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

NCT00958633 | Terminated Phase 3 Results DMC

• 1 other identifier: H09-01017
• Study Type: interventional
• Target: 237
• Locations: 1 country
• Sites: 1

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.

Conditions

Bipolar I Disorder

Keywords

Bipolar I disorder; Depression; Antidepressant

Outcome Measures

Primary Outcomes (1)

• Double-Blind Phase: Number of Participants With an Occurrence of Any Mood Episode (Manic, Hypo-manic, Depressive) During the 52 Week Study Period.

  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.

  52 weeks

Secondary Outcomes (1)

• Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period.

  52 weeks

Study Arms (2)

8 week arm

ACTIVE COMPARATOR

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

Drug: Escitalopram; Drug: Bupropion XL

52 week arm

ACTIVE COMPARATOR

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

Drug: Escitalopram; Drug: Bupropion XL

Interventions

Escitalopram DRUG

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. Patients randomized to the "52 week arm" will continue treatment with their antidepressant medication for 52 weeks, or until withdrawal from the study.

Also known as: Lexapro/Cipralex

52 week arm; 8 week arm

Bupropion XL DRUG

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. Patients randomized to the "52 week arm" will continue treatment with their antidepressant medication for 52 weeks, or until withdrawal from the study.

Also known as: Wellbutrin

52 week arm; 8 week arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of British Columbia: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• GlaxoSmithKline: collaborator
• Lundbeck Canada Inc.: collaborator
• Lupin Limited: collaborator

Study Sites (1)

University of British Columbia

Vancouver, British Columbia, V6T 2A1, Canada

Location

Related Publications (1)

• Yatham LN, Arumugham SS, Kesavan M, Ramachandran K, Murthy NS, Saraf G, Ouyang Y, Bond DJ, Schaffer A, Ravindran A, Ravindran N, Frey BN, Daigneault A, Beaulieu S, Lam RW, Kondapuram N, Reddy MS, Bhandary RP, Ashok MV, Ha K, Ahn YM, Milev R, Wong H, Reddy YCJ; BEAM-BD Trial Group. Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression. N Engl J Med. 2023 Aug 3;389(5):430-440. doi: 10.1056/NEJMoa2300184.

  PMID: 37530824 DERIVED

MeSH Terms

Conditions

Depression

Interventions

Escitalopram; Dexetimide; Bupropion

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Propiophenones; Ketones

Limitations and Caveats

Recruitment was stopped before the planned sample size was reached owing to the Covid-19 pandemic and expiration of funding.

Results Point of Contact

• Title: Dr. Lakshmi Yatham
• Organization: University Of British Columbia

yatham@mail.ubc.ca

604-822-7310

Study Officials

• Lakshmi Yatham, Dr.

  University of British Columbia

  PRINCIPAL INVESTIGATOR

• B. Frey, Dr.

  St. Joseph's Healthcare, Hamilton, Ont.

  STUDY DIRECTOR

• S. Beaulieu, Dr.

  Douglas Mental Health University Institute, Montreal, Quebec

  STUDY DIRECTOR

• A. Daigneault, Dr.

  Douglas Mental Health University Institute, Montreal, Quebec

  STUDY DIRECTOR

• A. Ravindran, Dr.

  Centre for Addictions and Mental Health, Toronto, Ont.

  STUDY DIRECTOR

• A. Schaffer, Dr.

  Sunnybrook Health Sciences Centre, Toronto, Ont.

  STUDY DIRECTOR

• R. Milev, Dr.

  Queen's University, Kingston, Ontario

  STUDY DIRECTOR

• P. Cervantes, Dr.

  McGill University Health Centre, Montreal, Que

  STUDY DIRECTOR

• T. H. Ha, Dr.

  Seoul National University Bundang Hospital

  STUDY DIRECTOR

• Y. M. Ahn, Dr.

  Seoul National University Hospital

  STUDY DIRECTOR

• Y. H. Joo, Dr.

  Asan Medical Centre, Korea

  STUDY DIRECTOR

• S. Won, Dr.

  Kyungpook National University Hospital, Korea

  STUDY DIRECTOR

• J. Y. Reddy, Dr.

  National Institute of Mental Health and Neuro sciences, Bangalore, India

  STUDY DIRECTOR

• P.S. Sharma, Dr.

  Kasturba Medical College Manipal, India

  STUDY DIRECTOR

• M.S. Reddy, Dr.

  Asha Hospital, Hyderabad, India

  STUDY DIRECTOR

• A.V. Mysore, Dr.

  St. John's hospital, Bangalore, India

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 11, 2009
• First Posted: August 13, 2009
• Study Start: November 1, 2010
• Primary Completion: March 31, 2020
• Study Completion: May 20, 2020
• Last Updated: May 15, 2025
• Results First Posted: May 15, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)