Evaluation of Buprenorphine as an Adjunctive Treatment for Severe Suicidal Ideation in Major Depressive Episode: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to demonstrate a significant effect of **buprenorphine** compared to placebo in the treatment of severe suicidal ideas during a major depressive episode by Day 7. Additionally, the study aims to assess the most effective dosage between 0.8 mg and 0.4 mg of buprenorphine. This is clinically relevant as it addresses the urgent need for effective interventions in managing suicidal ideation, a critical component of mental disorders.

Secondary objectives include:

• To show maintenance of a significant effect of buprenorphine on suicidal ideas from Day 0 to Day 42.
• To demonstrate a significant effect of buprenorphine on psychological pain from Day 0 to Day 14 and its mediating effect in the relationship between buprenorphine and suicidal ideas.
• To determine the effect of buprenorphine on the depressive syndrome in general, excluding suicidal ideas and psychological pain, from Day 0 to Day 14.
• To identify the treatment arm with the lowest number of discontinuations for inefficacy according to the patient from Day 0 to Day 14.
• To determine the number of suicide attempts or completed suicides during follow-up from Day 0 to Day 90.
• To identify the dose of buprenorphine with the best tolerance profile from Day 0 to Day 14.
• To determine the frequency of withdrawal symptoms from Day 14 to Day 21 for each dose.
• To identify the physiological mechanisms underlying psychological pain and suicidal ideation, the biological mechanisms of response to buprenorphine treatment, and the predictive factors of response to buprenorphine by neuropsychological and brain processes.
• To explore biochemical processes, including epigenetic markers, inflammatory markers, and intestinal microbiota, with the creation of a biobank for future ancillary studies.

The clinical trial involves participants diagnosed with **mental disorders**, specifically those experiencing a current major depressive episode without psychotic features, as defined by DSM-5 criteria. The study population includes both male and female subjects, aged between 18 and 65 years. Participants are required to be hospitalized and must have a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than 20, alongside a Scale for Suicidal Ideation (SSI) score exceeding 8. The trial does not focus on a vulnerable population. Participants must have provided informed consent and be insured or beneficiaries of a health insurance plan. The sponsor has not provided information regarding the total number of participants. 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 **buprenorphine** in treating severe suicidal ideation during a major depressive episode. This is a Phase 4, randomized, double-blind, controlled trial with three arms: placebo, and two fixed doses of buprenorphine (0.4 mg and 0.8 mg per day). The primary objective is to demonstrate a significant effect of buprenorphine compared to placebo in reducing suicidal ideation at Day 7. The trial is expected to run from October 8, 2021, to October 7, 2026, with participant involvement lasting up to 42 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-65 years), hospitalization status, and a current major depressive episode without psychotic features. The inclusion visit will also ensure a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than 20 and a Scale for Suicidal Ideation (SSI) score greater than 8. Informed consent and health insurance coverage are mandatory for participation.

Following the screening, participants will be randomized into one of the three study arms. The trial includes multiple follow-up visits to monitor the primary endpoint, which is the SSI score at Day 7, and secondary endpoints such as SSI scores from Day 7 to Day 42, psychological pain evaluation, and depression inventory scores. Additional assessments include neuropsychological tests, 3T Magnetic Resonance Imaging, and biobank sample collection. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any adverse events.

Participants may be withdrawn from the study early due to reasons such as significant adverse effects, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide comprehensive data on the safety and efficacy of buprenorphine in this patient population, contributing to the understanding of its role in managing severe suicidal ideation associated with major depressive episodes.

The clinical trial involves the administration of **BUPRENORPHINE** as the experimental medication. **BUPRENORPHINE** is provided in the form of a sublingual tablet, with two different dosages being evaluated: 0.8 mg and 0.4 mg. The route of administration is oral, specifically sublingual, and the medication is administered once daily. The maximum treatment period for each participant is 14 days. The primary objective of the trial is to assess the efficacy of **BUPRENORPHINE** in reducing severe suicidal ideation during a major depressive episode, comparing the two dosages to determine the most effective one. Participant compliance with the dosing schedule is monitored throughout the study period.

In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo is designed to mimic the appearance and administration route of the **BUPRENORPHINE** sublingual tablet, ensuring blinding of both participants and investigators. The placebo is administered under the same conditions as the active treatment, with a daily sublingual administration for a maximum of 14 days. This allows for a controlled comparison to evaluate the true efficacy of **BUPRENORPHINE** against a non-active treatment.

**Lactose monohydrate** is included in the trial as a non-active substance. It serves as an excipient in the formulation of the placebo, ensuring that the placebo tablets are indistinguishable from the active medication in terms of appearance and administration. The use of lactose monohydrate is standard in clinical trials to maintain the integrity of the blinding process. No specific dosage or administration frequency is associated with lactose monohydrate, as it is not an active treatment component.

Efficacy in this clinical trial will be assessed primarily through the evaluation of scores on the **Scale for Suicidal Ideation (SSI)** at Day 7, covering the last 7 days. This primary endpoint aims to demonstrate a significant effect of buprenorphine compared to placebo in the treatment of suicidal ideas during a major depressive episode. Secondary endpoints include the SSI score from Day 7 to Day 42, psychological pain evaluation using a Visual Analog Scale (PPP-VAS) from Day 0 to Day 42, and scores on the Beck Depression Inventory (BDI-II) and Montgomery-Asberg Depression Rating Scale (MADRS), excluding suicidal ideation items, for the last 7 days.

Additional secondary endpoints involve reports on reasons for discontinuing treatment, suicide attempts, suicide completion post-treatment, side effects, withdrawal symptoms, neuropsychological test scores, 3T Magnetic Resonance Imaging measurements, and the collection of blood and stool samples for biobank creation. The trial will assess the most effective dosage of buprenorphine, comparing 0.8 mg and 0.4 mg doses. The trial is designed as a randomized, double-blind, multicenter study with three arms: placebo, and two fixed doses of buprenorphine. The trial phase is categorized as Phase 4, with an estimated end date of October 7, 2026.