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\begin{document}

\title{Improvement of Depression in a Patient with Hypothyroidism and
Deiodinase Polymorphism with LT3 Therapy}



\author[1]{Ziyan Ahmed}%
\author[1]{Rinsha Sherin}%
\author[1]{Thanh Hoang}%
\author[2]{Tatiana Fonseca}%
\author[1]{Mohamed Shakir}%
\affil[1]{Walter Reed National Military Medical Center}%
\affil[2]{University of Chicago Andy Minn Oncology Lab}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
We report a 54-year-old man with treatment-resistant depression (TRD)
and hypothyroidism who responded to LT3/LT4 combination, rather than LT4
alone. He was able to discontinue all antidepressant medications
eventually. Interestingly, the patient has a DIO2 polymorphism.%
\end{abstract}%



\sloppy


\textbf{Improvement of Depression in a Patient with Hypothyroidism and
Deiodinase Polymorphism with LT3 Therapy}

Ziyan S. Ahmed\textsuperscript{1}, Rinsha PV Sherin\textsuperscript{1},
Tatiana L. Fonseca\textsuperscript{2}, Thanh D.
Hoang\textsuperscript{1,3}, and Mohamed KM. Shakir\textsuperscript{1,3}

\textsuperscript{1}Endocrinology Division, Walter Reed National Military
Medical Center, Bethesda, MD

\textsuperscript{2}Section of Adult and Pediatric Endocrinology,
Diabetes \& Metabolism,

University of Chicago, Chicago, IL

\textsuperscript{3}Endocrinology Division, Uniformed Services University
of the Health Sciences, Bethesda, MD

\textbf{Short title} : Improvement of Depression with LT3/LT4

\textbf{Keywords:} depression, T3, hypothyroidism, polymorphism

\textbf{Corresponding Author} : Dr. Thanh D. Hoang

Division of Endocrinology

Walter Reed National Military Medical Center,

8901 Wisconsin Ave,

Bethesda, MD 20889.

E-mail: \emph{tdhdthanh@gmail.com}

\textbf{Disclaimer:} The views expressed in this article are those of
the authors and do not reflect the official policy of the Department of
Army/Navy/Air Force, Department of Defense, or the U.S. Government.

\textbf{Disclosure Statement} : The authors have nothing to disclose.
The patient was originally enrolled in study protocol Clinical Trials
\#NCT02317926.

\textbf{Funding statement} : None

\textbf{ABSTRACT}

We report a 54-year-old man with treatment-resistant depression (TRD)
and hypothyroidism who responded to LT3/LT4 combination, rather than LT4
alone. He was able to discontinue all antidepressant medications
eventually. Interestingly, the patient has a DIO2 polymorphism.

\par\null

\textbf{Key Clinical Message}

There is a good correlation between the depression scores and the serum
T3 levels. In hypothyroid patients with functional DIO2 polymorphism,
thrice-daily LT3 dosing may significantly improve depression. Additional
studies are needed.

\section*{INTRODUCTION}

{\label{introduction}}

Previous studies have shown a strong association between hypothyroidism
and depressive disorders (1-3). Treatment-resistant depression (TRD) is
traditionally defined as depression with inadequate clinical response
usually following the traditional antidepressant therapy (4,5). Patients
with depression who fail to achieve symptom remission may pose
significant clinical challenges and need augmentation pharmacology
approach (4,5). We report a patient with TRD, hypothyroidism, and Thr92
Ala-DIO\textsubscript{2} polymorphism who has responded well to T3
therapy, given in 3 divided doses.

\section*{METHODS}

{\label{methods}}

Because of the ongoing TRD he was followed only with General health
questionnaire (GHQ), Thyroid symptom questionnaire (TSQ), Beck
Depression inventory scores (BDI-II) (6-8) and measurements of thyroid
functions. Genotyping was performed per Allelic Discrimination protocol
from real-time PCR machine (Applied Biosciences) using Taqman reagents
and rs225014 SNP primer (9,10). Statistical analysis was performed by
analysis of variance (ANOVA) and post-hoc analysis by Tukey test.

\section*{CASE REPORT}

{\label{case-report}}

A 54-year-old man presented to the emergency room with suicidal ideation
5 years ago. Additionally, patient had severe depression and an immense
desire to surf the internet, generally prohibited sites. He also noted a
12-pound weight gain, dry skin, and cold intolerance. Family history was
significant for Hashimoto's thyroiditis in one daughter. Physical
examination showed HR 64 bpm, BP 140/90 mm Hg. Thyroid was diffusely
enlarged, approximately 40 grams without palpable nodules. Rest of the
examination was normal, except for delayed deep tendon reflexes.
Laboratory values at admission: normal CBC, CMP, and serum B12 level.
Thyroid functions: serum TSH 560 \selectlanguage{greek}µ\selectlanguage{english}IU/mL (normal 0.41--4.2), FT4 0.20
ng/dL (normal 0.90-2.18), total T3 38 ng/dL (normal 59-174), TPO
antibody 278 IU/mL (normal 0-34), TG antibody 9.8 ng/dL (normal
0.0-0.9). Ultrasound confirmed a heterogeneously enlarged thyroid
consistent with Hashimoto's thyroiditis. Diagnoses of major depressive
disorder and primary hypothyroidism were made. GHQ, TSQ and BDI-II
scores obtained 2 days after admission were markedly abnormal (during
the 8 week basal period, the symptom scores and thyroid functions were
measured at 2 to 3 week intervals (n=4) and these functions were GHQ,
26.0 \selectlanguage{ngerman}± 8.49, TSQ 28.5 ± 7.77, BDI-II 45.0 ± 6.18, TSH 165 ± 133 \selectlanguage{greek}µ\selectlanguage{english}IU/mL,
Free T4 0.79 \selectlanguage{ngerman}± 0.25 ng/dL, and total T3 60.5 ± 7.89 ng/dL) . Patient was
treated with levothyroxine (LT4) 175mcg daily and citalopram 20mg daily.
The dose of citalopram was gradually increased to 40mg daily and
amitriptyline 50mg at bedtime was added along with twice weekly
psychotherapy sessions. After 8 weeks of treatment there was modest
improvement in GHQ, TSQ, and BDI-II despite normal serum TSH 1.34 \selectlanguage{greek}µ\selectlanguage{english}IU/mL
(Table 1, Figures 1, 2). Three months later, because of the poor
response to antidepressant drugs aripiprazole and buspirone were added.
After 9 months, LT3 5 mcg once daily was added. Patient continued LT4 +
LT3 5mcg combination for another 13 months and at this time the
treatment was changed to LT4 only. Despite being on 4 antidepressant
drugs and LT4, his depression scores and internet addiction did not
improve significantly (Table 1). Approximately 2 \selectlanguage{ngerman}½ years after the
initial visit, patient was placed on LT3 5mcg thrice daily with reduced
dose of LT4. Within 4 weeks of starting LT4 + LT3 TID dosing, patient
noted remarkable improvement in depression, suicidal ideation, and
internet addiction. It was possible to gradually discontinue all the
antidepressant drugs over the next 9 months (Table 1). However, the
psychiatrist prescribed over the counter antidepressant drugs,
S-adenosylmethionine (SAMe), (Pure Encapsulations \textsuperscript{TM},
Sudbury MA) 1600 mg/day, and Rhodiola rosea (rosavins \textgreater{}
3.0\%, salidroside \textgreater{} 0.8\% at a ratio of 3:1, Pure
Encapsulations \textsuperscript{TM}, Sudbury MA) 200mg twice daily. The
serum total T3 levels remained in the upper normal range while the
patient was taking LT4 +LT3 5mcg TID dosing and the serum TSH levels
remained in the lower normal range. A follow up cardiac evaluation was
completely normal. He presently continues psychotherapy visits only
every 3 months. Additionally, he is gainfully employed and also
continues a happy married life. A genetic screen performed for DIO2
polymorphism confirmed that the patient carries one allele of Thr92
Ala-DIO\textsubscript{2} polymorphism. The GHQ, TSQ and BDI-II scores
correlated well with serum TSH and T3 levels (Figures 1,2), but less
significant with serum free T4 levels (correlation coefficient (r) for
GHQ: 0.52, r for TSQ: 0.62, r for BDI-II 0.66, Figure 3)

\section*{DISCUSSION}

{\label{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 DIO\textsubscript{2} 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 D\textsubscript{2} in the brain which converts LT4
to LT3, it is possible that when hypothyroid patients with Thr92
Ala-DIO\textsubscript{2} 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-DIO\textsubscript{2} polymorphism, there may be subtle changes
in thyroid hormone homeostasis and accumulation of
Ala92-D\textsubscript{2} 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-DIO\textsubscript{2} polymorphism, thrice daily administration
of low doses of LT3 improved his depression significantly. Further
studies are needed.

\section*{Statement of author
contribution:}

{\label{statement-of-author-contribution}}

ZSA -- author

RPVS -- reviewer

TLF- reviewer, genetic researcher

TDH- reviewer

MKMS- reviewer

\textbf{Conflict of interest:} None to declare.

\textbf{Ethical approval statement} : The manuscript has been reviewed
and approved by the IRB and Public Affairs Office.

\textbf{Consent statement:} the authors have confirmed that patient
consent has been signed and collected in accordance with the journal's
patient consent policy.

\section*{References}

{\label{references}}

1.Ittermann T, Völzke H, Baumeister SE, Appel K, Grabe HJ. Diagnosed
thyroid disorders are associated with depression and anxiety. Soc
Psychiatry Psychiatr Epidemiol. 2015;50(9):1417-25.

2. Demartini B, Masu A, Scarone S, Pontiroli AE, Gambini O. Prevalence
of depression in patients affected by subclinical hypothyroidism.
Panminerva Med. 2010;52(4):277-82.

3 Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism
increases the risk for depression in the elderly. Arch Gerontol Geriatr.
2007;44(1):21-8

4. Ruberto VL, Jha MK, Murrough JW. Pharmacological Treatments for
Patients with Treatment-Resistant Depression. Pharmaceuticals (Basel).
2020;13(6):E116.

5. Lam RW, Hossie H, Solomons K, Yatham LN. Citalopram and bupropion-SR:
combining versus switching in patients with treatment-resistant
depression. J Clin Psychiatry. 2004;65(3):337-40.

6. Clyde PW, Harari AE, Getka EJ, Shakir KMM. Combined Levothyroxine
Plus Liothyronine Compared With Levothyroxine Alone in Primary
Hypothyroidism:~A Randomized Controlled Trial.~\emph{JAMA.}
~2003;290(22):2952--2958.

7. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid
extract compared with levothyroxine in the treatment of hypothyroidism:
a randomized, double-blind, crossover study. J Clin Endocrinol Metab.
2013 May;98(5):1982-90.

8. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression
Inventories -IA and -II in psychiatric outpatients. J Pers Assess.
1996;67(3):588-97.9

9. Peeters RP, van Toor H, Klootwijk W, et al. Polymorphisms in thyroid
hormone pathway genes are associated with plasma TSH and iodothyronine
levels in healthy subjects. J Clin Endocrinol Metab. 2003;88(6):2880-8.

10. Mentuccia D, Proietti-Pannunzi L, Tanner K, et al. Association
between a novel variant of the human type 2 deiodinase gene Thr92Ala and
insulin resistance: evidence of interaction with the Trp64Arg variant of
the beta-3-adrenergic receptor. Diabetes. 2002;51(3):880-3.

11 Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment
of hypothyroidism: prepared by the american thyroid association task
force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-751.

12 Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R.
Levothyroxine monotherapy cannot guarantee euthyroidism in all
athyreotic patients. PLoS One. 2011;6(8):e22552.

13 Cuomo A, Beccarini Crescenzi B, Bolognesi S, et al.
S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): a
clinician-oriented systematic review. Ann Gen Psychiatry. 2020;19:50.

14 Konstantinos, Fanaras \& Heun, Reinhard. (2020). The effects of
Rhodiola Rosea supplementation on depression, anxiety and mood -- A
Systematic Review. Global Psychiatry. 3. 10.2478/gp-2019-0022.

15 .Kelly TF, Lieberman DZ. Long term augmentation with T3 in refractory
major depression. J Affect Disord. 2009;115(1-2):230-3.

16. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium
and T(3) augmentation following two failed medication treatments for
depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-30.

17. Kim JS, Zhang Y, Chang Y, et al. Subclinical Hypothyroidism and
Incident Depression in Young and Middle-Age Adults. J Clin Endocrinol
Metab. 2018;103(5):1827-33.

18. Pop VJ, Maartens LH, Leusink G, et al. Are autoimmune thyroid
dysfunction and depression related. J Clin Endocrinol Metab.
1998;83(9):3194-7.19. Kirim S, Keskek SO, Köksal F, 19. Haydardedeoglu
FE, Bozkirli E, Toledano Y. Depression in patients with euthyroid
chronic autoimmune thyroiditis. Endocr J. 2012;59(8):705-8.

20. Engum A, Bjøro T, Mykletun A, Dahl AA. Thyroid autoimmunity,
depression and anxiety; are there any connections? An epidemiological
study of a large population. J Psychosom Res. 2005;59(5):263-8.

21. Panicker V, Saravanan P, Vaidya B, et al. Common variation in the
DIO2 gene predicts baseline psychological well-being and response to
combination thyroxine plus triiodothyronine therapy in hypothyroid
patients. J Clin Endocrinol Metab. 2009;94(5):1623-9.

22. McAninch EA, Rajan KB, Evans DA, et al. A Common DIO2 Polymorphism
and Alzheimer Disease Dementia in African and European Americans. J Clin
Endocrinol Metab. 2018;103(5):1818-26.23.

23.Jo S, Fonseca TL, Bocco BMLC, et al. Type 2 deiodinase polymorphism
causes ER stress and hypothyroidism in the brain. J Clin Invest.
2019;129(1):230-45.

\textbf{Abbreviations:}

BDI-II: Beck Depression Inventory

TSH: Thyroid Stimulating Hormone

Free T4: Free Thyroxine

Total T3: Total Triiodothyronine

\section*{Legends to Figures}

{\label{legends-to-figures}}

Figure 1: Showing the relationship between serum TSH (thyroid
stimulating hormone) and GHQ, TSQ and BDI-II.

Figure 2: Showing the relationship between serum total T3
(triiodothyronine) levels and GHQ, TSQ, and BDI-II.

Figure 3: Showing the relationship between free T4 (thyroxine) levels
and GHQ, TSQ, and BDI-II.

\textbf{Notes for the table}

Beck Depression Inventory\selectlanguage{english}-II (BDI\selectlanguage{english}-II), consisting of 21 items assessing
specific cognitive, affective, and physical symptoms of depression,
corresponds well to a clinical diagnosis of depressive disorders
outlined in the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (8-10). The total BDI\selectlanguage{english}-II is the sum of all item scores.
The minimum score is 0, and maximum score is 63. The BDI\selectlanguage{english}-II scores of
0\selectlanguage{english}-13 denote no/minimal depression, scores of 14\selectlanguage{english}-19 denote mild
depression, scores of 20\selectlanguage{english}-28 denote moderate depression, and scores of
29\selectlanguage{english}-63 denote severe depression.

Validity of these tests in patients with hypothyroidism has been well
established previously (8.9). Serum TSH, free T4, and total T3 were
measured by the electrochemiluminescence immunoassay (ECLIA, Cobas 8000,
K Diagnostics, Indianapolis, IN). DNA was extracted from blood samples.\selectlanguage{english}
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