New directions in neurosteroid therapeutics in neuropsychiatry

In recent years three neuroactive steroids (NAS), brexanolone (allopregnanolone, AlloP), ganaxolone and zuranolone, have been approved for the treatment of neuropsychiatric illnesses including postpartum depression and seizures in a neurodevelopmental syndrome. The approved agents are pregnane steroids and strong positive allosteric modulators (PAMs) of gamma-aminobutyric acid type A receptors (GABA_ARs). Broad effects on GABA_ARs play important roles in therapeutic benefits. However, these NAS also have actions on non-GABAR targets that could be important for clinical outcomes. Thus, understanding the broader effects of NAS is potentially important for expanding the therapeutic landscape of these important modulators. The approved NAS as well as other structurally distinct NAS and oxysterols have effects on non-GABA_AR receptors and ion channels, along with intracellular actions that could have therapeutic importance, including modulation of cellular stress mechanisms, neuroinflammation, mitochondrial function and autophagy, among others. In this review, we explore GABAergic and other cellular effects of pregnane steroids including novel molecules that have potential therapeutic importance. This work discusses the complex chemical nature of NAS and what is being learned at cellular, molecular, synaptic and brain network levels about key sites of action including GABA_ARs and other targets.