Bipolar I Disorder
Conditions
Keywords
Bipolar I disorder, Depression, Antidepressant
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.
Interventions
DRUGEscitalopram
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.
DRUGBupropion 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 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.
Sponsors
Lundbeck Canada Inc.
Canadian Institutes of Health Research (CIHR)
GlaxoSmithKline
Lupin Limited
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
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 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. 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 their anti-manic medication. 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 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 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, 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Double-blind 8 Week Arm 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 daily or Bupropion XL 150 - 450 mg daily | 87 |
| Double-blind 52 Week Arm 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 daily or Bupropion XL 150 - 450 mg daily | 90 |
| Open-Label Phase (4-16 Weeks) Patients with BD depression who are receiving treatment with antimanic medication(s) 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. | 206 |
| Total | 383 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Phase (up to 52 Weeks) | Excluded due to missing baseline and follow-up data. | 1 | 0 | 0 |
| Open-Label (up to 16 Weeks) | Lack of Efficacy | 0 | 0 | 8 |
| Open-Label (up to 16 Weeks) | Lost to Follow-up | 0 | 0 | 14 |
| Open-Label (up to 16 Weeks) | Non-adherence | 0 | 0 | 2 |
| Open-Label (up to 16 Weeks) | Physician Decision | 0 | 0 | 4 |
| Open-Label (up to 16 Weeks) | Withdrawal by Subject | 0 | 0 | 18 |
| Open-Label (up to 16 Weeks) | Worsening of symptoms | 0 | 0 | 13 |
Baseline characteristics
| Characteristic | Double-blind 52 Week Arm | Total | Double-blind 8 Week Arm | Open-Label Phase (4-16 Weeks) |
|---|---|---|---|---|
| Age, Categorical Double-blind 8 week and 52 week arm <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Double-blind 8 week and 52 week arm >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Double-blind 8 week and 52 week arm Between 18 and 65 years | 90 Participants | 177 Participants | 87 Participants | 0 Participants |
| Age, Categorical Open-Label 4-16 week arm <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Open-Label 4-16 week arm >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Open-Label 4-16 week arm Between 18 and 65 years | 0 Participants | 206 Participants | 0 Participants | 206 Participants |
| Age, Continuous Double-Blind Phase | 39.3 years STANDARD_DEVIATION 11.3 | 41.1 years STANDARD_DEVIATION 11.3 | 42.9 years STANDARD_DEVIATION 11.1 | — |
| Age, Continuous Open-Label Phase | — | 40.1 years STANDARD_DEVIATION 10.9 | — | 40.1 years STANDARD_DEVIATION 10.9 |
| Drug Combination - No. Double-Blind Phase Bupropion XL plus Mood Stabilizer | 16 Participants | 33 Participants | 17 Participants | — |
| Drug Combination - No. Double-Blind Phase Bupropion XL plus Mood Stabilizer plus SGA | 16 Participants | 30 Participants | 14 Participants | — |
| Drug Combination - No. Double-Blind Phase Bupropion XL plus SGA | 3 Participants | 4 Participants | 1 Participants | — |
| Drug Combination - No. Double-Blind Phase Escitalopram plus Mood Stabilizer | 24 Participants | 48 Participants | 24 Participants | — |
| Drug Combination - No. Double-Blind Phase Escitalopram plus Mood Stabilizer plus SGA | 27 Participants | 54 Participants | 27 Participants | — |
| Drug Combination - No. Double-Blind Phase Escitalopram plus SGA | 4 Participants | 8 Participants | 4 Participants | — |
| Drug Combination - No. Open-Label Phase Bupropion XL plus Mood Stabilizer | — | 35 Participants | — | 35 Participants |
| Drug Combination - No. Open-Label Phase Bupropion XL plus Mood Stabilizer plus SGA | — | 33 Participants | — | 33 Participants |
| Drug Combination - No. Open-Label Phase Bupropion XL plus SGA | — | 7 Participants | — | 7 Participants |
| Drug Combination - No. Open-Label Phase Escitalopram plus Mood Stabilizer | — | 53 Participants | — | 53 Participants |
| Drug Combination - No. Open-Label Phase Escitalopram plus Mood Stabilizer plus SGA | — | 64 Participants | — | 64 Participants |
| Drug Combination - No. Open-Label Phase Escitalopram plus SGA | — | 14 Participants | — | 14 Participants |
| Montgomery Asberg Depression Rating Scale Score Double-Blind Phase | 3.1 units on a scale STANDARD_DEVIATION 2.5 | 3.2 units on a scale STANDARD_DEVIATION 2.3 | 3.2 units on a scale STANDARD_DEVIATION 2 | — |
| Montgomery Asberg Depression Rating Scale Score Open-Label Phase | — | 26.6 units on a scale STANDARD_DEVIATION 4.9 | — | 26.6 units on a scale STANDARD_DEVIATION 4.9 |
| Race/Ethnicity, Customized Double-Blind Phase Asian | 78 Participants | 154 Participants | 76 Participants | — |
| Race/Ethnicity, Customized Double-Blind Phase Black | 0 Participants | 1 Participants | 1 Participants | — |
| Race/Ethnicity, Customized Double-Blind Phase Other | 1 Participants | 1 Participants | 0 Participants | — |
| Race/Ethnicity, Customized Double-Blind Phase White | 11 Participants | 21 Participants | 10 Participants | — |
| Race/Ethnicity, Customized Open-Label Phase Asian | — | 176 Participants | — | 176 Participants |
| Race/Ethnicity, Customized Open-Label Phase Black | — | 1 Participants | — | 1 Participants |
| Race/Ethnicity, Customized Open-Label Phase Other | — | 1 Participants | — | 1 Participants |
| Race/Ethnicity, Customized Open-Label Phase White | — | 28 Participants | — | 28 Participants |
| Region of Enrollment, Customized Double-Blind Phase Canada | 12 Participants | 22 Participants | 10 Participants | 0 Participants |
| Region of Enrollment, Customized Double-Blind Phase India | 76 Participants | 152 Participants | 76 Participants | 0 Participants |
| Region of Enrollment, Customized Double-Blind Phase South Korea | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Region of Enrollment, Customized Open-Label Phase Canada | 0 Participants | 29 Participants | 0 Participants | 29 Participants |
| Region of Enrollment, Customized Open-Label Phase India | 0 Participants | 168 Participants | 0 Participants | 168 Participants |
| Region of Enrollment, Customized Open-Label Phase South Korea | 0 Participants | 9 Participants | 0 Participants | 9 Participants |
| Sex: Female, Male Double-blind 8 week arm Female | 44 Participants | 92 Participants | 48 Participants | 0 Participants |
| Sex: Female, Male Double-blind 8 week arm Male | 46 Participants | 85 Participants | 39 Participants | 0 Participants |
| Sex: Female, Male Open-Label Phase Female | 0 Participants | 107 Participants | 0 Participants | 107 Participants |
| Sex: Female, Male Open-Label Phase Male | 0 Participants | 99 Participants | 0 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 87 | 0 / 90 | 0 / 206 |
| other Total, other adverse events | 59 / 87 | 57 / 90 | 87 / 206 |
| serious Total, serious adverse events | 0 / 87 | 0 / 90 | 1 / 206 |
Outcome results
Primary
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.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 8 Week Arm | Double-Blind Phase: Number of Participants With an Occurrence of Any Mood Episode (Manic, Hypo-manic, Depressive) During the 52 Week Study Period. | 40 Participants |
| 52 Week Arm | Double-Blind Phase: Number of Participants With an Occurrence of Any Mood Episode (Manic, Hypo-manic, Depressive) During the 52 Week Study Period. | 28 Participants |
p-value: 0.1295% CI: [0.43, 1.1]Log Rank
Secondary
Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period.
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.
Time frame: 52 weeks
Population: Of the total 178 patients who underwent randomization, 1 had missing data for baseline and post baseline visits and was excluded from the analysis. Thus, the primary analysis included 177 patients, of whom 90 were assigned to the 52-week group and 87 to the 8-week group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 8 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Subsyndromal manic symptoms | 0 Participants |
| 8 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Mixed episode | 0 Participants |
| 8 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Subsyndromal depressive symptoms | 8 Participants |
| 8 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Depressive events | 35 Participants |
| 8 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Manic or hypomanic events | 5 Participants |
| 52 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Subsyndromal manic symptoms | 0 Participants |
| 52 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Manic or hypomanic events | 11 Participants |
| 52 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Depressive events | 15 Participants |
| 52 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Subsyndromal depressive symptoms | 8 Participants |
| 52 Week Arm | Double-Blind Phase: Number of Participants Who Had an Episode of Mania/Hypomania, Depression or Mixed During the 52 Week Study Period. | Mixed episode | 2 Participants |
Comparison: Manic or Hypomanic events95% CI: [0.86, 6.08]
Comparison: Depressive Events95% CI: [0.25, 0.75]