A Trial to Evaluate the Efficacy, Safety & Tolerability of Brexpiprazole in the Maintenance Treatment of Adults With Major Depressive Disorder

Inclusion Criteria:

• Participants with both a diagnosis of recurrent major depressive disorder, and in acurrent major depressive episode of ≥ 8 weeks in duration, as defined by Diagnosticand Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and confirmed by boththe Mini International Neuropsychiatric Interview (MINI) and an adequate clinicalpsychiatric evaluation.
• Participants must have reported a history for the current major depressive episode ofan inadequate response to 1 or 2 adequate antidepressant treatments, and participantsmust currently be taking a protocol-mandated antidepressant treatment at an adequatedose and duration, and most not have reported ≥ 50% improvement. For participants whoare currently on an adequate dose of protocol-mandated antidepressant therapy (ADT),but for an inadequate duration, can use the screening period to achieve adequateduration. At Phase A baseline visit, all participants must have either 2 or 3documented inadequate responses to antidepressant treatment in total for the currentepisode as defined by the Massachusetts General Hospital Antidepressant TreatmentResponse Questionnaire (ATRQ).
• Participants with a Hamilton Rating Scale for Depression (HAM-D17) total score ≥ 18 atthe screening visit, and Phase A baseline visits.
• Participants willing to discontinue all prohibited psychotropic medications to meetprotocol-required washouts prior to and during the trial period.

Exclusion Criteria:

• Females who are breast-feeding and/or who have a positive pregnancy test result priorto receiving investigational medicinal product (IMP).
• Sexually active males or females of childbearing potential who do not agree topractice 2 different methods of birth control or remain abstinent during the trial andfor 30 days after the last dose of IMP.
• Participants who report treatment with adjunctive antipsychotic medication with anantidepressant for a minimum of 3 weeks during the current major depressive episode.
• Participants who report allergies or an intolerability (lifetime treatment history) totrial-provided ADTs that have not been prescribed to the participant during thecurrent major depressive episode.
• Participants who have received electroconvulsive therapy (ECT) for the current majordepressive episode.
• Participants who have had an inadequate response to ECT at any time in the past or whohave had a vagus nerve stimulation or deep brain stimulation device implanted at anytime for the management of treatment-resistant depression. Participants who have hadtranscranial magnetic stimulation during the current major depressive episode.
• Participants with a current need for involuntary commitment or who have beenhospitalized within 4 weeks of screening for the current major depressive episode.
• Participants with a primary DSM-5 diagnosis of:

1. Schizophrenia Spectrum and Other Psychotic Disorders
2. Bipolar and Related Disorders
3. Obsessive Compulsive Disorders
4. Feeding and Eating Disorders
5. Neurocognitive Disorders
6. Panic Disorder
7. Post-Traumatic Stress Disorder

• Participants with a current DSM-5 diagnosis of borderline, antisocial, paranoid,schizoid, schizotypal, or histrionic personality disorder or intellectual disability.
• Participants experiencing hallucinations, delusions, or any psychotic symptomatologyin the current major depressive episode.
• Participants receiving new onset psychotherapy (individual, group, marriage or familytherapy) within 42 days of screening or at any time during participation in the trial.
• Participants who have met DSM-5 criteria for substance use disorder (moderate orsevere) within the past 60 days; including alcohol and benzodiazepines, but excludingnicotine.
• Participants with hypothyroidism or hyperthyroidism (unless condition has beenstabilized with medications for at least the past 90 days) and/or an abnormal resultfor free T4 at screening.
• Participants who currently have clinically significant neurological, hepatic, renal,metabolic, hematological, immunological, cardiovascular, pulmonary, orgastrointestinal disorders such as any history of myocardial infarction, congestiveheart failure, HIV seropositive status/acquired immunodeficiency syndrome, chronichepatitis B or C.
• Participants with diabetes mellitus (IDDM and non-IDDM) are ineligible for the trialunless their condition is stable and well-controlled.
• Participants with uncontrolled hypertension (DBP > 95 millimetres of mercury [mmHg])or symptomatic hypotension, or orthostatic hypotension which is defined as a decreaseof ≥ 30 mmHg in systolic blood pressure (SBP) and/or decrease of ≥ 20 mmHg indiastolic blood pressure (DBP) after at least 3 minutes standing compared to theprevious supine blood pressure OR development of symptoms.
• Participants with known ischemic heart disease or history of myocardial infarction-orcongestive heart failure (whether controlled or uncontrolled).
• Participants with epilepsy or a history of seizures, except for a single seizureepisode.
• Participants with a positive drug screen for cocaine or other drugs of abuse (excluding known prescription stimulants and other medications and marijuana).Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screenare not exclusionary if, in the investigator's documented opinion, the participantdoes not meet DSM-5 criteria for moderate to severe substance use disorder and thepositive test does not signal a clinical condition that would impact the safety of theparticipant or interpretation of the trial results, and participation is agreed to bythe medical monitor prior to treatment.
• Treatment with a monoamine oxidase inhibitor (MAOI) within 14 day prior to the firstdose of IMP in Phase A.
• Use of benzodiazepines and/or hypnotics (including non-benzodiazepine sleep aids)within 7 days prior to first dose of IMP in Phase A.
• Use of varenicline within 5 days prior to the first dose of IMP in Phase A.
• Use of oral (or immediate release intramuscular) neuroleptics within 7 days prior orlong-acting approved neuroleptics ≤ 1 full cycle plus 1/2 cycle prior to the firstdose of IMP in Phase A.
• Participants who would be likely to require prohibited concomitant therapy during thetrial.
• Participants who have been exposed to brexpiprazole in any prior clinical trial or hasreceived commercial brexpiprazole (Rexulti).
• Participants with a history of neuroleptic malignant syndrome or serotonin syndrome.
• Participants with a history of true allergic response to more than one class ofmedications.
• Prisoners or participants who are compulsorily detained for treatment of either apsychiatric or physical illness.
• Participants who participated in any clinical trial within the last 60 days or whoparticipated in more than 2 clinical trials within the past year.