Previous studies by a number have investigators have documented a decreased adrenocortotropic hormone (ACTH) and β-lipotropin/ β-endorphin ( β-End) response to ovine corticotropin-releasing factor (oCRF) in depressed patients. Since depressed patients demonstrate higher plasma cortisol concentrations at the time of oCRF challenge, it is difficult to determine if the decreased ACTH response is due to enhanced negative feedback of cortisol on ACTH release or an alteration in CRF receptors in depressed patients. To evaluate the response to oCRF in an “open feedback loop” system, we administered metyrapone 750 mg at 4 pm and 7:30 pm, followed by administration of oCRF 0.3 μg/kg at 8 pm in 10 normal controls and 10 depressed patients. Administration of metyrapone at this time in the circadian rhythm clamped plasma cortisol concentrations to less than 2 μg/dl but did not result in rebound ACTH or β-End secretion in control subjects. In control subjects, metyrapone administration produced a 85% blockade of the cortisol response as well as a 3-fold greater β-End response compared to administration of the same dose of oCRF without metyrapone. The 10 depressed patients and their matched controls demonstrated identical β-End responses (integrated response for controls = 291 ± 61, for patients = 352 ± 86) and cortisol responses (integrated response for controls = 187 ± 38, for patients = 206 ± 52) to oCRF following metyrapone pretreatment. These data confirm that corticotroph CRF receptors are normal in depressed patients, and that cortisol feedback plays an essential role in the abnormal ACTH and β-End response to oCRF in depressed patients.