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

Phase 1

Completed

Interventions: Drug: Ketamine + Naltrexone
Drug: Placebo (psychoactive placebo midazolam) + Placebo
Drug: Ketamine + Placebo

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Ketamine + Naltrexone	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).
Placebo (psychoactive placebo midazolam) + Placebo	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).
Ketamine + Placebo	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).

Primary Outcome Measures

Name	Time	Method
Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline	Day 21 (after 4th infusion, 240 minutes)	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).
Rate of Complete Abstinence From Alcohol	Day 28	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.

Secondary Outcome Measures