The neurosteroid paradigm in perinatal depression: From pathophysiology to precision therapeutics

Abstract

Neurosteroids and their role in the pathophysiology of perinatal depression have been in the focus of scientific investigation for several decades. Recently, two synthetic analogs of the neurosteroid allopregnanolone—brexanolone and zuranolone—received approval in the United States for the treatment of postpartum depression (PPD) exhibiting a rapid, long‐lasting antidepressant effect through a novel mechanism of action. These developments mark a milestone in psychiatric research and advancement in available treatment options. In this review, we examine the role of neurosteroids in perinatal depression, with particular emphasis on their impact on network states and functional connectivity. We synthesize current clinical experience with brexanolone and zuranolone in the treatment of PPD, highlighting efficacy and practical considerations. Finally, we explore emerging precision medicine approaches that leverage the heterogeneity of clinical presentations and treatment responses in PPD to guide the development of targeted therapeutic strategies for this widely prevalent and debilitating condition.