Ketamine given intravenously at subanesthetic doses (0.5–0.75 mg/kg) or as esketamine (28–84 mg) appears safe and effective as an add-on treatment for bipolar depression when combined with a mood stabilizer. Across eight studies (235 participants), 48% of those receiving ketamine achieved at least a 50% reduction in depression severity, compared with 5% on placebo. Real-world response rates were lower (30%) than in clinical trials (63%). Some studies noted reductions in suicidal ideation, though not all findings were statistically significant. Ketamine was generally well tolerated, but 2% of participants (five receiving ketamine) developed hypomanic or manic symptoms, and significant dissociative effects occurred at 40 minutes in some trials.
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.