Evaluation of Psilocybin and Trazodone Efficacy in Adult Patients with Treatment-Resistant Depression: A Randomized Controlled Proof-of-Concept Study

The primary objective of this study is to evaluate the **efficacy** of a single administration of a combination of psilocybin 25 mg and trazodone 30 mg, compared to placebo, in adult patients with treatment-resistant depression (TRD). This is assessed by the improvement in symptoms of depression at one month, with the treatment administered alongside psychotherapeutic support. This objective is clinically relevant as it aims to address the challenge of TRD, a condition where patients do not respond to standard antidepressant therapies, by exploring novel treatment combinations that could offer new therapeutic avenues.

Secondary objectives include:

• Comparing the efficacy of psilocybin without trazodone pretreatment, psilocybin plus trazodone at different dosages, and trazodone monotherapy in improving depression symptoms at one month.
• Evaluating the efficacy of a single administration of these treatments at various time points from H7 (V3) to the end of the study visit compared to baseline (V2).
• Comparing response and remission rates between groups from D7 (V5) to the end of the study.
• Assessing the tolerance of study treatments from administration to the end of the study.
• Investigating the influence of the intensity of the psychedelic experience on therapeutic efficacy in patients with resistant depressive disorder.
• Evaluating the role of expectations in treatment efficacy from D7 (V5) to the end of the study visit.
• Assessing patients' quality of life before and after treatment administration.
• Evaluating neuro-cognitive mechanisms involved in the subjective effects of psilocybin using EEG and cognitive tasks.
• Studying the biological correlates of psilocybin ± trazodone in the short and mid-term period post-treatment according to response and remission rates and efficacy parameters.
• Assessing demographic, clinical, neurocognitive, and biological factors associated with clinical response.
• Studying brain activity and functioning before and after the effects of the study treatments.
• Measuring the cross-over within-subject efficacy of psilocybin by comparing its efficacy during the open-label extension phase to placebo during the initial phase in improving depression symptoms at one month.
• Assessing the influence of blindness by comparing the efficacy of psilocybin during the open-label extension phase to its efficacy during the initial phase in improving depression symptoms at one month.

The clinical trial focuses on adult patients diagnosed with **treatment-resistant depression** (TRD), characterized by a major depressive episode without psychotic features, as per DSM-5 criteria. The study population includes both male and female participants aged 18 years and older. Participants are required to have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher and must have experienced a depressive episode that did not respond to at least two lines of antidepressant medication at an adequate dose for a sufficient period. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to provide free, informed, and prior written consent and must be covered by the social security system. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** of a single administration of a combination of **psilocybin** 25 mg and **trazodone** 30 mg, compared to placebo, in adult patients with treatment-resistant depression. This study is a randomized, controlled, double-blind, proof-of-concept trial. The primary objective is to assess the improvement in depression symptoms at one month post-administration, with the primary endpoint being the mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) scores between baseline and one month. The trial is expected to commence recruitment on April 14, 2025, and conclude by April 14, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), a major depressive episode without psychotic features, and a history of treatment-resistant depression. Following the screening, baseline assessments will be conducted, including MADRS, Beck Depression Inventory (BDI), and other relevant scales. The study drug will be administered with psychotherapeutic support, and follow-up visits will occur at various intervals: H7 (7 hours post-administration), D1 (1 day), D7 (7 days), M1 (1 month), M2 (2 months), and M3 (3 months). Each visit will involve assessments of depression severity, side effects, and other secondary endpoints such as quality of life and cognitive performance.

The expected duration of participant involvement is approximately three months, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study procedures. The trial will employ a placebo-controlled design, with participants randomly assigned to receive either the active treatment or placebo. The double-blind nature ensures that neither participants nor investigators are aware of the treatment allocation, maintaining the integrity of the study results. The trial will adhere to Good Clinical Practice guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Psilocybin 25 mg Capsules** as an experimental treatment. The active substance in these capsules is a **dry extract from Psilocybe cubensis** (15-25:1), with methanol as the extraction solvent. The pharmaceutical form is a capsule, and the route of administration is oral. Participants will receive a single dose of 25 mg, with the maximum treatment period being one day. The product is not a paediatric formulation and is not classified as an orphan drug. The sponsor product code for this medication is PEX010.

In addition to the experimental treatment, the study includes the administration of **TRITTICO 60 mg/ml oral drops, solution**, which contains **trazodone hydrochloride** as the active substance. This medication is administered orally, with a maximum daily dose of 30 mg. The treatment period is limited to one day. The dosage used in this trial is lower than the approved indication for use in this population. The product is manufactured by Angelini Pharma S.P.A. and is not a paediatric formulation.

The trial also utilizes two placebo treatments. The first is the **Trazodone placebo**, which is a pharmaceutical master preparation prepared according to Good Pharmacy Practice. The second is **PCB2 (Placebo of psilocybin 25 mg)**, which mimics the psilocybin capsules. Both placebos are used to ensure the integrity of the study's double-blind design. The PCB2 placebo is administered orally, with a maximum daily dose of 25 mg, and the treatment period is one day. The trazodone placebo does not have a specified pharmaceutical form or route of administration.

The efficacy of the combination of psilocybin 25 mg and trazodone 30 mg in treating **treatment-resistant depression** will be assessed through a randomized controlled proof-of-concept study. The primary endpoint for evaluating efficacy is the mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) scores between one month post-treatment (M1, V6) and baseline (V2). This comparison will be made between the group receiving psilocybin and trazodone (Group 3) and the placebo group receiving trazodone (Group 4).

Secondary endpoints include MADRS scores at various timepoints: Inclusion (V1), Baseline (V2), H7 (V3), D1 (V4), D7 (V5), M2 (V7), and M3 (V8) across all groups. Additional assessments involve the Beck Depression Inventory (BDI), Columbia-Suicide Severity Rating Scale (C-SSRS), and Young Mania Rating Scale (YMRS) scores at the same timepoints. The response rate, defined as a 50% reduction in MADRS score, and the remission rate, defined as a MADRS score below 10, will be evaluated at D7 (V5), M1 (V6), M2 (V7), and M3 (V8).

Other measures include side effects, vital signs, and biological adverse events, as well as cognitive task performance and brain activity measured by EEG. Quality of life will be assessed using the Quality of Life in Depression Scale (QLDS). The study will also explore correlations between maximal 5D-ASC and Mystical Experience Questionnaire (MEQ30) scores and therapeutic efficacy. The Stanford Expectations of Treatment Scale (SETS) and the Credibility/Expectancy Questionnaire (CEQ) will be used to evaluate treatment expectations. Biomarkers related to immune and neuroplasticity will be measured before and after treatment. Brain structure and activity will be assessed using MRI and EEG in specific groups during the open-label extension phase.