This is a feasibility study of performing repeated EEG recordings and assessment of affective states during open-label administration of BRX to women with postpartum depression. Study phases will include screening, enrollment, intervention, and follow-up. Subjects will be screened for study eligibility criteria through clinical assessments and self-report. Enrolled subjects will be admitted to the UNC Women's Hospital, where five serial EEG recordings will be obtained, along with frequent assessments of affective state, before, during, and after a 60-hour IV infusion of BRX. Follow-up procedures will include assessments of PPD and affective symptoms, as well as an exit interview with the study team. If feasibility outcomes are achieved, exploratory EEG analyses will be performed with AMICA (adaptive mixture independent component analysis), community detection, and microstate assessment. Exploratory analyses of data collected by facial expression detection software (iMotions Affectiva) are also planned.

Inclusion Criteria:

• Signed informed consent.
• Documented proof of full COVID-19 vaccination
• Ambulatory, female, aged 18-45
• ≤ 8 months postpartum
• Agrees to adhere to the study requirements.
• Onset of depression in 3rd trimester or within 4 weeks of delivery
• Meets DSM-V criteria for major depressive disorder with peripartum onset.
• 17-item HAM-D total score ≥20 at screening
• Stopped breastfeeding or agrees to temporarily stop for 7 days including 4 days of hospitalization and 3 days after
• No new psychotropic drugs during screening and active treatment of study
• Stable use of any current psychotropic drugs for at least 28 days prior to enrollment, with stable dosage for at least 14 days prior to enrollment
• Must be on documented contraceptive.
• Must have a caregiver or family member with them to help care for the subject's child(ren) during the infusion and to be in the room with the subject if the child(ren) are present during the infusion

Exclusion Criteria:

• Positive pregnancy test at screening or day 1
• Pregnancy that resulted in a stillbirth, termination, or child that was placed for adoption.
• Renal impairment or failure, hepatic impairment or failure, or anemia
• Untreated or inadequately treated hypothyroidism or hyperthyroidism
• Known allergy to progesterone or allopregnanolone.
• Suicide attempt at this episode
• Medical history of schizophrenia, and/or schizoaffective disorder
• Current psychotic symptoms including delusions, hallucinations, or formal thought disorder.
• Concurrent substance abuse
• Exposure to another investigational medication or device within 30 days
• Has previously participated in any study employing brexanolone or SAGE-217.
• Subject is investigative site personnel, sponsor personnel, or an immediate member of their family.
• Has received electroconvulsive therapy during current episode.
• History of seizure disorder
• On anticonvulsant agents
• On benzodiazepines

Women with moderate to severe PPD, medically eligible to receive FDA-approved BRX infusion, recruited from current inpatient and outpatient population in the Women's Mood Disorders Clinic at UNC and through local advertisements. Subjects recruited from outpatient setting will be individuals for whom BRX is the chosen recommended course of treatment.

From first dose of study drug up to end of follow-up period (up to Day 30)