Psilocybin versus ketamine – fast acting antidepressant strategies in treatment-resistant depression (NU21-04-00307)

Basic informations

Investigator: MUDr. Tomáš Páleníček, PhD.
Main recipient: National Institute of Mental Health (NIMH)
Co-recipient: University of Chemistry and Technology, Faculty of Food and Biochemical Technology
Research period: 1/5/2021 – 31/12/2024
Total budget: 12,029,000 CZK
NIMH budget: 10,223,000 CZK
Supported by: Czech Health Research Council (AZV ČR)


Depression is the 4 most common cause of disability worldwide, with 20-30% of patients fulfilling the criteria for treatment-resistant depression (TRD). The unique rapid onset of antidepressant effect with subanesthetic / psychedelic doses of the dissociative anesthetic ketamine in TRD has been confirmed based on several meta-analyzes, however, it usually does not last longer than 7-10 days. Recent studies with serotonergic psychedelics psilocybin and ayahuasca describe the significant antidepressant potential of these agents in TRD. However, unlike ketamine, these effects last much longer, in the order of weeks to months. Although two large multicenter trials with psilocybin in depression are currently underway and one comparing the effect versus citalopram, there is no direct comparison between the two treatment strategies with a rapid onset of action. Our main goal is to compare the antidepressant effects of psilocybin and ketamine in patients with TRD versus the antidepressant inactive substance midazolam. The primary endpoint will be the antidepressant effect on the Montgomery-Asberg Depression Rating Scale (MADRS) 24 hours after treatment, the key secondary endpoints being the duration of antidepressant effect, the number of responses and remissions, and the time to standard antidepressant treatment during 3 months of observation. The exploratory part of the study aims to monitor changes in the functional brain states using simultaneous EEG / fMRI, before treatment versus 1 day and 1 week after. Based on literature data and recent data from healthy volunteers who participated in our study with psilocybin, we will correlate antidepressant effects of drugs (using psychometric scales and reactions to emotionally salient stimuli (eye tracker)) with entropy and functional connectivity measures. Finally we will explore the role of plasmatic neurobiological biomarkers in depression (BDNF, prolactin, ACTH and oxytocin).