Exogenous or endogenous stress may impair certain functions in the HPA axis, such as glucocorticoid resistance, i.e., dysfunction of the glucocorticoid receptor (GR), which impairs the negative feedback it mediates, and cause the pituitary gland and adrenal glands to enlarge, resulting in the disruption of the overstimulated HPA axis and increased levels of cortisol (CORT) in patients with depression (Figure 3) (Anacker et al., 2011; Nikkheslat et al., 2020). Here, NR3C1 is linked to major depressive disorder.