Background: Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. Methods: In the Leiden substudy of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), thyroid-stimulating hormone and free T4 levels were measured at baseline and repeated after 6 months in adults aged 70-82 years with preexisting cardiovascular disease or known cardiovascular risk factors to define persistent thyroid functional status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS-15) at baseline and after 3 years. All analyses were adjusted for age, gender and education. Results: In 606 participants (41% women; mean age 75 years) without antidepressant medication, GDS-15 scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS-15 score 1.75, 95% CI 1.29-2.20, p = 0.53) or subclinical hyperthyroidism (n = 13; GDS-15 score 1.64, 95% CI 0.78-2.51, p = 0.96) compared to euthyroid participants (n = 546; mean GDS-15 score 1.60, 95% CI 1.46-1.73). After 3 years, compared to the euthyroid participants, changes in GDS-15 scores did not differ for participants with subclinical hypothyroidism (ΔGDS-15 score -0.03, 95% CI -0.50 to 0.44, p = 0.83), while subclinical hyperthyroidism was associated with an increase in GDS scores (ΔGDS-15 score 1.13, 95% CI 0.32-1.93, p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. Conclusions: In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study.

Keywords:
Subclinical dysfunction, Elderly subjects, Longitudinal design, PROSPER study, Thyroid, Depression
1.
Jones DD, May KE, Geraci SA: Subclinical thyroid disease. Am J Med 2010;123:502-504.
2.
Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J: Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304:1365-1374.
3.
Villar HC, Saconato H, Valente O, Atallah AN: Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev 2007;3:CD003419.
4.
Biondi B, Cooper DS: The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76-131.
5.
Bauer M, Goetz T, Glenn T, Whybrow PC: The thyroid-brain interaction in thyroid disorders and mood disorders. J Neuroendocrinol 2008;20:1101-1114.
6.
Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, Van Rhoads RS: Practice guideline for the treatment of patients with major depressive disorder, ed 3. Suppl Am J Psychiatry 2010;167:1-118.
7.
Cooper-Kazaz R, Apter JT, Cohen R, Karagichev L, Muhammed-Moussa S, Grupper D, Drori T, Newman ME, Sackeim HA, Glaser B, Lerer B: Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2007;64:679-688.
8.
Chang CM, Sato S, Han C: Evidence for the benefits of nonantipsychotic pharmacological augmentation in the treatment of depression. CNS Drugs 2013;27(suppl 1):S21-S27.
9.
Chueire VB, Romaldini JH, Ward LS: Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr 2007;44:21-28.
10.
Carta MG, Loviselli A, Hardoy MC, Massa S, Cadeddu M, Sardu C, Carpiniello B, Dell'Osso L, Mariotti S: The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future. BMC Psychiatry 2004;4:25.
11.
Jaracz J, Kucharska A, Rajewska-Rager A, Lacka K: Cognitive functions and mood during chronic thyrotropin-suppressive therapy with L-thyroxine in patients with differentiated thyroid carcinoma. J Endocrinol Invest 2012;35:760-765.
12.
Nemeroff CB, Simon JS, Haggerty JJ Jr, Evans DL: Antithyroid antibodies in depressed patients. Am J Psychiatry 1985;142:840-843.
13.
Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG: Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;292:2591-2599.
14.
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;19:763-770.
15.
Shepherd J, Blauw GJ, Murphy MB, Cobbe SM, Bollen EL, Buckley BM, Ford I, Jukema JW, Hyland M, Gaw A, Lagaay AM, Perry IJ, Macfarlane PW, Meinders AE, Sweeney BJ, Packard CJ, Westendorp RG, Twomey C, Stott DJ: The design of a Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER study group. Prospective Study of Pravastatin in the Elderly at Risk. Am J Cardiol 1999;84:1192-1197.
16.
van den Heuvel DM, Admiraal-Behloul F, ten Dam VH, Olofsen H, Bollen EL, Murray HM, Blauw GJ, Westendorp RG, de Craen AJ, van Buchem MA: Different progression rates for deep white matter hyperintensities in elderly men and women. Neurology 2004;63:1699-1701.
17.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630.
18.
Nanchen D, Gussekloo J, Westendorp RG, Stott DJ, Jukema JW, Trompet S, Ford I, Welsh P, Sattar N, Macfarlane PW, Mooijaart SP, Rodondi N, de Craen AJ: Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk. J Clin Endocrinol Metab 2012;97:852-861.
19.
Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, Iervasi G, Asvold BO, Sgarbi JA, Völzke H, Gencer B, Maciel RM, Molinaro S, Bremner A, Luben RN, Maisonneuve P, Cornuz J, Newman AB, Khaw KT, Westendorp RG, Franklyn JA, Vittinghoff E, Walsh JP, Rodondi N: Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012;172:799-809.
20.
Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, Nanchen D, den Elzen WP, Balmer P, Luben RN, Iacoviello M, Triggiani V, Cornuz J, Newman AB, Khaw KT, Jukema JW, Westendorp RG, Vittinghoff E, Aujesky D, Rodondi N: Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation 2012;126:1040-1049.
21.
Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, Wemeau JL: 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J 2013;2:215-228.
22.
Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE: Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499.
23.
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ: Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-238.
24.
Meyerovitch J, Rotman-Pikielny P, Sherf M, Battat E, Levy Y, Surks MI: Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians. Arch Intern Med 2007;167:1533-1538.
25.
Diez JJ, Iglesias P, Burman KD: Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2005;90:4124-4127.
26.
Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC: Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol 1991;34:77-83.
27.
Virgini V, Wijsman L, Rodondi N, Bauer D, Kearney P, Gussekloo J, den Elzen W, Jukema W, Westendorp R, Ford I, Stott D, Mooijaart S: Subclinical thyroid dysfunction and functional capacity among elderly. Thyroid 2013;24:208-214.
28.
Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982;17:37-49.
29.
D'Ath P, Katona P, Mullan E, Evans S, Katona C: Screening, detection and management of depression in elderly primary care attenders. I. The acceptability and performance of the 15-item Geriatric Depression Scale (GDS15) and the development of short versions. Fam Pract 1994;11:260-266.
30.
de Craen AJ, Heeren TJ, Gussekloo J: Accuracy of the 15-item Geriatric Depression Scale (GDS-15) in a community sample of the oldest old. Int J Geriatr Psychiatry 2003;18:63-66.
31.
Dennis M, Kadri A, Coffey J: Depression in older people in the general hospital: a systematic review of screening instruments. Age Ageing 2012;41:148-154.
32.
Vinkers DJ, Gussekloo J, Stek ML, Westendorp RG, Van Der Mast RC: The 15-item Geriatric Depression Scale (GDS-15) detects changes in depressive symptoms after a major negative life event. The Leiden 85-plus Study. Int J Geriatr Psychiatry 2004;19:80-84.
33.
de Waal MW, van der Weele GM, van der Mast RC, Assendelft WJ, Gussekloo J: The influence of the administration method on scores of the 15-item Geriatric Depression Scale in old age. Psychiatry Res 2012;197:280-284.
34.
Oomen HA, Schipperijn AJ, Drexhage HA: The prevalence of affective disorder and in particular of a rapid cycling of bipolar disorder in patients with abnormal thyroid function tests. Clin Endocrinol 1996;45:215-223.
35.
Gulseren S, Gulseren L, Hekimsoy Z, Cetinay P, Ozen C, Tokatlioglu B: Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch Med Res 2006;37:133-139.
36.
Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS: Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis. J Clin Endocrinol Metab 2008;93:1730-1736.
37.
Larisch R, Kley K, Nikolaus S, Sitte W, Franz M, Hautzel H, Tress W, Müller HW: Depression and anxiety in different thyroid function states. Horm Metab Res 2004;36:650-653.
38.
de Jongh RT, Lips P, van Schoor NM, Rijs KJ, Deeg DJ, Comijs HC, Kramer MH, Vandenbroucke JP, Dekkers OM: Endogenous subclinical thyroid disorders, physical and cognitive function, depression, and mortality in older individuals. Eur J Endocrinol 2011;165:545-554.
39.
Engum A, Bjøro T, Mykletun A, Dahl AA: An association between depression, anxiety and thyroid function - a clinical fact or an artefact? Acta Psychiatr Scand 2002;106:27-34.
40.
Vreeburg SA, Hoogendijk WJ, van Pelt J, Derijk RH, Verhagen JC, van Dyck R, Smit JH, Zitman FG, Penninx BW: Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry 2009;66:617-626.
41.
Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, Parle JV: Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 2006;145:573-581.
42.
Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, Dore CJ, Finer N: A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med 2002;112:348-354.
43.
Blum MR, Bauer DC, Collet TH, et al: Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA 2015;313:2055-2065.
44.
Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy RP, Ladenson PW: Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;295:1033-1041.
45.
Svare A, Nilsen TI, Asvold BO, Forsmo S, Schei B, Bjøro T, Langhammer A: Does thyroid function influence fracture risk? Prospective data from the HUNT2 study, Norway. Eur J Endocrinol 2013;169:845-852.
46.
Waring AC, Harrison S, Fink HA, Samuels MH, Cawthon PM, Zmuda JM, Orwoll ES, Bauer DC: A prospective study of thyroid function, bone loss, and fractures in older men: the MrOS study. J Bone Miner Res 2013;28:472-479.
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