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

Phase 3

Completed

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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Lithium plus placebo	Placebo	Patients assigned to lithium monotherapy underwent divalproex-placebo substitution at a rate of 250 mg decrements every week until discontinued.
Lithium plus Divalproex	Lithium	Patients assigned to the combination group were continued on lithium and blinded divalproex.
Lithium plus Divalproex	Divalproex	Patients assigned to the combination group were continued on lithium and blinded divalproex.
Lithium plus placebo	Lithium	Patients assigned to lithium monotherapy underwent divalproex-placebo substitution at a rate of 250 mg decrements every week until discontinued.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Time to Treatment for Emerging Symptoms of a Depressive Episode	Up to 6 months
Time to Treatment for Emerging Symptoms of a Manic/Hypomanic/Mixed 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