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Allopregnanolone, today best known as brexanolone and marketed as Zulresso for the treatment of postpartum depression is part of only two recently Food and Drug Administration (FDA)approved fast-acting antidepressants, with esketamine nasal spray, an NMDA receptor antagonist used in treatment-resistant depression with suicidality being the other (1). The trajectory, lasting 80 years, that brought allopregnanolone from its discovery (2) in 1938 in the adrenal glands, to understanding its fast non-genomic mechanism in potentiating membrane neurotransmitter receptors, including GABAA receptors (3, 4), underlying its role in acute and chronic stress (5–7), discovering its powerful non-sedative pharmacological effects as anxiolytic and antidepressant agent in animal models and humans (8–10), to the design of the first clinical trials for postpartum depression (11), and finally to the shelves of the clinics in 2019, is regarded as one of the best examples of translational drug development in neuropsychopharmacology (12, 13). This article redraws the most significant milestones in allopregnanolone discoveries and evaluates future perspective for a new generation of neurosteroid-based treatments in neuropsychiatry. The role of allopregnanolone as a potential biomarker for mood disorders and its pharmacological mechanism in improving behavioral deficits will be discussed.

Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next?