GABA_A receptors as targets for treating affective and cognitive symptoms of depression

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_AR) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABA_ARs with neuroactive steroids (NASs) or of α5-containing GABA_ARs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABA_AR-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented.