• The serum cortisol concentration following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, a precursor of serotonin (5-HT), was significantly greater in unmedicated depressed and manic patients than in normal controls. Increases in serum cortisol levels greater than 5 ug/dL were significantly more frequent in both unmedicated depressed and manic patients than in the normal controls. There was significant test-retest reliability. Baseline serum cortisol concentration correlated negatively with the cortisol response to 5-HTP in normal controls. These results suggest increased 5-HT receptor sensitivity may be present, possibly in the hypothalamus or pituitary, in some patients with affective disorders. These results are consistent with the hypothesis that decreased serotonergic activity, which would be expected to produce increased 5-HT receptor sensitivity, may be present in both depression and mania.