Decreased turnover of thyroid indices and blunting of TSH release after TRH administration has been associated with depressive disorder. A further decrease in plasma thyroid hormone; during antidepressant treatment has been reported. However, the putative association between the plasma thyroid indices' concentration and response has not been addressed. In the present study 21 depressed inpatients underwent a four-week double blind antidepressant with amitriptyline and mianserin; their plasma thyroid hormone indices (total thyroxine [TT4], free thyroxine [FT4], total triiodothyronine [TT3], free triiodothyronine [FT3], thyrotropin [TSH], and thyroglobulin [TBG]) were quantified to elucidate their involvement in depression and during antidepressant drug treatment. Depressed patients' plasma TSH, when corrected for age, was significantly lower than that of healthy subjects. During antidepressant treatment the entire patient cohort showed a significant decrease in plasma TT4 and FT4 concentrations. Responders showed a significant drop in TT4 FT4, FT3, and T4/TBG, but nonresponders only a decrease in FT4. During mianserin treatment, a decrease was observed in TT4, FT4, FT3, and T4/TBG. FT4 and FT3 baseline levels correlated positively with the improvement in the Hamilton Depression Rating Score (HDRS). These findings show that depressed inpatients' serum TSH levels are within the reference range, but significantly lower than those of healthy subjects, and those patients who turn out to be nonresponders have potentially lower availability of thyroid hormones than responders. Therefore, we hypothesize that in order to assure clinical improvement in depression, an adequate capacity of the thyroid hormone pool is necessary to compensate for the additional antidepressant-provoked decrease in serum thyroid hormone availability.