Evaluation of Ketamine Hydrochloride Combined with Electroconvulsive Therapy in Treatment-Resistant Major Depressive Disorder

The primary objective of this study is to evaluate the **antidepressant** effect of ketamine in combination with electroconvulsive therapy (ECT) in patients with treatment-resistant depression. This is clinically relevant as it aims to address the challenge of managing Major Depressive Disorder (MDD) in patients who do not respond to conventional treatments, potentially offering a novel therapeutic approach.

The secondary objectives of this study are to explore the biochemical, cognitive, and behavioral effects of ketamine combined with ECT. Specifically, the study will evaluate how this combination modulates plasma levels of key biochemical markers, such as glutamate, d-aspartate, tryptophan (Trp), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). It also aims to assess whether ketamine potentiates the antidepressant effects of ECT without inducing cognitive impairment.

The clinical trial involves participants diagnosed with **Major Depressive Disorder (MDD)**, specifically those affected by treatment-resistant depression. The study population includes both male and female subjects, 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 the total number of participants involved in the study. The trial includes a vulnerable population, and the participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data.

The clinical trial is designed to evaluate the **antidepressant** effect of **ketamine** in combination with electroconvulsive therapy (ECT) in patients diagnosed with **major depressive disorder** (MDD) who have not responded to at least two different antidepressant agents. This is a randomized, double-blind, controlled trial, categorized as a Phase 3 study. The trial will involve the administration of **ketamine hydrochloride** and a placebo, **sodium chloride** solution, both delivered via intravenous infusion. The primary endpoint is the mean change in depressive symptoms, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), from baseline to Day 28, assessing the short-term efficacy of the treatment. Secondary endpoints include the evaluation of long-term effects on depressive symptoms and cognitive outcomes at Week 12.

The trial is expected to commence recruitment on January 2, 2025, and conclude by December 31, 2025. Participants will be involved in the study for a maximum treatment period of 5 days, with follow-up assessments extending to 12 weeks. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (18-70 years), diagnosis of MDD, and adequacy of anesthesia score. Women of childbearing potential must adhere to effective contraception methods. Follow-up visits will occur at Day 28 and Week 12 to monitor changes in depressive symptoms and cognitive function. The end-of-study visit will finalize data collection and assess the overall impact of the treatment.

Participants may be terminated early from the study if they experience adverse effects, fail to comply with study protocols, or withdraw consent. The trial's design ensures rigorous monitoring and adherence to ethical standards, with informed consent obtained from all participants. The study aims to provide valuable insights into the potential benefits of combining ketamine with ECT in treatment-resistant depression.

The clinical trial involves the administration of **ketamine hydrochloride** as the experimental medication. The product, marketed under the name "KETAMINA MOLTENI 50 mg/ml soluzione iniettabile," is a **solution for injection**. The active substance, ketamine hydrochloride, is of chemical origin. The medication is administered via **intravenous infusion** at a maximum daily dose of 0.5 mg/kg, with the total dose not exceeding 0.5 mg/kg over a treatment period of up to 5 days. The pharmaceutical form is specifically designed for injection, ensuring precise dosing and rapid onset of action. The administration schedule is carefully monitored to ensure participant compliance and to evaluate the antidepressant effect of ketamine in combination with electroconvulsive therapy in patients with treatment-resistant depression.

The study also includes the use of a non-experimental treatment, **sodium chloride**, which serves as a comparator. The product, known as "SODIO CLORURO 0,9% BAXTER Soluzione per infusione," is a **solution for infusion**. Sodium chloride, also of chemical origin, is administered via intravenous infusion. The dosing regimen mirrors that of the experimental treatment, with a maximum daily dose of 0.5 mg/kg and a total dose not exceeding 0.5 mg/kg over a 5-day period. This comparator treatment is utilized to assess the additive effect of ketamine when combined with electroconvulsive therapy, providing a baseline for evaluating the efficacy of the experimental medication.

The efficacy of the treatment in this clinical trial will be assessed primarily through the evaluation of depressive symptoms in patients diagnosed with **major depressive disorder**. 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. The MADRS is a validated scale commonly used in clinical settings to quantify the severity of depressive episodes.

Secondary endpoints will include the mean change in MADRS scores from baseline to Week 12, which will help 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 appropriate cognitive testing tools to ensure accurate and reliable data collection.