A network meta-analysis of 27 randomized trials found that NMDA-targeting medications (e.g., ketamine) are markedly more effective than placebo for augmenting treatment-resistant depression (effect size 0.91). Antipsychotics, mood stabilizers, and other pharmacological augmenters were also compared, but NMDA therapies had the highest probability of being effective. No psychological augmentation trials could be included due to the lack of a common comparator. The evidence is limited by few trials, heterogeneity, and inconsistent safety reporting.
Psychedelic therapy is transforming treatment for treatment-resistant depression (TRD) by increasing benefits and reducing risks. Psilocybin shows promise as a potential game-changer, with initial evidence indicating a rapid antidepressant effect that lasts at least three months for some responders. However, more rigorous, double-blind, comparator-controlled trials with adequate statistical power are needed to understand how psychedelics work and their long-term effects in TRD. Psychedelics may also benefit other psychiatric conditions like bipolar depression and post-traumatic stress disorder.