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.
A network meta-analysis of 35 randomized controlled trials involving 2109 participants compared electroconvulsive therapy (ECT), intravenous racemic ketamine, and repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression. No significant differences emerged in response rate, remission rate, or tolerability among the three treatments. Intravenous ketamine showed significantly higher acceptability than rTMS and ECT. The confidence in the evidence for efficacy, tolerability, and acceptability was very low, largely due to small-study bias. The authors suggest that both ketamine and rTMS may be viable alternatives to ECT, but caution that larger studies are needed to confirm these findings.