Prolonged HPA axis dysregulation in postpartum depression associated with adverse life experiences during development: a cross-species translational study for a novel therapeutic approach

Stress during childhood and adolescence increases the risk for postpartum depression (PPD). Patients with depression who have experienced adverse life events tend to be treatment refractory. However, the mechanism by which stress during childhood and adolescence are involved in the pathophysiology of PPD remains unclear. We investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and behaviors in the postpartum period through mouse and human studies. We observed that adolescent social isolation caused an aberrantly sustained elevation of glucocorticoids via dysregulation of the HPA axis, leading to long-lasting postpartum behavioral changes in female mice. The postpartum behavioral changes elicited by this adolescent stress were not ameliorated by the medicines currently used for PPD treatment. However, a post-delivery treatment with a glucocorticoid receptor antagonist effectively ameliorated the behavioral changes in mice. We also demonstrated a significant impact of stress during childhood and adolescence on the HPA axis dysregulation and PPD in women. We provide experimental evidence that suggests a mechanism-driven therapeutic strategy (repurposing a GR antagonist) for at least some cases of treatment refractory PPD.