The most primarily reported HPA axis changes related with depression included suppressed cortisol circadian rhythms with higher levels late in the day [120], negative feedback insensitivity, as characterized by inability of morning cortisol suppression after dexamethasone administration [121], increased CRF concentrations in the CSF [122, 123], and brain CRHR-1 receptors and mRNA down-regulation. Here, CRH is linked to major depressive disorder.