Alcohol Abuse, Alcohol Dependence, Major Depressive Disorder
Conditions
Keywords
Major depressive disorder, Alcoholism, Alcohol abuse, Alcohol dependence
Brief summary
This is a study about treatment for people who suffer from both major depression and alcohol abuse or dependence. The study will examine whether the addition of acamprosate to escitalopram and behavioral interventions will improve outcomes for this population.
Detailed description
Depression and alcohol use disorders contribute to a significant proportion of the burden of disease, in the United States and abroad. Patients who suffer from co-morbid depression and alcohol abuse/dependence have illnesses that are more severe, persistent and costly than people with either depression or an alcohol use disorder alone. The treatment of these patients remains controversial. Several studies have demonstrated that antidepressants can be safe and efficacious in the treatment of depression in people who continue to drink, and it is now considered the standard of care to provide such treatment. Other studies have shown that pharmacotherapy with naltrexone or acamprosate can help reduce drinking in alcoholics without co-morbid depression. A logical extension of these findings would be to study the treatment of depressed alcoholics with dual pharmacotherapy, combining an anti-depressant with a medication aimed at treating the alcohol use disorder. We will conduct a randomized, double-blind, placebo controlled trial of escitalopram plus acamprosate and behavioral treatment vs. escitalopram plus placebo and behavioral treatment in 20 depressed alcoholics. Outcome measures will include depression, alcohol use and global functioning.
Interventions
DRUGacamprosate
Acamprosate 333mg, 2 capsules by mouth (i.e., PO), three times per day (i.e., TID), for 12 weeks.
DRUGescitalopram
Escitalopram is given for 12 weeks. Dosing is flexible, starting at 10mg PO once per day (i.e., QD) with the possibility of increasing to 30mg PO QD.
BEHAVIORALMedical management
Based on the COMBINE study. 1 hour of medical management / behavioral intervention at every study visit (7 times over 12 weeks).
DRUGPlacebo
Placebo, 2 capsules PO TID, for 12 weeks
Sponsors
National Alliance for Research on Schizophrenia and Depression
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
1. DSM-IV diagnostic criteria for MDD (diagnosis based on Structured Clinical Interview for DSM-IV, Patient Edition; SCID I/P) 2. Written informed consent 3. Men and women aged 18-64 years 4. Current diagnosis of alcohol abuse/dependence as per SCID I/P
Exclusion criteria
1. Subjects with suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment. 2. Pregnant women or women of childbearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, spermicide, IUD, s/p tubal ligation, partner with vasectomy). 3. Known history of serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease. 4. History of seizure disorder, brain injury, any history of known neurological disease (multiple sclerosis, degenerative disease such as ALS, Parkinson disease and any movement disorders, etc.). 5. Clinical or lab evidence of untreated hypothyroidism. 6. History or current diagnosis of the following DSM-IV psychiatric illness: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, patients with mood congruent or mood incongruent psychotic features, patients with substance use disorders (excluding alcohol and nicotine) active within the last 12 months. 7. Current use of other psychotropic drugs, including current use of benzodiazepines, hypnotics, anticonvulsants. Concomitant use of antihistamine drugs will be allowed. Patients will need to be off all antidepressants for at least two weeks by the time of the baseline visit, and four weeks for fluoxetine, and off benzodiazepines and other psychotropics for at least one week. The decision about whether to taper existing medications should be made by the individual and their primary treater based on clinical care and will not be made for purposes of study enrollment. allowed. 8. Patients who have failed to respond during the course of their current major depressive episode to at least two adequate antidepressant trials. An adequate antidepressant trial is defined as six weeks or more of treatment with escitalopram \> 20mg/day or its antidepressant equivalent: (fluoxetine 40mg/day, sertraline \> 100 mg/day, paroxetine \> 40 mg/day, fluvoxamine \> 100 mg/day, citalopram \> 40 mg/day, escitalopram \> 20 mg/day, venlafaxine \> 150 mg/day, and duloxetine \> 60 mg/day). 9. Any depression-focused or substance-abuse focused psychotherapy (family or marital counseling would be allowed). 10. Patients who have taken an investigational psychotropic drug within the past year. 11. Need for medical or inpatient detoxification from alcohol. This determination will be made by the screening clinician, based on clinical judgement as in the multicenter STAR\*D study (PHRC #2000-P-001955 in accordance with methods used in the multi-center STAR-D study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Score on the Hamilton Rating Scale for Depression -- 17 Items (HAM-D-17) | From baseline visit to Week 12 (or early discontinuation visit) | Scores on the HAM-D-17 typically fall into the following ranges: a) Not depressed: 0-7; b) Mildly depressed: 7-15; c) Moderately depressed: 15-25; d) Severely depressed: over 25. A decrease of 50% or more in the Hamilton-D score is considered to be a positive response to treatment, while a score of 7 or less is considered typical of remission. We measure the change in total score from Baseline to Week 12 or week of early termination visit. |
| Total Drinking Days on the Alcohol Timeline Followback (TLFB) | From Baseline visit to Week 12 (or early discontinuation visit) | The TLFB assesses recent drinking behavior. On the TLFB, clients retrospectively estimate their daily alcohol consumption in standard drinks over a time period ranging from 7 days to 24 months prior to the interview, and thus the measure provides quantitative estimates of alcohol use. One standard drink on the TLFB was defined as: 12 oz beer (5% alcohol by volume), 5 oz of wine (10-12% abv), 3 oz of fortified wine (16-18% abv), or 1-1.2 oz of hard liquor (86-100 proof; 43-50% abv). We measure the change from Baseline to Week 12 or week of early termination visit. |
| Total Drinks Consumed Per Week on the TLFB | From Baseline visit to Week 12 (or early discontinuation visit) | Total Drinks Consumed per Week on the Time Line Follow Back. We measure the change from Baseline to Week 12 or week of early termination visit. |
| Total Drinks Consumed Per Drinking Day on the TLFB | From Baseline visit to Week 12 (or early discontinuation visit) | Total Drinks Consumed per Drinking Day on the Time Line Follow Back. We measure the change from Baseline to Week 12 or week of early termination visit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram Plus Acamprosate Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid | 12 |
| Escitalopram Plus Placebo Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate | 11 |
| Total | 23 |
Baseline characteristics
| Characteristic | Escitalopram Plus Placebo | Escitalopram Plus Acamprosate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 12 Participants | 23 Participants |
| Age Continuous | 43 years STANDARD_DEVIATION 14 | 49 years STANDARD_DEVIATION 13 | 47 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 11 participants | 12 participants | 23 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 12 | 5 / 11 |
| serious Total, serious adverse events | 2 / 12 | 0 / 11 |
Outcome results
Primary
Change in Mean Score on the Hamilton Rating Scale for Depression -- 17 Items (HAM-D-17)
Scores on the HAM-D-17 typically fall into the following ranges: a) Not depressed: 0-7; b) Mildly depressed: 7-15; c) Moderately depressed: 15-25; d) Severely depressed: over 25. A decrease of 50% or more in the Hamilton-D score is considered to be a positive response to treatment, while a score of 7 or less is considered typical of remission. We measure the change in total score from Baseline to Week 12 or week of early termination visit.
Time frame: From baseline visit to Week 12 (or early discontinuation visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram Plus Acamprosate | Change in Mean Score on the Hamilton Rating Scale for Depression -- 17 Items (HAM-D-17) | -5.6 Scores on a scale | Standard Deviation 8.5 |
| Escitalopram Plus Placebo | Change in Mean Score on the Hamilton Rating Scale for Depression -- 17 Items (HAM-D-17) | -7.8 Scores on a scale | Standard Deviation 9.9 |
Primary
Total Drinking Days on the Alcohol Timeline Followback (TLFB)
The TLFB assesses recent drinking behavior. On the TLFB, clients retrospectively estimate their daily alcohol consumption in standard drinks over a time period ranging from 7 days to 24 months prior to the interview, and thus the measure provides quantitative estimates of alcohol use. One standard drink on the TLFB was defined as: 12 oz beer (5% alcohol by volume), 5 oz of wine (10-12% abv), 3 oz of fortified wine (16-18% abv), or 1-1.2 oz of hard liquor (86-100 proof; 43-50% abv). We measure the change from Baseline to Week 12 or week of early termination visit.
Time frame: From Baseline visit to Week 12 (or early discontinuation visit)
Population: Intent to treat sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram Plus Acamprosate | Total Drinking Days on the Alcohol Timeline Followback (TLFB) | 61 Drinking days | Standard Deviation 53 |
| Escitalopram Plus Placebo | Total Drinking Days on the Alcohol Timeline Followback (TLFB) | 61 Drinking days | Standard Deviation 86 |
Comparison: Statistical analyses evaluated the null hypothesis that there would be no difference in the effect of acamprosate vs. placebo on total drinking days.Power analysis was originally based on ITT analysis with 40 subjects, and assumed 30% difference in alcohol consumption (50% vs. 20% reduction in the acamprosate and placebo groups, respectively). With alpha of 0.05, we estimated 74% power to detect a difference between the two groups.p-value: <0.05Wilcoxon (Mann-Whitney)
Primary
Total Drinks Consumed Per Drinking Day on the TLFB
Total Drinks Consumed per Drinking Day on the Time Line Follow Back. We measure the change from Baseline to Week 12 or week of early termination visit.
Time frame: From Baseline visit to Week 12 (or early discontinuation visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram Plus Acamprosate | Total Drinks Consumed Per Drinking Day on the TLFB | 4 Drinks consumed per drinking day | Standard Deviation 2 |
| Escitalopram Plus Placebo | Total Drinks Consumed Per Drinking Day on the TLFB | 4 Drinks consumed per drinking day | Standard Deviation 4 |
Comparison: Statistical analyses evaluated the null hypothesis that there would be no difference in the effect of acamprosate vs. placebo on total drinks consumed per drinking day.~Power analysis was originally based on ITT analysis with 40 subjects, and assumed 30% difference in alcohol consumption (50% vs. 20% reduction in the acamprosate and placebo groups, respectively). With alpha of 0.05, we estimated 74% power to detect a difference between the two groups.p-value: <0.05Wilcoxon (Mann-Whitney)
Primary
Total Drinks Consumed Per Week on the TLFB
Total Drinks Consumed per Week on the Time Line Follow Back. We measure the change from Baseline to Week 12 or week of early termination visit.
Time frame: From Baseline visit to Week 12 (or early discontinuation visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram Plus Acamprosate | Total Drinks Consumed Per Week on the TLFB | 15 Drinks consumed per week | Standard Deviation 13 |
| Escitalopram Plus Placebo | Total Drinks Consumed Per Week on the TLFB | 15 Drinks consumed per week | Standard Deviation 21 |
Comparison: Statistical analyses evaluated the null hypothesis that there would be no difference in the effect of acamprosate vs. placebo on total drinks consumed per week.Power analysis was originally based on ITT analysis with 40 subjects, and assumed 30% difference in alcohol consumption (50% vs. 20% reduction in the acamprosate and placebo groups, respectively). With alpha of 0.05, we estimated 74% power to detect a difference between the two groups.p-value: <0.05Wilcoxon (Mann-Whitney)