Evaluation of Ketamine Hydrochloride and Electroconvulsive Stimulation in Treatment-Resistant Major Depressive Disorder

The primary objective of this study is to identify the **phenotypic** and **neurochemical** determinants of response to **ketamine** and **electroconvulsive therapy (ECT)** in patients with treatment-resistant **major depressive disorder (MDD)**. This is clinically relevant as it aims to enhance understanding of the biological factors influencing treatment outcomes in MDD, potentially leading to more personalized and effective therapeutic strategies for individuals who do not respond to conventional treatments.

The clinical trial focuses on individuals diagnosed with **Major Depressive Disorder (MDD)**, specifically those experiencing treatment-resistant depression. The study population includes both male and female participants aged between 18 and 70 years. Participants are required to be in general good health, aside from their depressive condition, and must have previously used at least two different antidepressant agents without success. The trial population was selected based on their willingness and ability to provide informed consent, and women of childbearing potential are required to use highly effective contraception methods. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and participants must have an adequate score for anesthesia. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **additive effect** of **ketamine** in combination with electroconvulsive stimulation (ECS) in patients diagnosed with **major depressive disorder** (MDD), specifically those with treatment-resistant depression. This study is a **randomized, double-blind, controlled trial** aimed at identifying the phenotypic and neurochemical determinants of response to the treatment. The trial is categorized as a Phase 3 clinical trial and is considered a low-intervention study as per the Regulation (EU) 536/2014. The trial is expected to commence recruitment on September 1, 2024, and conclude by December 31, 2025.

Participants will be involved in the study for a total duration of 12 weeks. The sequence of study visits includes an initial **screening visit** to assess eligibility based on inclusion criteria such as age (18-70 years), diagnosis of MDD, and treatment-resistant depression. Women of childbearing potential must adhere to effective contraceptive methods. The primary endpoint is the mean change in depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to Day 28. Secondary endpoints include the evaluation of long-term effects on depressive symptoms and cognitive outcomes at Week 12.

Following the screening, participants will undergo a series of follow-up visits to monitor treatment efficacy and safety. The treatment involves the administration of **ketamine hydrochloride** via intravenous infusion, with a maximum daily dose of 0.5 mg/kg over a treatment period of 5 days. **Sodium chloride** solution will be used as a placebo. The end-of-study visit will assess the overall impact of the treatment on depressive symptoms and cognitive function. Participants may be withdrawn from the study if they experience adverse effects or fail to comply with the study protocol. The trial's design ensures rigorous monitoring to maintain participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of **ketamine hydrochloride** as an experimental treatment. The pharmaceutical form of this medication is a **solution for injection**, marketed under the name "KETAMINA MOLTENI 50 mg/ml soluzione iniettabile" by L. Molteni and C. Dei F.lli Alitti Società di Esercizio S.P.A. The active substance, ketamine hydrochloride, is of chemical origin. The medication is administered via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 0.5 mg/kg, with a total maximum dose of 0.5 mg/kg over a treatment period not exceeding 5 days. The administration schedule is designed to ensure participant compliance, with monitoring protocols in place to assess adherence to the dosing regimen.

In addition to the experimental treatment, the study utilizes **sodium chloride** as a non-experimental treatment. This is provided in the form of a **solution for infusion**, specifically "SODIO CLORURO 0,9% BAXTER Soluzione per infusione," produced by Baxter S.P.A. The sodium chloride solution serves as a standard-of-care therapy and is also administered via intravenous infusion. The use of sodium chloride in this context is to maintain electrolyte balance and hydration during the trial. The administration of sodium chloride follows a similar dosing schedule to ensure consistency and participant safety throughout the study duration.

Efficacy in this clinical trial will be assessed primarily through the evaluation of depressive symptoms in patients with treatment-resistant **major depressive disorder** (MDD). The primary endpoint is defined as the mean change in depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), from baseline to Day 28 (Week 4). This measurement will provide an assessment of the short-term efficacy of the treatment involving ketamine in combination with electroconvulsive therapy (ECT).

Secondary endpoints will include the mean change in MADRS scores from baseline to Week 12, which will evaluate the long-term effects of the treatment. Additionally, cognitive outcomes will be assessed at both Day 28 and Week 12 to examine the impact of the treatment on cognitive function. These assessments will be conducted using validated scales and will be collected at specified timepoints to ensure consistency and reliability in the evaluation of treatment efficacy.