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With regard to the course of basal human hypothalamus-pituitary-adrenal (HPA) system activity, there is a lack of data for comparing different classes of antidepressants. Ninety-four patients were included in a study comparing standardized treatment with paroxetine (PAROX) and amitriptyline (AMI) after a drug-free period of at least 6 days. Saliva for measurement of cortisol concentrations was obtained daily at 0800, 1600, and 2200 during the 6 days of drug-free washout and 35 days of active treatment. The course of HPA system activity and psychopathology, as assessed by the Hamilton Depression Scale, was compared by means of repeated-measurement analyses of variance (ANOVA-rm). Only AMI responders—not PAROX responders or nonresponders to either antidepressant—had a significant decline in saliva cortisol concentrations. In hypercortisolemically depressed patients, treatment with AMI may be preferable to PAROX in order to lower HPA system activity.