|Year : 2015 | Volume
| Issue : 1 | Page : 54-58
Depression and thyroid function tests
Satish Kumar Budania1, Monika Rathi2, Shalini Singh3, Suresh Yadav4, Nidhi Verma1
1 Department of Psychiatry, Subharti Medical College, Meerut, India
2 Department of Pathology, Lala Lajpat Rai Memorial Medical College, Meerut, India
3 Department of Psychiatry, Lady Hardinge Medical College, New Delhi, India
4 Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Web Publication||8-Dec-2014|
228/16, Saket Colony, North Civil Lines, Muzaffarnagar - 251 001, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
The thyroid hormone plays an important role in regulating the mood and cognitive functions of the body. Studies have revealed that although a majority of the cases of depression are associated with euthyroidism, thyroid dysfunction has commonly been seen associated with depression. The most commonly seen thyroid abnormality in the thyroid patients are raised levothyroxine (T4), decreased tri-iodothyronine (T3), and raised thyrotropin release hormone (TRH) levels, and a blunted thyroid stimulating hormone (TSH) response. A majority of the patients with abnormal thyroid function tests are associated with subclinical hypothyroidism. It is also believed that T3 supplementation, even in the euthyroid patients with depression, is associated with improvement in their depression scores.
Keywords: Depression, hypothyroidism, thyrotoxicosis
|How to cite this article:|
Budania SK, Rathi M, Singh S, Yadav S, Verma N. Depression and thyroid function tests. Muller J Med Sci Res 2015;6:54-8
|How to cite this URL:|
Budania SK, Rathi M, Singh S, Yadav S, Verma N. Depression and thyroid function tests. Muller J Med Sci Res [serial online] 2015 [cited 2019 Sep 18];6:54-8. Available from: http://www.mjmsr.net/text.asp?2015/6/1/54/146427
| Introduction|| |
It has been proved that clinical or subclinical hypothyroidism is associated with depression.  Still it is believed that a vast majority of depressive patients are euthyroid.  Various pathophysiological mechanisms describing the association between depression and thyroid hormones have been described as follows.
The thyroid hormone is regulated by the thyrotropin release hormone (TRH). TRH is produced from the hypothalamus and acts by regulating the thyroid stimulating hormone or thyrotropin (TSH) produced from the pituitary.  The thyroid hormone produces two major hormones: Levothyroxine (T4) and tri-iodothyronine (T3). T4 is the major hormone produced from the thyroid. Twenty percent of the T3 is secreted from the thyroid, whereas, 80% of T3 is derived from the T4 hormone, by its conversion to T3. ,, T4 enters the brain by a transporter protein known as transthyretin. After entering the brain, T4 enters the glial cells through some proteins. These proteins are organic anion transporters, polypeptide 1 (OATP1C1) and monocarboxylase transporter 8 (MCT8). In the brain T4 is converted to T3 by deiodinase type 2 (D2) and the actions of T3 are mediated in the brain. Studies done on mice have proved that mutation in transthyretin receptor alfa 1 and MCT 8 is associated with depressive behavior. ,, Studies have also reported decreased cerebrospinal fluid (CSF) transthyretin in depression resulting in brain hypothyroidism.  It has also been postulated that polymorphisms in the brain-specific thyroid hormone transporter, OATP1C1, and genetic variants of deiodinase I and deiodinase II are associated with depression and fatigue. ,
Furthermore, it has also been postulated that in depressive patients there is impaired function of the hippocampus, which executes a negative feedback on glucocorticoids via the hypothalamic-hypophyseal-adrenal (HPA) axis. This results in hypercortisolism and consequently an increase in T4 in some patients with depression. , It is also proposed that in depression the function of D2 is decreased, which is responsible for the conversion of T4 to T3. Thus, it finally results in the T4 levels being raised, T3 being decreased, and reverse T3 being increased due to the inhibition of D2 (as inhibition of D2 facilitates the formation of reverse T3). Also, there is increased TRH, a blunted TSH response (25-30%), and the presence of antithyroid antibodies in up to 20% of the depressed cases. ,,,,
Few researchers have suggested that most patients with depression along with blunted TSH response to TRH stimulation also have loss of nocturnal TSH rise. These patients also have a slight elevation in serum T4 levels, but they actually suffer from brain hypothyroidism. , This is the reason why T3 is the main hormone used for the adjuvant treatment of depression and T4 the major hormone used for thyroid replacement therapy. 
Researchers have also suggested that serum thyroid and TSH levels do not necessarily reflect the action of the thyroid hormone in the brain. There may be some other mediator of the thyroid hormone in the brain that regulates thyroid hormones in a tightly tissue-specific fashion. 
We did an extensive literature search on PubMed, EBSCO, MedLine, from 2004 to 2014, to collect all the relevant literature available on this topic. We also checked the reference list of all the relevant articles. We consulted the researchers on this topic as well, to incorporate their valuable ideas.
Studies Linking the Thyroid Hormone with Depression
Various studies have found the evidence of subclinical hypothyroidism in depressive patients. A case-control study done on 1546 participants with recurrent depression revealed that depression is associated with various physical disorders including gastric ulcer, rhinitis, hay fever, osteoarthritis, thyroid disease, hypertension, and asthma. , Thyroid dysfunction is one of the major abnormalities associated with depression. Thyroid dysfunction is also associated with a large number of other psychiatric diseases such as obsessive compulsive disorders, phobias, panic disorder, major depressive disorder, and cyclothymia or bipolar disorders. Studies have also proved that lithium bicarbonate, which is given as a treatment for bipolar disorders decreases the release of the thyroid hormone. ,,, Thyroid hormones not only regulate the basal metabolic rate, but they also affect the calorie weight changes, and hence, body weight.  It has been postulated that thyroid hormones are also important for neurogenesis, myelination, dendrite proliferation, and formation of synapses. 
Samuel et al., did a double-blinded, randomized, cross-over study on 33 hypothyroid subjects and evaluated their mood by using a profile of mood states (POMS) after inducing subclinical thyrotoxicosis, by giving them a low dose of l-T4 and a higher dose of l-T4 treatment. They concluded that along with improvements in mood and cognition, minor decrements in general and physical health were also seen in those patients in whom subclinical thyrotoxicosis was induced.  In another study done by the same authors, it was found that subclinical hypothyroidism is associated with decrement of mood on the POMS scale. 
A retrospective study done on 468 inpatients, out of which 185 patients had mood disorders, revealed that an abnormal thyroid status, hypothyroidism, and hyperthyroidism were seen in 23.24, 21.62, and 1.62% of the patients with mood disorders. 
Other studies have also proved that thyroid hormones and cognition and depressive symptoms are closely linked.  Some studies have also suggested that the risk of depression in patients with autoimmune thyroiditis and normal thyroid function is increased. 
A study done on 70 adults diagnosed with depression, as per the International Classification of Disease, tenth revision, Diagnostic Criteria for Research (ICD 10 DCR) criteria, selected by simple random sampling concluded that 21% of the patients showed thyroid dysfunction, subclinical hypothyroidism being the most common (seen in 11% of the patients). 
A study done to investigate the effect of catecholamine depletion on the thyroid hormone and depression by a randomized, placebo-controlled, and double-blind cross-over trial on 15 unmedicated subjects, revealed that serum concentrations of free T3 (FT3), free T4 (FT4), and TSH were less suppressed (on catecholamine depletion) in remitted major depressive disorder than in the healthy controls. This again supports the fact that hypercortisolism results in the rise of T4 in some patients. Also, it was found that the free triiodothyronine (FT3) and free thyroxine (FT4) levels correlated positively with the depressive symptoms. 
Not only is hypothyroidism associated with depression, but depressive patients also have a higher frequency of developing hypothyroidism.  The most commonly seen thyroid abnormalities in patients with depression are elevated T4 levels, low T3, elevated reverse triiodothyronine (rT3), a blunted TSH response to TRH, positive antithyroid antibodies, and elevated CSF TRH concentrations. 
Along with human studies, the experimental studies done on rats have also concluded that induction of subclinical hypothyroidism in rats is associated with depression-like features. 
Studies Done on Special Population
A prospective, six-week study done on 39 premenopausal and postmenopausal women with major depression revealed that subclinical hypothyroidism (raised TSH, normal T3 and T4) is associated with a poor response to antidepressant treatment.  They also conclude that the total thyroxine levels were associated with a better response to antidepressants.
A study was done on 51 subjects, in which their TSH, FT4, thyroid peroxidase, and thyroglobulin levels were assessed prenatally and four weeks postpartum. It was found that higher TSH levels and thyroid antibodies were associated with dysphoric and depressive symptoms.  Other researchers have also suggested that euthyroid pregnant and postpartum women with thyroid peroxidase (TPO) antibodies have higher chances of developing depression. 
A cohort study done on 1503 elderly subjects (>70 years), with a thyroid function of normal range, concluded (by assessing their depressive symptoms on a 'center for epidemiological studies depression scale' (CES-D)) that persons with low to normal TSH levels had a higher risk of developing depressive symptoms in later years. 
Thyroid Hormones and Recurrence Prediction in Depressive Patients
A prospective study on 25 patients with major depression, with a 10-year follow-up period revealed that patients with a higher TSH response to TRH at the time of admission had higher chances of recurrence after remission. 
Few researchers have recommended the inclusion of a thyroid screening test among the depressive patients, for proper management of the cases. 
Thyroid Hormone Augmentation and Treatment of Depression
The major methods in which the thyroid hormone can be used in depressed patients are:
- Acceleration method: The thyroid hormone is supplemented in the initial few weeks of an antidepressant trial to reduce the delay in the antidepressant effect.
- Augmentation studies: Thyroid hormone supplementation is done in those who are already on antidepressants, but are not responding well.
- Enhancement studies: Here the thyroid hormone is used throughout the antidepressant trial to improve the response of the antidepressants. ,
A majority of the acceleration studies were done a long time ago. In these studies 25 μg / day of T3 was added to imipramine for about 28 days and a positive result was found. ,, Other studies have also supported the augmentation of selective serotonin re-uptake inhibitors (SSRIs) with tri-iodothyronin to treat depressive disorder.  It has also been found that major depressive patients (DSM IV) with SSRI-resistant depression showed improvement in their mood scores when augmented with 25 to 50 μg of tri-iodothyronin (T3). , Other placebo-controlled, random control trials, have also shown a statistically significant response with 50 μg of T3 / day. ,, Although studies have also been done to identify the role of T4 in the augmentation of treatment in depressive illness by using around 150 μg / day of T4, they are few in number and a majority have shown that T3 is more beneficial than T4. ,
Various studies state that levothyroxine should be used as an adjunctive therapy with antidepressants, even in euthyroid patients.  Researchers have rated the depressive scores of patients on the Hamilton rating scale for depression (HDRS) and measured the free thyroxine (FT4) and tri-iodothyronine (FT3). They have found that a significant correlation exists between the FT4 levels and the severity of depression. They have also concluded that treatment with tri-iodothyronine instead of levothyroxine accelerates the treatment of depression. They have also found that male patients responded better to tri-iodothyronine than the female patients.  Prospective clinical trials done on bipolar I and bipolar II patients (DSM IV) have suggested that patients treated with levothyroxine have done better on the HDRS as compared to the placebo group. 
Twenty depressive patients with treatment-resistant depression were treated with right prefrontal transcranial magnetic stimulation (TMS). Their pretreatment levels of the thyroid stimulating hormone (TSH), FT3 and FT4 were analyzed and it was concluded that the TSH levels of the responders were significantly elevated after treatment. However, the FT3 and FT4 levels did not show any significant changes. They concluded that the lower TSH levels at pre-treatment were correlated with better therapeutic efficacy. It was concluded that the hypothalamic pituitary thyroid axis (HPT) was associated with antidepressant effects of the right prefrontal TMS.  Thus, it was found that not only did the thyroid hormone act as an adjuvant to antidepressant treatment, but it had also been seen to be associated with right prefrontal TMS treatment.
Studies Finding no Difference After Thyroid Augmentation
Garlow did a clinical trial on 153 adult patients with major depression by giving sertraline with placebo to one group and tri-iodothyronine (25 μg to 20 μg) with sertraline to the other group. They did not find any difference between the two groups, when rated on the HDRS scale, at the end of eight weeks.  Other studies have also supported the view that treatment of euthyroid depression with LT3 in addition to antidepressant therapy lacks convincing outcomes.  A cross-sectional study done on 3,932 men of age 69 to 87 years, free of overt thyroid disease, concluded that subclinical thyroid disease is not associated with depression in the elderly. 
Safety of Selective Serotonin Re-uptake Inhibitors in Patients with Thyroid Disorders
We found only one study on this topic. A prospective study done on 67 patients with major depression proved that all the pretreatment euthyroid patients showed all thyroid parameters within normal range even after treatment with fluoxetine and sertraline. Hypothyroid patients who were treated with thyroid replacement therapy and SSRIs also showed no changes in the thyroid parameters after treatment with SSRIs. The study proved that SSRIs were safe for the treatment of depression in euthyroid as well as hypothyroid patients. 
| Conclusion|| |
Not only all depressive patients should be screened for thyroid function abnormality, but antidepressant treatment should also be augmented with T3, whenever subclinical hypothyroidism is found.
| Acknowledgment|| |
The authors acknowledge Engineer AYUSH for his technical help.
| References|| |
Loosen PT. Hormones of the hypothalamic-pituitary-thyroid axis: A psychoneuroendocrine perspective. Pharmacopsychiatry 1986;19:401-15.
Joffe RT, Pearce EN, Hennessey JV, Ryan JJ, Stern RA. Subclinical hypothyroidism, mood, and cognition in older adults: A review. Int J Geriatr Psychiatry 2013;28:111-8.
Griffiths EC. Thyrotrophin releasing hormone: Endocrine and central effects. Psychoneuroendocrinology 1985;10:225-35.
Hage MP, Azar ST. The link between thyroid function and depression. J Thyroid Res 2012;2012:590648.
Larsen PR, Silva JE, Kaplan MM. Relationships between circulating and intracellular thyroid hormones: Physiological and clinical implications. Endocr Rev 1981;2:87-102.
van Doorn J, Roelfsema F, van der Heide D. Concentrations of thyroxine and 3,5,3'-triiodothyronine at 34 different sites in euthyroid rats as determined by an isotopic equilibrium technique. Endocrinology 1985;117:1201-8.
Williams GR. Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol 2008;20:784-94.
Pilhatsch M, Winter C, Nordström K, Vennström B, Bauer M, Juckel G. Increased depressive behaviour in mice harboring the mutant thyroid hormone receptor alpha 1. Behav Brain Res 2010;214:187-92.
Suzuki T, Abe T. Thyroid hormone transporters in the brain. Cerebellum 2008;7:75-83.
Hatterer JA, Herbert J, Hidaka C, Roose SP, Gorman JM. CSF transthyretin in patients with depression. Am J Psychiatry 1993;150:813-5.
van der Deure WM, Appelhof BC, Peeters RP, Wiersinga WM, Wekking EM, Huyser J, et al
. Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients. Clin Endocrinol (Oxf) 2008;69:804-11.
Duntas LH, Maillis A. Hypothyroidism and depression: Salient aspects of pathogenesis and management. Minerva Endocrinol 2013;38:365-77.
Jackson IM, Asamoah EO. Thyroid function in clinical depression: Insights and uncertainties. Thyroid Today 1999;22:1-11.
Kamble MT, Nandedkar PD, Dharme PV, L LS, Bhosale PG. Thyroid function and mental disorders: An insight into the complex interaction. J Clin Diagn Res 2013;7:11-4.
Nemeroff CB, Simon JS, Haggerty JJ Jr, Evans DL. Antithyroid antibodies in depressed patients. Am J Psychiatry 1985;142:840-3.
Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement of the imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 1969;126:457-69.
Bahls SC, de Carvalho GA. The relation between thyroid function and depression: A review. Rev Bras Psiquiatr 2004;26:41-9.
Linnoila M, Cowdry R, Lamberg BA, Makinen T, Rubinow D. CSF triiodothyronine (rT3) levels in patients with affective disorders. Biol Psychiatry 1983;18:1489-92.
St Germain DL. Regulatory effect of lithium onthyroxine metabolism in murine neural and anterior pituitary tissue. Endocrinology 1987;120:1430-8.
Chan BL, Singer W. The hypothalamic-pituitary-thyroid axis: Clinical and theoretical principles. In: Joffe RT, Levitt AJ, editors. The Thyroid Axis and Psychiatric Illness. Washington, DC: American Psychiatric Press, Inc.; 1993. p. 147-68.
Bernal J.Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007;3:249-59.
Farmer A, Korszun A, Owen MJ, Craddock N, Jones L, Jones I, et al
. Medical disorders in people with recurrent depression. Br J Psychiatry 2008;192:351-5.
Patten SB, Beck CA, Kassam A, Williams JV, Barbui C, Metz LM. Long-term medical conditions and major depression: Strength of association for specific conditions in the general population. Can J Psychiatry 2005;50:195-202.
Sierra P, Cámara R, Tobella H, Livianos L. What is the real significance and management of major thyroid disorders in bipolar patients? Rev Psiquiatr Salud Ment 2014;7:88-95.
Radhakrishnan R, Calvin S, Singh JK, Thomas B, Srinivasan K. Thyroid dysfunction in major psychiatric disorders in a hospital based sample. Indian J Med Res 2013;138:888-93.
Joffe RT. Hormone treatment of depression. Dialogues Clin Neurosci 2011;13:127-38.
Joffe RT, Levitt AJ. The thyroid and depression. In: Joffe RT, Levitt AJ, editors. The Thyroid Axis and Psychiatric Illness. Washington, DC: American Psychiatric Press; 1993. p. 195-254.
Zach J, Ackerman SH. Thyroid function, metabolic regulation, and depression. Psychosom Med 1988;50:454-68.
Samuels MH, Schuff KG, Carlson NE, Carello JP, Janowsky JS. Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis. J Clin Endocrinol Metab 2008;93:1730-6.
Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, mood and cognition in experimentallyinduced subclinical hypothyroidism. J Clin Endocrinol Metab 2007;92:2545-51.
Beydoun MA, Beydoun HA, Kitner-Triolo MH, Kaufman JS, Evans MK, Zonderman AB. Thyroid hormones are associated with cognitive function: Moderation by sex, race, and depressive symptoms. J Clin Endocrinol Metab 2013;98:3470-81.
Kirim S, Keskek SO, Köksal F, Haydardedeoglu FE, Bozkirli E, Toledano Y. Depression in patients with euthyroid chronic autoimmune thyroiditis. Endocr J 2012;59:705-8.
Ojha SP, Dhungana S, Chapagain M, Tulachan P. Association of thyroid dysfunction with depression in a teaching hospital. J Nepal Health Res Counc 2013;11:30-4.
Homan P, Drevets WC, Hasler G. Neural correlates of free T3 alteration after catecholamine depletion in subjects with remitted major depressive disorder and in controls. Psychopharmacology (Berl) 2014;231:409-17.
Ge JF, Peng YY, Qi CC, Chen FH, Zhou JN. Depression-like behavior in subclinical hypothyroidism rat induced by hemi-thyroid electrocauterization. Endocrine 2014;45:430-8.
Pae CU, Mandelli L, Han C, Ham BJ, Masand PS, Patkar AA, et al
. Thyroid hormones affect recovery from depression during antidepressant treatment. Psychiatry Clin Neurosci 2009;63:305-13.
McCoy SJ, Beal JM, Payton ME, Stewart AL, DeMers AM, Watson GH. Postpartum thyroid measures and depressive symptomology: A pilot study. J Am Osteopath Assoc 2008;108:503-7.
Groer MW, Vaughan JH. Positive thyroid peroxidase antibody titer is associated with dysphoric moods during pregnancy and postpartum. J Obstet Gynecol Neonatal Nurs 2013;42:E26-32.
Medici M, Direk N, Visser WE, Korevaar TI, Hofman A, Visser TJ, et al
. Thyroidfunction within the normal range and the risk of depression: A population-based cohort study. J Clin Endocrinol Metab 2014;99:1213-9.
Tsuru J, Ishitobi Y, Ninomiya T, Kanehisa M, Imanaga J, Inoue A, et al
. The thyrotropin-releasing hormone test may predict recurrence of clinical depression within ten years after discharge. Neuro Endocrinol Lett 2013;34:409-17.
Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Res 1990;32:241-51.
Prange AJ Jr, Lara PP, Wilson IC, Alltop LB, Breese GR. Effects of thyrotropin-releasing hormone in depression. Lancet 1972;2:999-1002.
Wilson IC, Prange AJ Jr, McClane TK, Rabon AM, Lipton MA. Thyroid-hormone enhancement of imipramine in nonretarded depressions. N Engl J Med 1970;282:1063-7.
Coppen A, Whybrow PC, Noguera R, Maggs R, Prange AJ Jr. The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine. Arch Gen Psychiatry1972;26:234-41.
Berent D, Zboralski K, Orzechowska A, Ga³ecki P. Thyroid hormones association with depression severity and clinical outcome in patients with major depressive disorder. Mol Biol Rep 2014;41:2419-25.
Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI resistant depression. J Affect Disord 2006;91:211-5.
Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J Affect Disord 2009;116:222-6.
Appelhof BC, Brouwer JP, van Dyck R, Fliers E, Hoogendijk WJ, Huyser J, et al
. Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. J Clin Endocrinol Metab 2004;89:6271-6.
Cooper-Kazaz R, Apter JT, Cohen R, Karagichev L, Muhammed-Moussa S, Grupper D, et al
. Combined treatment with sertraline and liothyronine in major depression: A randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2007;64:679-88.
Posternak M, Novak S, Stern R, Hennessey J, Joffe R, Prange A Jr, et al
. A pilot effectiveness study: Placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int J Neuropsychopharmacol 2008;11:15-25.
Kalra S, Balhara YP. Euthyroid depression: The role of thyroid hormone. Recent Pat Endocr Metab Immune Drug Discov 2014;8:38-41.
Stamm TJ, Lewitzka U, Sauer C, Pilhatsch M, Smolka MN, Koeberle U, et al
. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2014;75:162-8.
Kito S, Hasegawa T, Fujita K, Koga Y. Changes in hypothalamic-pituitary-thyroid axis following successful treatment with low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression. Psychiatry Res 2010;175:74-7.
Garlow SJ, Dunlop BW, Ninan PT, Nemeroff CB. The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder. J Psychiatr Res 2012;46:1406-13.
Feldman AZ, Shrestha RT, Hennessey JV. Neuropsychiatric manifestations of thyroid disease. Endocrinol Metab Clin North Am 2013;42:453-76.
Almeida OP, Alfonso H, Flicker L, Hankey G, Chubb SA, Yeap BB. Thyroid hormones and depression: The Health in Men study. Am J Geriatr Psychiatry 2011;19:763-70.
deCarvalho GA, Bahls SC, Boeving A, Graf H. Effects of selective serotonin reuptake inhibitors on thyroid function in depressed patients with primary hypothyroidism or normal thyroid function. Thyroid 2009;19:691-7.