Alcohol Dependence, Bipolar Disorder, Depression, Mania, Psychosis
Conditions
Keywords
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
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.
Interventions
DRUGLamotrigine
Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks
DRUGPlacebo
Placebo once daily for 12 weeks
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Lamotrigine: Six week titration from 25 mg/day to 200 mg/day, then 200 mg/day maintenance for additional six weeks | 21 |
| Placebo Add-on placebo plus pre-existing mood stabilization regimen for 12 weeks
Placebo: Placebo once daily for 12 weeks | 22 |
| Total | 43 |
Baseline characteristics
| Characteristic | Lamotrigine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 44.48 years STANDARD_DEVIATION 11.46 | 44.30 years STANDARD_DEVIATION 10.67 | 44.14 years STANDARD_DEVIATION 10.13 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 36 Participants | 20 Participants |
| Region of Enrollment United States | 21 participants | 43 participants | 22 participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Male | 15 Participants | 30 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 22 |
| other Total, other adverse events | 9 / 21 | 9 / 22 |
| serious Total, serious adverse events | 1 / 21 | 1 / 22 |
Outcome results
Primary
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.
Time frame: 12 weeks
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | Percent Days Abstinent From Alcohol | 78.7 Percentage of days abstinent | Standard Deviation 30 |
| Placebo | Percent Days Abstinent From Alcohol | 80.1 Percentage of days abstinent | Standard Deviation 28.4 |
Secondary
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
Time frame: 12 weeks after randomization
Population: The sample analyzed is limited to study completers (total n=25) due to this measure being obtained at study endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | Biomarkers of Alcohol Use: Carbohydrate-deficient Transferrin (CDT) | 1.41 percent CDT | Standard Deviation 0.48 |
| Placebo | Biomarkers of Alcohol Use: Carbohydrate-deficient Transferrin (CDT) | 1.26 percent CDT | Standard Deviation 0.18 |
Secondary
Biomarkers of Alcohol Use: Gamma-glutamyltransferase (GGT)
Serum levels of biomarkers of alcohol use: Gamma-glutamyltransferase (GGT) at study endpoint in study completers
Time frame: 12 weeks after randomization
Population: Sample in this analysis is limited to study completers only (total n=25) because this measure was obtained at study endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | Biomarkers of Alcohol Use: Gamma-glutamyltransferase (GGT) | 62.5 Units per liter (U/L) | Standard Deviation 139.4 |
| Placebo | Biomarkers of Alcohol Use: Gamma-glutamyltransferase (GGT) | 22.9 Units per liter (U/L) | Standard Deviation 10.7 |
Secondary
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.
Time frame: Baseline and 12 weeks
Population: All randomized subjects (total n=43) included in analysis at baseline. Study completers only (total n=25) included in analysis at study endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lamotrigine | Montgomery-Asberg Depression Rating Scale (MADRS) Score | MADRS score at study endpoint | 6.93 units on a scale | Standard Deviation 5.36 |
| Lamotrigine | Montgomery-Asberg Depression Rating Scale (MADRS) Score | Baseline MADRS score | 9.86 units on a scale | Standard Deviation 5.34 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Score | Baseline MADRS score | 12.05 units on a scale | Standard Deviation 6.21 |
| Placebo | Montgomery-Asberg Depression Rating Scale (MADRS) Score | MADRS score at study endpoint | 9.18 units on a scale | Standard Deviation 5.67 |
Secondary
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.
Time frame: Study endpoint 12 weeks after randomization
Population: Sample analyzed includes study completers only (total n=25) as this measure was obtained at study endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | Neurocognitive Performance (California Verbal Learning Test) | 58.9 T scores | Standard Deviation 14.6 |
| Placebo | Neurocognitive Performance (California Verbal Learning Test) | 52.1 T scores | Standard Deviation 12.5 |
Secondary
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.
Time frame: 12 weeks
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | Percent Heavy Drinking Days | 8.1 Percentage of heavy drinking days | Standard Deviation 12.8 |
| Placebo | Percent Heavy Drinking Days | 11.6 Percentage of heavy drinking days | Standard Deviation 21.1 |
Secondary
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.
Time frame: Baseline and 12 weeks
Population: Baseline YMRS scores include all randomized subjects (total n=43). Study endpoint YMRS scores include study completers only (total n=25).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lamotrigine | Young Mania Rating Scale (YMRS) Scores | Baseline YMRS scores | 7.30 score on a scale | Standard Deviation 4.5 |
| Lamotrigine | Young Mania Rating Scale (YMRS) Scores | Endpoint YMRS scores | 5.50 score on a scale | Standard Deviation 2.65 |
| Placebo | Young Mania Rating Scale (YMRS) Scores | Baseline YMRS scores | 9.25 score on a scale | Standard Deviation 5.58 |
| Placebo | Young Mania Rating Scale (YMRS) Scores | Endpoint YMRS scores | 7.40 score on a scale | Standard Deviation 4.03 |