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

NCT ID: NCT02461927

Last Updated: 2025-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-01
• Study Completion Date: 2023-10-30

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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).

Group Type: EXPERIMENTAL

Ketamine + Naltrexone

Intervention Type: 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 + 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).

Group Type: EXPERIMENTAL

Ketamine + Placebo

Intervention Type: 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).

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).

Group Type: PLACEBO_COMPARATOR

Placebo (psychoactive placebo midazolam) + Placebo

Intervention Type: 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).

Interventions

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).

Intervention Type: 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).

Intervention Type: 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).

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gihyun Yoon, MD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

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

West Haven, Connecticut, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 40795937 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

GY 0002

Identifier Type: OTHER

Identifier Source: secondary_id

MHBB-009-16F

Identifier Type: -

Identifier Source: org_study_id