Psilocybin Versus Ketamine in Treatment-Resistant Depression

Inclusion Criteria:

1. Men and women aged 18-65
2. Diagnosis of moderate to severe depressive disorder without psychotic symptoms - ICD-10 criteria F32.1-2 or F33.1-2 and at the same time MADRS score \> 20
3. The duration of the current depressive episode is at least 3 months and maximum 2 years
4. Treatment-resistant depression defined as:

   1. Failure of at least 2 and at most 4 adequate treatments (6 weeks of full therapeutic dose of antidepressant or adequate non-pharmacological treatment - e.g. psychotherapy, neurostimulation treatment, phototherapy, etc.) within the current depressive episode, using at least 2 types of antidepressants with different pharmacological mechanisms of action (augmentation is taken as a second treatment) or
   2. Intolerance of 2 different treatments and 1 adequate treatment or
   3. Intolerance of 3 different antidepressant treatments.
5. Ability to understand the study protocol and to be able to complete all study visits and examinations as defined per protocol.
6. Participants in a clinical trial of childbearing potential must agree to the use of prescribed contraceptive methods for the duration of the study

Exclusion Criteria:

1. Severe psychiatric comorbidity (axis I MINI, ICD-10 F0.X - F99.X, the intensity of the disorder will be clinically assessed by the study clinician)
2. The current depressive phase is severe with psychotic symptoms (ICD-10: F32.3, F33.3)
3. MADRS suicidality score (item 10)\> 4
4. Duration of the current depressive episode longer than 2 years
5. Current drug or alcohol dependence (ICD-10: F17.x) with the exception of tobacco and with the exception of abstinence lasting more than 2 years
6. Claustrophobia, inability to undergo MR examination
7. Pregnancy or breast-feeding or plan to become pregnant within the next 12 months
8. Intracranial hypertension, pulmonary hypertension, uncorrected arterial hypertension (BP\> 150/100 mmHg)
9. Condition after stroke, myocardial infarction in the last 6 months
10. Heart failure
11. Untreated or decompensated hyperthyroidism
12. Glaucoma
13. Severe respiratory failure or acute respiratory depression
14. History of seizures
15. Other serious somatic disease or any other circumstance in which a significant increase in blood pressure would pose a serious threat to health (to be assessed by the study clinician)
16. Pacemaker
17. Metal implants made of MR incompatible materials
18. Regular use of medication that could interact with psilocybin (to be assessed by the investigator)
19. Regular use of antipsychotics with 5-HT2A receptor antagonist activity or discontinuation of their use for less than 14 days (eg risperidone, olanzapine, clozapine, quetiapine, ziprasidone)
20. Current use of monoamine oxidase inhibitors (MAOIs)
21. Previous experience with psilocybin, hallucinogenic mushrooms or ketamine is possible in a maximum of 10% of patients. This experience must not be during the last 12 months or during the current depressive episode.
22. Recent use of antidepressants with a direct antagonistic effect on 5-HT2A receptors such as SARI and tetracyclic antidepressants (eg trazodone, mirtazapine, mianserin) or discontinuation of their use for less than 14 days
23. Electroconvulsive therapy in the previous 3 months
24. Daily use of benzodiazepine anxiolytics higher than the equivalent of 10 mg diazepam
25. Allergy to any of the components of study drugs