Ketamine for the Rapid Treatment of Major Depressive Disorder and Alcohol Use Disorder

Ketamine for The Rapid Treatment of Major Depression and Alcohol Use Disorder

The investigators will compare 3 treatment groups (ketamine plus naltrexone vs. ketamine alone vs. placebo) for treating major depressive disorder (MDD) and alcohol use disorder (AUD) in an 8-week randomized, double-blind, placebo-controlled, between-subjects trial. First, prior to the double-blind trial, the investigators will conduct an open-label trial that will include 5 patients with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) with a follow-up of 4 weeks. Second, after reviewing the safety and efficacy of repeated ketamine treatment from the open-label trial, the investigators will conduct an 8-week, randomized, double-blind, placebo-controlled trial that will include 60 patients with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) plus naltrexone with a follow-up of 4 weeks. The 4-month follow-up session will also occur.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder; Alcohol Use Disorder
• Intervention / Treatment: Drug: Ketamine + Naltrexone; Drug: Ketamine + Placebo; Drug: Placebo (psychoactive placebo midazolam) + Placebo

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516-2770
      • VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female veterans and civilians, 21-65 years old
• Current major depressive disorder without psychotic features by DSM-5 (antidepressant regimens can be allowed and changed during the trial)
• Montgomery-Asberg Depression Rating Scale (MADRS) 20 or higher
• A minimum of 4 of 11 current alcohol use disorder symptoms by DSM-5
• Heavy drinking at least 4 times in the past month ('heavy drinking' defined as 5 standard drinks per day for men and 4 standard drinks per day for women
• Able to provide written informed consent

Exclusion Criteria:

• Current substance use disorder by DSM-5 in the past 3 months (except alcohol, tobacco, or cannabis)
• Current or past history of psychotic features or psychotic disorder
• Current dementia
• Current uncontrolled hypertension (systolic BP > 170 mm Hg or diastolic BP > 100 mm Hg)
• Unstable medical condition or allergy to ketamine, midazolam, naltrexone, or lorazepam---clinically determined by a physician
• Imminent suicidal or homicidal risk
• Pregnant or nursing women, positive pregnancy test, or inadequate birth control methods in women of childbearing potential
• Positive opioid or illicit drug screen test (except marijuana)
• Opioid use within 10 days prior to study medication (injectable naltrexone) or risks for opioid use during the study
• Liver enzymes that are three times higher than the upper limit of normal
• Current use of benzodiazepine
• Acute narrow-angle glaucoma
• Severe sleep apnea---clinically determined by a physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine + Naltrexone; Subjects in this arm will receive (1) intravenous ketamine treatment once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular naltrexone once a month (a total of 2 injections).	Drug: Ketamine + Naltrexone; Subjects in this arm will receive (1) intravenous ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular naltrexone (380 mg) once a month (a total of 2 injections).
Experimental: Ketamine + Placebo; Subjects in this arm will receive (1) intravenous ketamine treatment once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular placebo once a month (a total of 2 injections).	Drug: Ketamine + Placebo; Subjects in this arm will receive (1) intravenous ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular placebo once a month (a total of 2 injections).
Placebo Comparator: Placebo (psychoactive placebo midazolam) + Placebo; Subjects in this arm will receive (1) intravenous placebo treatment (psychoactive placebo midazolam) once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular placebo once a month (a total of 2 injections).	Drug: Placebo (psychoactive placebo midazolam) + Placebo; Subjects in this arm will receive (1) intravenous psychoactive placebo midazolam (0.045 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular placebo once a month (a total of 2 injections).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline	Our primary analysis (severity of depression) was to compare the proportions of subjects with clinical response in symptoms of major depressive disorder (response defined as a 50% or greater improvement from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores) at the end-of-treatment time point (Day 21, after 4th infusion, T+240 minutes).	Day 21 (after 4th infusion, 240 minutes)
Rate of Complete Abstinence From Alcohol	Alcohol consumption was measured using the Time Line Follow Back (TLFB) method. The rates of complete abstinence from alcohol across visits 3 (day 0) through visit 7 (day 28) were compared among the three study groups.	Day 28

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Gihyun Yoon, MD, VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): October 30, 2023

Study Registration Dates

• First Submitted: June 1, 2015
• First Submitted That Met QC Criteria: June 1, 2015
• First Posted (Estimated): June 3, 2015

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Substance-Related Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Mood Disorders; Alcoholism; Alcohol Drinking; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics; Neurotransmitter Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Alcohol Deterrents; Excitatory Amino Acid Agents; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists; Narcotic Antagonists; Midazolam; Ketamine; Naltrexone
• Other Study ID Numbers: MHBB-009-16F; GY 0002 (Other Identifier: VA Connecticut Healthcare System)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes