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 of combined thyroxine (T4) and triiodothyronine (T3) in treating hypothyroid patients. However these studies may have been underpowered to detect differences in psychological well-being specifically related to thyroxine replacement. We conducted a large, double-blind, randomized controlled trial of partial substitution of 50 microg of T4 by 10 microg of T3 (T3) vs placebo (T4 alone - 50 microg of T4 replaced) in 697 hypothyroid patients. Thyroid function showed a rise in the TSH (132%), a fall in Free 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 Health Questionnaire 12 score (GHQ 12) in the control group compared with baseline and this was sustained at 12 months. Differences vs the intervention (T3) group were more modest with improvements in GHQ 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 mood and the initial differences were lost at 12 months. These results may be consistent with a subgroup of patients showing transient improvement following partial substitution with T3 but do not provide conclusive evidence of specific benefit from partial substitution of T4 by T3 in patients on thyroxine replacement. They also emphasize the large and sustained placebo effect, that can follow changes in thyroid hormone administration.