Brexpiprazole for Bipolar Depression

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.

Inclusion Criteria:

- 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

- Baseline MADRS score ≥ 20

Exclusion Criteria:

- 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

- History of neuroleptic malignant syndrome or tardive dyskinesia

- Prior history of brexpiprazole use

- Vulnerable populations (e.g., pregnant, nursing, cognitively impaired, incarcerated)

- 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 induces or inhibitors of CYP2D6 or CYP3A4