GABAergic Neuroactive Steroids and Network States: Relevance to Peripartum Depression

The Food and Drug Administration's approval of allopregnanolone analogs, which function as positive allosteric modulators at GABA_A (gamma-aminobutyric acid A) receptors, for the treatment of postpartum depression is a major advance in neuroscience research and psychiatry. Neuroactive steroid (NAS)-based antidepressant effects likely involve the ability to restore network states within and between emotional-processing hubs. Here, we review the role of steroid hormones and NASs, particularly progesterone and allopregnanolone, in preparing the brain for the transition to motherhood. We highlight preclinical and clinical findings that elucidate the networks that are altered in the maternal brain. Furthermore, we summarize the changes in brain networks implicated in peripartum depression (PPD). Preclinical and clinical evidence support disrupted network states contributing to PPD and a role for altered GABAergic and NAS signaling in its underlying pathophysiology. Recent advances continue in the identification of biomarkers for predicting PPD, and the development of the next generation of treatments offers additional promise for the prevention or treatment of PPD.