Development of neuroactive steroids for the treatment of postpartum depression

Abstract

Postpartum depression (PPD) is a common major depressive episode surrounding childbirth, with estimated rates ranging from 5.5% to 23.5% of all live births across Europe and the USA based on the presence of key symptoms. PPD has been associated with significant impairments in both maternal functioning and mother‐infant attachment, and these impairments can have lasting effects on the emotional and cognitive development of children. Although the precise pathophysiology of PPD is unknown, preclinical findings suggest that large fluctuations in neurosteroid hormone levels can induce physiological plasticity in the expression of functional GABAA receptors during pregnancy and the postpartum period, and that deficits in this plasticity may underpin a biological mechanism that contributes to the manifestation of depressive symptoms. Here, we review the controlled clinical trials to date that have assessed the efficacy of pharmacological treatments for PPD, including oestradiol, selective serotonin reuptake inhibitors, brexanolone (an iv formulation of allopregnanolone) and an investigational neuroactive steroid and GABAA positive allosteric modulator, zuranolone. Coupled with the GABAergic deficits implicated in major depressive disorder, these findings highlight not only the potential role of GABAA receptor plasticity in the pathophysiology of PPD, but also the novel therapeutic approach of using positive allosteric modulators targeting GABAergic transmission to treat women affected by PPD.

Prevalence and correlates of perinatal depression

“…Perinatal depression is defined as a non-psychotic depressive episode with various degrees of severity, from mild to major, occurring during pregnancy and up to one year following delivery [1][2][3][4][5], which has been shown to exert harmful effects on both mother and child [6][7][8][9]. Mothers may suffer from spontaneous abortion, bleeding during the gestational period, increased resistance of the uterine artery, preterm deliveries, and assisted deliveries, such as Caesarean section (CS), or the use of vaginal instruments [7].…”

Pregnane neurosteroids exert opposite effects on GABA and glycine‐induced chloride current in isolated rat neurons

“…In general, NSs are considered as potential therapeutics for the treatment of a variety of neurological and psychiatric conditions. The unique nature of NSs was proven in 2019 by the approval of allopregnanolone (ALLO, alternatively called brexanolone and sold under the brand name Zulresso) by the U.S. Food and Drug Administration as the first specific medicine for the treatment of postpartum depression in adults (Gunduz‐Bruce et al, 2021; Meltzer‐Brody et al, 2018). ALLO is a steroidal compound with a so‐called pregnane skeleton that is characterized by an acetyl side chain at position C‐17 (Figure 1).…”

Neuroactive steroids: From basic research to clinical use

“…Controlled clinical trials to date have assessed the efficacy of pharmacological treatments for postpartum depression, including estradiol, selective serotonin reuptake inhibitors, brexanolone and a neuroactive steroid positive allosteric modulator of GABA A , such as zuranolone 11 …”