For example, Cushing’s disease (in which the pituitary gland produces pathologically high ACTH levels, with ACTH signaling to the adrenal glands increasing cortisol production) and Cushing syndrome (caused by overuse of corticosteroid medications), increase vulnerability to depression because of peripheral TDO activation by cortisol. This evidence concerns the gene TDO2 and Cushing syndrome due to macronodular adrenal hyperplasia.