Comparative efficacy and acceptability of psilocybin-ketamine and typical antidepressants for major depressive disorder management: a network meta-analysis
DELOS Desarrollo Local Sostenible – December 11, 2025
Source: OpenAlex
Summary
Psilocybin and ketamine significantly outperform traditional antidepressants for Major Depressive Disorder. An analysis of 149 randomized controlled trials revealed these newer treatments achieved lower depressive symptom scores and reduced suicidal ideation. Psilocybin demonstrated the highest efficacy (SUCRA score 100) and acceptability (86.96), with ketamine close behind (efficacy 86.83, acceptability 84.56). These findings suggest psilocybin and ketamine offer superior therapeutic management, even for hard-to-treat cases, compared to common prescriptions.
Abstract
Objective: To compare acceptability and effectiveness of psilocybin, ketamine and commonly prescribed antidepressants in the management of Major Depressive Disorder (MDD). Methods: This is a systematic review with network meta-analysis. The survey was conducted between January and June 2023, employing MEDLINE, PsyINFO, Embase, Web of Science and ClinicalTrials.gov databases. Randomized controlled clinical trials involving escitalopram, bupropion, paroxetine, fluoxetine, sertraline, venlafaxine, ketamine or psilocybin in MDD were included. We analyzed effectiveness and acceptability of medications through depressive symptom scores and proportion of patients who dropped out, respectively. Results: 5845 documents were identified, of which 149 were reviewed. In terms of efficacy, all antidepressants were more effective than placebo, with psilocybin and ketamine achieving a lower depressive symptom score and suicide ideation . Regarding acceptability, the placebo obtained significantly better results than evaluated drugs. Psilocybin had the highest surface under the cumulative ranking curve (SUCRA) score among the interventions with 100 and 86.96 for efficacy and acceptability followed to ketamine with 86.83 and 84.56, respectively. Conclusions: Psilocybin and ketamine have been shown to be superior to all other interventions with regard to efficacy and acceptability, including the treatment-refractory MDD. Thus, the results seem to show in this study that the psilocybin e ketamine can serve for better decision-making by physicians in the therapeutic management of MDD.