To study putative differences in central neurotransmitter function in depressive subtypes, growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin responses to the alpha 2-noradrenergic receptor agonist clonidine (1.3 micrograms/kg i.v.) were examined in 26 subjects with major depression, 13 of whom had melancholia. The responses of 10 of these endogenous/melancholic subjects were compared with those of 10 controls who were matched to the patients on age, sex, and menopausal status. In 15 of the depressed subjects, prolactin and cortisol responses to the putative serotonergic agonist fenfluramine were also examined to test for associations between these challenges. There were no significant differences in any of the responses between melancholic and nonmelancholic depressive subgroups after controlling for age and sex. With the exception of a greater reduction in ACTH in the endogenous/melancholic subjects, there were also no significant differences in hormonal responses between these patients and controls. There was, however, a significantly greater reduction in systolic blood pressure in the control subjects. There were no significant correlations between the responses to clonidine and fenfluramine. The findings suggest that clonidine at a dosage of 1.3 micrograms/kg is neither able to differentiate reliably between depressive subtypes nor to differentiate reliably between depressed and control subjects.