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.
Intravenous racemic ketamine, psilocybin, and theta burst stimulation (TBS) all outperformed placebo for major depressive disorder in a network meta-analysis of 28 randomized controlled trials. Ketamine and psilocybin showed significantly greater antidepressant effects than TBS, with no differences in tolerability or acceptability compared to placebo. In periods of 1 week or less, only ketamine was significantly more effective than placebo. In periods of 4 weeks or longer, both ketamine and psilocybin were significantly better than placebo. Confidence in the evidence ranged from very low to moderate due to limited studies, especially for psilocybin, and a lack of direct comparison trials. These preliminary findings suggest ketamine and psilocybin may be more effective than TBS, with ketamine possibly offering faster onset.