Efficacy of Ketamine and Midazolam Hydrochloride in Adults with Comorbid Depression and Alcohol Use Disorder: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to assess the **efficacy** of **ketamine** for treating **depression** in adults who have both depression and **alcohol use disorder (AUD)** and are admitted for addiction therapy. This is clinically relevant as it explores the potential of ketamine to address depressive symptoms in a population with comorbid conditions, which could lead to improved therapeutic strategies and outcomes for these patients.

The secondary objective is to evaluate the safety of ketamine and to provide preliminary data on whether adding a treatment series of ketamine to inpatient addiction therapy for AUD will improve treatment outcomes. This could offer insights into the integration of ketamine into existing treatment protocols for AUD, potentially enhancing recovery rates and patient well-being.

The clinical trial involves a study population comprising adults aged **18-65 years** diagnosed with **depression** and **alcohol use disorder** (AUD). Both male and female participants are included, and the trial does not focus on a vulnerable population. Participants must exhibit at least moderate depression without psychotic features and have alcohol dependence as their primary substance use disorder. Additionally, they must be admitted to the hospital for inpatient addiction therapy at one of the inpatient units at the University Hospital of North Norway. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is specifically tailored to assess the efficacy of ketamine for depression in individuals undergoing addiction therapy.

The clinical trial is designed to evaluate the efficacy of **ketamine** in treating adults with **depression** and **alcohol use disorder** (AUD) who are admitted for inpatient addiction therapy. This study is a randomized, double-blind, active placebo-controlled trial. The trial is expected to commence recruitment on December 1, 2024, and is estimated to conclude by September 1, 2027. Participants will be randomly assigned to receive either ketamine or an active placebo, administered via intravenous infusion. The primary outcome measure is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to within three days after the final treatment session, comparing the intervention and control groups.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (18-65 years), presence of at least moderate depression without psychotic features, and alcohol dependence as the primary substance use disorder. Participants must be admitted to the hospital for inpatient addiction therapy. Follow-up visits will be scheduled to monitor changes in alcohol craving, consumption, and neurocognitive function, as well as to assess the frequency, severity, and duration of adverse reactions. The end-of-study visit will occur within three days of the final treatment session to evaluate the primary and secondary endpoints.

Participant involvement is expected to last from the start of the treatment until the end-of-study visit, with the total duration depending on the individual's treatment schedule. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide valuable insights into the potential benefits of ketamine for individuals with co-occurring depression and AUD, contributing to the development of more effective treatment strategies for these conditions.

The clinical trial involves the administration of **Midazolam Accord**, a pharmaceutical product formulated as a **solution for injection/infusion**. The active substance in this medication is **midazolam hydrochloride**, a chemical compound. The product is manufactured by Accord Healthcare B.V. and is authorized under the marketing authorization number 07-5068. The administration route for Midazolam Accord is via **intravenous infusion**. The dosage concentration is 1 mg/ml, and the frequency of administration will be determined according to the study protocol. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment regimen.

In addition to the experimental treatment, the study utilizes **Ketalar**, a comparator treatment, which is also a **solution for injection**. The active substance in Ketalar is **ketamine**, another chemical compound, produced by Pfizer AS. Ketalar is administered through **intravenous infusion** at a concentration of 50 mg/ml. The marketing authorization number for Ketalar is 5724. As with Midazolam Accord, the dosing schedule and frequency for Ketalar will be specified in the study protocol, and participant compliance will be closely monitored to maintain the integrity of the trial data.

The efficacy of **ketamine** in treating depression in adults with combined depression and alcohol use disorder (AUD) will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to within three days after the final treatment session, comparing the intervention group to the control group. Secondary endpoints include assessing group differences in alcohol craving changes from baseline, changes in alcohol consumption measured by the average number of alcohol units per week and the percentage of days abstinent from three months prior to admission until six months post-treatment, and the frequency, severity, and duration of adverse reactions (ARs) and serious adverse reactions (SARs). Additionally, tolerability for each treatment session will be assessed and compared between groups, using both participant- and physician-reported outcomes. Changes in neurocognitive function from baseline to within three days after the final treatment session will also be evaluated within and between groups.