One possible mechanism whereby ACTH contributes to this dysfunction may be through adaptations of the hypothalamic pituitary adrenal axis, which has consistently been shown to be hyperactive in patients suffering from depression.32 Daily administration of ACTH blocks antidepressant efficacy and alters the key PFC monoamine concentration following stress, and downregulates glucocorticoid responses.19 Mitochondria participate in stress responses in part by sensing levels of glucocorticoids. This evidence concerns the gene POMC and major depressive disorder.