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.