Novel neurosteroid therapeutics for post-partum depression: perspectives on clinical trials, program development, active research, and future directions

Abstract

This article reviews novel neurosteroid therapeutics for post-partum depression, with a focus on their development, clinical trial data, current practices, and future directions in this exciting field. We discuss the clinical impact of brexanolone and several other neurosteroids, particularly as they relate to the treatment of postpartum depression (PPD) and major depressive disorders outside of the perinatal period. There has been increasing interest in GABA signaling and modulation as it pertains to the development of altered circuity and depressive states. This scientific underpinning served as the rationale for the initial development of brexanolone. We review the clinical trials supporting its Food and Drug Administration (FDA) approval as the first rapidly acting antidepressant specific for PPD, and the subsequent development of a clinical brexanolone program at an academic medical center, highlighting new research and data from that site as well as the challenges with the delivery of this I.V. drug. In addition to the GABA signaling hypothesis, we discuss the new evidence demonstrating that brexanolone inhibits inflammatory signaling post-infusion, suggesting that inflammatory signaling may contribute to the etiology of PPD. Finally, we describe new and future directions in neurosteroid therapeutics, including the development of an oral agent, zuranolone, and the IV and oral formulations of ganaxolone. Ultimately, the hope is that these novel neurosteroid therapeutics will provide fast-acting treatment for these impairing disorders and improve our understanding of the underlying mechanisms of depressive disorders.