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

Abstract

Recent FDA approval of an allopregnanolone-based treatment specifically for postpartum depression, brexanolone, now commercially called Zulresso®, 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 GABAA receptors (GABAARs), 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.

Perinatal mental health: a review of progress and challenges

“…The novel medication brexanolone, a neurosteroid that acts as a positive neuromodulator at GABA‐A receptors 133,134 , has been developed for postpartum depression and approved by the US Food and Drug Administration for this condition in 2019 135 . Small RCTs (N=246) compared the efficacy and safety of a 60‐hr brexanolone infusion vs. placebo infusion, with the primary outcome being the mean Hamilton Depression Rating Scale (HAM‐D) score at the end of the infusion period.…”

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

“…During pregnancy, increased hormone production has been observed along with enhanced neurosteroid levels, such as allopregnanolone, and transient changes in allopregnanolone concentrations are implicated as a contributing factor to temporary changes in GABA-mediated inhibition, which can result in PPD-associated affective behaviors ( Frye et al, 2011 ; Schüle et al, 2014 ). The therapeutic utility of neurosteroids in other forms of depression, anxiety, and epilepsies are also currently being explored ( Lévesque et al, 2017 ; Czyk, 2019 ; Walton and Maguire, 2019 ; Zorumski et al, 2019 ; Belelli et al, 2020 ). We acknowledge that a variety of neurological and neuropsychiatric conditions involve GABA dysregulation ( Ramamoorthi and Lin, 2011 ; Mele et al, 2019 ), but we have chosen to focus on disorders where GABA A R pharmacology is currently and commonly used: benzodiazepines for epilepsy and anxiety, as well as neurosteroids for PPD.…”

Influence of ovarian hormones on value-based decision-making systems: Contribution to sexual dimorphisms in mental disorders

“…However, progesterone's impact on dopaminergic transmission seems dependent on baseline estradiol levels as stimulating effects on dopamine release were found in rats which were pre-exposed with estradiol (Becker, 1990a(Becker, , 1990b. Allopregnanolone, a neuroactive steroid, which can be synthesized from steroid hormone precursors, such as progesterone, or synthesized de novo from cholesterol (Walton & Maguire, 2019) has been shown to modulate cognitive functions (Marx et al, 2009), likely due to modulatory effects on GABAergic neurotransmission (Majewska et al, 1986). Just like progesterone and its derivative, GABA levels increase from the follicular to the luteal phase (Epperson et al, 2002).…”