Optimized Predictive Treatment In Medications for Unipolar Major Depression (OPTIMUM-D)

Patients Inclusion Criteria: * Outpatients 18 to 65 years of age. * Meet DSM-5 criteria for MDE in MDD as determined by SCID-5. * Free of psychotropic medications for at least 5 half-lives (e.g. 1 week for most antidepressants, 5 weeks for fluoxetine) before baseline Visit 1 (exceptions: stable use of hypnotics; stable use of stimulants for attention-deficit/hyperactive disorder). * MADRS score ≥ 24. * Fluency in English, sufficient to complete the interviews and self-report questionnaires. Exclusion Criteria: * Any diagnosis, other than MDD, that is considered the primary diagnosis. * Bipolar I or Bipolar-II diagnosis. * Presence of a significant Axis II diagnosis (borderline, antisocial). * High suicidal risk, defined by clinician judgment. * Substance dependence/abuse in the past 6 months. * Presence of significant neurological disorders, head trauma, or other unstable medical conditions. * Pregnant or breastfeeding. * Failure of 4 or more adequate pharmacologic interventions (as determined by the Antidepressant Treatment History Form). * Started psychological treatment within the past 3 months with the intent of continuing treatment. * Patients who have previously failed escitalopram or showed intolerance to escitalopram or brexpiprazole, and patients at risk for hypomanic switch (i.e. with a history of antidepressant induced hypomania). Healthy Comparison (HC) Participants Inclusion Criteria: * 18 to 65 years of age. * No history of psychiatric disorders (as determined by SCID-5) or significant physical conditions (e.g. arthritis, fibromyalgia). * Fluency in English, sufficient to complete the interviews and self-report questionnaires.