Evaluation of Psilocybine and Ketamine Hydrochloride as Rapid Antidepressants in Treatment-Resistant Depression: A Randomized Controlled Trial

The primary objective of this study is to verify the rapid **antidepressant** effect of psilocybin 25 mg in comparison with ketamine 250 mg, using the MADRS scale, 24 hours after a single application. This is clinically relevant as it aims to establish the efficacy of psilocybin as a fast-acting treatment for pharmaco-resistant depression, potentially offering an alternative to current treatment options.

Secondary objectives include:

• Evaluating the duration of the rapid antidepressant effect of psilocybin compared to ketamine over the first two weeks (days 3, 7, and 14) post-administration, using the MADRS scale.
• Comparing the duration of the antidepressant effect of psilocybin with ketamine and midazolam at 3, 4, 5, 6, 8, and 12 weeks post-application, using the MADRS scale.
• Assessing the antidepressant effect of a single application of psilocybin, ketamine, and midazolam at various intervals up to 12 weeks, based on patient self-evaluation using the QIDS scale.
• Comparing response rates (50% reduction in MADRS score) and remission rates (MADRS ≤10) for psilocybin, ketamine, and midazolam at multiple time points up to 12 weeks post-application.
• Comparing the time to return of depressive symptoms over 12 weeks following a single application of psilocybin, ketamine, and midazolam.
• Evaluating the safety profile of the study medications.

The clinical trial involves **participants** diagnosed with **pharmaco-resistant depression**. The study population includes both men and women over the age of 18, with a diagnosis of moderate to severe depressive disorder without psychotic symptoms, as defined by ICD-10 criteria F32.1-2 or F33.1-2, and a MADRS score of 20 or higher. The duration of the depressive episode for participants ranges from a minimum of 3 months to a maximum of 2 years. Participants are required to have a history of treatment-resistant depression, characterized by the failure of at least two and at most four adequate treatments, or intolerance to multiple treatments. The trial population was selected based on their ability to understand and independently complete all protocol-defined examinations and scales, and their availability to attend all study visits. Participants must have a secured caregiver available for personal contact five times a week. The study includes individuals of childbearing age who must agree to use prescribed methods of contraception throughout the trial. The sponsor has not provided information on the total number of participants. The trial includes both male and female subjects and considers vulnerable populations.

The clinical trial is designed to evaluate the rapid antidepressant effects of **psilocybin** in comparison to **ketamine hydrochloride** in individuals with pharmaco-resistant depression. This study is a randomized, double-blind, controlled trial, with a primary objective to assess the antidepressant effects using the MADRS scale 24 hours post-administration. The trial involves three groups: one receiving psilocybin 25 mg, another receiving ketamine 250 mg, and a control group receiving **midazolam** 5 mg, all administered orally in hard capsule form. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on July 14, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of moderate to severe depressive disorder, and treatment-resistant status. Following the screening, participants will be randomized into one of the treatment groups. The study includes follow-up visits to monitor the duration of antidepressant effects and safety, using scales such as MADRS and QIDS, over a two-week inpatient stay and subsequent outpatient follow-up. The end-of-study visit will assess the long-term safety profile and any persistent effects.

The expected length of participant involvement is approximately three months, including the inpatient and outpatient phases. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse reactions to the study medication, or withdrawal of consent. Participants must have a secured caregiver for support and adhere to prescribed contraceptive methods if of childbearing potential. The trial aims to provide insights into the efficacy and safety of psilocybin and ketamine as fast-acting antidepressants in a treatment-resistant population.

The clinical trial involves the administration of three distinct **experimental medications** in the form of hard capsules, each containing a different active substance. The first experimental medication is **midazolam**, a chemical compound administered orally. The dosage for midazolam is set at 5 mg per day, with a maximum total dose of 5 mg over a treatment period of one day. Midazolam serves as a comparator in this study, providing a baseline for evaluating the antidepressant effects of the other substances.

The second experimental medication is **psilocybine**, also administered in the form of a hard capsule. Psilocybine is given orally at a dosage of 25 mg per day, with a maximum total dose of 25 mg over a single day. This substance is the primary focus of the study, as the trial aims to verify its rapid antidepressant effect in comparison to ketamine. Psilocybine is expected to demonstrate a significant reduction in depressive symptoms, as measured by the MADRS scale, 24 hours post-administration.

The third experimental medication is **ketamine hydrochloride**, provided in a hard capsule form for oral administration. The dosage for ketamine hydrochloride is 250 mg per day, with a maximum total dose of 250 mg over one day. Ketamine serves as a comparator in the study, with its antidepressant effects being evaluated against those of psilocybine. The trial hypothesizes that both psilocybine and ketamine will exhibit similar antidepressant effects, with a more pronounced impact compared to midazolam.

All medications are administered orally, and the study ensures that the pharmaceutical form remains consistent across all treatments. Participant compliance is monitored throughout the trial to ensure accurate dosing and adherence to the treatment schedule. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The study is conducted under the auspices of the Narodni Ustav Dusevniho Zdravi, with all substances being of chemical origin and not formulated for pediatric use.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the rapid antidepressant effects of **psilocybin** compared to **ketamine**. The primary endpoint involves measuring the decrease in depressive symptoms using the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after a single application of the study medication. Secondary endpoints include the duration of the antidepressant effect of psilocybin, ketamine, and **midazolam** using the MADRS scale during a 2-week inpatient stay and after its termination. Additionally, the Quick Inventory of Depressive Symptomatology (QIDS) scale will be used to assess the duration of the antidepressant effect following a single application of the study drugs.

Further secondary endpoints involve comparing response rates, defined as a 50% reduction in MADRS scores, and remission rates, defined as a MADRS score of 10 or less, following treatment with psilocybin, ketamine, and midazolam. The time to reoccurrence of depressive symptoms within 12 weeks post-treatment will also be evaluated. Safety profiles will be assessed through both acute and long-term measures, including vital signs, Brief Psychiatric Rating Scale (BPRS), psilocin levels, and the Persistent Effects Questionnaire (PSQ).