Psilocybin for Hospitalized Patients with Treatment-resistant Depression

Inclusion Criteria:

1. Age 18 years or older.

2. Diagnosis of major depressive disorder (single and recurrent episodes) of moderateto severe degree (MADRS score ≥ 20) according to the Diagnostic and StatisticalManual of Mental Disorders (DSM-5), without psychotic features. Included ICD-11diagnoses are ICD-11: 6A70.1, 6A70.3, 6A71.1, 6A71.3.

3. Subjects have failed to respond to 2 or more antidepressants prescribed at theminimum effective dose for at least 6 weeks. Augmentation with an add-on treatmentcounts as a second treatment.

4. The subjects are abstinent from alcohol (breathalyzer blood alcohol concentration (BAC) level 0.00) and provide a negative urine drug screen at the dosing day.

5. The female subjects provide a negative pregnancy test at the dosing day.

6. The subjects must be medically stable based on clinical laboratory tests, medicalhistory, vital signs, and 12-lead ECG performed at screening.

• In 12-lead ECG, QTcF should be ≤ 450 ms for males or ≤ 470 ms for females andPR-interval < 220 ms at screening.

7. A partner is willing to participate in the study (a cohabiting relationship of atleast 1 year).

Exclusion Criteria:

1. Currently comorbid or previously diagnosed DSM-5 diagnosis of a

2. major depressive episode with psychotic features.

3. psychotic disorder (defined as meeting DSM-5 criteria for any psychoticdisorder) on the MINI 7.0, EXCEPT substance/medication induced psychoticdisorder where the duration was limited to the acute period of directintoxication with the substance/medication. Positive diagnoses on the MINI willbe subject to confirmation at clinical interview by a psychiatrist.

4. bipolar disorder (defined as meeting DSM-5 criteria for bipolar type 1 orbipolar type 2) on the MINI 7.0. Positive diagnoses on the MINI will be subjectto confirmation at clinical interview by a psychiatrist.

5. drug or alcohol dependence syndrome (defined as meeting DSM-5 criteria for anydependence syndrome) on the MINI 7.0. Positive diagnoses on the MINI will besubject to confirmation at clinical interview by a psychiatrist.

6. cluster B personality disorder. Subjects will be screened for the presence ofthose personality traits by using the NEO-FFI-3.

7. PTSD (defined as meeting DSM-5 criteria for PTSD) on the MINI 7.0. Positivediagnoses on the MINI will be subject to confirmation at clinical interview bya psychiatrist.

8. A family history (first-degree relative) of psychosis and/or bipolar disorder.

9. Current active suicidal ideations.

10. Depression secondary to other medical conditions.

11. Medical diagnosis incompatible with psilocybin treatment:

12. Cardiovascular conditions: recent stroke (< 1 year from signing of ICF), recentmyocardial infarction (< 1 year from signing of ICF), uncontrolled hypertension (blood pressure > 140/90 mmHg) or clinically significant arrhythmia within 1year of signing the ICF.

13. Uncontrolled insulin-dependent diabetes mellitus.

14. Uncontrolled epilepsy.

15. Biochemical or electrocardiographic abnormalities determined as clinicallysignificant by a medical doctor. PsiHos-D, Version 2.1 dd. 22/02/2024 page 59 of 114TMP_Protocol AGO CTR_Version 1.0_Effective Date 2022-07-18

16. Current intake of Lithium, Disulfiram, MAOIs or inhibitors of UGT1A9 and 1A10.

17. The subject has received any prior treatment with vagal nerve stimulation, or a deepbrain stimulation device.

18. Women of childbearing potential not using adequate contraception (methods that canachieve a failure rate of less than 1%: combined hormonal contraception,progestogen-only hormonal contraception associated with inhibition of ovulation,intrauterine device, intrauterine hormone-releasing system, bilateral tubalocclusion, vasectomized partner, sexual abstinence). A woman is considered ofchildbearing potential (WOCBP), i.e. fertile, following menarche and until becomingpost-menopausal unless permanently sterile. Permanent sterilization methods includehysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausalstate is defined as no menses for 12 months without an alternative medical cause.

19. Pregnant or breast-feeding women.

20. Those unable to give informed consent.

21. Those enrolled in another trial.