This Phase I, randomised, open-label, crossover trial (n=85) will assess whether psilocybin’s anti-anhedonic effects in people with major depressive disorder and anhedonia are linked to the psychedelic experience. Participants will receive two oral 25 mg doses of psilocybin across two sessions, with 1 mg oral risperidone given 30 minutes before psilocybin in one session to blunt acute psychedelic effects. The study includes two experimental sequences: psilocybin first followed by psilocybin plus risperidone, or the reverse order. Participants will undergo three MRI sessions: baseline before treatment, then one day after each psilocybin session. The trial will compare clinical, behavioural and imaging responses using fMRI tasks related to aesthetic processing, reward, sexual arousal and cognitive flexibility, alongside self-report measures of well-being, depression, anhedonia and altered states of consciousness, with follow-up extending to about 12 weeks after enrolment.
The goal of this clinical trial is to systematically categorize potential prohedonic effects of psilocybin in patients with anhedonia in depression. The main questions it aims to answer are:
Primary Objectives
1. Systematically categorize prohedonic effects (antianhedonic effects in patients with anhedonia in depression, increase in well-being in all participants).
2. Test effects of psilocybin on brain network complexity measures during the hedonic experience using fMRI as a correlate for prohedonic (anti-anhedonic and well-being increasing) effects.
3. Elucidate relevance of the psychedelic experience to these effects (clinical, behavioral, and imaging) in a pharmacological challenge using the 5-HT2A/D2 antagonist risperidone and extensive characterization of the psychedelic experience. Secondary Objectives 4. Test the differential effects of the psychedelic experience on fMRI paradigms measuring symptoms shown to be altered in anhedonia, more specifically reward processing and sexual arousal. 5. Test the relevance of neuroplasticity (BDNF) and inflammatory parameters to anti-anhedonic, well-being promoting, and brain network dynamic complexity effects. 6. Test the effects of the psychedelic experience on BDNF and inflammatory parameters.
Researchers will compare the effects of psilocybin in two separate sessions (one with psilocybin alone, one with co-administration of risperidone) in both patients with depression and anhedonia and healthy control participants.
Participants will:
* Take 25 mg of psilocybin p.o. in two sessions, in one of the two sessions they will take 1 mg risperidone p.o. before ingestion of psilocybin, to block psilocybin's acute psychedelic effects.
* Undergo 3 MRI sessions, one before the first psilocybin session ('baseline') and one session each on the day after each respective psilocybin session.
* Perform a variety of tasks during each fMRI session to asses the treatment's effects on anhedonia.
Participants recieve psilocybin alone in the first session, psilocybin and risperidone in the second session
Unmatched intervention: Risperidone 1 MG
Participants recieve psilocybin and risperidone in the first session, psilocybin alone in the second session
Unmatched intervention: Risperidone 1 MG