Efficacy, Effectiveness, and Safety of Psilocybin and Ketamine versus Conventional Treatments or Placebo in Adults with Treatment-Resistant Depression: A Systematic Review
DOI:
https://doi.org/10.69980/ajpr.v28i5.565Keywords:
Depressive Disorder; Treatment-Resistant; Psilocybin; Ketamine; Antidepressive Agents; Randomized Controlled Trials as TopicAbstract
Background: Treatment-resistant depression (TRD) is a severe form of major depressive disorder that does not respond to at least two adequate antidepressant trials. Emerging evidence suggests that psilocybin and ketamine may produce rapid, clinically meaningful antidepressant effects, but no prior systematic review has directly compared their efficacy, effectiveness, and safety in TRD.
Objective: To systematically assess the efficacy, real-world effectiveness, and safety of psilocybin and ketamine/esketamine compared with conventional pharmacologic treatments or placebo in adults with TRD.
Methods: Following PRISMA guidelines, we included randomized controlled trials (RCTs), open-label, and prospective observational studies in adults with TRD. Primary outcomes were changes in depressive symptoms (e.g., MADRS, QIDS-SR16), response/remission rates, and safety. Due to clinical heterogeneity, no meta-analysis was performed.
Results: Nine studies met inclusion criteria. Psilocybin (25 mg COMP360) reduced MADRS scores by 12.0 points at 3 weeks versus 5.4 with placebo (adjusted difference: −6.6; p < 0.001). In another RCT, remission rates were higher with psilocybin (57%) versus escitalopram (28%). Intravenous ketamine (0.5 mg/kg) produced ~8-point MADRS reductions at 24h, with 64% achieving response versus 28% with placebo. Intranasal esketamine showed 4–6 point greater MADRS reductions over 4 weeks compared to placebo. Adverse effects for both agents, including dissociation, nausea, and mild hypertension, were transient and manageable.
Conclusions: Both psilocybin and ketamine demonstrate rapid antidepressant effects with acceptable safety in TRD. Psilocybin may achieve sustained remission with minimal dosing, while ketamine/esketamine require ongoing administration. Further long-term, head-to-head trials are warranted to establish comparative effectiveness and durability of response.
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