Mood Stabilizer (MS)+ Antidepressant vs MS + Placebo in Maintenance of Bipolar Disorder.

Study Overview
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Brief Summary
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Patients with bipolar I disorder (BD) experience depression 3 times more frequently than mania, and antidepressants are prescribed as adjuncts to mood stabilizers in up to 70% of patients. However, no placebo-controlled trials have assessed the efficacy or safety of modern antidepressants in combination with mood stabilizers in the maintenance treatment of BD. The investigators propose a multicentre, randomized, double-blind clinical trial comparing mood stabilizer plus antidepressant (escitalopram or bupropion XL) to mood stabilizer plus placebo in the maintenance treatment of BD. The investigators hypothesize that in clinically representative patients with bipolar disorder, who respond to acute treatment with a newer antidepressant medication in conjunction with a mood stabilizing medication, continuing the antidepressant for 12 months will reduce the risk of relapse into any mood episode, including depression, mania, and hypomania, compared to stopping the antidepressant after 8 weeks.

Detailed Description
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Study Design: The investigators propose a multicentre, randomized, double-blind, placebo-controlled trial in patients with BD who are currently experiencing a depressive episode. The trial will consist of two phases: an open-label acute treatment phase, and a double-blind maintenance treatment phase. OPEN-LABEL ACUTE TREATMENT PHASE Experimental Design Patients with BD depression who are receiving treatment with antimanic medication(s), defined as: 1) a mood stabilizer (lithium or divalproex ), 2) a second-generation antipsychotic (SGA) (risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone), or 3) combination anti-manic therapy (two mood stabilizers; or a mood stabilizer plus an SGA (the SGA asenapine will also be permitted if prescribed with a mood stabilizer); or a mood stabilizer or SGA plus lamotrigine), will have open-label escitalopram 10-30 mg/day or bupropion XL 150-450 mg/day added to their medication(s) for up to 16 weeks.Patients who complete at least 4 weeks of treatment and achieve remission from their index depression which is maintained for ≥ 2 weeks will be eligible to enter the double-blind study phase. The duration of treatment in the open-label phase will be 4-16 weeks, depending on the time required to achieve remission. DOUBLE-BLIND MAINTENANCE TREATMENT PHASE Patients who are in remission from their index depression for ≥ 2 weeks and ≤ 8 weeks are eligible to take part in the double-blind maintenance phase. There are two routes to enter the double-blind phase: following completion of the open-label phase, or following a period of clinical treatment, not exceeding 16 weeks, with the same medications used in the open-label phase. Patients who respond to clinical treatment with carbamazepine plus an antidepressant may also enter the double-blind phase. Experimental Design During the double-blind phase, all patients will continue treatment with their anti-manic medication(s) and will be randomized to one of two treatment arms for up to 52 weeks: Patients randomized to the 8 week arm will discontinue antidepressant treatment after 8 weeks, as recommended in current clinical practice guidelines.. Patients randomized to the 52 week arm will continue treatment with their antidepressant medication for 52 weeks, or until withdrawal from the study.

Official Title
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Mood Stabilizer Plus Antidepressant Versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder

Conditions
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Bipolar I Disorder

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Wellbutrin XL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: OPEN-LABEL ACUTE TREATMENT PHASE Diagnosed with BD, current episode depressed, with a MADRS score ≥ 20 at both the screening and baseline assessments The duration of the current depressive episode is ≥ 2 weeks but ≤ 52 weeks Taking or initiating treatment with an anti-manic medication at a therapeutic dose. Anti-manic medications and therapeutic doses are: lithium, serum level 0.6-1.4 mEq/L; divalproex, serum level 350-700 mM; risperidone 1-6 mg/day; olanzapine 5-30 mg/day; quetiapine IR or XR 300-900 mg/day; aripiprazole 10-30 mg/day; and ziprasidone 80-160 mg/day. Combinations of these medications as outlined above, or the combination of any of them with lamotrigine 100-400 mg daily, or the combination of a mood stabilizer plus asenapine 5-20 mg/day, are also permitted. If taking any other psychoactive medication (other than lorazepam ≤ 4 mg/day or equivalent), is agreeable to tapering and discontinuing it over a period of ≤ 4 weeks If female and of childbearing potential, is using an adequate method of contraception. Aged 18-70 years, inclusive Fluent in English and capable of providing informed consent DOUBLE-BLIND MAINTENANCE TREATMENT PHASE • Patients meeting all of the following criteria will be eligible to be included in the double-blind study phase: Taking escitalopram 10-30 mg/day or bupropion XL 150-450 mg/day, in addition to their anti-manic medication. Has adequately tolerated the combination of antidepressant plus mood stabilizer, and is currently in remission for ≥ 2 weeks and ≤ 8 weeks If female and of childbearing potential, is using an adequate method of contraception Exclusion Criteria: OPEN-LABEL ACUTE TREATMENT PHASE Has a history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months Has current manic, hypomanic, or subsyndromal hypomanic symptoms, defined as a Young Mania Rating Scale (YMRS) score ≥ 8 at the screening or baseline visits Has previously been refractory to treatment with both escitalopram and bupropion XL, or has been unable to tolerate both medications due to intolerable side effects or an allergic reaction Is taking monoamine oxidase inhibitors, such as phenelzine or tranylcypromine Escitalopram is contraindicated in patients taking pimozide or ziprasidone. Patients on pimozide or ziprasidone can participate in the study and will be prescribed bupropion XL Bupropion XL is contraindicated in patients taking other preparations containing bupropion, in patients with active eating disorders, including anorexia nervosa and bulimia nervosa; and in patients with seizure disorders. Patients with any of these can still participate in the study and will be prescribed Escitalopram Has active substance dependence, other than caffeine or nicotine dependence, in the preceding 3 months. Otherwise, patients with comorbid substance abuse or other comorbid psychiatric illnesses will be eligible to participate in the study Is at high risk for suicide, as defined by a score of ≥ 4 on the suicide item of the MADRS, or in the opinion of the investigator Has an unstable medical illness, as defined by a change in medication or other treatment in the past 4 weeks, or in the opinion of the investigator Has significant abnormalities on an electrocardiogram Is pregnant or lactating DOUBLE-BLIND MAINTENANCE TREATMENT PHASE Has a history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months Has current manic, hypomanic, or subsyndromal hypomanic symptoms, defined as a YMRS score ≥ 8 at the screening or baseline visits Has active substance dependence, other than caffeine or nicotine dependence, in the preceding 3 months. Otherwise, patients with comorbid substance abuse or other comorbid psychiatric illnesses will be eligible to participate in the study Is at high risk for suicide, as defined by a score of ≥ 4 on the suicide item of the MADRS, or in the opinion of the investigator Has an unstable medical illness, as defined by a change in medication or other treatment in the past 4 weeks, or in the opinion of the investigator. Has significant abnormalities on an electrocardiogram Is pregnant or lactating Has experienced an episode of mania, hypomania, or a mixed episode during antidepressant treatment of the acute depression, defined as a YMRS score of ≥ 16 at any open-label study visit, or in the opinion of the study psychiatrist

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 8 week arm<br>During the double-blind phase, all patients will continue treatment with their anti-manic medication(s)and will be randomized to one of two treatment arms for up to 52 weeks: Group 1 patients randomized to the 8 week arm will discontinue antidepressant treatment after 8 weeks, as recommended in current clinical practice guidelines. The antidepressant will be tapered in a double-blind manner beginning at 6 weeks, and will be substituted with placebo by 8 weeks. Escitalopram 10 - 30 mg Wellbutrin XL 150 - 450 mg | Drug: Escitalopram<br>* Escitalopram will be prescribed in the dose range 10-30 mg daily. In patients randomized to the 8-week group, escitalopram will be tapered, discontinued, and replaced with placebo over a period of 2 weeks, beginning at the week 6 study visit. The dose of escitalopram (or matching placebo) may be decreased in 10 mg increments only in the case of intolerable side effects. The dose must remain within the protocol-defined range of 10-30 mg daily at all time points.<br>* Other names: Lexapro/Cipralex;|
| Active Comparator: 52 week arm<br>During the double-blind phase, all patients will continue treatment with their anti-manic medication(s) and will be randomized to one of two treatment arms for up to 52 weeks: Group 2 patients randomized to the 52 week arm will continue treatment with their antidepressant medication for 52 weeks, or until withdrawal from the study. Escitalopram 10 - 30 mg Wellbutrin XL 150 - 450 mg | Drug: Wellbutrin XL<br>* Bupropion XL will be prescribed in the dosage range 150-450 mg daily. In patients randomized to the 8-week group, bupropion XL will be tapered, discontinued, and replaced with placebo over a period of 2 weeks, beginning at the week 6 study visit. The dose of bupropion XL (or matching placebo) may be decreased in 150 mg increments only in the case of intolerable side effects. The dose must remain within the protocol-defined range of 150-450 mg daily at all time points.<br>* Other names: Wellbutrin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients who respond to acute treatment with an antidepressant in combination with a mood stabilizer. | In patients with BD depression who respond to acute treatment with escitalopram or bupropion XL in combination with a mood stabilizing medication,does continuing antidepressant treatment for 12 months reduce the risk of relapse compared to discontinuing the antidepressant after 2 months? Open-Label Phase: Mean improvement in Montgomery-Asberg Depression Rating Scales (MADRS) from baseline to endpoint. Double-Blind Phase: The primary outcome for the double-blind phase is mean survival time in the study until the occurrence of any mood episode (manic, hypomanic, or depressive). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Does continuing antidepressant treatment for 12 months increase the risk of developing a manic or hypomanic episode? | Open-Label Phase •Improvement in depression and anxiety scores; Rates of remission, treatment-emergent mania and hypomania; Overall psychiatric status improvement; Adverse events (AEs) and serious adverse events (SAEs). Double-Blind Phase • time to an episode, study discontinuation; intolerable side effects; percentage of patients who experience subsyndromal symptoms; Rates of adverse events and SAEs. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar I disorder, Depression, Antidepressant