Combination Therapy for the Treatment of Bipolar Disorders

Study Overview
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Brief Summary
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This study will compare triple and double drug regimens in the treatment of patients with depression, hypomania, or mania.

Detailed Description
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Early studies have shown lithium to produce a high percentage of satisfactory clinical response in patients with bipolar disorders. These studies, however, do not include lithium-refractory subgroups, such as bipolar II disorder patients. When the wide spectrum of bipolar disorders is considered, the lithium response rate decreases significantly. More broadly effective regimens are needed. Participants in this study will be randomly assigned to receive either lithium plus divalproex or lithium, divalproex, and lamotrigine for 7 months. Symptoms of depression and mania will be assessed with scales and patient questionnaires.

Official Title
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Combination Therapy in Bipolar Rapid Cycling

Conditions
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Bipolar Disorder

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bipolar I or II Disorder Meet criteria for rapid cycling, defined as four or more episodes over the past 12 months Meet criteria for a major depressive episode Exclusion Criteria: History of intolerability of lithium, divalproex, or lamotrigine

Ages Eligible for Study
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Minimum Age: 16 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 + divalproex + lamotrigine<br> | Drug: Lithium<br>* Lithium monotherapy was initiated at 450 mg once daily and titrated slowly over three weeks to a minimum blood level of 0.5 milliequivalent /L (mEq/L).<br>* Other names: Lithium Carbonate;Drug: Lamotrigine<br>* Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum dose of 200 mg per day.<br>* Other names: Lamictal;Drug: Divalproex<br>* Divalproex was then initiated at 250 mg twice daily and increased slowly over five weeks to a minimum blood level of 50 μg/mL.<br>* Other names: Valproic Acid;|
| Placebo Comparator: Lithium + divalproex + placebo<br> | Drug: Lithium<br>* Lithium monotherapy was initiated at 450 mg once daily and titrated slowly over three weeks to a minimum blood level of 0.5 milliequivalent /L (mEq/L).<br>* Other names: Lithium Carbonate;Drug: Divalproex<br>* Divalproex was then initiated at 250 mg twice daily and increased slowly over five weeks to a minimum blood level of 50 μg/mL.<br>* Other names: Valproic Acid;Drug: Placebo<br>* Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum dose of 200 mg per day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Patients Who Experience a Marked and Persistent Bimodal Response | A marked bimodal response is defined by the following three conditions over four consecutive weeks while on triple therapy and after three weeks of ltg: Montgomery Asberg Depression Rating Scale (MADRS) total score of <= 19 Young Mania Rating Scale (YMRS) total score of <= 12.5 Global Assessment Scale (GAS) score >= 51 The MADRS measures the severity of a subject's depression symptoms with a possible total score ranging from 0 - 60, with higher scores indicating more severe depression. The YMRS measures the severity of a subject's manic symptoms with a possible total score ranging from 0 - 60, with higher scores indicating more severe mania. The GAS measures a used to rate subjectively the social, occupational, and psychological functioning of a subject and ranges in score from 0-100, with a higher score indicating better social, occupational, and psychological functioning. | Baseline and Week 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression