Allopregnanolone: From molecular pathophysiology to therapeutics. A historical perspective

Allopregnanolone is synthesized in the central nervous system either de novo from cholesterol or from steroid hormone precursors like progesterone and pregnenolone. Over the past 30 years, direct and rapid, non-genomic actions of allopregnanolone and its derivatives via GABA_A receptors have been demonstrated. Changes in brain levels of allopregnanolone during pregnancy and in the postpartum period, or during exposure to protracted stress appear to play a crucial role in the pathophysiology of mood disorders. The discovery that allopregnanolone at low (nanomolar) concentrations elicits marked anxiolytic, anti-stress and antidepressant effects by facilitating allosterically the action of GABA at extrasynaptic GABA_A receptors has provided new perspectives for the discovery of novel drugs useful for the treatment of mood disorders. These findings have led to the seminal clinical studies that recently demonstrated that treatment with allopregnanolone (i.e., brexanolone) can dramatically and rapidly improve the symptoms of postpartum depression in many patients.