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

NCT02461927 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: MHBB-009-16FGY 0002
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Major Depressive Disorder; Alcohol Use Disorder

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (3)

Ketamine + Naltrexone

EXPERIMENTAL

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

Ketamine + Placebo

EXPERIMENTAL

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

Placebo (psychoactive placebo midazolam) + Placebo

PLACEBO COMPARATOR

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

Interventions

Ketamine + Naltrexone DRUG

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).

Ketamine + Naltrexone

Ketamine + Placebo DRUG

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).

Ketamine + Placebo

Placebo (psychoactive placebo midazolam) + Placebo DRUG

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).

Placebo (psychoactive placebo midazolam) + Placebo

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, 06516-2770, United States

Location

Related Publications (1)

• Yoon G, Pittman B, Ralevski E, Petrakis IL, Krystal JH. Antidepressant efficacy of ketamine plus naltrexone for major depression comorbid with alcohol use disorder: a randomized controlled trial. Int J Neuropsychopharmacol. 2025 Aug 1;28(8):pyaf056. doi: 10.1093/ijnp/pyaf056.

  PMID: 40795937 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Alcoholism

Interventions

Ketamine; Naltrexone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Gihyun Yoon
• Organization: VA CT Healthcare System, Yale University

gihyun.yoon@yale.edu

(203) 932-5711

Study Officials

• Gihyun Yoon, MD

  VA Connecticut Healthcare System West Haven Campus, West Haven, CT

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2015
• First Posted: June 3, 2015
• Study Start: January 1, 2015
• Primary Completion: October 30, 2023
• Study Completion: October 30, 2023
• Last Updated: April 10, 2025
• Results First Posted: April 10, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: ANALYTIC CODE

Locations

US (1)