Lithium and Divalproex for the Treatment of Comorbid Rapid Cycling Bipolar Disorder and Substance Abuse Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double Blind Comparison of Lithium Monotherapy Versus Lithium Plus Divalproex for the Outpatient Management of Hypomania/Mania in Patients With Rapid Cycling Bipolar Disorder Comorbid With Substance Abuse/Dependence

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Lithium
* Drug: Divalproex
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lithium plus Divalproex<br>Patients assigned to the combination group were continued on lithium and blinded divalproex. | Drug: Lithium<br>* Lithium monotherapy was initiated at 300 mg twice daily and titrated over 3-6 weeks to minimum blood levels of 0.8 meq/L.<br>* Other names: Lithium Carbonate;Drug: Divalproex<br>* Divalproex was then initiated at 250 mg twice daily and increased over 3-6 weeks to minimum blood levels of 50 ug/ml.<br>* Other names: Depakote;|
| Placebo Comparator: Lithium plus placebo<br>Patients assigned to lithium monotherapy underwent divalproex-placebo substitution at a rate of 250 mg decrements every week until discontinued. | Drug: Lithium<br>* Lithium monotherapy was initiated at 300 mg twice daily and titrated over 3-6 weeks to minimum blood levels of 0.8 meq/L.<br>* Other names: Lithium Carbonate;Drug: Placebo<br>* Placebo pills that looked exact to divaloproex were provided to subjects and take twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | Baseline to Month 6 | 
| 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 | Baseline to Month 6 | 
| 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 | Baseline to Month 6 |