NR3C1 and major depressive disorder: However, it is now known that many of these medications, particularly those inhibiting monoamine reuptake, can also act by targeting other pathophysiological mechanisms of depression [12], including dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which is classically characterized by increased cortisol levels and the desensitization of glucocorticoid receptors (GR) resulting in impaired glucocorticoid negative feedback [5,13,14,15] and alterations of hippocampal neuroplasticity, reflected in decreased brain derived neurotrophic factor (BDNF) levels [16,17,18].