The authors studied pituitary thyrotropin, i.e., thyroid-stimulating hormone (TSH), response to thyrotropin-releasing hormone (TRH) in patients with primary affective disorder. There were no overall differences between either depressed or manic patients and normal controls; however, the TSH response was significantly lower in the unipolar depressed patients than in either bipolar depressed patients or normal subjects. Bipolar patients in the manic phase tended to have a lower response than bipolar depressed patients. In the unipolar group, the TSH response showed a significant negative correlation with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. These neuroendocrine responses may constitute markers of specific monoamine dysfunction in subgroups of patients with affective illness.