Clinical trial NCT03427892
Conditions: Bipolar Depression
Keywords: mood bipolar depression
Sponsor: University of Texas Southwestern Medical Center
Start date: 2017-03-01; Completion date: 2018-03-15
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators will conduct an 8-week, non-randomized, open-label study of brexpiprazole in 20 persons with bipolar I or II disorder, depressed mood state. Primary aim will be to assess if brexpiprazole is associated with a reduction in depressive symptom severity using the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary aims will include an assessment of the following in patients with bipolar disorder taking brexpiprazole: manic symptoms, cognition, safety and tolerability of brexpiprazole, and quality of life.

Subjects will be discontinued from the study if any of the following conditions occurs: change in diagnosis to other than bipolar I or II disorder, development of active suicidal or homicidal ideation with plan and intent, worsening of mood symptoms, that in the opinion of the investigators requires discontinuation, pregnancy, development of severe life-threatening medical condition, involuntary psychiatric hospitalization or incarceration.

Detailed description:
We will conduct an 8-week, non-randomized, open label study of brexpiprazole in 20 persons with bipolar disorder. Primary Aim will be to determine if brexpiprazole is associated with a reduction in depressive symptom severity using the Montgomery-Asberg Depression Rating Scale (MADRS) in outpatients with bipolar disorder, depressed mood state. Secondary Aims will be: 1) Assess manic symptoms in patients with bipolar disorder receiving brexpiprazole, 2) Assess cognition in patients with bipolar disorder receiving brexpiprazole, 3) Assess the safety and tolerability of brexpiprazole in patients with bipolar disorder, 4) Assess quality of life in patients with bipolar disorder receiving brexpiprazole. Subjects will be discontinued from the study if any of the following conditions occurs: change in diagnosis to other than bipolar I or II disorder, development of active suicidal or homicidal ideation with plan and intent, worsening in mood symptoms, that in the opinion of the investigators requires discontinuation, pregnancy, development of severe or life-threatening medical condition, involuntary psychiatric hospitalization or incarceration.

Study Procedures:

Baseline: This visit will be split into two portions: Baseline 1 and Baseline 2.

For Baseline 1 (\~3 hours), the psychiatric diagnosis will be confirmed by the structured clinical interview for DSM-5 (SCID), mood assessed via the Montgomery-Asberg Depression Rating Scale (MADRS), depression via the Inventory of Depressive Symptomatology Self-Report (IDS-SR30), mania via the Young Mania Rating Scale, and quality of life via the Quality of Life in Bipolar Disorder (QOLBD). Blood will be drawn for complete blood count (CBC), Comprehensive Metabolic Panel (CMP, includes a liver panel with AST, ALT, as well as lipids), and high-sensitivity c-reactive protein (hs-CRP). A urine sample for drug screen and pregnancy test (if applicable), psychiatrist assessment, physical exam, collection of weight and vitals will be completed.

For Baseline 2 (\~2 hours), recent depressive symptoms will be assessed via the IDS-SR30 and MADRS, mania via the YMRS, current mood via Internal State Scale (ISS), suicidal ideation will be assessed via the Columbia Suicide Severity Rating Scale (CSSRS), safety and side effects will be assessed with the SAFTEE, the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Scale (BAS) and Simpson-Angus Scale (SAS). Subjects will also complete the The Ray Auditory Verbal Learning Test (RAVLT) to assess word memory, the Stroop test to measure attention, speed, and accuracy of thinking, and The Trail Making Test (TMT) to measure attention, speed and accuracy. A urine sample for drug screen and pregnancy test (if applicable) will also be completed. Brexpiprazole capsules will be initiated at 0.5 mg/day.

Baseline 2 to Week 1: Subjects will be given the ISS to fill out at home. Subjects will be asked to complete the scale at home on 7 consecutive days between Baseline 2 and Week 1 visits and return the filled out scales to the researcher's office. The scale will take approximately 3-5 minutes to fill out.

Week 1, 2, 3, 6 (\~1.5 hours each): Subjects will complete the MADRS, YMRS, IDS-SR30, ISS, SAFTEE, CSSRS, AIMS, BAS, SAS, and a urine sample will be collected for a drug screen. Subjects will meet with the psychiatrist for weekly assessment and vitals will be collected.

Week 4 (\~2 hours): Subjects will complete the MADRS, IDS-SR, YMRS, SAFTEE, ISS, C-SSRS, AIMS, BAS, SAS, RAVLT, Stroop, TMT, vital signs, a urine sample for a drug screen and a urine pregnancy test, and visit the doctor for a psychiatric evaluation.

Week 8 (final visit \~2.5 hours): Subjects will complete the MADRS, IDS-SR, YMRS, SAFTEE, ISS, C-SSRS, AIMS, BAS, SAS, RAVLT, Stroop, TMT, QOLBD, vital signs, a urine sample for drug screen, take a urine pregnancy test, have blood drawn for clinical testing (CBC, CMP, hs-CRP), and visit the doctor for a psychiatric evaluation and physical exam. During this visit, participants will also be provided with aftercare referral information and will begin their medication taper. The medication taper schedule is described below under "Study Medication and Intervention Description".

Safety Phone Call (\~15 min): Participants will receive a phone call from researchers 7-10 days following their Week 8 study visit (at the end of their tapering schedule). During this phone call, the researchers will assess any withdrawal effects or adverse events and check on the status of the aftercare referrals.

Participants will be paid for their time and inconvenience per visit as follows: $60 at Baseline 1, Baseline 2, weeks 1, 2, 3, 6; $70 at week 4; $90 for week 8. Participants will also be paid for each ISS scale they bring back at the rate of $1 per scale (maximum $7). These payments will be processed during Week 1 visit. These payments will be completed via the ClinCard system. Bus or rail passes will be provided. After study completion, standard psychiatric care will be provided until referral is arranged.

Study Medication and Intervention Description:

Participants will be initiated on a 0.5 mg/day brexpiprazole dose (week 0/baseline); after one week the dose will be increased to 1 mg/day (week 1), after another week to 2 mg/day (week 2). If any dose appears to be poorly tolerated, the dose titration can be slowed or stopped based on clinician judgment. If response in weeks 3-6, defined as a 50% reduction in the MADRS, has not been achieved, and the current dose is well tolerated, then additional dose increases to 3 mg/day and 4 mg/day (maximum allowed dose in protocol) will occur with at least a one week interval between dose increases.

Following the last study visit (Week 8), participants will be gradually tapered off the medication every 2 days until they stop taking the medication completely. For example, if a participants takes 4 mg of brexpiparzole at Week 8, then he/she will take 3 mg for 2 days, then 2 mg for 2 days, then 1 mg for 2 days, and then 0.5 mg for 2 days. At the end of the tapering period (7-10 days depending on the highest brexpiprazole dose at the end of the study), participants will receive a safety phone call from a research staff member to assess any withdrawal symptoms and check on the status of the aftercare referrals.

Biostatistics:

Primary Aim: Determine if brexpiprazole is associated with a reduction in depressive symptom severity in outpatients with bipolar disorder, depressed mood state.

1. The MADRS will be the primary outcome measure with the IDS-SR as a secondary outcome measure. Weekly scores on the MADRS and IDS-SR will be assessed using one-way repeated measures. Analysis of Covariance (rm-ANCOVA), controlling for age and sex as potential confounding variables, with time as the main effect. Participants will be included if they complete one post-baseline assessment (intent-to-treat sample). In addition, rates of depression response (≥ 50% reduction from baseline) and remission (≤10 on the MADRS and ≤12 on the IDS-SR) will be assessed. A significance level of 0.05 will be set for all analyses, with all tests being two-tailed.

   Secondary Aims:
2. Assess manic symptoms in patients with bipolar disorder receiving brexpiprazole. YMRS scores will be assessed as with the primary aim above.
3. Assess cognition in patients with bipolar disorder receiving brexpiprazole. Scores on the RAVLT, Stroop and TMT will be assessed at baseline compared to weeks 4 and 8 separately using paired t-tests or paired-sample Wilcoxon Signed Rank test.
4. Assess the safety and tolerability of brexpiprazole in patients with bipolar disorder. Scores on the SAFTEE, C-SSRS, AIMS, BAS and SAS will be assessed as with the primary aim.
5. Assess quality of life in patients with bipolar disorder receiving brexpiprazole. The QOLBD will be assessed as above for cognition.
6. Assess peripheral inflammation in patients with bipolar disorder receiving brexpiprazole. Values on hs-CRP will be compared between baseline and exit as with cognition above.
7. Assess relationships between changes in outcomes measures. Correlations between outcome measures (e.g. depressive symptoms and cognition, depressive symptoms and inflammation) will be assessed using Pearson's or Spearman's correlation coefficients.

Arms: arm 1: Brexipiprazole will be taken orally beginning at 0.5 mg/day with an increase to 1 mg/day at week 1 and 2 mg/day at week 2. If reduction in mood symptoms does not occur, the dose will increase to 3 mg/day and 4 mg/day.
Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: Brexpiprazole is an atypical antipsychotic drug that is used to treat mental/mood disorders.

Protocol documents:
Prot_SAP_000.pdf: 
Version #1, 10/21/16 
Page 1 of 9 
The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Protocol  
 
Title: Brexpiprazole for Bipolar Disorder  
 
Principal Investigator: E. Sherwood Brown, M.D., Ph.D.  
 
Funding Sponsor: Otsuka America Pharmaceuticals, Inc.  
 
1. Introduction and Purpose:  
Brexpiprazole is effective for both major depressive disorder and schizophrenia. However, to 
date no studies have examined its safety and efficacy in bipolar disorder. We hypothesize that 
brexpiprazole will be associated with a reduction in depressive symptom severity in outpatients with 
bipolar disorder, depressed mood state. The proposed open-label trial will examine brexpiprazole in a 
group of 20 bipolar depressed outpatients. 
 
Primary Aim: Determine if brexpiprazole is associated with a reduction in depressive symptom 
severity using The Montgomery-Asberg Depression Rating Scale (MADRS) in outpatients with bipolar 
disorder, depressed mood state.  
Secondary Aims: 
1) Assess manic symptoms in patients with bipolar disorder receiving brexpiprazole. 
2) Assess cognition in patients with bipolar disorder receiving brexpiprazole. 
3) Assess the safety and tolerability of brexpiprazole in patients with bipolar disorder. 
4) Assess quality of life in patients with bipolar disorder receiving brexpiprazole. 
Additional Exploratory Analyses: 
1) Assess peripheral inflammation in patients with bipolar disorder receiving brexpiprazole. 
2) Assess relationships between changes in outcome measures. 
 
2. Background: 
Bipolar depression is common and challenging to treat. Brexpiprazole may be a promising 
treatment for Bipolar Disorder (BPD), which is a severe and persistent psychiatric illness affecting 1.6-
3.5% of the population (6, 7). In addition to manic episodes, persons with BPD frequently experience 
depression. Depression in BPD may be particularly challenging to treat. Findings from the STEP-BD 
study indicate that bipolar depression may not respond well to selective serotonin reuptake inhibitors, 
which are a standard treatment for major depressive disorder (MDD) (8). Lamotrigine is commonly 
prescribed for bipolar depression, but it appears to be more effective than placebo only for severe 
depression (9). Only three medications (quetiapine, the combination of olanzapine and fluoxetine, and 
lurasidone) are FDA-approved for bipolar depression. Thus, new, safe, and effective treatments for 
the depressed phase of BPD are badly needed. Brexpiprazole is a partial agonist at dopamine D2 
receptors that is structurally similar to aripiprazole. Data suggest that brexpiprazole is effective both 
as an adjunct treatment for major depressive disorder (10) and as a treatment for schizophrenia (11), 
and has FDA approval for both indications. 
Given the promising findings in both major depressive disorder and schizophrenia, a proof-of-
concept study is proposed to examine the safety and tolerability, as well as efficacy of brexpiprazole 
in patients with bipolar depression. Depressive symptoms will be assessed using both observer-rated 
and self-rated depression scales. Manic symptoms and quality of life will also be assessed. Safety 
and tolerability will be assessed using a side-effects scale as well as standard antipsychotic 
extrapyramidal symptom rating scales. Cognitive domains relevant to bipolar depression will be 
assessed. Because bipolar depression is associated with high sensitivity elevated C-reactive protein 
levels (hs-CRP, an inflammatory biomarker) (12) and data suggest that brexpiprazole decreases hs-
CRP levels (13), hs-CRP levels will also be assessed at baseline and exit, and the relationships 
between changes in these levels and clinical outcomes explored. 


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3. Concise Summary of Project: 
 
We will conduct an 8-week, non-randomized, open label study of brexpiprazole in 20 persons 
with bipolar disorder. Primary Aim will be to determine if brexpiprazole is associated with a reduction 
in depressive symptom severity using the Montgomery-Asberg Depression Rating Scale (MADRS) in 
outpatients with bipolar disorder, depressed mood state. Secondary Aims will be:  1) Assess manic 
symptoms in patients with bipolar disorder receiving brexpiprazole, 2) Assess cognition in patients 
with bipolar disorder receiving brexpiprazole, 3) Assess the safety and tolerability of brexpiprazole in 
patients with bipolar disorder, 4) Assess quality of life in patients with bipolar disorder receiving 
brexpiprazole. 
Subjects will be discontinued from the study if any of the following conditions occurs: change 
in diagnosis to other than bipolar I or II disorder, development of active suicidal or homicidal ideation 
with plan and intent, worsening in mood symptoms, that in the opinion of the investigators requires 
discontinuation, pregnancy, development of severe or life-threatening medical condition, involuntary 
psychiatric hospitalization or incarceration.   
 
4. Study Procedures: 
Baseline: This visit will be split into two portions: Baseline 1 and Baseline 2.  
 
For Baseline 1 (~3 hours), the psychiatric diagnosis will be confirmed by the structured clinical 
interview for DSM-5 (SCID), mood assessed via the Montgomery-Asberg Depression Rating Scale 
(MADRS), depression via the Inventory of Depressive Symptomatology Self-Report (IDS-SR30), mania 
via the Young Mania Rating Scale, and quality of life via the Quality of Life in Bipolar Disorder 
(QOLBD). Blood will be drawn for complete blood count (CBC), Comprehensive Metabolic Panel 
(CMP, includes a liver panel with AST, ALT, as well as lipids), and high-sensitivity c-reactive protein 
(hs-CRP).  A urine sample for drug screen and pregnancy test (if applicable), psychiatrist assessment, 
physical exam, collection of weight and vitals will be completed.  
 
For Baseline 2 (~2 hours), recent depressive symptoms will be assessed via the IDS-SR30 and 
MADRS, mania via the YMRS, current mood via Internal State Scale (ISS), suicidal ideation will be 
assessed via the Columbia Suicide Severity Rating Scale (CSSRS), safety and side effects will be 
assessed with the SAFTEE, the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia 
Scale (BAS) and Simpson-Angus Scale (SAS). Subjects will also complete the The Ray Auditory 
Verbal Learning Test (RAVLT) to assess word memory, the Stroop test to measure attention, speed, 
and accuracy of thinking, and The Trail Making Test (TMT) to measure attention, speed and accuracy. 
A urine sample for drug screen and pregnancy test (if applicable) will also be completed. 
Brexpiprazole capsules will be initiated at 0.5 mg/day.  
 
Baseline 2 to Week 1: Subjects will be given the ISS to fill out at home. Subjects will be asked to 
complete the scale at home on 7 consecutive days between Baseline 2 and Week 1 visits and return 
the filled out scales to the researcher’s office. The scale will take approximately 3-5 minutes to fill out. 
 
Week 1, 2, 3, 6 (~1.5 hours each): Subjects will complete the MADRS, YMRS, IDS-SR30, ISS, 
SAFTEE, CSSRS, AIMS, BAS, SAS, and a urine sample will be collected for a drug screen. Subjects 
will meet with the psychiatrist for weekly assessment and vitals will be collected. 
 
Week 4 (~2 hours): Subjects will complete the MADRS, IDS-SR, YMRS, SAFTEE, ISS, C-SSRS, 
AIMS, BAS, SAS, RAVLT, Stroop, TMT, vital signs, a urine sample for a drug screen and a urine 
pregnancy test, and visit the doctor for a psychiatric evaluation. 
 
Week 8 (final visit ~2.5 hours): Subjects will complete the MADRS, IDS-SR, YMRS, SAFTEE, ISS,   
C-SSRS, AIMS, BAS, SAS, RAVLT, Stroop, TMT, QOLBD, vital signs, a urine sample for drug 
screen, take a urine pregnancy test, have blood drawn for clinical testing (CBC, CMP, hs-CRP), and 
visit the doctor for a psychiatric evaluation and physical exam. During this visit, participants will also 


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be provided with aftercare referral information and will begin their medication taper. The medication 
taper schedule is described below under “Study Medication and Intervention Description”. 
 
Safety Phone Call (~15 min): Participants will receive a phone call from researchers 7-10 days 
following their Week 8 study visit (at the end of their tapering schedule). During this phone call, the 
researchers will assess any withdrawal effects or adverse events and check on the status of the 
aftercare referrals. 
 
Participants will be paid for their time and inconvenience per visit as follows: $60 at Baseline 1, 
Baseline 2, weeks 1, 2, 3, 6; $70 at week 4; $90 for week 8. Participants will also be paid for each ISS 
scale they bring back at the rate of $1 per scale (maximum $7). These payments will be processed 
during Week 1 visit. These payments will be completed via the ClinCard system. Bus or rail passes 
will be provided. After study completion, standard psychiatric care will be provided until referral is 
arranged. 
 
Study Medication and Intervention Description: 
Participants will be initiated on a 0.5 mg/day brexpiprazole dose (week 0/baseline); after one 
week the dose will be increased to 1 mg/day (week 1), after another week to 2 mg/day (week 2). If 
any dose appears to be poorly tolerated, the dose titration can be slowed or stopped based on 
clinician judgment. If response in weeks 3-6, defined as a 50% reduction in the MADRS, has not been 
achieved, and the current dose is well tolerated, then additional dose increases to 3 mg/day and 4 
mg/day (maximum allowed dose in protocol) will occur with at least a one week interval between dose 
increases. 
Following the last study visit (Week 8), participants will be gradually tapered off the medication 
every 2 days until they stop taking the medication completely. For example, if a participants takes 4 
mg of brexpiparzole at Week 8, then he/she will take 3 mg for 2 days, then 2 mg for 2 days, then 1 mg 
for 2 days, and then 0.5 mg for 2 days. At the end of the tapering period (7-10 days depending on the 
highest brexpiprazole dose at the end of the study), participants will receive a safety phone call from a 
research staff member to assess any withdrawal symptoms and check on the status of the aftercare 
referrals. 
 
5. Sub-Study Procedures: 
No sub-study procedures are anticipated at this time. 
 
6. Criteria for Inclusion of Subjects: 
 
Outpatient men and women ages 18-65 
 
Bipolar I or II disorders, currently depressed mood state based on a SCID for DSM-5; Mixed 
features in DSM-5 are allowed, but those with a Young Mania Rating Scale score ≥ 15 will be 
excluded  
 
MADRS score ≥ 25 at baseline 2 visit. 
 
7. Criteria for Exclusion of Subjects: 
 
Mood disorders other than bipolar I or II disorders (e.g., bipolar NOS, or cyclothymic disorders, 
schizophrenia, schizoaffective disorder, or unipolar depression based on the SCID), other 
disorders, e.g. anxiety disorders, will be allowed  
 
Current (last 14 days) treatment with an antipsychotic or antidepressant. If a participant has been 
treated with any antipsychotic or antidepressant in the last 14 days, then they will not be enrolled 
in the study. No washout of antipsychotic or antidepressant will be done 
 
History of neuroleptic malignant syndrome or tardive dyskinesia  
 
Prior history of brexpiprazole use  
 
Vulnerable populations (e.g., pregnant, nursing, cognitively impaired, incarcerated) 


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 
High risk for suicide defined as > 1 attempt in past 12 months that required medical attention, any 
attempt in the past 3 months or current suicidal ideation with plan and intent such that outpatient 
care is precluded  
 
Severe or life-threatening medical condition, or laboratory or physical examination findings 
consistent with serious medical illness (e.g., dangerously abnormal electrolytes)  
 
Moderate or severe hepatic or renal impairment based on medical history and laboratory analyses 
 
Taking moderate or strong inducers or inhibitors of CYP2D6 or CYP3A4 
 
8. Sources of Research Material: 
 
Clinical information will be obtained via the Structured Clinical Interview for DSM (SCID), 
Montgomery-Asberg Depression Rating Scale (MADRS), Inventory of Depressive Symptomatology–
Self-Report 30-item version (IDS-SR30), Young Mania Rating Scale (YMRS), Columbia Suicide 
Severity Rating Scale (C-SSRS), Systematic Assessment for Treatment Emergent Effects (SAFTEE), 
Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Scale (BAS), Simpson-Angus Scale 
(SAS), Ray Auditory Verbal Learning Test (RAVLT), The Stroop and Trail Making Test (TMT).  
 
Biological information will be obtained via blood drawn (2 tbsp ~ 29mLs) for laboratory 
analyses including a complete blood count (CBC) and Comprehensive Metabolic Panel (CMP, 
includes a liver panel with AST, ALT, as well as lipids), high-sensitivity c-reactive protein (hs-CRP). A 
redraw may be requested if the first sample cannot be processed. A physical examination will be 
performed, weight obtained, and a urine sample collected for a drug screen and pregnancy testing. 
 
9. Recruitment Methods and Consenting Process: 
Participants will be recruited from the community through advertisements (flyers, newspaper 
ads, etc.), by previous contact with the Psychoneuroendocrinology Research Program (PNE), and by 
referrals. Dr. Brown has been successful in recruiting this patient population (bipolar depression) in 
the past, as evidenced by completion of recruitment (80 participants) for STU122009-069 (bipolar 
depression clinical trial), as well as ongoing clinical trials in bipolar disorder and substance use 
(STU112013-075, STU072014-005, STU102015-062). We will look to aforementioned studies for 
possible participants who expressed interest in future research.  
Our success in recruiting participants for our previous and ongoing large scale studies 
demonstrates that we have the resources and contacts necessary to recruit participants for this 
project, and that we already have established measures in place to accomplish our recruitment goals 
(20 participants).  
Potential participants who are referred to us or who respond via the various recruitment 
strategies will be contacted by telephone. Participants who remain interested and eligible for 
participation based on the telephone prescreen may be asked to come into our clinic for a diagnostic 
screening visit. Once noted as eligible, the staff member will discuss the procedures they will undergo 
if they choose to participate in the study. After reading the informed consent, study staff will discuss 
these issues with the potential participant and will answer any questions he or she may have about 
the study and participation. If the individual chooses to sign the informed consent document, he or she 
may begin testing for the study. All research procedures, risks and potential benefits, as well as 
incentives for participation are clearly and accurately explained in the consent. 
 
10. Potential Risks: 
Study Procedure/Intervention 
As per exclusion criteria, participants with any prior history of brexpiprazole use will be 
excluded from the study. However, to avoid unforeseen events, we will still inform participants that 
brexpiprazole is contraindicated in patients with a known hypersensitivity to brexpiprazole or any of its 
components. Adverse reactions have included rash, facial swelling, urticaria (hives), and anaphylaxis 
(a severe, potentially life-threatening allergic reaction). Components of brexpiprazole include 
brexpiprazole, lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, 
lowsubstituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc. 
 


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Brexpiprazole may cause some, all or none of the side-effects listed below. 
 
Most common (>10%) 
- 
Akathisia 
(agitation, 
restlessness) 
- 
Weight gain 
Less Common (1-10%) 
- 
Headache, drowsiness, fatigue, dizziness, anxiety, 
movement disorders, sedation, abnormal dreams, 
insomnia, excessive sweating, decreased cortisol, 
indigestion, increased appetite, constipation, diarrhea, 
abdominal pain, flatulence, nausea, excess drooling, 
dry mouth/throat, urinary tract infection, tremor, 
muscle pain, increased creatine, blurred vision, upper 
respiratory infection 
Serious but Rare 
- 
Dystonia (involuntary muscle contractions) 
- 
Hyperglycemia (high blood sugar) 
- 
Increased fat levels (cholesterol and triglycerides) in the blood. 
- 
Low white blood cell count. 
- 
Decreased blood pressure (orthostatic hypotension). 
- 
Seizures (convulsions). 
- 
Body temperature dysregulation. 
- 
Difficulty swallowing. 
 
 
Black Box Warning 
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED 
PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT 
DRUGS 
- 
Elderly patients with dementia-related psychosis treated with antipsychotic drugs 
are at increased risk of death. REXULTI (BREXPIPRAZOLE) is not approved for the 
treatment of patients with dementia-related psychosis. 
- 
Antidepressants increase the risk of suicidal thoughts and behaviors in patients 
aged 24 years and younger in short-term studies. Monitor closely for clinical 
worsening and for emergence of suicidal thoughts and behaviors. 
 
There are also certain medications that may have clinically significant interactions with 
brexpiprazole. These medications are moderate or strong inducers or inhibitors of CYP3A4 or 
CYP2D6. Examples of these medications include, but are not limited to, paroxetine, fluoxetine, 
quinidine, many HIV medications, etc. A full list of these medications will be made available to 
participants. This list will also be attached in the IRB application. Participants who currently take 
moderate or strong inducers or inhibitors of CYP3A4 or CYP2D6 will be excluded from the study. If 
participants start taking moderate or strong inducers or inhibitors of CYP3A4 or CYP2D6 during their 
study participation, they will be discontinued from the study and appropriate aftercare referral 
information will be provided. 
Participants will be instructed to let the researchers know of any prescription medications, 
over-the-counter medications, vitamins and herbal supplements they are currently taking or of ANY 
new medications they may start taking during their study participation. 
 
Participants will also be informed of potential interaction brexpiprazole may have with alcohol. 
 
 
Psychological Stress 


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Some of the questions we will ask you as part of this study may make you feel uncomfortable.  You 
may refuse to answer any of the questions, take a break or stop your participation in this study at any 
time. 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  Every effort will be 
made to keep your information confidential; however, this cannot be guaranteed.  
 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage sperm, which could cause harm to a child that a 
participant may father while on this study. Subjects who participate in this study and are sexually 
active, must agree to use a medically-acceptable form of birth control. Medically-acceptable forms of 
birth control include: 
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
 
Females: Subjects participating in this study while pregnant or breast-feeding an infant may expose 
the unborn child or infant to risks.  For that reason, pregnant and breast-feeding females cannot 
participate in the study.  If a participant becomes pregnant, a blood pregnancy test will be done (using 
1 teaspoon of blood drawn from a vein by needle-stick), and it must be negative before the subject 
participates in this study. Subjects who participate in this study and are sexually active, they and any 
person that they have sex with must use medically-acceptable birth control (contraceptives) during the 
study.  Medically-acceptable birth control (contraceptives) includes: 
(1) surgical sterilization (such as hysterectomy or “tubes tied”), 
(2) approved hormonal contraceptives ( such as birth control pills, patch or ring; Depo-Provera, 
Implanon), 
(3) barrier methods (such as condom or diaphragm) used with a spermicide (a substance that 
kills sperm), or  
(4) an intrauterine device (IUD). 
If a subject does become pregnant during this study, they are informed that they must tell the 
researchers immediately.  
 
Risks of Blood Drawing  
Risks associated with drawing blood from the arm include minimal discomfort and/or bruising. 
Infection, excess bleeding, clotting, and/or fainting also are possible, although unlikely. 
 
11. Subject Safety and Data Monitoring: 
 
The likely risks from the study are primarily medication side effects and the risk of untreated 
bipolar disorder and depressive symptoms. Brexpiprazole is reasonably well tolerated and may have 
metabolic side effects than most other atypical antipsychotics. All participants will receive active 
medication (brexpiprazole) during the study, as well as frequent monitoring and follow-up 
appointments with a psychiatrist and research coordinator. Thus, all participants will receive care for 
mood symptoms. At the end of study, patients will be given follow-up appointments at treatment 
facilities we have worked with in the past, and, if needed, we will provide a longer period of aftercare 
until treatment can be transitioned to another provider. These are our standard procedures for 
research studies and have been in place for over 17 years. Another potential risk is worsening of 
mood symptoms. If participants have a worsening of mood symptoms, such as active suicidal 
ideation, study participation will be discontinued, and we will provide them with referrals for 
appropriate care. Some level of suicidal ideation is common in the participants we research. However, 
we want to take steps to prevent risk of suicidal acts. Thus, the emergence of intense suicidal 
thoughts with a clear plan (e.g. overdose) and the intent to act on the plan would require 
discontinuation from the study. However, recurrent suicidal thoughts accompanied by a clear 


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understanding that the participant does not plan to act on these thoughts would not require 
discontinuation.  
Potential pharmacokinetic or pharmacodynamic drug-drug interactions will be managed using 
inclusion, exclusion, and discontinuation criteria and dose adjustments. Clinical assessments are 
collected by trained and experienced staff members who will be able to reassure participants if they 
are distressed during study visits. If participants become fatigued or stressed during the testing, rest 
periods will be provided. Standard, appropriate measures will be used to minimize risk of infection 
during venipuncture. 
All investigators and research staff will be available 24 hours a day. The consent form will 
have both daytime and nighttime numbers for reaching study personnel. Business cards for the 
research coordinator and psychiatrists will also be provided. In the event an investigator or research 
coordinator is on vacation or out-of-town, coverage will be provided, and both the research 
coordinator and UT Southwestern answering service are informed of the name and pager number of 
the physician-on-call. In the event of a medical or psychiatric emergency, appropriate medical advice 
will be provided including recommendations for emergency room evaluation if necessary. The PI and 
other physicians involved with the study have staff privileges at the Parkland and William P. Clements 
University Hospital Emergency Rooms, which are likely to be the most commonly used hospitals by 
the participants. The physicians and other staff have extensive experience working with patients with 
bipolar disorder and substance use disorders. 
All women of childbearing potential (premenopausal and without a clearly documented 
hysterectomy, ovariectomy or bilateral tubal ligation) must have a urine pregnancy test with negative 
results prior to receiving study medication. These participants will also be asked to use effective forms 
of contraception during the study. Pregnancy or failure to use contraceptives will result in 
discontinuation from the study. 
These are general guidelines. In all cases, physician judgment will be used to determine 
whether or not a participant can safely remain in the study. 
 
12. Procedures to Maintain Confidentiality: 
Blood specimens will be provided to Quest Diagnostics for analysis, removing identifying 
information (e.g., name) that could be linked to the patient’s identity prior to sending for analysis. The 
blood provided to Quest will have the participant’s date of birth to correctly link the results to the 
participant. The results of this test will be de-identified and added to the rest of the de-identified data. 
Once de-identified, only the identified investigators can learn/discover the names of participant. 
 
Data Management Plan  
All data related to the participant’s participation in this study will be given a study ID which cannot be 
traced back to the patient except by study staff. All personal information which can identify the 
patient’s identity will be kept separately from study documents and assessments. All clinical 
assessments will be collected in paper form and scores transferred to a computer database 
maintained on a password protected computer, on a secure server behind a firewall. The paper forms 
will be kept in binders marked only with the patient’s study ID and will be kept in a locked room for the 
required time period following the completion of this study.  
 
A Certificate of Confidentiality will be obtained for this study. 
 
13. Potential Benefits: 
This is a non-randomized open-label clinical trial, thus all participants will receive study 
medication. All participants may personally benefit from the study by experiencing a significant 
reduction in symptoms of depression associated with bipolar disorder. The researchers hope the 
information learned from this study will benefit others with bipolar depression in the future. Information 
gained from this research could lead to better treatment of patients with bipolar depression. 
 
14. Biostatistics: 


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Primary Aim: Determine if brexpiprazole is associated with a reduction in depressive symptom 
severity in outpatients with bipolar disorder, depressed mood state. 
1) The MADRS will be the primary outcome measure with the IDS-SR as a secondary 
outcome measure. Weekly scores on the MADRS and IDS-SR will be assessed using 
one-way repeated measures. Analysis of Covariance (rm-ANCOVA), controlling for age 
and sex as potential confounding variables, with time as the main effect. Participants 
will be included if they complete one post-baseline assessment (intent-to-treat sample). 
In addition, rates of depression response (≥ 50% reduction from baseline) and 
remission (≤10 on the MADRS and ≤12 on the IDS-SR) will be assessed. A 
significance level of 0.05 will be set for all analyses, with all tests being two-tailed. 
Secondary Aims: 
2) Assess manic symptoms in patients with bipolar disorder receiving brexpiprazole. 
YMRS scores will be assessed as with the primary aim above. 
3) Assess cognition in patients with bipolar disorder receiving brexpiprazole. Scores on 
the RAVLT, Stroop and TMT will be assessed at baseline compared to weeks 4 and 8 
separately using paired t-tests or paired-sample Wilcoxon Signed Rank test. 
4) Assess the safety and tolerability of brexpiprazole in patients with bipolar disorder. 
Scores on the SAFTEE, C-SSRS, AIMS, BAS and SAS will be assessed as with the 
primary aim. 
5) Assess quality of life in patients with bipolar disorder receiving brexpiprazole. The 
QOLBD will be assessed as above for cognition. 
6) Assess peripheral inflammation in patients with bipolar disorder receiving 
brexpiprazole. Values on hs-CRP will be compared between baseline and exit as with 
cognition above. 
7) Assess relationships between changes in outcomes measures. Correlations between 
outcome measures (e.g. depressive symptoms and cognition, depressive symptoms 
and inflammation) will be assessed using Pearson’s or Spearman’s correlation 
coefficients. 
 
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