Patient-Specific Considerations, the GABA Pathway, and New Clinical Trial Data on Neuroactive Steroids in MDD and PPD

Major depressive disorder (MDD) and major depressive episode with peripartum onset, commonly referred to as postpartum depression (PPD), are among the most common psychiatric illnesses and are leading contributors to disability and suicide. Standard of care antidepressants are the cornerstone of MDD treatment; however, nonadherence to antidepressants has been widely recognized as one of the reasons for treatment failure in MDD. Delayed response in current therapies can take up to 4 or even 8 weeks for patients to experience therapeutic benefits. Low treatment response rates are seen in a considerable amount of patients, with early-stage treatment-resistant depression (TRD) affecting 50% of patients receiving first-line treatments and 30% developing into substantive TRD. Given these treatment gaps, there is an urgent need to develop novel antidepressants with a faster onset of action and shorter treatment course, which could improve adherence and treatment response rates. The neurobiology of depression is multifactorial, with different pathways converging on the development of the neurocircuit dysfunction characteristic of depression. Neuroactive steroids play an important role in modulating acute and chronic stress via their phasic and tonic inhibitory effects on select GABA_A receptors, ultimately modulating neurocircuit function. With clinical recognition of the importance of neurosteroids in the modulation of GABAA signaling pathways, researchers have developed novel neuroactive steroid-based pharmacotherapies that have been tested in clinical studies. Given their rapid onset of action and shorter treatment course, these novel antidepressants have the potential to change the treatment paradigm for MDD and PPD.