Are Antidepressants More Effective Than Placebo, When Given in Combination With Mood Stabilizers, in Preventing Mood Episodes in People With Bipolar I Disorder?

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

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.

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 either a mood stabilizer (lithium or divalproex), an SGA (risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone), or the combination of a mood stabilizer plus an SGA will have open-label escitalopram 10-30 mg/day or bupropion XL 100-450 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

Experimental Design

During the double-blind phase, all patients will continue treatment with their mood stabilizer, SGA, or mood stabilizer plus SGA, 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.

Intervention(s) in this Clinical Trial

• Drug: Escitalopram
  • 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 tapering schedule for escitalopram is outlined in table 2. 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.
• Drug: Bupropion XL
  • 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 tapering schedule for bupropion XL is outlined in table 2. 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 10-30 mg daily at all time points.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • During the double-blind phase, all patients will continue treatment with their mood stabilizer, SGA, or mood stabilizer plus SGA, 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.
• Active Comparator: 2
  • During the double-blind phase, all patients will continue treatment with their mood stabilizer, SGA, or mood stabilizer plus SGA, 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.

Primary Measures

• Patients who respond to acute treatment with an antidepressant in combination with a mood stabilizer.
  • Time Frame: 12 months
    Safety Issue?: No

Secondary Measures

• Does continuing antidepressant treatment for 12 months increase the risk of developing a manic or hypomanic episode?
  • Time Frame: 12 months
    Safety Issue?: No

Inclusion Criteria:

• OPEN-LABEL ACUTE TREATMENT PHASE
• 1. Diagnosed with BD, current episode depressed, with a MADRS score ≥ 20 at both the screening and baseline assessments
• 2. The duration of the current depressive episode is ≥ 2 weeks but ≤ 52 weeks
• 3. Taking or initiating treatment with a mood stabilizing medication at a therapeutic dose. Mood stabilizing 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
• 4. 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
• 5. If female and of childbearing potential, is using an adequate method of contraception. Adequate methods of contraception include abstinence; oral contraceptive pill or surgically implanted device; intra-uterine device; condom plus spermicidal foam or jelly; or tubal ligation
• 6. Aged 18-70 years, inclusive
• 7. 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:
• 1. Taking escitalopram 10-30 mg/day or bupropion XL 150-450 mg/day, in addition to either a mood stabilizing medication (lithium, serum level 0.8-1.2 mEq/L or divalproex, serum level 350-700 mM), an SGA (risperidone 1-6 mg/day; olanzapine 5-30 mg/day; quetiapine IR or XR 150-900 mg/day; aripiprazole 10-30 mg/day; or ziprasidone 80-160 mg/day), or a mood stabilizer plus an SGA
• 2. Has adequately tolerated the combination of antidepressant plus mood stabilizer, and is currently in remission for ≥ 2 weeks and ≤ 8 weeks
• 3. If female and of childbearing potential, is using an adequate method of contraception

Exclusion Criteria:

• OPEN-LABEL ACUTE TREATMENT PHASE
• Patients meeting any of the following criteria will be excluded from the open-label study phase:
• 1. Has a history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months
• 2. Has current manic, hypomanic, or subsyndromal hypomanic symptoms, defined as a Young
• Mania Rating Scale (YMRS) score ≥ 8 at the screening or baseline visits
• 3. 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
• 4. Is taking monoamine oxidase inhibitors, such as phenelzine or tranylcypromine
• 5. Escitalopram is contraindicated in patients taking the antipsychotic medication pimozide. Patients on pimozide can participate in the study and will be prescribed bupropion XL
• 6. Bupropion XL is contraindicated in patients taking other preparations containing bupropion, such as Zyban and Wellbutrin SR; 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
• 7. 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
• 8. 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
• 9. 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
• 10. Is pregnant or lactating
• DOUBLE-BLIND MAINTENANCE TREATMENT PHASE
• Patients meeting any of the following criteria will be excluded from the double-blind study phase:
• 1. Has a history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months
• 2. Has current manic, hypomanic, or subsyndromal hypomanic symptoms, defined as a YMRS score ≥ 8 at the screening or baseline visits
• 3. 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
• 4. 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
• 5. 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.
• 6. Is pregnant or lactating
• 7. 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of British Columbia Other

Overall Clinical Trial Officials and Contacts

Lakshmi Yatham, Dr. Principal Investigator University of British Columbia  

Overall Contact: Nazil Walji 604-822-7294 nwalji@exchange.ubc.ca

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00958633

Study ID Number: H09-01017

ClinicalTrials.gov Identifier: NCT00958633

Health Authority: Canada: Health Canada