Abstract
In the past 20 years, our understanding of the pathophysiology of depression has evolved from a focus on an imbalance of monoaminergic neurotransmitters to a multifactorial picture including an improved understanding of the role of glutamatergic excitatory and GABAergic inhibitory neurotransmission. FDA-approved treatments targeting the glutamatergic [esketamine for major depressive disorder (MDD)] and GABAergic (brexanolone for peripartum depression) systems have become available. This review focuses on the GABA(A) receptor (GABA(A)R) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABA(A)Rs with neuroactive steroids (NASs) or of α5-containing GABA(A)Rs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABA(A)R-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented.