A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression

Abstract

Preclinical testing of treatments for postpartum depression (PPD) has been limited due to the lack of available animal models of such a complex disorder. To address this limitation, our laboratory has generated unique preclinical mouse models that exhibit abnormal postpartum behaviors. Mice with a loss or reduction in the expression of the GABAA receptor (GABAAR) δ subunit (Gabrd−/− or Gabrd+/−, respectively) and mice that lack the K+/Cl− co-transporter, KCC2, specifically in corticotropin-releasing hormone (CRH) neurons (KCC2/Crh mice) exhibit depression-like behaviors restricted to the postpartum period and deficits in maternal care, which serve as useful tools for testing novel therapeutic compounds. Utilizing these preclinical models, we tested the ability of a novel, synthetic, neuroactive steroid developed by SAGE Therapeutics, SGE-516, to improve abnormal postpartum behaviors. Gabrd−/−, Gabrd+/−, and KCC2/Crh dams treated with SGE-516 (450 mg/kg chow) during late pregnancy exhibit a decrease in depression-like behaviors and improvements in maternal care at 48 h postpartum. Interestingly, acute treatment with SGE-516 also exhibits robust therapeutic effects in these preclinical PPD models. We previously discovered abnormal stress reactivity associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with depression-like behaviors in the preclinical PPD models, evident from an increase in stress-induced corticosterone levels and dephosphorylation and downregulation of KCC2 in the paraventricular nucleus of the hypothalamus (PVN) during the peripartum period. Here we demonstrated that SGE-516 treatment is sufficient to prevent the stress-induced increase in corticosterone and dephosphorylation and downregulation of KCC2 in the PVN. In contrast, and consistent with the distinct pharmacology of SGE-516 compared to benzodiazepines, treatment with clobazam (250 mg/kg chow) did not alter the depression-like phenotype or deficits in maternal care observed in these preclinical models of PPD. These findings are consistent with the positive double-blind, randomized, placebo-controlled trial findings of a similar compound, brexanolone, in the treatment of patients with postpartum depression. Further, these findings validate the use of these preclinical models of PPD for screening novel compounds for the treatment of postpartum depression.

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

“…Mice which lack ( Gabrd −/− mice) or have deficits in GABA A R δ subunit expression ( Gabrd ± mice) exhibit depression-like behaviors restricted to the postpartum period and deficits in maternal care (Maguire and Mody, 2008). Similar to the robust antidepressant effects of neurosteroid-based treatments in patients with postpartum depression (Kanes et al, 2017a, 2017b; Meltzer-Brody et al, 2018a), a similar compound, SGE-516, exhibits robust antidepressant effects in preclinical mouse models of postpartum depression (Melón et al, 2018). Collectively, these findings suggest that deficits in neurosteroid signaling are sufficient to induce depression-like behaviors, with potential relevance to mood disorders related to the postpartum period.…”

“…These behavioral impairments are thought to be due to excessive glucocorticoid signaling given that exogenous corticosterone treatment can induce deficits in postpartum behaviors (Brummelte and Galea, 2010; Brummelte et al, 2006; Maguire and Mody, 2016b), similar to effects observed with chronic stress during late pregnancy (Maguire and Mody, 2016a). Interestingly, a neurosteroid-based treatment, related to the recently FDA-approved treatment for postpartum depression, is effective at restoring normal HPA axis function and decreasing depression-like behaviors and improving maternal care in two independent preclinical models of postpartum depression (Melón et al, 2018) ( Table 1 ) .…”

Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience

“…Postpartum depression (PPD) is an important public health issue as it affects women at a highly vulnerable time and can affect the cognitive and emotional development of the child 112 . The risk of depression in women becomes significantly increased during the postpartum period, and nearly 20% of mothers have PPD, which is frequently preceded by antenatal anxiety- and depression-related symptoms or chronic stress as the strongest predictors 113– 115 . PPD is frequently attributed to a maladaptation to peripartum fluctuations in reproductive hormone levels during pregnancy and the postpartum period 116, 117 .…”

Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond

“…3B, black line), and these changes contribute to a hyperexcitable state (Isaacson and Scanziani, 2011) that can be manifest as stress-like and depressive-like behaviors. These behaviors can be corrected by agents that enhance tonic inhibition including NAS (Maguire and Mody, 2008; Melon et al, 2018). Interestingly, one model for postpartum psychiatric illness involves knockout/knockdown of expression of δ-subunits.…”