Decreased feedback control of the hypothalamic-pituitary-adrenocortica
l (HPA) system as revealed by the combined dexamethasone and corticotr
opin-releasing hormone (DEX-CRH) test has been documented in the vast
majority of patients with affective disorders. This finding was interp
reted as a failure at the level of the glucocorticoid receptor (GR)-me
diated feedback action, which apparently fails to restrain HPA activit
y in the presence of elevated plasma corticosteroid levels. To test th
is hypothesis we conducted the DEX/CRH test using increasing doses of
DEX in order to establish a dose-response relationship. We used three
different DEX doses(0.75, 1.5, 3.0 mg) in three groups of depressed pa
tients and controls. As expected, increasing DEX doses were associated
with decreasing amounts of adrenocorticotropin (ACTH) and cortisol be
ing released after CRH injection. However, dose-response curves for bo
th plasma ACTH and cortisol concentrations were shifted to higher area
under the curve (AUG) values among patients compared to controls. Pre
treatment with 0.75 and 1.5 mg DEX produced significantly higher AUC v
alues for both plasma ACTH and cortisol values among patients. These d
ifferences became less obvious with the higher DEX doses, indicating t
hat the dose of 1.5 mg used in the majority of clinical studies so far
is well suited to differentiate between healthy controls and patients
. The reported data here are consistent with the hypothesis that an al
tered GR capacity or function underlies the exaggerated HPA activity i
n depression.