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

Study Overview
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Brief Summary
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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.

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

Conditions
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Major Depressive Disorder, Alcohol Use Disorder

Intervention / Treatment
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* Drug: Ketamine + Naltrexone
* Drug: Ketamine + Placebo
* Drug: Placebo (psychoactive placebo midazolam) + Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine + Naltrexone<br>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<br>* 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).<br>|
| Experimental: Ketamine + Placebo<br>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<br>* 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).<br>|
| Placebo Comparator: Placebo (psychoactive placebo midazolam) + Placebo<br>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<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) | Severity of depression | Day 21 (after 4th infusion, 240 minutes) | 
| Time Line Follow Back (TLFB) | Rate of complete abstinence from alcohol | Day 28 |