Treatment of Alcohol Dependence and Comorbid Bipolar Disorder

Study Overview
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Brief Summary
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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.

Official Title
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A Double-Blind, Placebo-Controlled Trial of Lamotrigine In Individuals With Bipolar Disorder and Comorbid Alcohol Dependence

Conditions
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Alcohol Dependence, Bipolar Disorder, Depression, Mania, Psychosis

Intervention / Treatment
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* Drug: Lamotrigine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lamotrigine<br>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<br>* Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks<br>|
| Placebo Comparator: Placebo<br>Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks | Drug: Placebo<br>* Placebo once daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Days Abstinent From Alcohol | 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. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Heavy Drinking Days | 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. | 12 weeks | 
| Biomarkers of Alcohol Use: Carbohydrate-deficient Transferrin (CDT) | Serum levels of biomarkers of alcohol use: carbohydrate-deficient transferrin (CDT) at study endpoint in study completers | 12 weeks after randomization | 
| Biomarkers of Alcohol Use: Gamma-glutamyltransferase (GGT) | Serum levels of biomarkers of alcohol use: Gamma-glutamyltransferase (GGT) at study endpoint in study completers | 12 weeks after randomization | 
| Montgomery-Asberg Depression Rating Scale (MADRS) Score | 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. | Baseline and 12 weeks | 
| Young Mania Rating Scale (YMRS) Scores | 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. | Baseline and 12 weeks | 
| Neurocognitive Performance (California Verbal Learning Test) | 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. | Study endpoint 12 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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