A neuroactive steroid (NAS) targeting δ-GABAA receptors has been approved for the treatment of peripartum depression; clinical trials of NASs for the treatment of major depressive disorder are ongoing.

Preclinical studies indicate that both positive and negative modulators of α5-GABAA receptors (α5-GABAARs) have antidepressant-like actions; we discuss a model that explains how bidirectional modulation of the same GABAA receptor population can result in antidepressant-like action.

A model for how positive allosteric modulation of α5-GABAARs may lead to an improved signal-to-noise ratio in cortical microcircuits and thus restored information processing and cognitive function is discussed.