Study on the Efficacy, Safety, and Tolerability of Cariprazine Relative to Placebo in Participants With Bipolar I Depression

Inclusion Criteria:

- Currently meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) criteria for bipolar I disorder without psychotic features confirmed
by the administration of the Mini International Neuropsychiatric Interview (MINI),
with a current major depressive episode of at least 4 weeks and not exceeding 12
months in duration

- Currently treated as an outpatient at the time of enrollment

- A verified previous manic or mixed episode. Verification must include one of the
following sources: --Treatment of mania with an anti-manic agent (eg, lithium or
divalproate) or antipsychotic medication with an approved indication for mania
--Hospital records/Medical records --Participant report corroborated by caretaker or
previous or current treating clinician

- 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≥ 20

- HAMD-17 item 1 score ≥ 2

- Clinical Global Impressions-Severity (CGI-S) score ≥ 4

- Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test (women of
childbearing potential only)

- Normal physical examination, clinical laboratory test results, and electrocardiogram
(ECG) results or abnormal findings that are judged not clinically significant by the
Principal Investigator (PI)

Exclusion Criteria:

- Young Mania Rating Scale (YMRS) total score > 12

- Four or more episodes of a mood disturbance (depression, mania, hypomania, or mixed
state) within the 12 months before Visit 1

- Any current axis 1 psychiatric diagnosis other than bipolar disorder with the
exception of specific phobias

- History of meeting DSM-5 criteria for: ○ Dementia, amnesic, or other cognitive
disorder ○ Schizophrenia, schizoaffective, or other psychotic disorder

○ Mental retardation - DSM-5-based diagnosis of borderline or antisocial personality
disorder or other axis II disorder of sufficient severity to interfere with
participation in this study

- History of meeting DSM-5 criteria for alcohol or substance abuse or dependence (other
than nicotine or caffeine) within the 6 months before Visit 1

- Positive result on blood alcohol test or urine drug screen for any prohibited
medication. Exception: ○ Participants with a positive cannabinoid on entry may be
retested before randomization. If the participant remains positive, the participant is
no longer eligible ○ Participants positive for opiates on entry, discussion with Study
Physician is required.

- Electroconvulsive therapy in the 3 months before Visit 1

- Previous lack of response to electroconvulsive therapy

- Treatment with a depot antipsychotic drug within 1 treatment cycle before Visit 1

- Treatment with clozapine in a dose of > 50 mg/day in the past 2 years

- Prior participation in any investigational study of RGH-188 or cariprazine within the
past 12 months

- Previous treatment with vagus nerve stimulation or transcranial magnetic stimulation
within 6 months before Visit 1

- Prior participation with any clinical trials, involving experimental or
investigational drugs, within 6 months before Visit 1 or during the study

- Initiation or termination of psychotherapy for depression within the 3 months
preceding Visit 1, or plans to initiate, terminate, or change such therapy during the
course of the study.

- Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study

- Gastric bypass or any condition that would be expected to affect drug absorption (lap
band procedures are acceptable if there is no problem with absorption)

- Known history of cataracts or retinal detachment

- Known human immunodeficiency virus infection

- Employee, or immediate relative of an employee, of the Sponsor, any of its affiliates
or partners, or the study center