Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis.

Summary

For treatment-resistant unipolar depression, intravenous racemic ketamine, intranasal esketamine, aripiprazole, and lithium are all more effective than placebo. Intravenous racemic ketamine is significantly more effective and acceptable than intranasal esketamine and aripiprazole. Unlike intranasal esketamine and aripiprazole, intravenous racemic ketamine does not differ from placebo in tolerability. Lithium and intravenous racemic ketamine show no significant differences in efficacy, tolerability, or acceptability. The sample size for intravenous racemic ketamine was small, and a larger head-to-head trial is needed to clarify whether intravenous racemic ketamine or lithium is superior.

Study at a glance

Abstract

BACKGROUND Intravenous racemic ketamine is a promising treatment for treatment-resistant depression. However, its clinical utility compared with intranasal esketamine and the other well-studied conventional pharmacological interventions (i.e., aripiprazole and lithium) as augmentative treatments for treatment-resistant unipolar depression in adults remains unclear. Therefore, we aimed to compare the efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium under such conditions. METHODS The Cochrane Library, PubMed, CINHAL and ClinicalTrials.gov databases were systematically searched from their inception to 10 May 2023. Randomised controlled trials evaluating these drugs were included. A random-effects network meta-analysis was also performed. RESULTS In the primary analysis, all four drugs were significantly more effective than placebo. In addition, intravenous racemic ketamine was significantly more effective and acceptable than intranasal esketamine and aripiprazole. Intravenous racemic ketamine was not significantly different from placebo in tolerability, whereas intranasal esketamine and aripiprazole were significantly less tolerable than placebo. Lithium did not differ significantly from intravenous racemic ketamine in efficacy, tolerability and acceptability. LIMITATIONS The sample size of patients treated with intravenous racemic ketamine was small. CONCLUSIONS Intravenous racemic ketamine may be a better augmentative treatment for treatment-resistant unipolar depression than intranasal esketamine and aripiprazole. Whether intravenous racemic ketamine or lithium is superior is unclear currently. A larger head-to-head trial of intravenous racemic ketamine versus conventional augmentative treatments for treatment-resistant unipolar depression is needed.