Exploring the Therapeutic Potential of Psilocybin and Ketamine in Major Depressive Disorder including Treatment-Resistant Depression: A Narrative Review
Biuletyn Głównej Biblioteki Lekarskiej June 1, 2025 Christian S. Skowron, Urszula Miłkowska, Gabriela Maria Piech et al.
Major depressive disorder and treatment-resistant depression are global health challenges where conventional therapies often fall short. This review examines psilocybin and ketamine, two agents with distinct mechanisms from traditional antidepressants. Psilocybin, a 5-HT2A receptor agonist, shows rapid and sustained antidepressant effects, with clinical trials reporting response rates of 54-71% in MDD. Ketamine, an NMDA receptor antagonist, acts via glutamatergic pathways and reduces suicidal ideation within hours. Psilocybin requires structured psychotherapeutic support during its acute effects, while ketamine offers flexible administration routes, some usable in emergencies. Both have favorable safety in controlled settings, with transient adverse effects like dissociation or nausea. Current research is limited by small samples, blinding challenges, and trial heterogeneity. Large-scale trials and standardized protocols are needed for clinical integration.