Evaluation of Intravenous Ketamine Versus Placebo as Adjunct to Venlafaxine in Severe Unipolar Major Depressive Episodes: A Double-Blind Randomized Controlled Trial

The primary objective of this study is to evaluate the early efficacy of **intravenous ketamine** compared to placebo as an add-on therapy to venlafaxine in patients hospitalized for severe major depressive episodes. This is assessed by measuring the improvement in depressive symptoms at day 7. The clinical relevance of this objective lies in addressing the urgent need for rapid-acting treatments in severe cases of major depressive disorder, where traditional antidepressants may take weeks to show effects.

Secondary objectives include:

• Comparing the efficacy of add-on ketamine at days 14, 28, and 48 post-acute treatment phase with placebo.
• Assessing whether add-on ketamine reduces hospitalization duration compared to placebo.
• Evaluating if early administration of ketamine decreases suicidal ideations compared to placebo.
• Determining if very early clinical improvement (day 1 or day 4) predicts clinical improvement at days 14, 28, and 42 in the ketamine group compared to placebo.
• Comparing side effects between ketamine and placebo groups.
• Comparing anxiolytic consumption in ketamine and placebo groups.
• Identifying predictive or associated biomarkers of venlafaxine and ketamine efficacy.

The clinical trial involves participants diagnosed with **major depressive disorder** experiencing a current severe major depressive episode. The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to be hospitalized for the current episode and must have a minimum HDRS score of 24, indicating severe depression. The trial does not include a vulnerable population. Participants must be eligible for venlafaxine treatment and have provided signed informed consent. Women of childbearing age are required to use effective contraception throughout the study. 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 early efficacy of **ketamine** compared to placebo, as an add-on therapy to **venlafaxine** for inpatients with severe unipolar major depressive episodes. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to commence on May 2, 2024, and conclude by June 22, 2025, with a total duration of approximately 14 months. Participants will be involved in the study for a maximum of 5 weeks, depending on their treatment allocation and response.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as a current major depressive episode, hospitalization, and a minimum Hamilton Depression Rating Scale (HDRS) score of 24. Participants must be aged between 18 and 65, provide informed consent, and meet other specified criteria. Following the screening, eligible participants will be randomized to receive either intravenous ketamine or placebo, in addition to venlafaxine. The primary endpoint is the change in HDRS score after 7 days of treatment, with secondary endpoints including response rate, remission, and safety assessments.

Study visits will include baseline assessments, treatment administration, and follow-up evaluations. The primary follow-up visit occurs on day 7, with additional assessments on day 14 to evaluate synaptic density changes using PET-MRI. The end-of-study visit will occur at the conclusion of the treatment period, or earlier if necessary. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. Safety will be monitored throughout the trial, with adverse events assessed using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

The clinical trial involves the administration of several treatments, including **ketamine**, **sodium chloride**, **11C-UCB-J**, and **venlafaxine**. The primary experimental medication is **ketamine**, which is administered as an intravenous perfusion. The pharmaceutical form of ketamine is not explicitly detailed, but it is used as an anesthetic. The dosing regimen for ketamine involves a maximum daily dose of 4.5 mg/kg and a total maximum dose of 13.5 mg/kg over a treatment period of 3 days. The efficacy of intravenous ketamine has been demonstrated for pharmacoresistant depressive episodes.

**Sodium chloride** is used as a placebo in this study. It is provided in the form of a 0.9% injectable solution, known as "CHLORURE DE SODIUM 0,9% RENAUDIN." The solution is administered intravenously, with a maximum daily dose of 50 ml and a total maximum dose of 150 ml over a 3-day period. Sodium chloride serves as an electrolyte for placebo purposes and is manufactured by LABORATOIRE RENAUDIN.

**11C-UCB-J** is utilized as an auxiliary treatment in the trial. It is a solution for injection, administered intravenously, with a maximum daily dose of 500 MBq and a total maximum dose of 1000 MBq over a 2-day period. The active substance is a chemical compound, (4R)-1-[(3-(11C)methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one, used for central nervous system diagnostic purposes.

**Venlafaxine** is included as a standard-of-care therapy in the trial. It is provided in the form of prolonged-release hard capsules and is administered orally. The maximum daily dose of venlafaxine is 375 mg, with a total maximum dose of 375 mg over a 5-day period. Venlafaxine is a chemical substance used in the treatment of major depressive episodes.

Efficacy in this clinical trial will be assessed primarily through the change in total score on the Hamilton Depression Rating Scale (HDRS) after 7 days of treatment. The HDRS is a validated scale with 17 items, each rated from 0 to 2 or 0 to 4, resulting in a total score range from 0 to 52. Secondary efficacy endpoints include several complementary criteria: the response rate defined as a ≥50% improvement in HDRS total score, remission indicated by an HDRS score of ≤7, changes in the Beck Depression Inventory (BDI), and the Clinical Global Impression (CGI) rating scale. Additional secondary endpoints involve the length of hospital stay, changes in the Columbia Suicide Risk Scale (C-SSRS) scores, safety assessments using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, cumulative consumption of cyamemazine, and biomarkers predictive or associated with the efficacy of ketamine as an add-on to venlafaxine.

The efficacy parameters will be measured at specific timepoints, including baseline (day 0), day 7, and day 14, with additional follow-up assessments over a 42-day period. The assessments will be conducted using standardized tools and scales, ensuring consistency and reliability in data collection. The trial aims to compare the early efficacy of intravenous ketamine versus placebo, in combination with venlafaxine, for patients hospitalized with severe **unipolar major depressive episodes**. The study will also explore synaptic density changes through PET-MRI imaging before and after the early add-on treatment, and assess the correlation between clinical improvement and synaptic density changes.