Bipolar Disorder
Conditions
Brief summary
This study will determine the efficacy and safety of combination therapy with divalproex and lithium for treating mania in people with rapid cycling bipolar disorder and a substance abuse disorder.
Detailed description
Longitudinal Evaluation of the Efficacy and Safety of Divalproex and Lithium in Dual Diagnosis Bipolar Rapid Cycling: This study recruits males and females age 18 and older who currently meet diagnostic criteria for rapid cycling bipolar disorder (type I or II) and who have met the criteria for substance abuse or dependence of cocaine, marijuana and/or alcohol within the past six months. Patients are initially stabilized on dual therapy of lithium and depakote and then randomly assigned to double-blind treatment with either lithium monotherapy or continued dual therapy. Patients remain in the study for six months or until they experience a relapse. Patients in this study are required to bring a friend or family member to all study visits as well as attend chemical dependency services. This study is sponsored by the NIMH. Subjects receive study-related care at no cost.
Interventions
DRUGLithium
Lithium monotherapy was initiated at 300 mg twice daily and titrated over 3-6 weeks to minimum blood levels of 0.8 meq/L.
DRUGDivalproex
Divalproex was then initiated at 250 mg twice daily and increased over 3-6 weeks to minimum blood levels of 50 ug/ml.
DRUGPlacebo
Placebo pills that looked exact to divaloproex were provided to subjects and take twice daily.
Sponsors
National Institute of Mental Health (NIMH)
Abbott
University Hospitals Cleveland Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* To be included in this study, patients will be required to be either acutely hypomanic or manic as defined by the Diagnostic and Statistical Manual -IV (DSM-IV) and meet criteria for current substance abuse and/or dependence disorder within the last six months. * Must have 4 or more episodes in the immediate 12 months prior to study entry. * Males or females 16 - 65 years of age. * A score of 60 or less on the Global Assessment Scale. * Have no medical illness precluding the use of lithium or divalproex.
Exclusion criteria
* Patients who have had intolerable side effects to lithium levels 0.8 meq/L or divalproex levels of 50 ug/ml. Patients who have been completely non-responsive to lithium in the past will be excluded, whereas patients who have had partial responses to lithium will be permitted into the study. * Patients with a prior history of seizure disorder, cerebral vascular disease, structural brain damage from trauma, clinically significant focal neurological abnormalities, EEG abnormalities with frank paroxysmal activity or a previous CT/MRI scan of the brain with gross structural abnormalities. * Patients who require anticoagulant drug therapy. * Patients who have uncontrolled gastrointestinal, renal, hepatic, endocrine, cardiovascular, pulmonary, immunological or hematological disease. Patients with alcohol-related liver disease as reflected by diffuse elevations in liver functions tests exceeding the upper limits of the normal range by 50% will be excluded. * Patients who are pregnant or plan to become pregnant during the study. * Patients who have received haloperidol decanoate or fluphenazine decanoate within the last 10 weeks. * Patients who have a central nervous system (CNS) neoplasm, uncontrolled metabolic, demyelinating or progressive disorder; active CNS infection; or any progressive neurological disorder. * Patients who are taking exogenous steroids. * Patients who do not meet criteria for substance abuse or dependence.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment for Emerging Symptoms of a Mood Relapse | Up to 6 months | A relapse is a return to either a depressive, manic, hypomanic or mixed episode after a period of not have any symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment for Emerging Symptoms of a Manic/Hypomanic/Mixed Episode | Up to 6 months | — |
| Time to Treatment for Emerging Symptoms of a Depressive Episode | Up to 6 months | — |
| Change in Rate of Alcohol Use Disorders After Open-label Treatment With Lithium and Divalproex | Baseline to Month 6 | Number of subjects who no longer met criteria for active abuse or had entered into early full remission after receiving up to 6 months of open-label treatment with lithium and divalproex |
| Change in Rate of Cannabis Use Disorders After Open-label Treatment With Lithium and Divalproex | Baseline to Month 6 | Number of subjects who no longer met criteria for active cannabis abuse or had entered into early full remission after receiving up to 6 months of open-label treatment with lithium and divalproex |
| Change in Rate of Cocaine Use Disorders After Open-label Treatment With Lithium and Divalproex | Baseline to Month 6 | Number of subjects who no longer met criteria for active cocaine abuse or had entered into early full remission after receiving up to 6 months of open-label treatment with lithium and divalproex |
Countries
United States
Participant flow
Recruitment details
The study was conducted at the outpatient Mood Disorders Program of Case Western Reserve University/University Hospitals Case Medical Center between October 1997 and October 2006.
Pre-assignment details
Patients meeting stabilization criteria for a minimum of 4 consecutive weeks were eligible for random assignment to double-blind maintenance treatment. Patients not meeting these criteria by 24 weeks were discontinued from the study.
Participants by arm
| Arm | Count |
|---|---|
| Lithium Plus Divalproex | 15 |
| Lithium Plus Placebo | 16 |
| Total | 31 |
Baseline characteristics
| Characteristic | Lithium Plus Placebo | Total | Lithium Plus Divalproex |
|---|---|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 10.6 | 38.4 years STANDARD_DEVIATION 10.7 | 37.1 years STANDARD_DEVIATION 10.9 |
| Illness Type Bipolar I disorder | 13 participants | 26 participants | 13 participants |
| Illness Type Bipolar II disorder | 3 participants | 5 participants | 2 participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 6 Participants |
| Sex: Female, Male Male | 12 Participants | 21 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 15 | 13 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 |
Outcome results
Primary
Time to Treatment for Emerging Symptoms of a Mood Relapse
A relapse is a return to either a depressive, manic, hypomanic or mixed episode after a period of not have any symptoms.
Time frame: Up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lithium Plus Divalproex | Time to Treatment for Emerging Symptoms of a Mood Relapse | 17.8 weeks |
| Lithium Plus Placebo | Time to Treatment for Emerging Symptoms of a Mood Relapse | 15.9 weeks |
Secondary
Change in Rate of Alcohol Use Disorders After Open-label Treatment With Lithium and Divalproex
Number of subjects who no longer met criteria for active abuse or had entered into early full remission after receiving up to 6 months of open-label treatment with lithium and divalproex
Time frame: Baseline to Month 6
Population: This only includes subjects who had an alcohol use disorder at study entry. The purpose of this analysis was to see if treatment with both open-label lithium and divalproex during the first phase of study participation (i.e. prior to randomization to lithium monotherapy or continued dual therapy) lead to a change in rates of alcohol use disorders.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lithium Plus Divalproex | Change in Rate of Alcohol Use Disorders After Open-label Treatment With Lithium and Divalproex | 11 Participants |
Secondary
Change in Rate of Cannabis Use Disorders After Open-label Treatment With Lithium and Divalproex
Number of subjects who no longer met criteria for active cannabis abuse or had entered into early full remission after receiving up to 6 months of open-label treatment with lithium and divalproex
Time frame: Baseline to Month 6
Population: This only includes subjects who had a cannabis use disorder at study entry. The purpose of this analysis was to see if treatment with both open-label lithium and divalproex during the first phase of study participation (i.e. prior to randomization to lithium monotherapy or continued dual therapy) lead to a change in rates of cannabis use disorders.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lithium Plus Divalproex | Change in Rate of Cannabis Use Disorders After Open-label Treatment With Lithium and Divalproex | 8 Participants |
Secondary
Change in Rate of Cocaine Use Disorders After Open-label Treatment With Lithium and Divalproex
Number of subjects who no longer met criteria for active cocaine abuse or had entered into early full remission after receiving up to 6 months of open-label treatment with lithium and divalproex
Time frame: Baseline to Month 6
Population: This only includes subjects who were using cocaine at the time of study entry. The purpose of this analysis was to see if treatment with both open-label lithium \& divalproex during the first phase of study participation (i.e. prior to randomization to lithium monotherapy or continued dual therapy) lead to a change in rates of cocaine use disorders.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lithium Plus Divalproex | Change in Rate of Cocaine Use Disorders After Open-label Treatment With Lithium and Divalproex | 7 Participants |
Secondary
Time to Treatment for Emerging Symptoms of a Depressive Episode
Time frame: Up to 6 months
Population: Due to the heavily censored nature of this data, the median survival for time to treatment for emerging depression symptoms in both arms is not evaluable. Statistics software was unable to analyze the data.
Secondary
Time to Treatment for Emerging Symptoms of a Manic/Hypomanic/Mixed Episode
Time frame: Up to 6 months
Population: Due to the heavily censored nature of this data, the median survival for time to treatment for emerging manic/hypomanic/mixed symptoms in both arms is not evaluable. Statistics software was unable to analyze the data.