DISCUSSION

While there is no universally agreed upon definition of TRD (4), it is well accepted that patients with TRD have a poor prognosis. Although our patient was treated with four antidepressant drugs, there was inadequate response in depression and internet addiction. With a diagnosis of primary hypothyroidism, patient was treated with a weight-based dose of levothyroxine as recommended by the American Thyroid Association (11) and the patient achieved euthyroid status within 6 weeks. However, his serum T3 levels were in the low normal range. In a significant proportion of patients with hypothyroidism treated with levothyroxine, serum T3 levels may remain in the low normal range and the exact significance of this is not known (12). Finally, when he received LT3 in 3 divided doses, there was a marked improvement in his depressive symptoms, internet addiction and GHQ, TSQ and BDI-II scores. However, it was noted that his serum TSH levels were in low normal range. Patient had no signs/symptoms of hyperthyroidism and a normal cardiac screening. He was able to discontinue all prescribed antidepressant drugs, and was treated with 2 over- the-counter drugs namely S-adenosylmethionine (SAMe) (13) and Rhodiola Rosea supplements (14). Additionally, our patient required psychotherapy sessions less frequently. Thus, the LT4 + LT3 TID, SAMe, and Rhodiola Rosea combination therapy resulted in significant improvement in his major depressive disorder and the associated internet addiction, an obsessive neurosis and he is able to lead a normal life. There have been considerable controversies regarding what constitutes TRD. However, the inadequate response to trials of 4 antidepressant drugs met to criteria of TRD in our patient. In contrast to the well-accepted treatment of hypothyroidism with LT4, LT3 is often prescribed in depression as an augmentation pharmacotherapy (15). Limited studies utilizing LT3 therapy were conducted as an augmentation of tricyclic antidepressant and found improvement in depression (15, 16). Open label studies have also shown some benefits (16). However, there was no superior benefit compared to lithium, although the side effects were much less (16).
Thyroid hormone may play a significant role in noradrenergic and serotonergic neurotransmission as well as in the pathogenesis of depression. However, screening patients with depression for hypothyroidism is not widely supported (17). Previous studies (18, 19) have shown an association between immune thyroid diseases and depression, although in one study of subjects with normal thyroid function there was no association between TPO antibodies and depression (20). Our patient had markedly elevated thyroid antibodies and it is not clear whether there was any association between the antibodies and depression.
The use of LT4/LT3 combination therapy or LT3 alone treatment in depression remains controversial. Panicker et al (21) showed that patients with a functional polymorphism in DIO2 may respond better with a LT4/LT3 combination treatment. Compared to previous studies in which T3 supplementation has not been beneficial, our patient differs in several ways. Our patient had complete failure of thyroid gland as evidenced by low T4 levels and the need for full body-weight adjusted replacement dose of LT4. It is also unlikely that the improvement resulted from a placebo effect for several reasons. Our patient had already taken T4 alone on 2 occasions and LT4+LT3 once daily previously without improvement. In addition to subjective sense of wellness, the GHQ, TSQ and BDI II scores previously documented as measures of improvements in hypothyroid patients from our institution (6, 7) also confirming the benefits on several occasions. Finally, our patient had well documented TRD. However, re-challenging the patient with a higher dose LT4 alone, to keep the TSH in the low normal range would have confirmed but we felt it is unethical. Additionally, since our patient noted significant improvements, he would have refused any modification of the current treatment utilizing LT4+LT3 combination. Since there is only D2 in the brain which converts LT4 to LT3, it is possible that when hypothyroid patients with Thr92 Ala-DIO2 polymorphism is treated with a thrice daily LT3 regimen, they may respond much better as evidenced by improvements in TRD and various scores. In patients with carriers of the Thr92Ala-DIO2 polymorphism, there may be subtle changes in thyroid hormone homeostasis and accumulation of Ala92-D2 in the trans-Golgi apparatus providing less T3 locally (22). These patients may be at higher risk for brain degenerative disease even if they maintain euthyroid. It is possible that the steady state of serum T3 levels¸ in the high normal range may have been able to at least partially overcome the monocarboxylate transporter (MCT) system especially MCT8 as suggested by Jo et al (23).
In conclusion in our hypothyroid patient with TRD and Thr92Ala-DIO2 polymorphism, thrice daily administration of low doses of LT3 improved his depression significantly. Further studies are needed.