Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy

Abstract

This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a first-in-class neurosteroid antidepressant with significant advantages over traditional antidepressants. PPD is a neuroendocrine disorder that affects about 20% of mothers after childbirth and is characterized by symptoms including persistent sadness, fatigue, dysphoria, as well as disturbances in cognition, emotion, appetite, and sleep. The main pathology behind PPD is the postpartum reduction of neurosteroids, referred to as neurosteroid withdrawal, a concept pioneered by our preclinical studies. We developed neurosteroid replacement therapy (NRT) as a rational approach for treating PPD and other conditions related to neurosteroid deficiency, unveiling the power of neurosteroids as novel anxiolytic-antidepressants. The neurosteroid, brexanolone (BX), is a progesterone-derived allopregnanolone that rapidly relieves anxiety and mood deficits by activating GABA-A receptors, making it a transformational treatment for PPD. In 2019, the FDA approved BX, an intravenous formulation of allopregnanolone, as an NRT to treat PPD. In clinical studies, BX significantly improved PPD symptoms within hours of administration, with tolerable side effects including headache, dizziness, and somnolence. We identified the molecular mechanism of BX in a neuronal PPD-like milieu. The mechanism of BX involves activation of both synaptic and extrasynaptic GABA-A receptors, which promote tonic inhibition and serve as a key target for PPD and related conditions. Neurosteroids offer several advantages over traditional antidepressants, including rapid onset, unique mechanism, and lack of tolerance upon repeated use. Some limitations of BX therapy include lack of aqueous solubility, limited accessibility, hospitalization for treatment, lack of oral product, and serious adverse events at high doses. However, the unmet need for synthetic neurosteroids to address this critical condition supersedes these limitations. Recently, we developed novel hydrophilic neurosteroids with a superior profile and improved drug delivery. Overall, approval of BX is a major milestone in the field of neurotherapeutics, paving the way for the development of novel synthetic neurosteroids to treat depression, epilepsy, and status epilepticus. Graphical abstract

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

“…The FDA approval of allopregnanolone (brexanolone) and the synthetic derivative SAGE-217 (zuranolone) to treat PPD has further encouraged targeting GABA A R isoforms to develop novel therapeutics for major depressive disorders [2][3][4][5][6][7][8][9]11]. In this regard, extrasynaptic GABA A Rs incorporating the δ-subunit have received particular attention, with much of the focus centred on their role in hippocampus and amygdala.…”

“…In the 1980s, neurosteroids, typified by allopregnanolone, were identified as endogenous, potent, positive allosteric modulators (PAMs) of the GABA A R [1]. This discovery encouraged exploration of the therapeutic potential of endogenous and synthetic neuroactive steroids including use as anticonvulsants, analgesics, anxiolytics, and antidepressants [2][3][4][5][6][7][8][9][10]. Recently, this potential was realised with the FDA approval of allopregnanolone (brexanolone)…”

“…Biomolecules 2024, 14, 460 2 of 22 and a synthetic derivative SAGE-217 (zuranolone) to treat PPD [2][3][4][5][6][7][8][9]11], reinvigorating interest in targeting GABA A Rs in relevant neural pathways for the treatment of depressive disorders [2][3][4][5][6][7][8][9]11].…”

“…We reported that mouse MSNs express synaptic α1and α2-βγ2 GABA A Rs that mediate fast phasic inhibition and extrasynaptic α4βδ GABA A Rs that underpin tonic inhibition [25][26][27]. Extrasynaptic δ-GABA A Rs are considered an important target in mediating the effects of allopregnanolone in PPD/MDD [2,[4][5][6]9] and in influencing behaviours induced by chronic stress [28]. Intriguingly, we found for dopamine 1 receptors (D1Rs) expressing MSNs that their selective agonist activation, or indirect activation by amphetamine, produced a rapid increase in the MSN tonic current mediated by α4βδ GABA A Rs [25].…”

Image_4.TIF

“…Therefore, δ subunitcontaining extrasynaptic GABA A receptor could largely contribute to difference in the efficacies. This concept has been proposed in recent studies (Meltzer-Brody and Kanes, 2020;Reddy et al, 2023).…”