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

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 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.
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 0.6-1.2 mEq/L, divalproex, serum level 350-700 mM or carbamazepine, serum level 20-50 umol/L), 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), two mood stabilizers, a mood stabilizer plus an SGA (including asenapine 5-20 mg/day), or a mood stabilizer or SGA plus lamotrigine (100-400 mg/day).
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 or ziprasidone. Patients on pimozide or ziprasidone 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. Has significant abnormalities on an electrocardiogram
11. 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. Has significant abnormalities on an electrocardiogram
  7. Is pregnant or lactating
  8. 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