Brexanolone, a First‐In‐Class Neurosteroid Medication: Mechanism of Action, Clinical, and Translational Science

ABSTRACT

Given the increasing prevalence of postpartum depression (PPD) and the stigma associated with this condition, it is essential to address this significant health concern. Brexanolone is an FDA‐approved treatment for PPD that works by positive‐allosteric modulation of type A γ‐aminobutyric acid (GABA _A ) receptors. As an intravenous version of allopregnanolone, brexanolone is known for its rapid onset of action and lasting impact on depressive symptoms in patients with PPD, with significant reductions in depressive symptoms observed by the end of the 60‐h infusion and improvements maintained through Day 30 of follow‐up. The quick onset is particularly important as traditional first‐line treatment for PPD can take up to several weeks to produce observable improvements. Despite its efficacy, the clinical use of brexanolone is limited by the need for a continuous 60‐h intravenous infusion and mandatory enrollment in Risk Evaluation and Mitigation Strategy (REMS) program due to risks of excessive sedation and sudden loss of consciousness. Brexanolone is metabolized through non‐CYP‐mediated pathways, including keto‐reduction, glucuronidation, and sulfation; therefore, no dose adjustments are required in patients with mild to severe renal impairment (eGFR 15–89 mL/min/1.73 m ² ). However, its use should be avoided in end‐stage renal disease (eGFR < 15 mL/min/1.73 m ² ) due to potential accumulation of its solubilizing vehicle, betadex sulfobutyl ether sodium. While primarily indicated for PPD, brexanolone is under investigation for post‐traumatic stress disorder, alcohol use disorder, postpartum psychosis, and tinnitus. Future research focusing on alternative delivery methods and expanded therapeutic indications could make brexanolone more accessible and broaden its clinical utility.