Decreased feedback control of the hypothalamic-pituitary-adrenocortical (HPA) system as revealed by the combined dexamethasone and corticotropin-releasing hormone (DEX-CRH) test has been documented in the vast majority of patients with affective disorders. This finding was interpreted as a failure at the level of the glucocorticoid receptor (GR)-mediated feedback action, which apparently fails to restrain HPA activity in the presence of elevated plasma corticosteroid levels. To test this 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 patients and controls. As expected, increasing DEX doses were associated with decreasing amounts of adrenocorticotropin (ACTH) and cortisol being released after CRH injection. However, dose-response curves for both plasma ACTH and cortisol concentrations were shifted to higher area under the curve (AUC) values among patients compared to controls. Pretreatment with 0.75 and 1.5 mg DEX produced significantly higher AUC values for both plasma ACTH and cortisol values among patients. These differences became less obvious with the higher DEX doses, indicating that 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 altered GR capacity or function underlies the exaggerated HPA activity in depression.