Does a Combination Regimen of Thyroxine (T₄) and 3,5,3′-Triiodothyronine Improve Depressive Symptoms Better Than T₄Alone in Patients with Hypothyroidism? Results of a Double-Blind, Randomized, Controlled Trial

Abstract

Some hypothyroid patients receiving levothyroxine replacement therapy complain of depressive symptoms despite normal TSH measurements. It is not known whether adding T(3) can reverse such symptoms. We randomized 40 individuals with depressive symptoms who were taking a stable dose of levothyroxine for treatment of hypothyroidism (excluding those who underwent thyroidectomy or radioactive iodine ablation of the thyroid) to receive T(4) plus placebo or the combination of T(4) plus T(3) in a double-blind manner for 15 wk. Participants receiving combination therapy had their prestudy dose of T(4) dropped by 50%, and T(3) was started at a dose of 12.5 micro g, twice daily. T(4) and T(3) doses were adjusted to keep goal TSH concentrations within the normal range. Compared with the group taking T(4) alone, the group taking both T(4) plus T(3) did not report any improvement in self-rated mood and well-being scores that included all subscales of the Symptom Check-List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study (P > 0.05 for all indexes). In conclusion, the current data do not support the routine use of combined T(3) and T(4) therapy in hypothyroid patients with depressive symptoms.

Psychosocial Factors in Patients with Thyroid Disease

“…Based on Grozinsky-Glasberg et al 's (2006) metaanalysis and Ma et al's (2009) systematic review it can be summed up that combined T4 and T3 treatment does not improve well-being, cognitive function, or health status compared with T4 itself. This is proved with works by Appelhof et al, 2005;Clyde et al, 2003;Joffe et al, 2004;Meng et al, 2004;Nygaard et al, 2009;Regalbuto et al, 2007;Saravanan et al, 2005;Sawka et al, 2003;Siegmund et al, 2004;Valizadeh et al, 2009;Walsh et al, 2003 and others. Whereas first works signalled differences in favour of combined T4 and T3 (Bunevičius et al, 1999(Bunevičius et al, , 2002Bunevičius & Prange, 2000).…”

Combined therapy with L-Thyroxine and L-Triiodothyronine compared to L-Thyroxine alone in the treatment of primary hypothyroidism

“…3,4 Other researchers, however, do not confirm the advantages of the combined therapy compared to monotherapy. [1][2][3][4][5][6][7][8][9] The objective of this study was to compare various parameters in patients with hypothyroidism receiving either monotherapy with L-T4 or combination therapy with L-T4 and L-T3.…”

Do we need still more trials on T4 and T3 combination therapy in hypothyroidism?

“…Although no relation was observed in the meta-analysis between the percentages of included athyreotic patients and the effect of combination therapy on symptoms, it is preferable to restrict inclusion to spontaneous autoimmune hypothyroidism as was done in the present RCT (2). Six studies in the meta-analysis had a crossover study design (5,6,7,10,12,13), and five studies had a parallel study design (8,9,11,14,15). Observations in crossover studies are not independent because the same patients receive both combination and monotherapy (1).…”

“…It follows that the serum FT 4 -FT 3 ratio is higher in T 4 -replaced hypothyroid patients than in controls. Indeed, the serum FT 4 -FT 3 ratio in patients randomized to receive T 4 monotherapy in the meta-analysis ranges from 4.0 to 6.7 (7,8,10,11,13), higher than the value of 3.3 observed in controls (18). The serum FT 4 -FT 3 ratio during combination therapy ranged from 2.2 to 4.8; in only two of the RCTs, the ratios (3.3 and 3.4 respectively) were close to control values, but both studies still failed to demonstrate superiority of combination therapy over monotherapy (7,13).…”