Alcohol Use Disorder, Major Depressive Disorder
Conditions
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.
Interventions
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).
DRUGKetamine + 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).
DRUGPlacebo (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).
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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).
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). | 20 |
| 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).
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). | 19 |
| 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).
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). | 19 |
| Total | 58 |
Baseline characteristics
| Characteristic | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 44.1 years STANDARD_DEVIATION 13.7 | 50.0 years STANDARD_DEVIATION 10.1 | 41.9 years STANDARD_DEVIATION 13.5 | 45.3 years STANDARD_DEVIATION 12.8 |
| Montgomery-Åsberg Depression Rating Scale (MADRS) score, mean (SD) | 27.8 units on a scale STANDARD_DEVIATION 6 | 30.3 units on a scale STANDARD_DEVIATION 6.1 | 30.3 units on a scale STANDARD_DEVIATION 7.1 | 29.4 units on a scale STANDARD_DEVIATION 6.4 |
| Race/Ethnicity, Customized Race/Ethnicity Black | 0 Participants | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic or Latino | 2 Participants | 1 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Other | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White | 18 Participants | 14 Participants | 7 Participants | 39 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 16 Participants | 15 Participants | 14 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 14 / 20 | 11 / 19 | 14 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 19 | 0 / 19 |
Outcome results
Primary
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).
Time frame: Day 21 (after 4th infusion, 240 minutes)
Population: Subjects who completed the outcome measure on Day 21 (after 4th infusion, 240 minutes)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine + Naltrexone | Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline | 15 Participants |
| Ketamine + Placebo | Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline | 9 Participants |
| Placebo (Psychoactive Placebo Midazolam) + Placebo | Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline | 13 Participants |
Primary
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.
Time frame: Day 28
Population: The total number of participants analyzed is inconsistent with the total number of participants reported in the same arm in the Participant Flow---because there is a lot of missing data in the TLFB.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine + Naltrexone | Rate of Complete Abstinence From Alcohol | 3 Participants |
| Ketamine + Placebo | Rate of Complete Abstinence From Alcohol | 6 Participants |
| Placebo (Psychoactive Placebo Midazolam) + Placebo | Rate of Complete Abstinence From Alcohol | 2 Participants |