Psilocybin - a strategy of rapid antidepressant response in depression comorbid with cancer,a randomized double-blind study with the possibility of entering open extension

INTERVENTION: Product Name: , Product Code:PRD11505378, Pharmaceutical Form: CAPSULE, HARD, Other descriptive name: , Strength: , Product Name: , Product Code:PRD11505372, Pharmaceutical Form: CAPSULE, HARD, Other descriptive name: , Strength: , Product Name: , Product Code:PRD11505223, Pharmaceutical Form: CAPSULE, HARD, Other descriptive name: , Strength: CONDITION: Depressive disorder comorbid with cancer ; MedDRA version: 20.0Level: PTClassification code: 10012378Term: Depression Class: 100000004873 Therapeutic area: Psychiatry and Psychology [F] ‐ Mental Disorders [F03] SECONDARY OUTCOME: Secondary end point(s):Efficacy will be assessed as change in HAM‐A objective scale and STAI self‐report scores at day 1, day 4, 1 week (day 7), 4 weeks (day 28), 8 weeks (day 56), 16. weeks (112th day) and 24 weeks (224th day) from administration of study medication compared to baseline. Secondary end point(s):Evaluation of the antidepressant effect in the open‐label part of the study will correspond to the primary (2.2), secondary (2.3) and exploratory (2.3) objectives, with the evaluation not being blinded and only psilocybin and ketamine being compared (midazolam will not be administered). Secondary end point(s):Evaluation of the antidepressant effect of psilocybin and ketamine depending on the intensity of acute psychological effects during a session with the substance. Acute effects will be assessed by the patient at the end of the day after each session with psilocybin, ketamine and midazolam using the subjective 5D‐ASCs and MEQ scales, which reflect the main psychological dimensions of intoxication affecting therapeutic antidepressant response. Secondary end point(s):PEQ scale will be assessed 4 weeks (day 28) and 24 weeks (day 224) after administration of the study medication and will be evaluated as a change from baseline. The effect of psilocybin on existential distress including patients' subjective attitude towards life (LAP‐R), subjectively perceived hopelessness (HAI) and demoralization (DS) will be assessed as change in scores on the respective scales at 1 week (day 7), 4 weeks (day 28 ) and 24 weeks (day 224) from administration of study medication. Secondary end point(s):Safety will be assessed by changes in vital signs (blood pressure [BP], heart rate [TF]) during drug sessions, the BPRS scale, and suicidal ideation/behavior scores assessed by the C‐SSRS, version Since Last Visit (SLV) at the end of the session with the substance, based on monitoring the incidence of adverse events throughout the study and further evaluating the persistent psychotropic effects of psilocybin using the PSQ scale 1 day after administration of the study medication. Secondary end point(s):The antidepressant effect will be compared in patients taking standard antidepressants during the clinical trial (AD‐plus group) versus a group of patients not taking antidepressants (AD‐free). We hypothesize that the clinical effect of psilocybin will be more pronounced in the AD‐plus group than in the AD‐free group. Secondary end point(s):The BECK self‐rating scale, which is administered before the administration of the study medication at the beginning of the day and after the administration of the study medication at the end of the day Secondary end point(s):The effect of psilocybin and ketamine on the patient's subjectively perceived quality of life and well‐being will be assessed as a change in the score on the FACIT scale and its sub‐scales 1 week (day 7), 4 weeks (day 28) and 24 weeks (day 224) from administration of study medication versus baseline. Secondary end point(s):The quality of the blinding of the study medication in the double‐blind part of the study will be monitored using the BQQ Questionnaire. The estimate of administered study medication will be determined independently of the participant, therapist and co‐therapist. The questionnaire will be filled in 4 weeks (day 28) from the administration of the study medication, at the end of Integration Session 3 after evaluation by an independent evaluator. Secondary end point(s):The rate of onset and duration of substance use will be assessed using the MADRS objective scale and the BECK self‐report scale as change scores on day 1, day 4, 1 week (day 7), 4 weeks (day 28), 8 weeks (day 56 ), 16 weeks (day 112) and 24 weeks (day 224) from administration of study medication compared to baseline. Secondary end point(s):This effect will be monitored using a pain visual analogue scale (VAS) at day 1, 1 week (day 7), 4 weeks (day 28) and 24 weeks (day 224) of study medication administration versus baseline. INCLUSION CRITERIA: Men and women aged 18‐75 years, A diagnosis meeting diagnostic criteria for a depressive syndrome (F41.2, F32.1, F32.2) comorbid with an oncological disease that: and) is at an advanced stage according to the judgment of the referring oncologist/hematoncologist/internist/paliatrician, or b) is with a poor prognosis (median survival of 5 years or less), or c) currently progressing, or d) shows recurrence, or e) is in the phase of controlled disease, since the oncological dg. at least 6 months have passed, but the patient still has reactive depressive comorbidity, In terms of antidepressant treatment, patients who: a) have not used and do not regularly use any standard antidepressants (SSRI, SNRI NaSSA, SARI, tricyclic and tetracyclic AD), b) are currently using standard antidepressants (SSRI, SNRI NaSSA, SARI, tricyclic and tetracyclic AD) for at least 6 weeks in a stable dose, but the treatment did not provide them with a satisfactory psychological state, c) they un PRIMARY OUTCOME: Main Objective: evaluation of the effectiveness of psilocybin (active substance 1) in depression comorbid to oncological disease treatement in 4 weeks; (day 28) from its administration, compared to ketamine (active substance 2) and midazolam (control; substance) Primary end point(s): The effectiveness of psilocybin will be evaluated by comparison with the antidepressant ketamine and midazolam using the MADRS scale. Response and remission will be evaluated. Baseline is defined as the score obtained at Preparation Session 1 (9 ‐ 7 days) prior to study medication administration. Response is defined as = 50% reduction in MADRS total score from baseline, and remission is defined as =10 MADRS Secondary Objective: evaluation of the onset and duration of the antidepressant effect of psilocybin and ketamine, evaluation of the rate of onset of the antidepressant effect of psilocybin and ketamine during the Substance Session (F4, OF4) using the BECK self‐rating scale, which will be administered before the administration of the study medication at the beginning of the day and after the administration of the study medication at the end of the day, evaluation of the effect of psilocybin and ketamine (compared to midazolam) on quality of life, well‐being and their potential mediators, evaluating the efficacy of psilocybin and ketamine (compared to midazolam) on nonspecific anxiety, the effect of psilocybin and ketamine on the patient subjectively perceived shift in life values ??and the effect of psilocybin on existential distress including the patient's subjective attitude to life, subjectively perceived hopelessness and demoralization, the effect of psilocybin and ketamine on the patient's subjective perception of pain, evaluation of potential mediators of clinical response, comparison of the antidepressant effect of psilocybin and ketamine depending on the use of standard antidepressants during the clinical trial, evaluation of the antidepressant effect of psilocybin and ketamine in the open label part of the study, evaluation of the quality of the blinding of the study medication, evaluation of the safety and tolerability of psilocybin in patients with comorbid depression