Allopregnanolone-based treatments for postpartum depression: Why/how do they work?

Recent FDA approval of an allopregnanolone-based treatment specifically for postpartum depression, brexanolone, now commercially called Zulresso (R), is an exciting development for patients and families impacted by postpartum depression and allows us to start asking questions about why and how this compound is so effective. Allopregnanolone is a neuroactive steroid, or neurosteroid, which can be synthesized from steroid hormone precursors, such as progesterone, or synthesized de novo from cholesterol. Neurosteroids are positive allosteric modulators at GABA(A) receptors (GABA(A)Rs), a property which is thought to mediate the therapeutic effects of these compounds. However, the durability of effect of brexanolone in clinical trials questions the mechanism of action mediating the remarkable antidepressant effects, leading us to ask why and how does this drug work. Asking why this drug is effective may provide insight into the underlying neurobiology of postpartum depression. Exploring how this drug works will potentially elucidate a novel antidepressant mechanism of action and may provide useful information for next generation drug development. In this review, we examine the clinical and preclinical evidence supporting a role for allopregnanolone in the underlying neurobiology of postpartum depression as well as foundational evidence supporting the therapeutic effects of allopregnanolone for treatment of postpartum depression.