Inclusion Criteria:  Primary Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition criteria Diagnosis of Major Depressive Disorder Currently receiving sertraline for at least 90 days and maintained on stable sertraline doses of ≥100 mg/day for at least 30 days at the time of Screening  Exclusion Criteria:  Sexually active males or females, who could become pregnant, not agreeing to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days at the end of the study Diagnosed hypertension (including treated or untreated hypertension), or orthostatic hypotension Epilepsy or a history of seizures History of neuroleptic malignant syndrome or serotonin syndrome. Primary DSM-5 diagnosis of Schizophrenia spectrum and other psychotic disorders, Bipolar and related disorders, Feeding and eating disorders (including anorexia nervosa or bulimia), Neurocognitive disorders (including but not limited to delirium, major or mild neurocognitive disorder due to Alzheimer's, Parkinson's, or traumatic brain injury) A significant risk of committing violent acts, serious self-harm, or suicide History of diabetes mellitus (type 1 or type 2) Subjects with any previous exposure to brexpiprazole, or subjects with chronic use of prazosin or propranolol in the 90 days prior to the screening visit or any use in the 21 days (3 weeks) prior to the screening visit.