-regression, and finding one unpublished DB-RCT that showed negative results.

Intranasal esketamine was effective in patients with MDD, including TRD and MDSI, and might have rapid antisuicidal effects.

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