Clinical trial NCT00958633
Conditions: Bipolar I Disorder
Keywords: Bipolar I disorder Depression Antidepressant
Sponsor: University of British Columbia
Start date: 2010-11-01; Completion date: 2020-05-20
Enrollment: 237 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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 arm 2: 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
Interventions: intervention 1: Escitalopram intervention 2: Bupropion XL
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the 
Maintenance Treatment of Bipolar Disorder  
 
 
 March 28, 2017 
 
 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
SUMMARY OF PROTOCOL 
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. We 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 trial will consist of two phases: 
 
Open-Label Acute Treatment Phase 
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. (Because of 
their potent antidepressant properties, patients who are taking lamotrigine or quetiapine in 
conjunction with a mood stabilizer, or who are taking quetiapine alone, must have non-
response to these medications established over a 6 week trial before antidepressants are 
commenced.) The primary outcome for the open-label phase is mean improvement in 
Montgomery-Asberg Depression Rating Scale (MADRS) scores from baseline to endpoint. 
We will also measure rates of response, remission, and treatment-emergent mania and 
hypomania; overall psychiatric status and improvement; rates of adverse events (AEs) and 
serious adverse events (SAEs); and quality of life. Patients who receive at least 4 weeks of 
treatment and achieve remission from their index depression for ≥ 2 weeks will be eligible to 
enter the double-blind maintenance study phase. Enrolment in the double-blind phase must 
occur within 8 weeks of remission. The duration of the open-label phase will be 4-16 weeks, 
depending on time to remission. 
 
Double-Blind Maintenance Treatment Phase 
Patients may enter the double-blind phase either 1) following completion of the open-label 
phase, or 2) within 2-8 weeks of remission from a documented depressive episode that was 
treated with the same medications used in the open-label phase. (Patients who are taking 
carbamazepine plus an antidepressant cannot enter the open-label phase, as carbamazepine 
can unpredictably reduce antidepressant serum levels, and this could affect the results of the 
open-label phase, but patients who respond to clinical treatment with carbamazepine plus an 
antidepressant will be assumed to have adequate antidepressant serum levels, and may thus 
be enrolled in the double-blind phase.) All patients entering the double-blind phase 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. The 
antidepressant will be tapered in a double-blind manner beginning at 6 weeks, and 
will be substituted with placebo by 8 weeks.  


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
• Patients randomized to the “52 week arm” will continue treatment with their 
antidepressant medication for 52 weeks, or until withdrawal from the study.  
The primary outcome measure for the double-blind phase is mean survival time in the study 
until the occurrence of any mood episode (manic, hypomanic, or depressive), as determined 
using Kaplan-Meier survival analysis. We will also measure mean time to manic or 
hypomanic episode; time to depressive episode; time to study discontinuation for any reason 
(eg. onset of mood episode, intolerable side effects, patient or clinician decision); the 
proportion of patients who experience any mood episode, a manic or hypomanic episode, or 
a depressive episode; the percentage of patients who experience subsyndromal symptoms 
and percentage of time spent with subsyndromal symptoms; rates of AEs and SAEs; and 
quality of life.  
 
BLOOD SAMPLES 
Pharmacogenetics and Epigenetics (Optional for Sites) 
The prediction of medication response and side effects based on individual genetic variation 
and the epigenetic regulation of gene expression is a rapidly growing area. However, few 
studies have examined the association between antidepressant response and single nucleotide 
polymorphisms, or between response and gene regulation via CpG methylation, histone 
acetylation, and other epigenetic mechanisms. The design of this study offers a unique 
opportunity to examine genetic and epigenetic predictors of drug response and side effects, 
such as antidepressant-induced mania. Examination of genetic and epigenetic markers 
associated with norepinephrine, serotonin, dopamine, GABA, glutamate, N-acetyl-aspartate 
and second messenger systems will be conducted. Cell lines will be established to allow for 
adequate testing timelines. Blood samples for genetic and epigenetic testing will be collected 
at four time points: 1) at enrolment into the study, 2) two weeks after the criteria for 
treatment response are met, 3) 12 weeks after randomization in the double-blind treatment 
phase, and 4) at study endpoint. All blood samples collected will be stored and analyzed at 
UBC. 
 
Measurement of Serum and Intracellular Neurochemicals (Optional for Sites) 
A variety of neurochemical markers have been implicated in the pathophysiology of bipolar 
disorder and its response to treatment. Many of these substances are easily measured in 
serum or in the cytoplasm of blood cells, and may reflect levels in the central nervous 
system. Examples of serum markers include the neurotrophins such as brain derived 
neurotrophic factor (BDNF), which are potential candidates in the pathophysiology of 
bipolar disorder, and in particular the cognitive impairment that is associated with it. Other 
neurotrophins like glial derived neurotrophic factor (GDNF) have been found to be altered 
during mood episodes. Data from preclinical studies also showed changes in nerve growth 
factor (NGF) in an animal model of mania. Intracellular biochemical cascades such as the 
oxidative stress cascade and second messenger systems will also be investigated, as 
substantial evidence from our group and others implicates them in the pathophysiology of 
bipolar disorder. Blood samples for the measurement of serum and intracellular 
neurochemicals will be collected at the same time points as above. All blood samples 
collected will be stored and analyzed at UBC. 
 
 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
NEUROCOGNITIVE ASSESSMENT(Optional for Sites) 
Emerging neuropsychological studies on cognition in euthymic bipolar patients confirm that 
there are deficits in multiple domains that persist even after the mood symptoms remit. The 
majority of these studies do not account for the possible effects of treatment, in part due to 
the lack of homogenicity between samples. By utilizing a neurocognitive battery during the 
double-blind phase at baseline, week 10, and week 24 we will be able to compare the effects 
of bupropion and escitalopram to placebo in domains of processing speed, 
attention/vigilance, as well as verbal and working memory using tests that have been utilized 
in studies of bipolar and unipolar depression. 
 
The battery will consist of the NAART (at baseline only to control for the effects of IQ on 
other measures), Verbal Fluency (animal naming), HVLT, Trail Making Tests parts A and B,  
WAIS-IV Letter/Number Subtest, WAIS-IV Digit/Symbol Subtest, and the Stroop Task. 
 
FINGERNAIL SAMPLING (Optional for Sites) 
Measurement of Cortisol:DHEA ratio 
The hypothalamic-pituitary-adrenal (HPA) axis, which has consistently been found 
dysfunctional in patients suffering from a mood disorder, mediates the body’s response to 
stress through secretion of neurosteroids such as cortisol and dehydroepiandosterone 
(DHEA). These hormones have receptors in limbic regions including the prefrontal cortex 
and hippocampus; supporting findings that suggests HPA hyperactivity and raised cortisol 
secretion may cause or exacerbate cognitive impairment and depressive symptomology, 
although difficulties in interpreting this data arise due to limitations in current sampling 
techniques which only provide information on hormonal levels over a short time period. By 
using fingernail analysis of the cortisol:DHEA ratio, we will be able to assess long term 
HPA activity (as DHEA is thought to play a role in protecting the brain from the negative 
effects of cortisol, the cortisol:DHEA ratio is considered to be the more accurate 
measurement of functional hypercortisolemia).  
 
We will take fingernail clippings from subjects at the double blind phase weeks 12, 24, and 
36 which are reflective of chronic HPA activity levels surrounding cognitive testing sessions 
at weeks 0, 10, and 24 respectively, corresponding with different stages of antidepressant 
treatment or withdrawal. Participants will be asked to trim their nails 2 weeks prior to 
collection so that samples acquired represent 2 weeks of growth. As phase of menstrual 
cycle has been known to affect HPA activity, this information will also be collected for 
premenopausal female participants. All fingernail samples collected will be stored and 
analyzed at UBC. 
 
INTRODUCTION 
     Although bipolar I disorder (BD) is defined by the occurrence of manic episodes, patients 
experience depression 3 times more frequently than mania 1. While the consequences of 
mania are well known – occupational disability; relationship difficulties; the consequences 
of spending, drug use, impulsive sexual activity - depressive symptoms have at least as 
severe an impact on health and functioning 2. The mood stabilizing medications lithium and 
divalproex and the second-generation antipsychotics (SGAs) risperidone, olanzapine, 
quetiapine, aripiprazole, and ziprasidone have all been demonstrated to prevent mood 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
episodes during the long-term treatment of BD. However, commonly-used maintenance 
treatments are more effective in preventing mania than depression 3-5. Not surprisingly, then, 
antidepressants are prescribed for up to 70% of patients with BD 6-8, and half of 
patients prescribed antidepressants continue to take them for one year or longer 9.  
     However, to date no double-blind placebo-controlled RCTs have directly assessed 
the efficacy and safety of modern antidepressants such as escitalopram or bupropion 
when given as adjuncts to mood stabilizing medications or SGAs in the maintenance 
treatment of BD. Given the lack of evidence from well-designed placebo-controlled trials, 
Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical practice 
guidelines recommend that antidepressants be discontinued 2-4 months after the remission of 
an acute depression 10. However, if escitalopram and bupropion are effective in preventing 
depression without increasing the risk of mania, then clinicians who follow clinical practice 
guidelines are putting their patients in jeopardy of increased depressive relapses. If, on the 
other hand, escitalopram and bupropion are ineffective in preventing depressive episodes, or 
if they lead to an increased frequency of manic episodes that outweighs their antidepressant 
effect, then large numbers of patients are being prescribed unnecessary and potentially 
dangerous medications. The paucity of truly effective treatments for the prevention of 
BD depression, the frequency of prescription of antidepressants, and the lack of data 
regarding their effectiveness provide a compelling rationale for a well-designed double-
blind placebo-controlled trial to assess their long-term efficacy and safety.  
 
OBJECTIVES AND STUDY DESIGN 
 
Our primary objective is to answer a highly relevant clinical question:   
 
In clinically representative patients with BD depression who respond to acute treatment 
with escitalopram or bupropion XL in combination with anti-manic medication(s), does 
continuing antidepressant treatment for 12 months reduce the risk of relapse into any 
mood episode, including depression, mania, and hypomania, compared to discontinuing 
the antidepressant and substituting it with placebo after 2 months?  
 
Our secondary objectives are to answer the following questions: 
 
1. Does continuing antidepressant treatment for 12 months reduce the risk of relapse into 
depression? 
2. Does continuing antidepressant treatment for 12 months increase the risk of developing a 
manic or hypomanic episode? 
3. Do rates of subsyndromal mood symptoms and adverse events differ between patients 
who continue antidepressant treatment for 12 months compared to those who stop the 
antidepressant after 2 months? 
4. Does 12-month antidepressant treatment improve overall health and quality of life for 
patients, compared to stopping treatment after 2 months? 
 
 
 
 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
Study Design 
We 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. Participants will be recruited from 7 Canadian Centres and 4 Korean Centres. 
 
OPEN-LABEL ACUTE TREATMENT PHASE 
 
Experimental Design 
Patients with BD depression (defined as a Montgomery-Asberg Depression Rating Scale 
(MADRS) score of ≥ 20) who are receiving treatment with either a mood stabilizer (lithium 
or divalproex ), an SGA (risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone), 
or combination treatment with two mood stabilizers, or a mood stabilizer plus an 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 
100-450 mg/day added to their anti-manic medication(s) for up to 16 weeks. 
• The choice of the antidepressant (escitalopram or bupropion XL) will be made 
clinically by the study psychiatrist in collaboration with the patient.  
• Patients may add the antidepressant to ongoing anti-manic treatment, or may 
commence treatment with anti-manic medication(s) and an antidepressant 
concurrently. Patients who are taking lamotrigine or quetiapine in conjunction with a 
mood stabilizer, or patients who are taking quetiapine alone, must have non-response 
to these medications established over a 6 week trial before antidepressants are 
commenced, as these medications themselves have well-established antidepressant 
properties. 
• The dose of the antidepressant will be titrated by the study psychiatrist as needed and 
as tolerated until the patient achieves remission from the index depression. 
• Dosage changes in the anti-manic medication(s) will also be permitted, as needed and 
as tolerated, at the discretion of the study psychiatrist.  
 
Patients will be assessed every 2 weeks, or more frequently if clinically indicated, during the 
open-label phase.  
 
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. Enrolment in the double-blind phase must occur within 8 weeks of remission. The 
duration of treatment in the open-label phase will be 4-16 weeks, depending on the time 
required to achieve remission. 
 
Inclusion Criteria 
Patients meeting all of the following criteria will be eligible for inclusion in the open-label 
study 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. 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
3. Taking or initiating treatment with an anti-manic medication at a therapeutic dose. If 
commencing treatment with lithium or divalproex at the screen visit, serum levels 
must be within the therapeutic range prior to randomization in the double blind 
phase. 
4. 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. 
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. 
 
 
Exclusion Criteria 
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 medications 
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.  


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
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. 
 
Medications and Dosages 
 
Study Medications  
Escitalopram will be provided in 10 mg tablets. Bupropion XL will be provided in 150 mg 
tablets. Placebo tablets identical in appearance to the study medications will also be 
provided.  
 
Mood Stabilizers and SGAs 
All of the mood stabilizers and SGAs we have chosen for this study are routinely prescribed 
in the clinical management of BD. Patients will be responsible for covering the cost of these 
medications. 
 
Open label phase treatment 
All patients will be treated with one antidepressant (escitalopram or bupropion XL) in 
combination with either:  
1. one  or two mood stabilizers (lithium or divalproex), or 
2. one SGA (risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone), or 
3. one mood stabilizer plus one SGA (including asenapine), or 
4. one mood stabilizer or one SGA plus lamotrigine 
 
Antidepressants 
Escitalopram will be initiated at a dose of 10 mg daily.  
• The dose may be increased in increments of 10 mg at the discretion of the study 
psychiatrist, until remission of the index depression.  
• In patients who develop intolerable side effects, the dose may be decreased in 10 mg 
increments.  
• The total dose must remain within the range of 10-30 mg daily. Patients who are 
unable to tolerate a minimum dose of 10 mg daily will be discontinued from the 
study.  
 
Bupropion XL will be initiated at a dose of 150-300 mg daily  
• The dose may be increased in increments of 150 mg, at the discretion of the study 
psychiatrist, until remission of the index depression.  
• In patients who develop intolerable side effects, the dose may be decreased in 150 
mg increments.  
• The total dose must remain within the range of 150-450 mg daily. Patients who are 
unable to tolerate a minimum dose of 150 mg daily will be discontinued from the 
study.  
 
Mood Stabilizers and SGAs 
Mood stabilizers and SGAs will be prescribed in the following doses: 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
• Lithium will be prescribed at a dose sufficient to produce a serum level of 0.6-1.4 
mEq/L. This usually requires 900-1800 mg/day 
• Divalproex will be prescribed at a dose sufficient to produce a serum level of 350-
700 mM. This usually requires a dose of 750-1750 mg/day 
• Risperidone 1-6 mg/day 
• Olanzapine 5-30 mg/day 
• Quetiapine IR or XR 300-900 mg/day 
• Aripiprazole 10-30 mg/day 
• Ziprasidone 80-160 mg/day 
• Asenapine 5-20 mg/day 
• Lamotrigine 100-400 mg/day 
 
Mood stabilizer dosages may be increased in the usual increments at the discretion of the 
study psychiatrist:  
• lithium 150-600 mg 
• divalproex 250-500 mg 
• risperidone 1-2 mg 
• olanzapine 5-10 mg 
• quetiapine IR or XR 50-100 mg 
• aripiprazole 5-10 mg 
• ziprasidone 40-80 mg  
• asenapine 5-10 mg 
• lamotrigine 25-50 mg 
 
In patients who develop intolerable side effects, the doses may be decreased in the same 
increments. The total dose must remain within the specified ranges. Patients who are unable 
to tolerate the minimum doses will be discontinued from the study.  
 
A blood sample will be drawn to measure serum levels of lithium or divalproex in patients 
taking these medications at the screening visit, 8 weeks, at endpoint of the open-label phase, 
and as clinically indicated. 
 
Concomitant Psychiatric Treatments 
Concomitant psychiatric medications permitted to control anxiety or insomnia during the 
open-label study phase include: 
• Lorazepam (maximum dose 4 mg daily) 
• Clonazepam (maximum dose 2 mg daily) 
• Temazepam (maximum dose 30 mg daily) 
• Zopiclone (maximum dose 15 mg daily).  
 
No other psychoactive medications are permitted.  
 
Other psychiatric treatments, including ECT, light therapy, and psychotherapy are not 
permitted. All patients will receive psychoeducation and counselling regarding sleep 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
hygiene, healthy daily routines, substance abuse, anxiety management, conflict resolution, 
and problem solving as clinically indicated. 
 
 
 
Concomitant Non-Psychiatric Treatments 
Medications used to treat underlying stable organic illnesses (eg. antihypertensives, thyroid 
supplements) are permitted, provided the dose of the medication has been stable for at least 4 
weeks prior to trial entry, and the dose is expected to remain stable throughout the trial.  
 
Use of herbal medicines such as St. John’s Wort is not permitted during the study. 
 
All concomitant medications must be documented on the Case Report Form (CRF). For any 
concomitant therapy given as a treatment for a new condition or a worsening of an existing 
condition, the condition must be documented on the Adverse Event Form of the CRF. 
 
Study Visits and Measures 
Procedures for study visits during the open-label phase are summarized in Table 1. 
 
Screening Visit 
Procedures during the screening visit include: 
• Written informed consent will be obtained. 
• A complete psychiatric and medical history will be acquired.  
• The diagnosis of BD and current depression will be confirmed using the Mini 
International Neuropsychiatric Interview (MINI) 
• The severity of depression will be ascertained using the MADRS, and the clinician 
rated and subject rated Inventory of Depressive Symptoms Scales (IDS-S and IDS-
CR). 
• The YMRS, Clinical Global Impression – Severity Scale (CGI-S-BD), Hamilton 
Anxiety Rating Scale (HAM-A) and Mood Disorders Centre Side Effects Scale 
(MDCSES) will also be administered. 
• Information about concomitant medication use will be obtained. 
• A physical examination will be performed including: vital signs, weight, hip and 
waist measurements. 
• Subjects with a personal or family history of significant cardiovascular problems or 
with cardiac abnormalities on physical exam will have an EKG. Laboratory measures 
will be obtained, including hematology, serum chemistry, liver and kidney function, 
thyroid function, cholesterol lipid screen, quantative beta Hcg levels (for all females 
of childbearing age), and urine drug screen. 
• Trough (12-hour post-dose) serum lithium or divalproex levels will be obtained in 
patients taking these medications.  
• Blood samples will be collected for genetic and epigenetic testing as well as for 
measurements of serum and intracellular neurochemicals in patients who have 
consented to this. 
• Patients taking medications not permitted by the study protocol will begin tapering 
them. The medications must be discontinued within 4 weeks. 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
 
 
 
 
 
Baseline Visit and Randomization 
 
NOTE: The baseline visit is to be conducted  within one week after the screening visit  
 
Procedures during the baseline visit include: 
• The MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, MDCSES, Quality of 
Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) will be administered  
• Information about concomitant medication use will be obtained.  
• Vital signs, weight, hip and waist measurements will be taken.  
• Patients who continue to meet all inclusion criteria and no exclusion criteria will be 
prescribed either escitalopram 10 mg daily or bupropion XL 150 mg daily for 
treatment of their depression. NOTE: Patients who are taking lamotrigine or 
quetiapine plus a mood stabilizer, or patients who are taking quetiapine alone, must 
have been on these medications for a minimum of 6 weeks prior to starting 
antidepressant medication. 
• Patients not currently taking a mood stabilizer or an SGA will be prescribed one or 
both at a therapeutic dose  
 
Weeks 2, 4, 6, 8, 10, 12, and 14 
At each follow-up visit: 
• The MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, CGI-Improvement 
(CGI-I-BD), and MDCSES will be administered.  
• Medication adherence will be assessed by patient interview and pill counts.  
• Information about concomitant medication use will be obtained 
• Vital signs, weight, hip and waist measurements will be taken.  
• Trough serum lithium or divalproex levels in patients taking these medications will 
be obtained as clinically indicated. 
 
Week 16 or Endpoint Visit 
The final study visit will occur at week 16, or when the patient has completed at least 4 
weeks of treatment, has been in remission that is maintained for ≥ 2 weeks and ≤ 8 weeks, 
and elects to enroll in the double-blind phase, or when the patient is withdrawn from the 
study for any reason.  
 
At the endpoint visit: 
• The MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, CGI-I-BD, MDCSES, 
and Q-LES-Q.  
• Medication adherence will be assessed by patient interview and pill counts.  
• Information about concomitant medication use will be obtained.  
• Vital signs, weight, hip and waist measurements will be taken, and a physical 
examination will be carried out. 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
• Laboratory investigations including hematology, serum chemistry, liver and kidney 
function, thyroid function, cholesterol, lipid screen, quantitative beta Hcg levels (for 
all females of childbearing age), urine drug screen and trough serum lithium or 
divalproex levels in patients taking these medications will be obtained.   
• Blood samples will be collected for genetic and epigenetic testing as well as for 
measurements of serum and intracellular neurochemicals 2 weeks after criteria for 
treatment response is met. 
 
Withdrawal Criteria 
A patient will be withdrawn from the open-label study phase if: 
• s/he experiences a manic or hypomanic episode  
• s/he experiences a SAE (see section below on AEs and SAEs)  
• s/he is non-adherent with study medication or anti-manic medication(s) (defined as 
missing ≥ 25% of doses of medication(s) in a 4-week period) 
• s/he withdraws consent 
• in the opinion of the study psychiatrist, it is in the patient’s best interest to be 
withdrawn from the study 
 
Data Analysis 
Analysis of data for the primary and secondary endpoints will be conducted on an intent-to-
treat basis, with the last observation carried forward for subjects who do not complete the 
open-label study phase. All statistical tests will be two-tailed, with a significance level of 
0.05. 
 
Primary Outcome 
The primary outcome for the open-label phase is mean improvement in MADRS score 
from baseline to endpoint. Improvement in MADRS scores will be analyzed using t-tests.  
 
Secondary Outcomes 
Secondary outcomes include: 
• Improvement in IDS-CR and IDS-S scores 
• Improvement in HAM-A scores 
• Rates of response, defined as ≥ 50% improvement in baseline MADRS score  
• Rates of remission, defined as a MADRS score ≤ 8 and YMRS score ≤ 8 for ≥ 2 
weeks, or a score of ≤ 2 (borderline mentally ill) on the CGI-S- BD for ≥ 2 weeks 
• Rates of treatment-emergent mania and hypomania, defined as a YMRS score ≥ 
16 for hypomania and ≥ 20 for mania at any study visit 
• Overall psychiatric status and overall improvement, using the CGI-S-BD and 
CGI-I-BD scales 
• Rates of adverse events (AEs) and serious adverse events (SAEs), using the 
MDCSES 
• Quality of life, using the Q-LES-Q. 
 
Changes from baseline to endpoint in scores on the MADRS, IDS-CR, IDS-S, HAM-A, 
YMRS, CGI-S-BD, CGI-I-BD, and Q-LES-Q will be analyzed with t-tests or ANOVA. 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
Changes from baseline to endpoint on categorical measures, including response and 
remission rates and rates of adverse events, will be analyzed using Chi-square tests.  
 
 
 
Descriptive Statistics  
Data on the following demographic and illness variables will also be gathered: 
• Age 
• Gender 
• Ethnicity 
• Marital status 
• Occupational status 
• Treatment location (inpatient versus outpatient) 
• Age at onset of illness 
• Numbers of previous depressive, manic, and hypomanic episodes 
• Length of current depressive episode 
• Number of previous trials of antidepressants, mood stabilizers, and second generation 
antipsychotic medications 
 
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. In addition, patients who respond to 
clinical treatment with carbamazepine (serum level 20-50 umol/L) 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 10. The 
antidepressant will be tapered in a double-blind manner beginning at 6 weeks, and 
will be substituted with placebo by 8 weeks.  
• Patients randomized to the “52 week arm” will continue treatment with their 
antidepressant medication for 52 weeks, or until withdrawal from the study.  
 
Allocation to the “8-week” or “52-week” arms will be done in a double-blind manner using a 
central  data centre . Randomization will be stratified in permuted blocks of size 4 based on: 
• antidepressant type (escitalopram or bupropion XL) 
• anti-manic medication(s) 
• study site 
 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
At the beginning of the double-blind phase, antidepressant medications and anti-manic 
medication(s) will be prescribed in the same dose patients received at the end of the open-
label phase.  
• A reduction in the dose of the study medication (antidepressant or placebo) will be 
permitted only in the case of intolerable side effects. The dose of the study 
medication cannot be increased during the double-blind phase. 
• A reduction in the dose of anti-manic medication(s) will be permitted only in the case 
of intolerable side effects. In addition, in patients taking lithium, divalproex, or 
carbamazepine, the dose may be increased or decreased if the serum level falls 
outside the therapeutic range (see Inclusion and Exclusion Criteria, below). 
• Any change in the dose of study medication, mood stabilizer, or SGA must be 
documented on the CRF. 
 
Patients will be assessed every 2 weeks from baseline to week 12, and then monthly until 
study endpoint, or more frequently if clinically indicated.  
 
Inclusion Criteria 
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 
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. 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
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. 
 
Medications and Dosages 
 
Antidepressants 
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. 
  
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. 
  
Pre-packaged blister packs with unique patient identification numbers will include tapering 
schedules incorporated, so that regardless of the group to which the patients are assigned, the 
number and appearance of the tablets will remain constant through the tapering process.  
 
Anti-manic medications 
Anti-manic medication doses will remain constant during the double-blind phase. The only 
exception is in the case of intolerable side effects, or if the serum level of lithium, 
divalproex, or carbamazepine falls outside of the therapeutic ranges in patients taking these 
medications.  
 
A blood sample will be drawn to measure serum levels of lithium, divalproex and 
carbamazepine, in patients taking these medications, at baseline, 24 weeks, endpoint, and at 
any other time if clinically indicated.  
 
Concomitant Psychiatric Treatments 
Concomitant psychiatric medications permitted to control anxiety or insomnia during the 
double-blind study phase include: 
• Lorazepam (maximum dose 4 mg daily) 
• Clonazepam (maximum dose 2 mg daily) 
• Temazepam (maximum dose 30 mg daily) 
• Zopiclone (maximum dose 15 mg daily).  


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
 
 
Concomitant Non-Psychiatric Treatments 
Patients may continue taking previously prescribed medications used to treat underlying 
stable organic illnesses. The use of herbal medicines is not permitted. 
 
All concomitant medications must be documented on the Case Report Form. For any 
concomitant therapy given as a treatment for a new condition or a worsening of an existing 
condition, the condition must be documented on the Adverse Event Form of the CRF. 
 
Study Visits and Measures 
Procedures for study visits during the maintenance phase are summarized in Table 3. 
 
Patients who were not enrolled in the open-label phase will need to complete the 
double-blind screening visit. In addition, a 1 page summary from the patient’s GP or a 
copy of the intake assessment will be obtained. The summary or intake assessment 
should be faxed to the PI prior to randomizing the patient.  For patients who completed 
the open-label study phase, a screening visit is not necessary.  
 
Screening Visit (for patients who were not enrolled in the open-label phase)  
Procedures during the screening visit include: 
• Written informed consent will be obtained. 
• A complete psychiatric and medical history will be acquired.  
• The diagnosis of BD and current euthymia will be confirmed using the Mini 
International Neuropsychiatric Interview (MINI) 
• The MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, and MDCSES will also 
be administered.  
• A physical examination will be performed including: vital signs, weight, hip and 
waist measurements.  
• Subjects with a personal or family history of significant cardiovascular problems or 
with cardiac abnormalities on physical exam will have an EKG.Laboratory measures 
will be obtained, including hematology, serum chemistry, liver and kidney function, 
thyroid function, cholesterol and lipid screen, quantitative beta Hcg levels (for all 
females of childbearing age), and urine drug screen.  
• Trough (12-hour post-dose) serum lithium,divalproex or carbamazepine levels will 
be obtained in patients taking these medications.  
• Patients taking medications not permitted by the study protocol will begin tapering 
them. The medications must be discontinued within 4 weeks. 
 
Baseline Visit  
NOTE: The baseline visit is to be conducted  a) within one week after the endpoint 
visit of the open label phase OR b) for those patients who were not enrolled in the 
open-label phase, within one week after the screening visit  
 
At the baseline visit: 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
• The MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, CGI-I-BD, MDCSES, 
and Q-LES-Q.  
• Medication adherence will be assessed by patient interview and pill counts (in 
patients who completed the open-label phase).  
• Information about concomitant medication use will be obtained.  
• Vital signs, weight, hip and waist measurements will be taken. 
• Neurocognitive Testing will be conducted. 
• For premenopausal women participating in nail sampling, phase of the menstrual 
cycle will be recorded 
 
Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 
Patients will be assessed every two weeks for the first 12 weeks of the double-blind phase, 
and every 4 weeks therafter.  
• The MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, CGI-I-BD, and 
MDCSES will be administered.  
• The Q-LES-Q will be administered at week 24.  
• Medication adherence will be assessed by patient interview and pill counts. 
• Information about concomitant medication use will be obtained 
• Vital signs, weight, hip and waist measurements will be taken. 
• Laboratory investigations including trough serum lithium, divalproex or 
carbamazepine levels in patients taking these medications will be obtained at week 
24, and as clinically indicated. 
• Blood samples will be collected at week 12 for genetic and epigenetic testing as well 
as for measurements of serum and intracellular neurochemicals in patients who have 
consented to this. 
• Neurocognitive Testing will be conducted only at weeks 10 and 24. 
• Nail samples will be collected at weeks 12, 24, and 36. Participants will be asked to 
trim their nails two weeks prior (to ensure 2 weeks of growth at time of collection)- 
at weeks 10, 22, 34. 
• For premenopausal women participating in nail sampling, phase of the menstrual 
cycle will be recorded at weeks 10 and 24 
 
Week 52 or Endpoint Visit 
The final study visit will occur at week 52, or when the patient is withdrawn from the study 
for any reason.  
 
At the final visit:  
• the MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, CGI-I-BD, MDCSES, 
and Q-LES-Q will be administered.  
• Medication adherence will be assessed by patient interview and pill counts. 
• Information about concomitant medication use will be obtained  
• Vital signs, weight, hip and waist measurements will be taken, and a physical 
examination will be carried out.  
• Laboratory investigations including hematology, serum chemistry, liver and kidney 
function, thyroid function, cholesterol and lipid screen, quantative beta Hcg levels 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
(for all females of childbearing age), urine drug screen and trough serum lithium or 
divalproex levels in patients taking these medications will be obtained. 
• Blood samples will be collected for genetic and epigenetic testing as well as for 
measurements of serum and intracellular neurochemicals in patients who have 
consented to this. 
 
 
Withdrawal Criteria 
A patient will be withdrawn from the double-blind study phase if: 
• s/he reaches a primary endpoint (see below)  
• s/he experiences a SAE  
• s/he is non-adherent with study medication, mood stabilizer,  SGA, or Lamotrigine 
(defined as missing ≥ 25% of doses of medication(s) in a 4-week period) 
• s/he withdraws consent 
• in the opinion of the study psychiatrist, it is in the patient’s best interest to be 
withdrawn from the study 
 
Data Analysis 
 
Primary outcome 
The primary outcome for the double-blind phase is mean survival time in the study until 
the occurrence of any mood episode (manic, hypomanic, or depressive), as determined 
using Kaplan-Meier survival analysis. A hypomanic episode is defined as a YMRS score ≥ 
16, a manic episode as a YMRS score of ≥ 20, and a depressive episode as a MADRS score 
≥ 20. The primary outcome will also be reached in any patient who  
• has a CGI-S-BD of ≥ 4 at any visit 
• is hospitalized for a mood episode 
• requires additional treatment for a mood episode in the judgment of the study 
psychiatrist.  
• has a MADRS suicide item score ≥ 4 at any visit 
• attempts or completes suicide 
 
A Cox proportional hazards model will be used to assess the difference in relapse rates 
between the “8 week” and “52 week” groups, adjusted for pre-randomization covariates, 
including drug combination and baseline patient characteristics (e.g. number of previous 
episodes). This analysis will be intention-to-treat. Patients who do not reach the endpoint 
will be included in the analysis but will have their event time censored as of the last 
completed visit. 
 
Secondary outcomes  
Secondary outcomes include: 
• time to manic or hypomanic episode 
• time to depressive episode  
• time to study discontinuation for any reason (eg. onset of mood episode, intolerable 
side effects, patient or clinician decision) 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
• the percentages of patients who experience any mood episode, a manic or hypomanic 
episode, or a depressive episode 
• the percentage of patients who experience subsyndromal symptoms and the 
percentage of time spent with subsyndromal symptoms 
• rates of adverse events and SAEs 
• mean endpoint scores on the clinical rating scales. 
 
 
Descriptive Statistics  
Data on the following demographic and illness variables will be also gathered: 
• Age 
• Gender 
• Ethnicity 
• Marital status 
• Occupational status 
• Treatment location (inpatient versus outpatient) 
• Age at onset of illness 
• Numbers of previous depressive, manic, and hypomanic episodes 
• Length of current depressive episode 
• Number of previous trials of antidepressants, mood stabilizers, and second generation 
antipsychotic medications 
• Baseline MADRS, IDS-S, IDS-CR, HAM-A, YMRS, CGI-S-BD, and QLESQ scores 
 
Changes in MADRS, IDS-CR, IDS-S, HAM-A, YMRS, CGI-S-BD, and CGI-I-BD scores 
will be analyzed using methods for longitudinal data (hierarchical/random effects models). 
The percentage or number of subjects experiencing mood episodes, depressive episodes, and 
manic episodes, as well as differences in baseline patient characteristics (severity of 
depressive episode, number of previous episodes, absence/presence of comorbidity, etc) will 
be examined using analysis of variance, Kruskal-Wallis tests, or chi-square tests of 
contingency tables as appropriate. All statistical tests will be two-tailed with a significance 
level of 0.05. 
 
ADVERSE EVENT REPORTING 
 
Adverse Event (AE) Definition 
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered a pharmaceutical product. It does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal physical exam or laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the 
investigational product. 
 
This definition includes any occurrence that is new in onset, or aggravated in severity or 
frequency from the baseline condition. An abnormal result of a diagnostic procedure, 
including a laboratory test abnormality, is considered an AE if it: 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
• Results in discontinuation from the study 
• Requires treatment or any other therapeutic intervention 
• Requires further diagnostic evaluation, excluding a repetition of the same 
procedure to confirm the abnormality 
• Is associated with clinical signs or symptoms judged by the investigator to have a 
significant clinical impact. 
 
 
Serious Adverse Event (SAE) 
Any untoward medical occurrence which: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
 
Hospitalizations due to a relapse of mania or depression will not be considered as SAEs 
since this is a normal course of the illness and is an expected occurrence. 
 
Any patient who experiences an SAE will be withdrawn from the study. All SAEs must be 
reported to the Principal Investigator within 24 hours. Medical and scientific judgment will 
be exercised in deciding whether expedited reporting of AEs other than SAEs is appropriate, 
for example adverse events that may not be immediately life-threatening or result in death or 
hospitalization, but which may jeopardize the subject or may require intervention to prevent 
one of the outcomes listed in the definition above. 
 
Unexpected Adverse Event (UAE)  
An unexpected adverse event (UAE) is any adverse event, the nature or severity of which is 
not consistent with the applicable product information, eg., investigator's brochure for an 
unapproved investigational product, or product monograph for an approved product. 
 
Associated With Use of the Drug(s) 
An AE will be considered associated with use of study medication if the attribution is 
possible, probable or very likely. 
 
Attribution Definitions 
Not Related: An AE which is not related to use of the drug(s). 
 
Doubtful: An AE for which an alternative explanation is more likely, eg. concomitant 
drug(s), concomitant disease(s), and / or the relationship in time suggests that a causal 
relationship is unlikely. 
 
Possible: An AE which may be due to use of the drug(s). An alternative explanation, eg. 
concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable, and therefore the causal relationship cannot be excluded. 
 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
Probable:  An AE which is likely due to use of the drug(s).  The relationship in time is 
suggestive, eg. it is confirmed by de-challenge. An alternative explanation, eg. concomitant 
drug(s), concomitant disease(s)is less likely. 
  
Very Likely: An AE which is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation, eg. concomitant drug(s), concomitant disease(s).  
The relationship in time is very suggestive, eg. it is confirmed by de-challenge and re-
challenge. 
 
Procedures 
All AE’s which occur between the first trial procedure, ie. administration of scales after 
signed consent, and last dose of investigational product administration, will be reported. 
Those meeting the definition of SAE must be reported within 24 hours using the SAE form.  
 
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must 
be recorded using medical terminology in the source document. Wherever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (e.g., 
cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection").  Investigators must record their opinion concerning the relationship 
of the AE to study therapy.  All measures required for AE management must be recorded in 
the source document. 
 
Serious Adverse Events 
Patients who experience a SAE will be discontinued from the trial. All SAEs occurring 
during the course of the trial must be reported within 24 hours to the Principal Investigator. 
The cause of death of a subject in a clinical trial, regardless of whether the event is expected 
or presumed to be associated with the investigational agent, is an SAE. 
 
The report must include protocol title, the subject’s study initials and date of birth, the 
subject’s unique identification number or medication code number, the period of intake of 
study medication, nature of the adverse event, and investigator's attribution. All oral reports 
of an SAE must be confirmed within five days by a written, more detailed report and signed 
by the local investigator 
 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until either: 
• the event resolves 
• the event stabilizes  
• the event returns to baseline, if a baseline value is available 
• the event can be attributed to a source other than the study drug, or to other than 
study contact 
• one month elapses after the subject’s discontinuation from the study.  
 
Pregnancies 
Pregnancies occurring after the first intake of the study medication are considered 
immediately reportable events. They must be reported to the Principal Investigator within 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
one working day after the investigator has gained knowledge of them, using the Pregnancy 
Notification Form for Clinical Trials. The subject must immediately be withdrawn  from the 
trial. Follow-up information regarding the outcome of the pregnancy and any potential 
sequelae in the infant will be required. 
Emergency Breaking of the Study Blind 
The study blind can be broken at the discretion of the study psychiatrist in exceptional 
circumstances, for example in the case of a serious adverse event in which knowledge of 
whether the patient is taking antidepressant or placebo will affect the medical care that the 
patient receives. If the study psychiatrist breaks the study blind, the reason must be 
documented in a report forwarded to the principal investigator and the Data Safety and 
Monitoring Board.  
 
SAMPLE SIZE CALCULATIONS 
Based on previous studies, we predict that half of the patients in the “8 week” study arm will 
experience a relapse of a mood episode. The relapse rates in the “52 week” study arm is 
unknown. We will power the study to detect a 20% difference in overall relapse rates (i.e, a 
50% relapse rate in the “8 week” arm and a 30% relapse rate in the “52 week” arm), as a 
difference in rates lower than this are unlikely to be clinically significant. A difference of 
20% between the groups would mean a number needed to treat (NTT) of 5, that is, one needs 
to treat 5 patients with the combination to improve outcome in one patient.  
 
Based on one year event rates of 50% and 30% in the 8-week and 52-week arms, 
respectively, the required sample size for the double-blind study phase is 95 patients per arm 
if there are no dropouts and 108 patients if the cumulative dropout rate is 25%. Thus the total 
number of patients that will be recruited to provide 80% power to detect a difference 
between the two treatment arms on the primary comparison is 216, factoring in a 25% drop-
out rate. These calculations are based on the method of Lachin and Foulkes 11. 
 
 


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Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
 
Table1: Procedures for the Open Label Study Phase 
 Visit Window: 
Every 2 weeks : +/- 2 
days 
Every 4 weeks : +/- 4 
days 
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 14 
Week  16/ 
Termination 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
MINI (5.0.0) 
X 
 
 
 
 
 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
 
 
 
 
 
Family Psychiatric 
History 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
Lab Tests 
X 
 
 
 
 
X 
 
 
 
X 
EKG 
**X 
 
 
 
 
 
 
 
 
 
Genetic/ 
Neurochemical Blood 
Samples 
X 
 
 
 
 
 
 
 
 
*X 
Vital Signs/Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hip/Waist 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IDS-CR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IDS-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
YMRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI BP-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI BP-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
MDCSES 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q-LES-Q 
 
X 
 
 
 
 
 
 
 
X 
HAM-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Count 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Samples will be collected 2 weeks after criteria for treatment response has been met. 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
**An EKG will be performed on any subject with a personal or family history of significant 
cardiovascular problems or with cardiac abnormalities on physical exam 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
Table 2: Discontinuation Schedule for Escitalopram and Bupropion XL in Patients Randomized 
to the “8-week” Study Arm 
 
Week 6 
Week 7 
Week 8 
Escitalopram 
 
 
 
30 mg daily 
20 mg daily 
10 mg daily 
STOP 
20 mg daily 
10 mg daily 
10 mg daily 
STOP 
10 mg daily 
10 mg daily 
10 mg daily 
STOP 
Bupropion XL 
 
 
 
450 mg daily 
300 mg daily 
150 mg daily 
STOP 
300 mg daily 
150 mg daily 
150 mg daily 
STOP 
150 mg daily 
150 mg daily 
150 mg daily 
STOP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
Table 3: Procedures for Double-Blind Study Phase 
 
Screening
*
Baseline 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48 
Week 52/ 
Terminat
ion 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI (5.0.0) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family 
Psychiatric 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EKG**** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab Tests 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Genetic/ 
Neurochemical 
Blood Samples 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Vital Signs/ 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hip/Waist 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IDS-CR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IDS-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
YMRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-BP-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-BP-I 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDCSES 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q-LES-Q 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
HAM-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication 
Count 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cognitive 
Testing 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Nail 
Samples** 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Phase of 
Menstrual 
Cycle*** 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
*Screening visit omitted for those participants who enter through the Open Label Phase 
Order medications 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
** Participant needs to trim nails 2 weeks prior to sample collection*** For premenopausal 
women participating in nail sampling only 
**** An EKG will be performed on any subject with a personal or family history of 
significant cardiovascular problems or with cardiac abnormalities on physical exam 


March 28, 2017 
 
Mood Stabilizer Plus Antidepressant versus Mood Stabilizer Plus Placebo in the Maintenance Treatment of Bipolar Disorder  
 
References 
1. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, 
Keller MB. The long-term natural history of the weekly symptomatic status of bipolar I 
disorder. Arch Gen Psychiatry 2002;59:530-7. 
2. Calabrese JR, Hirschfeld RM, Frye MA, Reed ML. Impact of depressive symptoms 
compared with manic symptoms in bipolar disorder: Results of a U.S. community-based 
sample. J Clin Psychiatry 2004;65:1499-504. 
3. Tohen M, Calabrese JR, Sachs GS, Banov MD, Detke HC, Risser R, Baker RW, Chou JC, 
Bowden CL. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in 
patients with bipolar I disorder responding to acute treatment with olanzapine. Am J 
Psychiatry 2006;163:247-56. 
4. Calabrese JR, Bowden CL, Sachs G, Yatham LN, Behnke K, Mehtonen OP, Montgomery 
P, Ascher J, Paska W, Earl N, DeVeaugh-Geiss J. A placebo-controlled 18-month trial of 
lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I 
disorder. J Clin Psychiatry 2003;64:1013-24. 
5. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou 
JC, Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ. A randomized, 
placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with 
bipolar I disorder. Arch Gen Psychiatry 2000;57:481-9. 
6. Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J. Patterns of 
psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. 
Psychiatr Serv 2007;58:85-91. 
7. Baillargeon J, Black SA, Contreras S, Grady J, Pulvino J. Anti-depressant prescribing 
patterns for prison inmates with depressive disorders. J Affect Disord 2001;63:225-31. 
8. Ghaemi SN, Hsu DJ, Thase ME, Wisniewski SR, Nierenberg AA, Miyahara S, Sachs G. 
Pharmacological treatment patterns at study entry for the first 500 STEP-BD participants. 
Psychiatr Serv 2006;57:660-5. 
9. Fu AZ, Krishnan AA, Harris SD, Thompson TR. The economic burden of bipolar-related 
phases of depression versus mania. Drug Benefit Trends 2004;16:569-75. 
10. Yatham LN, Kennedy SH, O'Donovan C, Parikh S, MacQueen G, McIntyre R, Sharma 
V, Silverstone P, Alda M, Baruch P, Beaulieu S, Daigneault A, Milev R, Young LT, 
Ravindran A, Schaffer A, Connolly M, Gorman CP, Canadian Network for Mood and 
Anxiety Treatments. Canadian Network for Mood and Anxiety Treatments (CANMAT) 
guidelines for the management of patients with bipolar disorder: Consensus and 
controversies. Bipolar Disord 2005;7 Suppl 3:5-69. 
11. Lachin JM FM. Evaluation of sample size and power for analyses of survival with 
allowance for nonuniform patient entry, losses to follow-up, noncompliance, and 
stratification. Biometrics 1986;42:507-19. 

SAP_001.pdf: 
 Document Title: 
Statistical Analysis Plan 
Version: 
3.0 
Date: 
April 1, 2021 
Author: 
Yongdong Ouyang, Hong Qian, Hubert Wong 
Protocol Number: 
Study Title: 
Mood Stabilizer Plus Antidepressant versus Mood 
Stabilizer Plus Placebo in the Maintenance Treatment 
of Bipolar Disorder – Randomized Trial Phase 
Sponsor-
Investigator: 
Lakshmi N. Yatham 
This document has been reviewed and approved by: 
Signature 
Date 
Study Statistician 
Yongdong Ouyang 
April 1, 2021 
[list other SAP Review 
Team members as 
appropriate] 
Hubert Wong 
April 1, 2021 
Sponsor Representative 
or Sponsor-Investigator 
Lakshmi Yatham 
April 1, 2021 
FINAL STATISTICAL ANALYSIS PLAN
60


 
 
 
SAP_V3.0_2021-04-01 
 
 
SOPSM_01_T01_04 – Statistical Analysis Plan 
 
Page 2 of 8 
TABLE OF CONTENTS 
1.0 INTRODUCTION ....................................................................................................... 3 
1.1 Study Description ............................................................................................... 3 
1.2 Trial Design ........................................................................................................ 3 
1.3 Objectives .......................................................................................................... 3 
1.3.1 Primary .................................................................................................... 3 
1.3.2 Secondary ............................................................................................... 3 
1.3.3 Additional ................................................................................................ 3 
1.4 Eligibility Criteria ................................................................................................ 3 
1.4.1 Inclusion .................................................................................................. 3 
1.4.2 Exclusion ................................................................................................. 3 
2.0 DATA SUMMARIES AND ANALYSES ...................................................................... 3 
2.1 Trial Information and Patient Disposition ........................................................... 3 
2.2 Baseline and Demographic Variables ................................................................ 3 
2.3 Primary Outcome ............................................................................................... 4 
2.3.1 Primary Analysis ..................................................................................... 4 
2.3.2 Sensitivity Analyses ................................................................................ 4 
2.4 Secondary Outcome .......................................................................................... 4 
2.5 Other Outcomes ................................................................................................ 4 
2.6 Sub-Studies in the Appendix of the Protocol ...................................................... 4 
2.7 Interim Analyses ................................................................................................ 4 
2.8 Safety Data ........................................................................................................ 4 
2.8.1 Adverse Events (AEs) ............................................................................. 4 
2.8.2 Serious Adverse Events (SAEs) .............................................................. 4 
2.9 Concomitant Medications ................................................................................... 4 
3.0 ADDITIONAL METHODOLOGICAL DETAILS ........................................................... 4 
3.1 Statistical Tests .................................................................................................. 4 
3.2 Software to be Used .......................................................................................... 4 
4.0 REVISION HISTORY ................................................................................................. 5 
 
 
 
 
 
 
 
 
1.0 
INTRODUCTION 
1.1 
Study Description 
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. This 
study is to assess the safety and the efficacy of antidepressants combined with mood stabilizers 
61


in comparison to placebo plus mood stabilizers in the maintenance treatment of bipolar disorder. 
1.2 
Trial Design 
The study is a multicenter, randomized, double-blind clinical trial to compare mood stabilizer 
plus antidepressant (escitalopram or bupropion XL) to mood stabilizer plus placebo in the 
maintenance treatment of Bipolar disease (BD). This trial consists of two separate phases: Open-
label Acute Treatment Phase and Double-blind Maintenance Treatment Phase. This SAP is for 
the Double-blind Maintenance Treatment Phase (DBMTP).  
Patients may enter the DBMTP either: (1) following successful completion of the open-label 
phase, defined as have adequately tolerated the combination of antidepressant plus mood 
stabilizer, and is currently in remission for ≥ 2 weeks and ≤ 8 weeks, (2) directly (without having 
been enrolled in the open-label phase) if there is evidence that the patient had entered remission 
with antidepressant plus antimanic mood stabilizing medication and the remission was within 2 
to 8 weeks.  
The patients continue treatment with their anti-manic medication(s), and will be randomized to 
1) the “8 week arm”: the antidepressant is tapered in a double-blind manner beginning at 6 
weeks, and will be substituted with placebo by 8 weeks and continued up to 52 weeks; or 2) the 
“52 week arm”: the antidepressant medication is continued up to 52 weeks. Randomization was 
stratified in permuted blocks of size 4 within combinations of: 
• antidepressant type (escitalopram or bupropion XL)  
• anti-manic medication(s)  
• study site (Canada, India, Korean) 
Patients visits occurs at baseline then week 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48 and a final visit at week 52 (or when they withdraw from the study). 
1.3 
Objectives 
1.3.1 Primary 
To assess whether continuing antidepressant treatment for 12 months reduces the risk of relapse 
into any mood episode, including depression, mania, and hypomania, compared to discontinuing 
the antidepressant and substituting it with placebo after 2 months.  
 
1.3.2 Secondary 
1) Does continuing antidepressant treatment for 12 months reduce the risk of relapse into 
depression?  
2) Does continuing antidepressant treatment for 12 months increase the risk of developing a 
manic or hypomanic episode?  
3) Do rates of subsyndromal mood symptoms and adverse events differ between patients who 
continue antidepressant treatment for 12 months compared to those who stop the 
antidepressant after 2 months?  
4) Does 12-month antidepressant treatment improve overall health and quality of life for 
patients, compared to stopping treatment after 2 months? 
 
 
62


1.4 
Eligibility Criteria 
1.4.1 Inclusion 
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.  
 
1.4.2 Exclusion 
If a patient meets any of following criteria, she/he was excluded from the study: 
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. 
 
 
2.0 
DATA SUMMARIES AND ANALYSES 
2.1 
Data analysis general information 
Study data will be analyzed using the most updated SAS version and/or R in PC environment. 
All statistical tests will be two-sided, with significance levels of 0.05. 
2.2 
Trial Information and Patient Disposition 
The following information will be presented: 
• number of participants enrolled 
• number of participants completing each visit of follow-up 
• median follow-up time 
• frequency table for the reasons for going off-study (from the “Off Study” CRF)  
• frequency table for the reasons for discontinuation (from the “Permanent Discontinuation 
63


from Protocol” CRF) 
•
a CONSORT Flow Diagram
2.3 
Baseline and Demographic Variables 
Summary statistics such as the mean, median, standard deviation, minimum, maximum and inter-
quartile range for continuous variables and the number and percentage of participants with 
various levels of categorical variables will be calculated for all participants enrolled for the 
following variables. All summary statistics will be calculated for each treatment group 
individually as well as for all treatment groups combined. Also, these summaries will be 
computed separately for the escitalopram and bupropion XL groups. 
CRF 
Field 
E.g., Screening -
Demographics
•
Age
•
Gender
•
Ethnicity
•
Marital status
•
Occupational status
•
Treatment location (inpatient versus outpatient)
•
Age at onset of illness
•
Numbers of previous depressive, manic, and
hypomanic episodes
•
Length of current depressive episode
•
Drug combination
•
Baseline MADRS, IDS-S, IDS-CR, HAM-A,
YMRS, CGI-S-BD, and QLESQ scores
2.4 
Primary Outcome 
2.4.1 Primary Analysis 
The primary outcome is time to occurrence of any mood episode (manic, hypo-manic, 
depressive). Occurrence of mood episode was defined as any one of following: 
1) hypomanic episode defined as a YMRS score ≥ 16;
2) manic episode defined as a YMRS score of ≥ 20;
3) depressive episode defined as a MADRS score ≥ 20;
4) a CGI-S-BD of ≥ 4;
5) hospitalization for a mood episode;
6) additional treatment required for a mood episode in the judgment of the treating psychiatrist;
7) a MADRS suicide item score ≥ 4;
8) attempted or completed suicide.
Kaplan-Meier curve will be used to summarize the time to any mood episode by treatment arm.
Ae Cox proportional hazards model will be used to compare the outcome between the two arms
with adjustment for drug combinations (anti-manic medication and antidepressants), age and sex.
64


The time origin of the survival analysis is the time of enrollment. A patient who do not 
experience a primary outcome will be censored at the time of the patient’s last visit.  
Results will be reported using hazard ratios with 95% confidence intervals, and the number 
needed to treat to avoid one outcome event by 52 weeks. 
 
2.4.2 Sensitivity Analyses 
 
To account for the intervention being identical in the two arms during the first six weeks, 
the primary analysis will be repeated with all events prior to and including the six-week 
follow-up visit excluded and the time origin of the survival analysis is set to the six-week 
follow-up visit. 
 
2.4.3 Subgroup Analyses 
 
Subgroup analyses for the primary outcome will be conducted for the two antidepressant 
medications (escitalopram or bupropion). Country will be included to check if the conclusions 
similar using data from India alone. 
 
2.5 
Secondary Outcome 
• Time to manic or hypomanic episode  
• Time to depressive episode  
• Time to study discontinuation for any reason (e.g. onset of mood episode, intolerable side 
effects, patient or clinician decision) 
Analogous to the primary analysis, Kaplan-Meier curves and Cox proportional hazard models 
will be used to summarize and to compare the time to each of these events of interest between 
the two arms. Patients who do not experience the event of interest will be censored at the time of 
the last follow-visit. 
• The number of weeks the patient was “healthy” (defined as MADRS <=8)  
Poisson regression will be used to compare two arms. If a substantial number of patients have no 
subsyndromal symptoms (or overdispersion observed), negative binomial regression will be used 
instead. 
• The percentage of patients who experience subsyndromal symptoms 
• The percentages of patients who experience any mood episode, a manic or hypomanic 
episode, or a depressive episode 
• Rates of adverse events and SAEs 
• Mean endpoint scores on the clinical rating scales. 
 
Summary statistics will be provided by groups.  
 
2.6 
Other Outcomes 
2.7 
Sub-Studies in the Appendix of the Protocol 
2.8 
Interim Analyses 
65


N/A 
2.9 
Safety Data 
2.9.1 Adverse Events (AEs) 
 
Number (proportions) of AEs defined in the proposal in each group will be summarized and 
reported by groups 
2.9.2 Serious Adverse Events (SAEs) 
 
Number (proportions) of SAEs defined in the proposal in each group will be summarized and 
reported by groups 
 
2.10 Concomitant Medications 
All concomitant medications must be documented on the Case Report Form (CRF) 
 
3.0 
ADDITIONAL METHODOLOGICAL DETAILS 
3.1 
Statistical Tests 
Cox proportional hazard model 
Linear-mixed effect model 
3.2 
Software to be Used 
Study data will be analyzed using the most updated SAS version and/or R 
4.0 
REVISION HISTORY 
Version 
Date 
Summary of Changes 
2.0 
May 22, 
2020  
Separate open-label phase and double blinded phase 
3.0 
April 1, 
2021 
Finalized selection of adjustment variables 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
66