Major depressive disorder affects over 300 million people worldwide, and about one-third of patients do not achieve remission with standard antidepressants, a condition known as treatment-resistant depression (TRD). Psilocybin, a classic hallucinogen from Psilocybe mushrooms, acts on serotonergic and glutamatergic systems. A narrative literature review of two clinical trials involving 32 patients with TRD found that two doses of psilocybin combined with psychological support significantly reduced depressive symptoms. All patients showed some symptom reduction one week after the second dose, with immediate and substantial improvements that could last up to six months. Due to small sample sizes, further research is needed to confirm these findings and understand psilocybin's mechanisms.
A narrative review examined whether ketamine, a dissociative anesthetic, could improve the antidepressant effects of electroconvulsive therapy (ECT) for treatment-resistant depression. ECT is a standard end-line therapy but can cause memory impairment, possibly from overstimulation of glutamate receptors in the hippocampus. Ketamine blocks NMDA receptors and stimulates glutamate release, so it was proposed as an ECT adjuvant to reduce cognitive side effects and speed response. However, response and remission rates with ketamine in ECT showed no significant difference from comparator groups, and it was linked to more psychiatric and cardiovascular adverse events. The findings do not support combining ketamine and propofol as anesthetics for ECT in major depressive disorder.