Critical appraisal: Combined T3 and T4 replacement therapy is not better than replacement with T4 alone

Conflicting results have recently been published about the benefits ofcombined thyroxine (T4) and triiodothyronine (T3) in treating hypothyroid patients. However thesestudies may have been underpowered to detect differences in psychological well-being specificallyrelated to thyroxine replacement. We conducted a large, double-blind, randomized controlled trial ofpartial substitution of 50 microg of T4 by 10 microg of T3 (T3) vs placebo (T4 alone - 50 microg of T4replaced) in 697 hypothyroid patients. Thyroid function showed a rise in the TSH (132%), a fall inFree T4 (35%, P <0.001) and unchanged basal Free T3 levels (P=0.92). At 3 months there was a large(39%) «placebo effect» improvement in «psychiatric caseness» defined by the General HealthQuestionnaire 12 score (GHQ 12) in the control group compared with baseline and this was sustainedat 12 months. Differences vs the intervention (T3) group were more modest with improvements inGHQ caseness (OR - 0.61; 95% CI: 0.42, 0.90; P=0.01) and HADS anxiety scores at 3 months (P<0.03) but not GHQ Likert scores, HADS depression, thyroid symptoms or visual analog scales of moodand the initial differences were lost at 12 months. These results may be consistent with a subgroup ofpatients showing transient improvement following partial substitution with T3 but do not provideconclusive evidence of specific benefit from partial substitution of T4 by T3 in patients on thyroxinereplacement. They also emphasize the large and sustained «placebo effect» that can follow changes inthyroid hormone administration.