Human corticotropin releasing hormone (h-CRH) was administered to 14 patients with major depression, after premedication with an overnight dose of 1.5 mg dexamethasone. Cortisol response, expressed as area under the time course curve (AUC), was significantly higher in the 14 patients than in a group of 13 age-matched control subjects (9.4 +/- 7.6 ng x min x 1,000/ml vs. 3.1 +/- 3.6 ng x min x 1,000/ml). Corresponding AUC values for plasma adrenocorticotropic hormone (ACTH) were also significantly higher in patients than in control subjects (4.9 +/- 1.4 pg x min x 1,000/ml vs. 2.6 +/- 0.9 pg x min x 1,000/ml). After patients were treated with trimipramine (200 mg/day) for 6 weeks, the combined dexamethasone/h-CRH test was repeated. At that time, depression scores were significantly improved and the patients' cortisol response pattern became indistinguishable from that of controls. While plasma cortisol output normalized during treatment with trimipramine, ACTH release remained exaggerated. The combined dexamethasone/h-CRH challenge test may be of particular value in the detection of state-dependent changes of pituitary-adrenocortical neuroregulation.