Objective:

To evaluate the differences in depressive symptom reductions between control groups in psilocybin trials and those in trials of esketamine and selective serotonin reuptake inhibitors (SSRIs).

Approach:

• Meta-analysis: Included 17 randomized clinical trials involving adults with major depressive disorder (MDD) or treatment-resistant depression (TRD), comparing psilocybin, esketamine, and SSRIs.

Key Findings:

• Control group standardized mean changes (SMCs): 0.50 for psilocybin, 1.12 for esketamine, and 1.00 for SSRIs.
• Active treatment SMCs: 1.21 for psilocybin, 1.43 for esketamine, and 1.28 for SSRIs.
• Between-group standardized mean differences (SMDs): 0.70 for psilocybin, 0.30 for esketamine, and 0.27 for SSRIs.
• Control group response rates: 19% for psilocybin, 33% for SSRIs, and 42% for esketamine.
• Active treatment response rates: 48% for psilocybin, 46% for SSRIs, and 52% for esketamine.
• Dropout rates varied: 11% control vs 5% active for psilocybin, 8% control vs 12% active for esketamine, and 35% control vs 32% active for SSRIs.

Interpretation:

Limitations:

• The analysis could not determine specific factors explaining the differences in control group outcomes.
• Functional unblinding due to psilocybin's psychoactive effects may have influenced results.

Conclusion:

Sources:

• JAMA Network Open