Acamprosate Added to Escitalopram and Behavioral Treatment for Comorbid Depression and Alcoholism

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00452543
• Collaborator: National Alliance for Research on Schizophrenia and Depression (Other)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder; Alcohol Abuse; Alcohol Dependence	Drug: acamprosate; Drug: escitalopram; Behavioral: Medical management; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled Study of Acamprosate Added to Escitalopram and Behavioral Treatment in Major Depressive Disorder (MDD) With Comorbid Alcohol Abuse/Dependence
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Escitalopram plus acamprosate	Drug: acamprosate; Acamprosate 333mg, 2 capsules by mouth (i.e., PO), three times per day (i.e., TID), for 12 weeks.; Other Names: Campral ; Drug: escitalopram; 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.; Other Names: Lexapro ; Behavioral: Medical management; Based on the COMBINE study. 1 hour of medical management / behavioral intervention at every study visit (7 times over 12 weeks).; Other Names: Campral and Lexapro
Placebo Comparator: Escitalopram plus placebo	Drug: escitalopram; 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.; Other Names: Lexapro ; Behavioral: Medical management; Based on the COMBINE study. 1 hour of medical management / behavioral intervention at every study visit (7 times over 12 weeks).; Other Names: Campral and Lexapro ; Drug: Placebo; Placebo, 2 capsules PO TID, for 12 weeks; Other Names: Campral and Lexapro

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Alliance for Research on Schizophrenia and Depression

Investigators

• Principal Investigator: Janet M Witte, MD, Massachusetts General Hospital
• Principal Investigator: Nicholas Bolo, PhD, Mclean Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janet Melissa Witte, Dr., Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00452543
• Other Study ID Numbers: 2006-P-001592/1
• First Posted: Mar 27, 2007
• Last Update Posted: Jul 9, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Janet Melissa Witte, Dr., Massachusetts General Hospital: Major depressive disorder; Alcoholism; Alcohol abuse; Alcohol dependence
• Additional relevant MeSH terms: Alcoholism; Depressive Disorder; Depression; Depressive Disorder, Major; Acamprosate; Dexetimide; Citalopram

Study Results

Participant Flow

Arm/Group Title	Escitalopram Plus Acamprosate	Escitalopram Plus Placebo
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid	Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate
Period Title: Overall Study
STARTED	12	11
COMPLETED	7	5
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Escitalopram Plus Acamprosate	Escitalopram Plus Placebo	Total
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid	Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate	Total of all reporting groups
Overall Participants	12	11	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	11 100%	23 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49 (13)	43 (14)	47 (12)
Sex: Female, Male (Count of Participants)
Female	4 33.3%	6 54.5%	10 43.5%
Male	8 66.7%	5 45.5%	13 56.5%
Region of Enrollment (participants) [Number]
United States	12 100%	11 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Change in Mean Score on the Hamilton Rating Scale for Depression -- 17 Items (HAM-D-17)
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Escitalopram Plus Acamprosate	Escitalopram Plus Placebo
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid	Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate
Measure Participants	12	11
Mean (Standard Deviation) [Scores on a scale]	-5.6 (8.5)	-7.8 (9.9)

2. Primary Outcome

Title	Total Drinking Days on the Alcohol Timeline Followback (TLFB)
Description	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)

Outcome Measure Data

Analysis Population Description

Intent to treat sample

Arm/Group Title	Escitalopram Plus Acamprosate	Escitalopram Plus Placebo
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid	Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate
Measure Participants	12	11
Mean (Standard Deviation) [Drinking days]	61 (53)	61 (86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Escitalopram Plus Acamprosate, Escitalopram Plus Placebo
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This was a test of non-inferiority between the effects of acamprosate vs. placebo. 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. Results would be used to estimate effect size to set the stage for an adequately powered larger study in the future.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Threshold for significance was set a priori at p<0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Primary Outcome

Title	Total Drinks Consumed Per Week on the TLFB
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Escitalopram Plus Acamprosate	Escitalopram Plus Placebo
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid	Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate
Measure Participants	12	11
Mean (Standard Deviation) [Drinks consumed per week]	15 (13)	15 (21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Escitalopram Plus Acamprosate, Escitalopram Plus Placebo
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This was a test of non-inferiority between the effects of acamprosate vs. placebo.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	This p <0.05 was set a priori.
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Primary Outcome

Title	Total Drinks Consumed Per Drinking Day on the TLFB
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Escitalopram Plus Acamprosate	Escitalopram Plus Placebo
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid	Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate
Measure Participants	12	11
Mean (Standard Deviation) [Drinks consumed per drinking day]	4 (2)	4 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Escitalopram Plus Acamprosate, Escitalopram Plus Placebo
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This was a test of non-inferiority between the effects of acamprosate vs. placebo. 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 is discussed above.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	This p<0.05 was set a priori.
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Arm/Group Title	Escitalopram Plus Acamprosate		Escitalopram Plus Placebo
Arm/Group Description	Escitalopram 10-30mg/day plus acamprosate 333mg, 2 tabs tid		Escitalopram 10-30mg/day plus placebo 2 tabs tid that resembles acamprosate
All Cause Mortality
	Escitalopram Plus Acamprosate		Escitalopram Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Escitalopram Plus Acamprosate		Escitalopram Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		0/11 (0%)
Cardiac disorders
Blockage in the coronary artery	1/12 (8.3%)	1	0/11 (0%)	0
Psychiatric disorders
Hospitalization for alcohol intoxication	1/12 (8.3%)	1	0/11 (0%)	0
Other (Not Including Serious) Adverse Events
	Escitalopram Plus Acamprosate		Escitalopram Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)		5/11 (45.5%)
Gastrointestinal disorders
Increased gag reflex	1/12 (8.3%)	1	0/11 (0%)	0
Diarrhea	4/12 (33.3%)	4	0/11 (0%)	0
Nausea	2/12 (16.7%)	2	1/11 (9.1%)	1
Stomach pain	1/12 (8.3%)	1	0/11 (0%)	0
GI upset	1/12 (8.3%)	1	1/11 (9.1%)	1
Soft stools	1/12 (8.3%)	1	0/11 (0%)	0
General disorders
Dry mouth	1/12 (8.3%)	1	0/11 (0%)	0
Insomnia	1/12 (8.3%)	1	2/11 (18.2%)	2
Headache	1/12 (8.3%)	1	2/11 (18.2%)	2
Jaw tightening	0/12 (0%)	0	1/11 (9.1%)	1
Dry lips	0/12 (0%)	0	1/11 (9.1%)	1
Increased sweating	0/12 (0%)	0	1/11 (9.1%)	1
Tension	0/12 (0%)	0	1/11 (9.1%)	1
Psychiatric disorders
Anxiety	0/12 (0%)	0	1/11 (9.1%)	1
Renal and urinary disorders
Urinary respiratory infection	1/12 (8.3%)	1	0/11 (0%)	0
Urinary retention	0/12 (0%)	0	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Acne	1/12 (8.3%)	1	0/11 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.