Psilocybin and Ketamine Efficacy Compared Against Midazolam in Treatment-Resistant Depression Trial

Treatment-resistant depression (TRD) affects patients who fail to respond to two or more full-dose antidepressant treatments, leading to increased suicide risk, higher medical expenditure, and significantly reduced quality of life. Current standard-of-care often falls short, necessitating novel therapeutic approaches. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid antidepressant effects at subanesthetic doses, but concerns persist regarding its potential for misuse, overdose, and cognitive side effects. This highlights an urgent need for alternative, potentially safer, rapid-acting antidepressants.

This study is a clinical trial protocol designed to compare the antidepressant efficacy of psilocybin and ketamine against an inactive control, midazolam, in patients diagnosed with treatment-resistant depression (TRD). The primary endpoint is the antidepressant effect measured by the Montgomery-Asberg Depression Rating Scale (MADRS) 24 hours post-treatment. Key secondary endpoints include the duration of antidepressant effect, the number of responders and remitters, and the time until standard antidepressant treatment is resumed over a 3-month observation period. Exploratory analyses involve monitoring changes in functional brain states using simultaneous EEG/fMRI before and after treatment, correlating psychometric scales with entropy and functional connectivity, and exploring plasmatic neurobiological biomarkers like BDNF, prolactin, ACTH, and oxytocin.