Patients  Inclusion Criteria:  Outpatients 18 to 60 years of age. Meet DSM-5 criteria for MDE in MDD as determined by the MINI. Episode duration ≥ 3 months. 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. 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 60 years of age. No history of psychiatric disorders (as determined by the modified MINI v.6.0.) or significant physical conditions (e.g. arthritis, fibromyalgia). Fluency in English, sufficient to complete the interviews and self-report questionnaires.