Treatment of Alcohol Dependence and Comorbid Bipolar Disorder

• Sponsor: Medical University of South Carolina (Other)
• Overall Status: Completed
• CT.gov ID: NCT01015586
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH)
• Enrollment: 43
• Location: 1
• Arms: 2
• Duration (Months): 55
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The study will determine if individuals with co-occurring bipolar disorder and alcohol dependence report reduced alcohol consumption, improvement in mood symptoms, and cognitive performance if treated with lamotrigine plus their usual mood stabilizing medications relative to subjects treated with placebo plus usual mood stabilizing medications over a 16 week period.

Condition or Disease	Intervention/Treatment	Phase
Alcohol Dependence; Bipolar Disorder; Depression; Mania; Psychosis	Drug: Lamotrigine; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled Trial of Lamotrigine In Individuals With Bipolar Disorder and Comorbid Alcohol Dependence
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lamotrigine Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks	Drug: Lamotrigine; Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks
Placebo Comparator: Placebo Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks	Drug: Placebo; Placebo once daily for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Percent Days Abstinent From Alcohol [12 weeks]

   Percentage of days in trial without consumption of alcoholic beverages per participant self-report; minimum = 0, maximum = 100; higher numbers indicate better outcome. Percent days abstinent was calculated as: (number of days abstinent per self-report / total number of days in trial)*100.

Secondary Outcome Measures

1. Percent Heavy Drinking Days [12 weeks]

   Percentage of days in trial that were heavy drinking days (5 or more drinks/day for men, 4 or more drinks/day for women); minimum = 0, maximum = 100; lower numbers indicate better outcome. Percent heavy drinking days was calculated as: (number of days of heavy drinking per self-report / total number of days in trial)*100.

2. Biomarkers of Alcohol Use: Carbohydrate-deficient Transferrin (CDT) [12 weeks after randomization]

   Serum levels of biomarkers of alcohol use: carbohydrate-deficient transferrin (CDT) at study endpoint in study completers

3. Biomarkers of Alcohol Use: Gamma-glutamyltransferase (GGT) [12 weeks after randomization]

   Serum levels of biomarkers of alcohol use: Gamma-glutamyltransferase (GGT) at study endpoint in study completers

4. Montgomery-Asberg Depression Rating Scale (MADRS) Score [Baseline and 12 weeks]

   Scores on the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline (all randomized subjects) and at study endpoint (study completers). Scores represent total summed score of ten (10) subscale items; minimum = 0, maximum = 60, higher scores indicate worse outcomes.

5. Young Mania Rating Scale (YMRS) Scores [Baseline and 12 weeks]

   Mania/hypomania symptoms at study endpoint as assessed by the Young Mania Rating Scale (YMRS) at baseline (all randomized subjects) and at study endpoint (study completers). Scores represent total summed score of eleven (11) subscale items; minimum = 0, maximum = 60, higher scores indicate worse outcomes.

6. Neurocognitive Performance (California Verbal Learning Test) [Study endpoint 12 weeks after randomization]

   Adjusted scale scores (T scores) on the California Verbal Learning Test (CVLT) of verbal working memory at study endpoint. CVLT Trials 1-5 Free Recall Total measures the sum of all word list items correctly recalled on learning trials 1 through 5. This raw score is converted to a T-score (mean = 50; SD=10) with higher scores indicating better performance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18-65

• Meet DSM-IV-TR criteria for current alcohol dependence with active alcohol use in the past 30 days

• Meet DSM-IV-TR criteria for bipolar I or bipolar II disorder

• Have average alcohol consumption of at least 35 drinks/week for men, 28 drinks/week for women in the last 4 weeks of active drinking prior to enrollment.

• Able to provide informed consent and function at an intellectual level sufficient to allow accurate completion of the assessment instruments.

• Must consent to random assignment and be willing to commit to medication treatment and follow-up assessments.

• Currently under the care of a psychiatrist.

• Must consent to sign a release of information allowing investigators to communicate with his/her psychiatrist to verify treatment history and facilitate care should treatment-emergent psychiatric symptoms develop during the trial.

• Currently taking a therapeutic dosage of one or more mood stabilizing medications as defined by one or more of the following:

• Lithium level of 0.6 - 1.2 mEq/L

• Prescribed daily use of first generation antipsychotic agents including chlorpromazine, fluphenazine, or haloperidol or their injectible depot (decanoate) equivalents at a dose adequate to maintain clinical stability as documented by the subject's outpatient psychiatric provider c) Prescribed daily use of second generation antipsychotic agents including olanzapine, risperidone, paliperidone, quetiapine, aripiprazole, or ziprasidone or their injectible depot equivalent at a dose adequate to maintain clinical stability as documented by the subject's outpatient psychiatric provider

• Stable psychiatric symptoms as defined by no changes to psychotropic drug regimen for 30 days

• Must agree to identify collateral individuals for contact to facilitate follow-up appointments

Exclusion Criteria:

• A primary psychiatric diagnosis other than bipolar disorder

• Any uncontrolled neurologic condition (e.g. epilepsy) that could confound the results of the study

• Any history of Stevens-Johnson syndrome or other severe rash requiring hospitalization

• Any history of head injury with loss of consciousness greater than 30 minutes

• Any history of learning disability, alcoholic dementia, or electroconvulsive therapy in the past 3 months

• Any uncontrolled medical condition that may adversely affect the conduct of the trial or jeopardize the safety of the subject

• Plasma levels of liver transaminases (AST, ALT) greater than 3 times the normal range

• Concomitant use of valproic acid

• Concomitant use of carbamazepine, oxcarbazepine, phenytoin, primidone, or phenobarbital

• Concomitant use of disulfiram, naltrexone, acamprosate, or topiramate

• Concomitant use of benzodiazepines or any other medications not allowed per the protocol

• Women of childbearing potential who are pregnant, lactating, or refuse adequate forms of contraception

• Current suicidal or homicidal risk

• Baseline scores of more than 35 on the Montgomery-Asberg Depression Rating Scale or more than 16 on the Young Mania Rating Scale

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Neuroscience Division, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina	Charleston	South Carolina	United States	29425

Sponsors and Collaborators

• Medical University of South Carolina
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Bryan K Tolliver, MD, PhD, Medical University of South Carolina
• Study Director: Kathleen T Brady, M.D., Ph.D., Medical University of South Carolina

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Medical University of South Carolina
• ClinicalTrials.gov Identifier: NCT01015586
• Other Study ID Numbers: HR#19550; K23AA017666
• First Posted: Nov 18, 2009
• Last Update Posted: Jan 9, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Medical University of South Carolina: Alcohol; Bipolar Disorder; Manic depression; Addiction; Alcoholism; Cognitive impairment; Executive function; Anxiety; Depression; Mania; Affective disorder; Psychosis; Carbohydrate deficient transferrin; Gammaglutamyltransferase; California Verbal Learning Test; Montgomery Asberg Depression Rating Scale; Young Mania Rating Scale; Timeline Follow Back
• Additional relevant MeSH terms: Mania; Disease; Alcoholism; Depression; Bipolar Disorder; Psychotic Disorders; Mental Disorders; Lamotrigine

Study Results

Participant Flow

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Period Title: Overall Study
STARTED	21	22
COMPLETED	14	11
NOT COMPLETED	7	11

Baseline Characteristics

Arm/Group Title	Lamotrigine	Placebo	Total
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks	Total of all reporting groups
Overall Participants	21	22	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.48 (11.46)	44.14 (10.13)	44.30 (10.67)
Sex: Female, Male (Count of Participants)
Female	6 28.6%	7 31.8%	13 30.2%
Male	15 71.4%	15 68.2%	30 69.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 23.8%	2 9.1%	7 16.3%
White	16 76.2%	20 90.9%	36 83.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%	22 100%	43 100%

Outcome Measures

1. Primary Outcome

Title	Percent Days Abstinent From Alcohol
Description	Percentage of days in trial without consumption of alcoholic beverages per participant self-report; minimum = 0, maximum = 100; higher numbers indicate better outcome. Percent days abstinent was calculated as: (number of days abstinent per self-report / total number of days in trial)*100.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis is of modified intention to treat (ITT) sample comprised of all randomized subjects who returned for at least one study visit after randomization.

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	20	17
Mean (Standard Deviation) [Percentage of days abstinent]	78.7 (30.0)	80.1 (28.4)

2. Secondary Outcome

Title	Percent Heavy Drinking Days
Description	Percentage of days in trial that were heavy drinking days (5 or more drinks/day for men, 4 or more drinks/day for women); minimum = 0, maximum = 100; lower numbers indicate better outcome. Percent heavy drinking days was calculated as: (number of days of heavy drinking per self-report / total number of days in trial)*100.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis is of modified intention to treat (mITT) sample comprised of all randomized subjects who returned for at least one study visit after randomization (total mITT sample n=37).

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	20	17
Mean (Standard Deviation) [Percentage of heavy drinking days]	8.1 (12.8)	11.6 (21.1)

3. Secondary Outcome

Title	Biomarkers of Alcohol Use: Carbohydrate-deficient Transferrin (CDT)
Description	Serum levels of biomarkers of alcohol use: carbohydrate-deficient transferrin (CDT) at study endpoint in study completers
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

The sample analyzed is limited to study completers (total n=25) due to this measure being obtained at study endpoint.

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	13	12
Mean (Standard Deviation) ["percent CDT"]	1.41 (.48)	1.26 (.18)

4. Secondary Outcome

Title	Biomarkers of Alcohol Use: Gamma-glutamyltransferase (GGT)
Description	Serum levels of biomarkers of alcohol use: Gamma-glutamyltransferase (GGT) at study endpoint in study completers
Time Frame	12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Sample in this analysis is limited to study completers only (total n=25) because this measure was obtained at study endpoint.

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	13	12
Mean (Standard Deviation) [Units per liter (U/L)]	62.5 (139.4)	22.9 (10.7)

5. Secondary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS) Score
Description	Scores on the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline (all randomized subjects) and at study endpoint (study completers). Scores represent total summed score of ten (10) subscale items; minimum = 0, maximum = 60, higher scores indicate worse outcomes.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects (total n=43) included in analysis at baseline. Study completers only (total n=25) included in analysis at study endpoint.

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	21	22
Baseline MADRS score	9.86 (5.34)	12.05 (6.21)
MADRS score at study endpoint	6.93 (5.36)	9.18 (5.67)

6. Secondary Outcome

Title	Young Mania Rating Scale (YMRS) Scores
Description	Mania/hypomania symptoms at study endpoint as assessed by the Young Mania Rating Scale (YMRS) at baseline (all randomized subjects) and at study endpoint (study completers). Scores represent total summed score of eleven (11) subscale items; minimum = 0, maximum = 60, higher scores indicate worse outcomes.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Baseline YMRS scores include all randomized subjects (total n=43). Study endpoint YMRS scores include study completers only (total n=25).

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	21	22
Baseline YMRS scores	7.30 (4.50)	9.25 (5.58)
Endpoint YMRS scores	5.50 (2.65)	7.40 (4.03)

7. Secondary Outcome

Title	Neurocognitive Performance (California Verbal Learning Test)
Description	Adjusted scale scores (T scores) on the California Verbal Learning Test (CVLT) of verbal working memory at study endpoint. CVLT Trials 1-5 Free Recall Total measures the sum of all word list items correctly recalled on learning trials 1 through 5. This raw score is converted to a T-score (mean = 50; SD=10) with higher scores indicating better performance.
Time Frame	Study endpoint 12 weeks after randomization

Outcome Measure Data

Analysis Population Description

Sample analyzed includes study completers only (total n=25) as this measure was obtained at study endpoint.

Arm/Group Title	Lamotrigine	Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks	Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
Measure Participants	13	12
Mean (Standard Deviation) [T scores]	58.9 (14.6)	52.1 (12.5)

Adverse Events

Time Frame	18 weeks (two-week baseline assessment phase, 12 week active medication phase, 4 week safety phase after medication discontinuation)
Arm/Group Title	Lamotrigine		Placebo
Arm/Group Description	Add-on lamotrigine plus pre-existing mood stabilizing medication regimen. Active fixed-dose drug titration from 25-200 mg/day over first six weeks, 200 mg/day fixed-dose maintenance for second six weeks Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks		Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks Placebo: Placebo once daily for 12 weeks
All Cause Mortality
	Lamotrigine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/22 (0%)
Serious Adverse Events
	Lamotrigine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		1/22 (4.5%)
Psychiatric disorders
Hospitalization	1/21 (4.8%)	1	1/22 (4.5%)	1
Surgical and medical procedures
Hospitalization (medical) after assault	0/21 (0%)	0	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Lamotrigine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/21 (42.9%)		9/22 (40.9%)
Gastrointestinal disorders
Nausea	2/21 (9.5%)	2	1/22 (4.5%)	1
General disorders
Headache	3/21 (14.3%)	3	1/22 (4.5%)	1
Flu-like symptoms	1/21 (4.8%)	1	1/22 (4.5%)	1
Nervous system disorders
Tremor	0/21 (0%)	0	2/22 (9.1%)	2
Skin and subcutaneous tissue disorders
Erythema / skin discoloration	2/21 (9.5%)	2	2/22 (9.1%)	2
Papular skin eruption	2/21 (9.5%)	2	1/22 (4.5%)	1
Pruritus	1/21 (4.8%)	1	1/22 (4.5%)	1

Limitations/Caveats

Relatively small sample size, suboptimal retention rate (58% of all randomized subjects)

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.