Adrenal cortical responses to low- and high-dose ACTH(1-24) administration in major depressives vs. matched controls

Increased hypothalamo-pituitary-adrenocortical (HPA) axis activity occurs in 30-50% of patients with major depression. This includes normal-to-increased adrenal cortical hormone (cortisol) secretion in spite of reduced corticotropin (ACTH) stimulation. A possible explanation is increased adrenal responsiveness to ACTH. Supporting this possibility is the finding of increased adrenal volume, which reverts to normal with successful treatment. Eight female and six male patients with major depression, and eight female and six male individually matched controls, underwent two test sessions 5-7 days apart. On the first day, a low ACTH(1-24) dose (0.014 microg/kg i.v.), equivalent to 1 microg in a 70-kg individual, was given. On the second day, a supramaximal stimulating dose (250 microg i.v.) was given. Serial blood samples were analyzed for immunoreactive (IR-)ACTH, ACTH(1-39), and cortisol. There were no significant sex or patient-control differences in IR-ACTH areas under the curve (AUCs) following low-dose ACTH(1-24), and the correlation between patient and matched control AUCs was +0.71, indicating good correspondence in the amount of circulating ACTH(1-24) available for adrenal stimulation. There were no significant sex or patient-control differences in cortisol response and no significant interaction between dose and subject group, indicating that patients did not differ from controls in their cortisol responses to either low- or high-dose ACTH(1-24). These findings do not indicate increased adrenal cortical responsiveness in patients with major depression. Neurochemical/neurohormonal and neural stimulatory factors other than ACTH might be responsible for the increased adrenal gland size and cortisol secretion, in spite of reduced pituitary ACTH secretion, that has been reported in this illness.