Despite a lack of documented efficacy in controlled trials, triiodothyronine (T3) is frequently administered as an adjunctive therapy for tricyclic resistant depressions. In this study, we tested the efficacy of T3 as an adjunctive treatment using a double-blind, placebo-controlled crossover design. Sixteen depressed patients who were unresponsive to 4 weeks of imipramine therapy (mean dose = 206 +/- 54 mg daily, mean combined blood level = 220 +/- 132 ng/dl) received T3 25 micrograms and placebo for 2 weeks each. There was no evidence of a T3 effect using both Hamilton depression scores and global improvement. No subgroup of responders using baseline TRH stimulation tests could be identified. T3 treatment lowered plasma free T4 (P = 0.001) and TSH (P greater than 0.02) while raising plasma T3 levels (P less than 0.01), indicating the physiological effect of the drug.