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

Phase 3

Terminated

Conditions: Bipolar I Disorder

Interventions: Drug: Escitalopram
Drug: Bupropion XL

Registration Number: NCT00958633

Lead Sponsor: University of British Columbia

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 237

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
8 week arm	Escitalopram	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 or Bupropion XL 150 - 450 mg
8 week arm	Bupropion XL	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 or Bupropion XL 150 - 450 mg
52 week arm	Escitalopram	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 or Bupropion XL 150 - 450 mg
52 week arm	Bupropion XL	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 or Bupropion XL 150 - 450 mg

Primary Outcome Measures

Name	Time	Method
Double-Blind Phase: Number of Participants With an Occurrence of Any Mood Episode (Manic, Hypo-manic, Depressive) During the 52 Week Study Period.	52 weeks	The primary outcome, assessed in a time-to-event analysis, was any mood episode, defined as any of the following: a Young Mania Rating Scale (YMRS) score of at least 16 (mild mania), a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 20 (moderate depression), a Clinical Global Impressions Scale, Bipolar Version, Severity (CGI-S-BD) score of at least 4 for mania or depression (moderately ill), hospitalization for mood symptoms, necessity of additional pharmacotherapy for emerging mood symptoms, a MADRS suicide item score of at least 4 (scores range from 0 to 6, with higher scores indicating greater suicide risk), or a suicide attempt or suicide death. Young Mania Rating Scale:Scores range from 0 to 60,lower scores reflect better clinical outcomes. Montgomery-Åsberg Depression Rating Scale: Scores range from 0 to 60, lower scores reflect better clinical outcomes. Clinical Global Impression scale: Scores range from 3 to 42, higher scores reflect worsening status.

Secondary Outcome Measures

Name	Time	Method
Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period.	52 weeks	Time to a depressive episode, a manic or hypomanic episode, discontinuation from the trial for any clinical reason (e.g., occurrence of a mood event, withdrawal of informed consent, or adverse event), any mood episode or subsyndromal symptoms, time spent in these episodes, and scores on the CGI-BD, YMRS, and MADRS clinical rating scales. Young Mania Rating Scale:Scores range from 0 to 60,lower scores reflect better clinical outcomes. Montgomery-Åsberg Depression Rating Scale: Scores range from 0 to 60, lower scores reflect better clinical outcomes. Clinical Global Impression scale: Scores range from 3 to 42, higher scores reflect worsening status.