A single infusion of ketamine reduces depressive symptoms more than an active placebo (midazolam) in people with treatment-resistant depression 24 hours after treatment. Repeated infusions produce cumulative antidepressant effects and double the response rate; 59% of participants responded after a median of three infusions. Weekly maintenance infusions sustain the reduction in depressive symptoms among responders but do not produce further improvement. The findings suggest that repeated ketamine infusions offer a viable strategy for prolonging antidepressant effects in this population.
The antidepressant effects of psilocybin, the active compound in magic mushrooms, may not require its psychedelic effects. Psilocybin's psychedelic effects depend on activation of the serotonin 2A receptor, and blocking that receptor with drugs like risperidone or ketanserin eliminates the psychedelic experience in healthy volunteers. A mouse study showed that ketanserin did not reduce psilocybin's antidepressant effect. This proposed three-arm, double-blind, proof-of-concept randomized controlled trial in adults with treatment-resistant depression will test whether giving psilocybin with risperidone blocks psychedelic effects without reducing antidepressant effects. If so, psilocybin-assisted psychotherapy, which currently requires intensive therapist support, could become more scalable and accessible.