Comparative Efficacy of Psilocybin and Personalized Repetitive Transcranial Magnetic Stimulation in Treatment-Resistant Depression

The primary objective of this study is to **compare the effectiveness** of psilocybin and personalized repetitive transcranial magnetic stimulation (rTMS) in individuals with **Treatment Resistant Depression (TRD)**. This comparison is clinically relevant as it aims to identify more effective treatment options for patients who do not respond to conventional antidepressant therapies, potentially improving patient outcomes and quality of life.

Secondary objectives include exploring the different trajectories of antidepressant response associated with psilocybin and personalized rTMS, specifically focusing on their impact on the brain networks involved in TRD. Understanding these trajectories could provide insights into the mechanisms of action of these treatments and help tailor interventions to individual patient needs.

The clinical trial focuses on individuals diagnosed with **Treatment Resistant Depression (TRD)**, specifically targeting a study population aged between 18 and 65 years. Both male and female participants are included, with no vulnerable populations selected. The trial aims to compare the effectiveness of psilocybin and personalized rTMS in treating TRD. Participants are required to have a diagnosis of major depressive disorder (MDD) and must have been non-responsive to at least two antidepressant medications administered at adequate doses for a period of 4-6 weeks. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the effectiveness of **psilocybin** and personalized repetitive transcranial magnetic stimulation (rTMS) in individuals with **Treatment Resistant Depression (TRD)**. This study is a randomized, double-blind, controlled trial, categorized as Phase IV, and is not considered low intervention. The trial aims to compare the therapeutic outcomes of psilocybin capsules, each containing 25 mg of psilocybin, against a placebo containing maltodextrin. The trial is expected to commence recruitment on May 31, 2025, and conclude by May 30, 2027.

Participants will undergo a series of study visits, beginning with an inclusion visit to screen for eligibility based on criteria such as age (18-65 years) and a confirmed diagnosis of TRD. The primary endpoint is to establish non-inferiority in terms of clinical response, defined as a ≥50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) scores after 60 days. Secondary endpoints include assessments using the Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), and other psychiatric and cognitive measures.

The trial will involve multiple follow-up visits to monitor the participants' progress and collect data on various scales and imaging techniques, such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), to observe changes in brain connectivity patterns. The expected duration of participant involvement is up to three months, with conditions for early termination including adverse reactions or non-compliance with the study protocol.

The clinical trial involves the administration of **PEX010 Psilocybin Capsules**, which contain 25 mg of psilocybin as the active substance. The psilocybin is derived from a **dry extract from Psilocybe cubensis** with an extraction ratio of 15-25:1, using methanol as the solvent. The pharmaceutical form of the experimental medication is a capsule, and it is administered orally. The maximum daily dose is 25 mg, with a total maximum dose of 50 mg over the treatment period. The treatment period is limited to a maximum of 3 days. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the study utilizes **PCB2**, an inert placebo containing maltodextrin. The placebo is designed to mimic the appearance and administration route of the psilocybin capsules, ensuring blinding of the study. The placebo is administered orally in a similar capsule form, maintaining consistency in the administration process. The use of the placebo allows for a controlled comparison of the effects of the psilocybin treatment in participants with Treatment Resistant Depression (TRD).

The efficacy of the clinical trial titled "Advancing PRecise Interventions for resistant DEpression: rebalancing brain networks and investigating the trajectories of antidepressant effect with psilocybin and personalized neuromodulation (PRIDE)" will be assessed using both primary and secondary endpoints. The primary endpoint is the non-inferiority of psilocybin compared to personalized rTMS in terms of the percentage of clinical responders. This is defined as a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) scores by 50% or more, evaluated 60 days from the start of the trial.

Secondary endpoints include a range of validated scales and assessments to measure various aspects of mental health and cognitive function. These include the Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), and Snaith-Hamilton Pleasure Scale (SHAPS) for anhedonia. Additionally, the Columbia–Suicide Severity Rating Scale and Beck Hopelessness Scale will be used to assess suicide risk. Cognitive and functional assessments will be conducted using the Trail Making Test for attention and executive functions, and the Clinical Global Impression Severity (CGIS) and Health Status Questionnaire will evaluate the impact of symptoms on health.

Furthermore, changes in brain connectivity patterns related to Treatment Resistant Depression (TRD) will be analyzed using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to assess changes in functional connectivity. These assessments will provide a comprehensive evaluation of the efficacy of the interventions in this trial.