“Neurosteroids: Uses and Mechanisms”

Steven Mennerick, PhD
Associate Dean of Graduate Education
Professor of Psychiatry and Neuroscience
John P. Feighner Professor of Neuropsychopharmacology
Scientific Director, Taylor Family Institute for Innovative Psychiatric Research
WashU Medicine

Neurosteroids have emerged as a novel class of therapeutics in neuropsychiatry, particularly for postpartum depression (PPD), where brexanolone and zuranolone represent landmark FDA-approved treatments. These agents act as potent positive allosteric modulators (PAMs) of GABAA receptors, with high efficacy and unique receptor subtype selectivity. Broader applications require deeper mechanistic understanding, which in turn requires new approaches. Recent studies integrating machine learning with medium-throughput biological screening have uncovered new potential mechanisms of neurosteroid action. These findings suggest that neurosteroids may engage autophagy pathways, exert anti-inflammatory effects and interact with GPCRs, supporting their promise as multi-target therapeutics. Innovative structures, such as analogues suitable for DART and for BIOTAC, promise to reveal additional insights. Structural analogues and cell-type selectivity may fine-tune receptor interactions and minimize side effects. This translational narrative, from endogenous steroid biology to clinical application, underscores the importance of mechanistic insight in drug development and highlights opportunities for innovation in treating mood disorders.