Thyroxine (T 4), free T 4, triiodothyronine (T 3), free T 3 (fT 3), and reverse T 3 (rT 3) were measured in 31 patients with major depressive disorder and 15 severely ill schizophrenic patients on admission, after 4 weeks' treatment with antidepressants and neuroleptics, respectively, and following recovery. On admission T 4 and fT 4 were normal in the depressed patients and elevated in the schizophrenic patients. T 3 was normal in both groups, and rises in rT 3 also occurred in both groups. They were correlated to postdexamethasone cortisol concentrations. After recovery T 4, fT 4, and rT 3 fell to below normal values in both groups, whereas T 3 and fT 3 remained unchanged. There were significant correlations between the T 4, fT 4, and rT 3 values of the patients and controls, whereas the correlations between T 3 and fT 3 were much closer in healthy subjects and schizophrenic patients than in depressed patients: this abnormality of the fT 3 values in depression was correlated to weight loss. The results indicate a complex disturbance consisting of elevated T 4 production in schizophrenia, inhibition of the conversion of T 4 to T 3 in most schizophrenic and some depressed patients, and disturbed protein binding of T 3 in some depressed patients. Most surprisingly, the declines of T 4, fT 4, and fT 3 were significantly correlated to clinical response in depression, but not in schizophrenia. As production of thyroid-stimulating hormone remained unaltered, the decreases in thyroid hormone levels might be due to a rise in intracellular concentrations rather than to increased metabolization or diminished production. In the light of the known interactions between catecholamines and thyroid hormones and a possible role of the latter as neuromodulators in the central nervous system, a direct involvement of these hormones in the mechanism of action of antidepressant drugs seems conceivable.