Alcohol Dependence, Bipolar Disorder
Conditions
Keywords
bipolar disorder, alcohol dependence, mania, manic disorder, depression
Brief summary
The purpose of this study is to find out whether an investigational drug called quetiapine can treat bipolar disorder, improve mood and reduce alcohol use and craving.
Detailed description
The primary aim in the study is to determine if quetiapine treatment is associated with greater reduction in alcohol use than placebo in outpatients with bipolar disorder and alcohol dependence. We will also examine if quetiapine treatment is associated with greater reduction in alcohol craving than placebo in outpatients with bipolar disorder and alcohol dependence and if quetiapine treatment is associated with greater improvement in depressive symptoms than placebo in outpatients with bipolar disorder and alcohol dependence.
Interventions
DRUGPlacebo
Inactive ingredient matching the active medication in appearance.
DRUGQuetiapine
Quetiapine is an atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and in the XR version along with an SSRI to treat major depressive disorder.
Sponsors
University of Texas Southwestern Medical Center
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Outpatients with a diagnosis of bipolar I or II disorder, depressed or mixed phase on the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (SCID) and confirmed by interview with PI or co-I. * Current diagnosis of alcohol dependence. * Alcohol use (by self-report) of at least 15 drinks in the 7 days prior to baseline. * Currently taking a mood stabilizer defined as lithium, divalproex/valproic acid, oxcarbazepine, or lamotrigine at a stable dose for \> 14 days. * Men and women age 18-65 years old. * English or Spanish speaking.
Exclusion criteria
* Bipolar disorders other than bipolar I or II (e.g., not otherwise specified or cyclothymic disorders) based on the SCID and confirmed through clinical assessment by PI or co-I. * Baseline Young Mania Rating Scale (YMRS) score \> 35 or Hamilton Depression Rating Scale (HRSD) 17 score \> 35. * Current clinically significant psychotic features (hallucinations, delusions, disorganized thought processes). * Evidence of clinically significant alcohol withdrawal symptoms defined as a Clinical Institute Withdrawal Assessment (CIWA-AR) score of \> 8. * History of hepatic cirrhosis or baseline AST or ALT \> 3X upper limit of normal or other clinically significant findings on physical or laboratory examination. * Mental retardation or other severe cognitive impairment. * Prison or jail inmates. * Pregnant or nursing women or women of childbearing age who will not use oral contraceptives, abstinence, or other acceptable methods of birth control during the study. * Antipsychotic therapy within 14 days prior to randomization. * Current carbamazepine or benzodiazepine therapy. * Current treatment with medications shown to reduce alcohol consumption (naltrexone, acamprosate, disulfiram, or topiramate) in large randomized, controlled trials. * Initiation of antidepressants or mood stabilizers or psychotherapy within past 2 weeks. * High risk for suicide, defined as any suicide attempts in the past 3 months or current suicidal ideation with plan and intent. * Intensive outpatient treatment for substance abuse (AA, NA meetings, or other 12-step programs or weekly psychotherapy that started at least 14 days prior to randomization will be allowed). * Current treatment with ketoconazole, itraconazole, erythromycin, or nefazodone. * Severe or life-threatening medical condition (e.g., congestive heart failure, terminal cancer) or laboratory or physical examination findings consistent with serious medical illness (e.g., severe edema, atrial fibrillation, dangerously abnormal electrolytes). * Diabetes mellitus by history or suspected from baseline blood sugar. * History of cataracts or suspected cataracts on ophthalmic exam * History of seizure disorder of any etiology; if a subject develops a seizure episode, s/he will be discontinued from the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Number of Standard Drinks/Day Will Serve as the Primary Outcome Measure. | 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gamma-glutamyltransferase (GGT) | 12 weeks | GGT is a liver enzyme measurement (IU/I) |
| Aspartate Aminotransferase (AST) | 12 weeks | AST is a liver enzyme measurement (IU/I) |
| Alanine Aminotransferase (ALT) | 12 weeks | ALT is a liver enzyme measurement (IU/I). |
| Percent of Heavy Drinking Days | 12 weeks | — |
| Inventory of Depressive Symptomatology-Self Report (IDS-SR) | 12 weeks | IDS-SR is a self reported 30 item assessment to diagnose a major depressive episode. Score: Minimum: 0 Maximum: 84 Lower score associated with better outcome |
| Young Mania Rating Scale (YMRS) | 12 weeks | This is an 11-item, observer rated measure of the severity of manic symptoms on a 5 point scale. The total score indicates overall severity of mania with a minimum of zero (indicating normalcy) and a maximum of 60 (indicating very severe). Score: Minimum: 0 Maximum: 60 Lower score associated with better outcome |
| Penn Alcohol Craving Scale (PACS) | 12 weeks | The PACS is a five-item self-administered instrument for assessing craving, frequency, intensity, and duration of thoughts about drinking are assessed along with ability to resist drinking Score: Minimum: 0 Maximum: 30 Lower score associated with better outcome. |
| Hamilton Rating Scale for Depression (HRSD) | 12 weeks | The assessment is a clinician administered rating of depression with 17 questions. The total score is indicates level of depression within the following ranges: none (0-5), mild (6-10), moderate (11-15), severe (16-20), and very severe (21+). Scale: Minimum: 0 Maximum: 50 Lower score associated with better outcome |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo This group will be given placebo matching quetiapine for the course of the 12 weeks in the study.
Placebo: Inactive ingredient matching the active medication in appearance. | 44 |
| Quetiapine This group will be given 50mg Quetiapine per day baseline-week 1, 100mg Quetiapine per day week 1-week 2, 200mg Quetiapine per day week 2-week 3, 400mg Quetiapine per day week 3-week 4, and 600mg Quetiapine per day week 4 to week 12.
Quetiapine: Quetiapine is an atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and in the XR version along with an SSRI to treat major depressive disorder. | 44 |
| Total | 88 |
Baseline characteristics
| Characteristic | Placebo | Quetiapine | Total |
|---|---|---|---|
| Age, Continuous | 39.7 years STANDARD_DEVIATION 10.1 | 43.3 years STANDARD_DEVIATION 8.2 | 41.5 years STANDARD_DEVIATION 9.2 |
| Concomitant medications Anticonvulsants | 13 participants | 13 participants | 26 participants |
| Concomitant medications Antidepressants | 6 participants | 11 participants | 17 participants |
| Concomitant medications Lithium | 28 participants | 27 participants | 55 participants |
| Concomitant medications No anticonvulsants | 31 participants | 31 participants | 62 participants |
| Concomitant medications No antidepressants | 38 participants | 33 participants | 71 participants |
| Concomitant medications No Lithium | 16 participants | 17 participants | 33 participants |
| Concomitant medications No sedatives/hypnotics | 42 participants | 36 participants | 78 participants |
| Concomitant medications Sedatives/hypnotics | 2 participants | 8 participants | 10 participants |
| % Days Alcohol Use In Past Week | 74.6 days STANDARD_DEVIATION 26.1 | 74.2 days STANDARD_DEVIATION 27.3 | 74.4 days STANDARD_DEVIATION 26.7 |
| % Days Heavy Alcohol Use In Past Week | 60.0 Days STANDARD_DEVIATION 30.1 | 53.0 Days STANDARD_DEVIATION 30.9 | 56.5 Days STANDARD_DEVIATION 30.5 |
| Drinks per day | 6.5 drinks STANDARD_DEVIATION 3.4 | 6.0 drinks STANDARD_DEVIATION 3.4 | 6.3 drinks STANDARD_DEVIATION 3.4 |
| Education | 13.3 years STANDARD_DEVIATION 2.4 | 13.6 years STANDARD_DEVIATION 2.5 | 13.5 years STANDARD_DEVIATION 2.5 |
| History of treatment for drug/alcohol History | 25 participants | 30 participants | 55 participants |
| History of treatment for drug/alcohol No History | 19 participants | 14 participants | 33 participants |
| Liver enzymes ALT (alanine aminotransferase) | 29.0 IU/I STANDARD_DEVIATION 24.5 | 28.9 IU/I STANDARD_DEVIATION 17.3 | 29.0 IU/I STANDARD_DEVIATION 20.9 |
| Liver enzymes AST (aspartate aminotransferase) | 27.4 IU/I STANDARD_DEVIATION 14.8 | 29.7 IU/I STANDARD_DEVIATION 13.5 | 28.6 IU/I STANDARD_DEVIATION 14.2 |
| Liver enzymes GGT (gamma-glutamyltransferase | 47.8 IU/I STANDARD_DEVIATION 37.6 | 74.3 IU/I STANDARD_DEVIATION 69.3 | 61.05 IU/I STANDARD_DEVIATION 53.45 |
| Married Married | 8 participants | 10 participants | 18 participants |
| Married Not Married | 36 participants | 34 participants | 70 participants |
| Mood and craving scales: Hamilton Rating Scale for Depression | 18.3 units on a scale STANDARD_DEVIATION 6.7 | 18.6 units on a scale STANDARD_DEVIATION 7 | 18.5 units on a scale STANDARD_DEVIATION 6.9 |
| Mood and craving scales: Inventory of Depressive Symptomatology-Self-Report | 28.6 units on a scale STANDARD_DEVIATION 10.7 | 33.9 units on a scale STANDARD_DEVIATION 14.6 | 31.3 units on a scale STANDARD_DEVIATION 12.65 |
| Mood and craving scales: Penn Alcohol Craving Scale | 19.2 units on a scale STANDARD_DEVIATION 6.6 | 20.6 units on a scale STANDARD_DEVIATION 6.3 | 19.9 units on a scale STANDARD_DEVIATION 6.5 |
| Mood and craving scales: Young Mania Rating Scale | 13.6 units on a scale STANDARD_DEVIATION 8.2 | 13.9 units on a scale STANDARD_DEVIATION 6.7 | 13.8 units on a scale STANDARD_DEVIATION 7.5 |
| Mood states Depressed | 40 participants | 38 participants | 78 participants |
| Mood states Mixed (both depression and mania at same time) | 4 participants | 6 participants | 10 participants |
| Race/Ethnicity, Customized African American | 12 participants | 13 participants | 25 participants |
| Race/Ethnicity, Customized Caucasian | 21 participants | 21 participants | 42 participants |
| Race/Ethnicity, Customized Hispanic | 10 participants | 7 participants | 17 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Sex: Female, Male Female | 19 Participants | 17 Participants | 36 Participants |
| Sex: Female, Male Male | 25 Participants | 27 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 45 | 0 / 45 |
| serious Total, serious adverse events | 3 / 45 | 5 / 45 |
Outcome results
Primary
The Number of Standard Drinks/Day Will Serve as the Primary Outcome Measure.
Time frame: 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Number of Standard Drinks/Day Will Serve as the Primary Outcome Measure. | 10.6 drinks | Standard Error 2.465 |
| Quetiapine | The Number of Standard Drinks/Day Will Serve as the Primary Outcome Measure. | 8.09 drinks | Standard Error 2.465 |
Comparison: Baseline drinks/day used as covariate.p-value: 0.4709ANCOVA
Secondary
Alanine Aminotransferase (ALT)
ALT is a liver enzyme measurement (IU/I).
Time frame: 12 weeks
Population: Missing data for 17 participants in placebo group and 13 participants in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alanine Aminotransferase (ALT) | 25.1 IU/I | Standard Error 2.61 |
| Quetiapine | Alanine Aminotransferase (ALT) | 30.4 IU/I | Standard Error 2.43 |
Comparison: Baseline ALT used as covariate.p-value: 0.1412ANCOVA
Secondary
Aspartate Aminotransferase (AST)
AST is a liver enzyme measurement (IU/I)
Time frame: 12 weeks
Population: Missing data for 19 participants in placebo group and 11 participants in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Aspartate Aminotransferase (AST) | 29.7 IU/I | Standard Error 2.92 |
| Quetiapine | Aspartate Aminotransferase (AST) | 31.1 IU/I | Standard Error 2.54 |
Comparison: Baseline AST used as covariate.p-value: 0.7222ANCOVA
Secondary
Gamma-glutamyltransferase (GGT)
GGT is a liver enzyme measurement (IU/I)
Time frame: 12 weeks
Population: Missing data for 18 participants in placebo group and 11 participants in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Gamma-glutamyltransferase (GGT) | 66.6 IU/I | Standard Error 8.34 |
| Quetiapine | Gamma-glutamyltransferase (GGT) | 66.0 IU/I | Standard Error 7.38 |
Comparison: Baseline GGT used as covariate.p-value: 0.9642ANCOVA
Secondary
Hamilton Rating Scale for Depression (HRSD)
The assessment is a clinician administered rating of depression with 17 questions. The total score is indicates level of depression within the following ranges: none (0-5), mild (6-10), moderate (11-15), severe (16-20), and very severe (21+). Scale: Minimum: 0 Maximum: 50 Lower score associated with better outcome
Time frame: 12 weeks
Population: Missing data for 2 participants in placebo group and 3 participants in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Hamilton Rating Scale for Depression (HRSD) | 10.9 units on a scale | Standard Error 1.1 |
| Quetiapine | Hamilton Rating Scale for Depression (HRSD) | 10.3 units on a scale | Standard Error 1.12 |
Comparison: Baseline HRSD used as covariate.p-value: 0.7071ANCOVA
Secondary
Inventory of Depressive Symptomatology-Self Report (IDS-SR)
IDS-SR is a self reported 30 item assessment to diagnose a major depressive episode. Score: Minimum: 0 Maximum: 84 Lower score associated with better outcome
Time frame: 12 weeks
Population: Missing data for 4 participants in placebo group and 2 participants in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Inventory of Depressive Symptomatology-Self Report (IDS-SR) | 19.0 units on a scale | Standard Error 1.79 |
| Quetiapine | Inventory of Depressive Symptomatology-Self Report (IDS-SR) | 21.9 units on a scale | Standard Error 1.75 |
Comparison: Baseline IDS-SR used as a covariate.p-value: 0.2569ANCOVA
Secondary
Penn Alcohol Craving Scale (PACS)
The PACS is a five-item self-administered instrument for assessing craving, frequency, intensity, and duration of thoughts about drinking are assessed along with ability to resist drinking Score: Minimum: 0 Maximum: 30 Lower score associated with better outcome.
Time frame: 12 weeks
Population: Missing data for 1 participants in placebo group and 5 participants in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Penn Alcohol Craving Scale (PACS) | 14.1 units on a scale | Standard Error 1.03 |
| Quetiapine | Penn Alcohol Craving Scale (PACS) | 12.3 units on a scale | Standard Error 1.09 |
Comparison: Baseline PACS used as a covariate.p-value: 0.2473ANCOVA
Secondary
Percent of Heavy Drinking Days
Time frame: 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent of Heavy Drinking Days | 28.8 drinks | Standard Error 3.66 |
| Quetiapine | Percent of Heavy Drinking Days | 20.8 drinks | Standard Error 3.66 |
Comparison: Baseline percent heavy drinking days included as covariate.p-value: 0.1272ANCOVA
Secondary
Young Mania Rating Scale (YMRS)
This is an 11-item, observer rated measure of the severity of manic symptoms on a 5 point scale. The total score indicates overall severity of mania with a minimum of zero (indicating normalcy) and a maximum of 60 (indicating very severe). Score: Minimum: 0 Maximum: 60 Lower score associated with better outcome
Time frame: 12 weeks
Population: Missing data for 6 participants in placebo group and 1 participant in the quetiapine group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Young Mania Rating Scale (YMRS) | 8.70 units on a scale | Standard Error 1.09 |
| Quetiapine | Young Mania Rating Scale (YMRS) | 8.48 units on a scale | Standard Error 1.02 |
Comparison: Baseline YMRS used as a covariate.p-value: 0.8814ANCOVA