Elucidating the Relevance of the Psychedelic Experience to Psilocybin's Anti-Anhedonic Effects

Elucidating the Relevance of the Psychedelic Experience to Psilocybin's Anti-Anhedonic Effects: A Randomized, Open-Label, Cross-Over Functional Magnetic Resonance Imaging Trial

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.

Inclusion criteria:

All participants:

• General health based on medical history, physical examination, blood draw, and electrocardiogram
• Age 18 to 55 years
• Right-handedness (due to potential lateralization effects of left-handed subjects)
• Willingness and competence to sign the informed consent form
• Normal BMI weight range (18.5-24.9)

Specific to healthy subjects:

• Psychiatric health based on structured clinical interview for DSM-5 (SCID)
• No concomitant medication

Specific to anhedonia patients:

• Major depressive episode (first or recurrent) based on structured clinical interview for DSM-5 (SCID) and ICD-10
• Fulfilling the ICD-10 diagnostic criterion of anhedonia
• No concomitant medication, specifically also free of antidepressants or other psychopharmaceuticals (for at least 2 weeks, 5 weeks for fluoxetin)

Exclusion criteria:

All participants:

• Current or history of neurological disease
• Current medical illness requiring treatment
• Pregnancy or current breastfeeding
• Current or former substance dependency
• Any contraindication for MRI
• Failure to comply with the study protocol or to follow the instruction of the investigating team
• Failure to confirm effective use of contraception in females at least 8 weeks before and after study participation each
• First-degree relative with bipolar disorder or schizophrenia

Specific to healthy subjects:

- Psychiatric diagnosis

Specific to anhedonia patients:

- Psychiatric comorbidities excluding anxiety disorders and/or obsessive-compulsive disorders