Psilocybin treatment for patients with severe depression

Inclusion Criteria:

1. Age 18 years or older.
2. Diagnosis of major depressive disorder (single and recurrent episodes) of moderate to severe degree (MADRS score ≥ 20) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), without psychotic features. Included ICD-11 diagnoses are ICD-11: 6A70.1, 6A70.3, 6A71.1, 6A71.3.
3. Subjects have failed to respond to 2 or more antidepressants prescribed at the minimum effective dose for at least 6 weeks. Augmentation with an add-on treatment counts 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, medical history, 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 and PR-interval \< 220 ms at screening.
7. A partner is willing to participate in the study (a cohabiting relationship of at least 1 year).

Exclusion Criteria:

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

   1. major depressive episode with psychotic features.
   2. psychotic disorder (defined as meeting DSM-5 criteria for any psychotic disorder) on the MINI 7.0, EXCEPT substance/medication induced psychotic disorder where the duration was limited to the acute period of direct intoxication with the substance/medication. Positive diagnoses on the MINI will be subject to confirmation at clinical interview by a psychiatrist.
   3. bipolar disorder (defined as meeting DSM-5 criteria for bipolar type 1 or bipolar type 2) on the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at clinical interview by a psychiatrist.
   4. drug or alcohol dependence syndrome (defined as meeting DSM-5 criteria for any dependence syndrome) on the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at clinical interview by a psychiatrist.
   5. cluster B personality disorder. Subjects will be screened for the presence of those personality traits by using the NEO-FFI-3.
   6. PTSD (defined as meeting DSM-5 criteria for PTSD) on the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at clinical interview by a psychiatrist.
2. A family history (first-degree relative) of psychosis and/or bipolar disorder.
3. Current active suicidal ideations.
4. Depression secondary to other medical conditions.
5. Medical diagnosis incompatible with psilocybin treatment:

   1. Cardiovascular conditions: recent stroke (\< 1 year from signing of ICF), recent myocardial infarction (\< 1 year from signing of ICF), uncontrolled hypertension (blood pressure \> 140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF.
   2. Uncontrolled insulin-dependent diabetes mellitus.
   3. Uncontrolled epilepsy.
6. Biochemical or electrocardiographic abnormalities determined as clinically significant by a medical doctor. PsiHos-D, Version 2.1 dd. 22/02/2024 page 59 of 114 TMP\_Protocol AGO CTR\_Version 1.0\_Effective Date 2022-07-18
7. Current intake of Lithium, Disulfiram, MAOIs or inhibitors of UGT1A9 and 1A10.
8. The subject has received any prior treatment with vagal nerve stimulation, or a deep brain stimulation device.
9. Women of childbearing potential not using adequate contraception (methods that can achieve 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 tubal occlusion, vasectomized partner, sexual abstinence). A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
10. Pregnant or breast-feeding women.
11. Those unable to give informed consent.
12. Those enrolled in another trial.