Abstract
The association between thyroid function and depression is controversial. Both conditions express many similar symptoms, but the studies done give conflicting results. This study draws on a random, population-based sample of 4500 subjects aged 45–75 years old from Finland. The basic clinical study was done in 2007 for 1396 men and 1500 women (64% participation rate). Thyroid stimulating hormone (TSH), free thyroxine (F-T4), and free triiodothyronine (F-T3) were measured in 2013 from frozen samples. The 21-item Beck Depression Inventory (BDI-21) was applied to assess depressive symptoms (score ≥10 points). The prevalence of depressive symptoms was 17.5% in women and 12.5% in men. In women, the mean levels of TSH, F-T4, and F-T3 without depressive symptoms vs. with the presence of depressive symptoms were 1.92/1.97 mU/L, 13.1/13.1 pmol/L, and 3.91/3.87 pmol/L (NS), respectively. In men, the levels were 1.87/1.94 mU/L, 13.5/13.7 pmol/L, and 4.18/4.12 pmol/L (NS), respectively. In multiple regression analysis, TSH had no relationship to BDI-21 total score. We found no association between depressive symptoms and thyroid values.
Keywords: depressive symptoms, BDI-21, thyroid, population based
Introduction
The association between depression and thyroid function, especially hypothyroidism, is controversial. The idea of association comes from similarity of symptoms between severely depressed and hypothyroid patients, the therapeutic use of thyroid hormones in the management of depression, and the apparent abnormalities in the hypothalamic–pituitary–thyroid axis of subjects with depression.1
The many studies in this area give conflicting results. The larger studies have shown either no effect or an inverse relationship between thyroid function and mood.1 The largest study so far is the Norwegian HUNT study.2 The investigators found no association between depression, self-reported using the Hospital Anxiety and Depression Scale (HADS), and thyroid dysfunction in 30,589 individuals aged 40–89 years. The same group also analyzed the connections between thyroid autoimmunity, depression, and anxiety, finding no associations.3 A health database study from Taiwan of 1,000,000 random subjects found a higher prevalence (1.20% vs. 0.30%) and a higher annual incidence (0.40% vs. 0.13%) of hypothyroidism in patients with major depressive disorder than in the general population. The annual incidence of hyperthyroidism was also higher in patients with depression than in the general population (0.72% vs. 0.32%, risk ratio 2.06). The correlation was especially pronounced in the female subjects.4
Our aim was to study the relationship of thyroid function and depressive symptoms, measured with the 21-item Beck Depression Inventory (BDI-21),5 in this rather large Finnish adult population, because the results of previous studies are conflicting in various populations.
Materials and Methods
Study population
The FIN-D2D survey was carried out in the hospital districts of Pirkanmaa, the Southern Ostrobothnia, and Central Finland between October and December 2007.
A random sample of 4500 subjects aged 45–74 years, which was stratified according to gender, 10-year age groups (45–54, 55–64, and 65–74 years), and three geographical areas, was selected from the National Population Register in August 2007. The study participants were invited to a clinical examination by mail. The overall participation rate was 64%. Thus, the main study included 2896 individuals, of which 1396 were men (62% of men invited) and 1500 were women (66.7% of women invited).
Thyroid values were measured in 2741 subjects (1434 women and 1307 men). Thyroxin hormone was used by 79 subjects, and they were excluded from the analysis. The final study population was 2662 (1358 women and 1304 men).
The study protocol was approved by the ethics committee of the Hospital District of Helsinki. All participants gave their written, informed consent prior to participation in the study. The study was conducted in accordance with the principles of the Declaration of Helsinki. The health examination was carried out according to the World Health Organization’s (WHO’s) MONICA project (Multinational MONItoring of trends and determinants in CArdiovascular disease) and the WHO’s expert group for glucose assessments.
BDI-21 was applied to assess depressive symptoms.5 Subjects were categorized as having depression when they scored ≥10 points in the BDI-21. The cut-off point of 10 in the BDI-21 has been shown to be a useful measurement for detecting depression in various adult populations.6,7
Subjects were asked to rate 21 items from 0 to 3 according to how they felt at that time. The items were summed as a total score with a range from 0 to 63. The BDI-21 data were missing for eight women and five men.
The participants reported their leisure-time physical activity (LTPA) according to three categories: (1) low—almost completely inactivate, (2) moderate—some physical activity more than four hours per week, and (3) high—vigorous physical activity many times a week. Current smoking and the use of alcohol were also queried. The participants were also asked whether they were using thyroid hormones or lipid-lowering, antihypertensive, antidepressive, or antihyperglycemic medications.
Height, weight, and waist circumference were measured by nurses who were specially trained for the survey procedures. Height was measured to the nearest 0.1 cm, and weight was measured to the nearest 0.1 kg in light clothing. Body mass index (BMI) was calculated as weight (kg) divided by the height squared (m2). Blood pressure (BP) was measured twice, and the latter was used in the analysis, in a sitting position after a minimum of 15 minutes of acclimatization using a mercury sphygmomanometer.
Laboratory analysis
After an overnight fast, venous blood samples for serum lipid assays were drawn into a gel tube containing clot activator and samples for the plasma glucose assay into a fluoride citrate tube (Venosafe; Terumo Europe). The samples were immediately frozen after separating serum and plasma and transferred to the laboratory in dry ice once a week for analyses. The rest of samples were kept in −70°C.
All basic assays were performed at the Laboratory of Analytical Biochemistry at the National Public Health Institute, Helsinki (Disease Risk Unit, Institute for Health and Welfare since 2009), using an ARCHITECT ci8200 analyzer (Abbott Laboratories). High-sensitivity C-reactive protein (hs-CRP) was measured with an ultrasensitive immunoturbidimetric method using Abbott architect reagents.
Free thyroxine (F-T4), free triiodothyronine (F-T3), and thyroid stimulating hormone (TSH) were measured from frozen EDTA-plasma samples with Cobas e601 (Roche Diagnostics) automated analyzer in the Islab Laboratory of the University of Eastern Finland, Kuopio, in the year 2013. The reference values for free T4, free T3, and TSH were 11–22 pmol/L, 3.1–6.8 pmol/L, and 0.3–4.2 mU/L, respectively. Serum thyroid antiperoxidase antibodies were measured by Architect® (Abbott Laboratories) automated analyzer. Analytical sensitivity of the assay was 0.16 IU/mL. The upper reference limit was 6.0 IU/mL.
Statistical analysis
The comparisons between the groups in demographic, lifestyle, and biochemical characteristics and clinical and drug-treatment data were made by t-test, bootstrapped-type t-test, or chi-square test, as appropriate. The equality of distributions of the thyroid values was tested using the Epps–Singleton two-sample empirical characteristics function test and bootstrap-type analysis of covariance (ANCOVA) taking age, BMI, LTPA, current smoking, and alcohol use values as covariates. Linear regression analyses (bootstrap-type standard error) were used to identify the appropriate predictors of the BDI-21 total score, using standardized regression coefficient beta (β). Beta is measured in units of standard deviation, and value is a measure of how strongly each predictor variable influences the criterion (dependent) variable. Cohen’s standard for beta values above 0.10, 0.30, and 0.50 represents small, moderate, and large relationships, respectively.
Results
The mean age of the study population was 59.7 years (women 59.2 years and men 60.0 years). The mean BMI of both men and women was 27.4 kg/m2 (Table 1). Fasting plasma glucose values were 6.0 mmol/L in women and 6.5 mmol/L in men. The use of antihypertensive, lipid-lowering, and antidepressant medications was higher in men and women with depression. Hs-CRP was not statistically different in men or women with or without depression. LTPA was significantly higher both in men and women without depression. BP was the same in all groups.
Table 1.
The basic demographic, lifestyle and biochemical characteristics of study population according to BDI-21 values <10 and ≥10.
| WOMEN | MEN | |||||
|---|---|---|---|---|---|---|
| BDI-21 | BDI-21 | |||||
| <10 N = 1114 | ≥10 N = 236 | P-VALUE | <10 N = 1136 | ≥10 N = 163 | P-VALUE | |
| Demographic | ||||||
| Age, years, mean (SD) | 59 (8) | 61 (9) | <0.001 | 60 (8) | 62 (9) | <0.001 |
| Waist, cm, mean (SD) | 90 (13) | 94 (14) | <0.001 | 99 (11) | 104 (14) | <0.001 |
| BMI, mean (SD) | 27.2 (5.0) | 28.4 (5.4) | 0.001 | 27.3 (4.0) | 28.7 (5.0) | <0.001 |
| Clinical | ||||||
| Blood pressure, mmHg, mean (SD) | ||||||
| Systolic | 135 (19) | 135 (19) | 0.96 | 138 (18) | 138 (18) | 0.98 |
| Diastolic | 80 (9) | 80 (9) | 0.99 | 83 (10) | 83 (10) | 0.64 |
| Biochemical | ||||||
| Total cholesterol, mmol/l | 5.52 (0.96) | 5.60 (0.96) | 0.24 | 5.36 (1.01) | 5.10 (0.96) | <0.001 |
| HDL cholesterol, mmol/l | 1.56 (0.34) | 1.51 (0.32) | 0.017 | 1.33 (0.32) | 1.26 (0.28) | 0.013 |
| Total triglycerides, mmol/l | 1.24 (0.58) | 1.41 (0.72) | <0.001 | 1.49 (1.02) | 1.53 (0.84) | 0.56 |
| Fasting plasma glucose, mmol/l | 5.99 (0.93) | 6.18 (1.34) | 0.036 | 6.42 (1.26) | 6.50 (1.26) | 0.45 |
| hs-CRP, mg/L | 2.86 (8.24) | 3.21 (5.64) | 0.43 | 2.37 (6.26) | 3.51 (11.64) | 0.22 |
| Medication | ||||||
| Antihypertensive medication, n (%) | 354 (32) | 98 (42) | 0.004 | 382 (34) | 78 (48) | <0.001 |
| Lipid lowering medication, n (%) | 186 (17) | 52 (22) | 0.051 | 268 (24) | 57 (35) | 0.002 |
| Use of antidepressants, n (%) | 43 (4) | 47 (20) | <0.001 | 22 (2) | 28 (17) | <0.001 |
| Lifestyle factors | ||||||
| Current smoker, n (%) | 208 (19) | 59 (25) | 0.027 | 279 (25) | 44 (27) | 0.50 |
| Current use of alcohol, n (%) | 558 (50) | 111 (47) | 0.39 | 843 (74) | 102 (63) | 0.002 |
| LTPA | <0.001 | <0.001 | ||||
| Low | 164 (15) | 73 (33) | 191 (17) | 58 (38) | ||
| Moderate | 668 (61) | 122 (55) | 649 (58) | 81 (53) | ||
| High | 258 (24) | 27 (12) | 271 (24) | 15 (10) | ||
Abbreviations: BDI-21, The 21-item Beck Depression Inventory; BMI, body mass index; LTPA, leisure-time physical activity; hs-CRP, high sensitivity C-reactive protein; SD, standard deviation.
Subclinical hypothyroidism (TSH over reference range and normal F-T4) was found in 4.2% of subjects. Subclinical hyperthyroidism (TSH under reference rate) was found in 1.1% of subjects. The prevalence of undiagnosed hypothyroidism (TSH over and F-T4 under the reference rate) was 1.3%. The prevalence of these groups was the same in BDI-21 over and under 10 points compared to subjects with normal thyroid values.
Table 2 shows that the prevalence of depressive symptoms (BDI-21 ≥10 points) was 17.5% in women and 12.5% in men. The mean thyroid values for women without depressive symptoms (BDI-21 <10 points) vs. with depressive symptoms (BDI-21 ≥10 points) were 1.92/1.97 mU/L (NS) for TSH, 13.1/13.1 pmol/L (NS) for F-T4, and 3.91/3.87 pmol/L (NS) for F-T3. For men, the values were 1.87/1.94 mU/L (NS) for TSH, 13.5/13.7 pmol/L (NS) for F-T4, and 4.18/4.12 pmol/L (NS) for F-T3.
Table 2.
The association between Beck Depression Inventory (BDI-21) scores <10 and ≥10 and thyroid values (TSH, F-T4, F-T3) in men and women.
| WOMEN | MEN | |||||||
|---|---|---|---|---|---|---|---|---|
| BDI-21 | P-VALUE | BDI-21 | P-VALUE | |||||
| <10 N = 1114 | ≥10 N = 236 | CRUDE | ADJUSTED* | <10 N = 1136 | ≥10 N = 163 | CRUDE | ADJUSTED* | |
| TSH | ||||||||
| Mean (SD) | 1.92 (1.18) | 1.97 (1.38) | 0.61 | 0.63 | 1.87 (1.24) | 1.94 (1.25) | 0.54 | 0.85 |
| Median (IQR) | 1.68 (1.12, 2.48) | 1.67 (1.01, 2.49) | 1.58 (1.11, 2.25) | 1.58 (1.06, 2.53) | ||||
| F-T4 | ||||||||
| Mean (SD) | 13.1 (2.0) | 13.1 (2.1) | 0.50 | 0.10 | 13.5 (2.0) | 13.7 (2.4) | 0.25 | 0.39 |
| Median (IQR) | 13.0 (11.9, 14.3) | 12.7 (11.7, 14.3) | 13.4 (12.2, 14.9) | 13.7 (12.2, 15.2) | ||||
| F-T3 | ||||||||
| Mean (SD) | 3.91 (0.65) | 3.87 (0.64) | 0.38 | 0.18 | 4.18 (0.68) | 4.12 (0.68) | 0.32 | 0.13 |
| Median (IQR) | 3.88 (3.48, 4.30) | 3.87 (3.46, 4.25) | 4.17 (3.70, 4.63) | 4.12 (3.66, 4.50) | ||||
Notes:
Adjusted for age, BMI, current smoking, current alcohol use and LTPA.
Abbreviations: BDI-21, The 21 Item Beck Depression Inventory; F-T4, free thyroxine; F-T3, free triiodothyronine; TSH, thyroid-stimulating hormone; SD, standard deviation: IQR, interquartile range; LTPA, leisure-time physical activity.
Table 3 shows that in multiple regression analysis, TSH has no relationship to BDI-21 total score.
Table 3.
Multiple regression analysis for BDI-21 total score.
| VARIABLE | BETA* | P-VALUE |
|---|---|---|
| TSH | 0.02 (−0.02 to 0.05) | 0.39 |
| Male gender | −0.09 (−0.13 to −0.05) | <0.001 |
| Age | 0.10 (0.06 to 0.14) | >0.001 |
| BMI | 0.06 (0.01 to 0.10) | 0.008 |
| Current smoker | 0.06 (0.02 to 0.10) | 0.002 |
| Current use of alcohol | −0.05 (−0.09 to −0.01) | 0.012 |
| LTPA | ||
| Low | Reference | <0.001 (p for linearity) |
| Moderate | −0.18 (−0.23 to −0.13) | |
| High | −0.24 (−0.29 to −0.13) | |
| hs-CRP | 0.03 (−0.01 to 0.06) | 0.18 |
| Fasting plasma glucose | 0.01 (−0.03 to 0.05) | 0.62 |
| Lipid lowering medication | 0.04 (0.01 to 0.08) | 0.030 |
| Antihypertensive medication | −0.01 (−0.04 to 0.08) | 0.90 |
Note:
Standardized beta coefficients.
Discussion
This study found no association between depressive symptoms and TSH, F-T4, and F-T3 in this Finnish population-based cohort. The prevalence of depressive symptoms was 17.5% in women and 12.5% in men. This is in line with other studies assessing depressive symptoms in Finland.8 The prevalence of hypothyroidism or subclinical hypothyroidism in this population, measured by s-TSH over the reference range 4.2 mU/L, was 5.5%. The calculated lifetime risk for developing overt hypothyroidism in Denmark was 2.3%, with a threefold excess in women (3.5% vs. 1.0% in men).9
We, like many others, excluded the persons (N = 79) who used thyroxine from the analysis. This may be an important bias because subjects with depressive symptoms and subclinical hypothyroidism are likely to have been on thyroxine therapy in countries like Finland where medical care and thyroid function tests are easily available. As these subjects are excluded, the remaining subjects with clinical hypothyroidism are likely to be less symptomatic.1
Several studies have investigated thyroid autoimmunity and depression.3 The results are conflicting. Smaller studies, one with 583 women with TPO antibody levels >100 mU/L10 and one with 201 subjects,11 found an association with depressive scores and thyroid autoimmunity. However, the above-mentioned large Norwegian study found no relation.3
Both the symptoms of depression and biochemical subclinical hypothyroidism (slightly elevated TSH) are common, especially in the elderly female population. Thus, it is probable that they overlap, resulting in thyroxin therapy. Many studies have shown poor well-being in subjects on thyroxin, even if it was started with adequate biochemical values.12,13 The Danish study found that hypothyroidism presented with a broad spectrum of symptoms. However, many of these symptoms were also experienced by volunteer control subjects with normal thyroid values.9
Interestingly, a study of a Dutch population-based cohort of elderly people (mean age 71 years) found that subjects with low-normal TSH levels had more concurrent depressive symptoms than those with normal levels as well as a substantially increased risk of developing a depressive syndrome in the subsequent years.14
Systemic inflammation increases the risk of depression, especially in people with type 2 diabetes.15 The effect of low-grade inflammation in people with hypothyroidism is not known. In our study, we measured hs-CRP as a marker of systemic inflammation, but we did not find any differences between groups. On one hand, the depressive people had less LTPA than non-depressed people. On the other hand, people with depressive symptoms used more antihypertensive, lipid-lowering, and antidepressant medications.
The strength of this study is a rather large, randomly selected population, aged 45–74 years, with both men and women. The depressive symptoms were assessed by BDI-21, which is widely used and accepted in population-based studies.
The limitations of the study are that TPO-antibodies were measured only in 30% of subjects, and we do not have data about the subjects’ disease and family history, factors that may have important influence on depression. In the beginning, the study population was randomly selected from the National Population Register database, but only 64% of invited subjects enrolled, and we excluded subjects receiving thyroxin-hormone therapy. So, the final study population is not randomly selected population based.
Conclusion
The association of depressive symptoms and the levels of thyroid hormones has been controversial. This study did not find any association between TSH, F-T4, and F-T3 values and depressive symptoms.
Footnotes
ACADEMIC EDITOR: Nigel Irwin, Editor in Chief
FUNDING: FIN-D2D was supported by financing from hospital districts of Central Finland, Pirkanmaa, Southern Ostrobothnia, North Ostrobothnia, the Finnish National Public Health Institute, the Finnish Diabetes Association, the Ministry of Social Affairs and Health in Finland, and the Finland’s Slot Machine Association in cooperation with the FIN-D2D Study Group. The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal.
COMPETING INTERESTS: Authors disclose no potential conflicts of interest.
Paper subject to independent expert blind peer review by minimum of two reviewers. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties.
Author Contributions
Conceived and designed the experiments: JS, PM, MV. Analyzed the data: HK, JS, MV. Wrote the first draft of the manuscript: JS. Contributed to the writing of the manuscript: HK, PM, MV. Agree with manuscript results and conclusions. JS, HK, PM, AJ, SKK, EKH, HO, TS, MV. Jointly developed the structure and arguments for the paper: JS, HK, PM, AJ, MV. Made critical revisions and approved the final versions: JS, HK, PM, AJ, SKK, EKH, HO, TS, MV. All authors reviewed and approved of the final manuscript.
REFERENCES
- 1.Dayan CM, Panicker V. Hypothyroidism and depression. Eur Thyroid J. 2013;2:168–179. doi: 10.1159/000353777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Engum A, Bjøro T, Mykletun A, Dahl AA. An association between depression, anxiety and thyroid function—a clinical fact or artifact? Acta Psychiatr Scand. 2002;106:27–34. doi: 10.1034/j.1600-0447.2002.01250.x. [DOI] [PubMed] [Google Scholar]
- 3.Engum A, Bjøro T, Mykletun A, Dahl AA. Thyroid autoimmunity, depression and anxiety; are there connections? An epidemiological study of a large population. J Psychosom Res. 2005;59:263–268. doi: 10.1016/j.jpsychores.2005.04.002. [DOI] [PubMed] [Google Scholar]
- 4.Wu EL, Chien IC, Lin CH, Chou YJ, Chou P. Increased risk of hypothyroidism and hyperthyroidism in patients with major depressive disorder: a population-based study. J Psychosom Res. 2013;74:233–237. doi: 10.1016/j.jpsychores.2012.12.016. [DOI] [PubMed] [Google Scholar]
- 5.Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561–571. doi: 10.1001/archpsyc.1961.01710120031004. [DOI] [PubMed] [Google Scholar]
- 6.Beck AT, Sterr RA, Garben MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77–100. [Google Scholar]
- 7.Mäntyselkä P, Korniloff K, Saaristo T, et al. Association of depressive symptoms with impaired glucose regulation, screen-detected, and previously known type 2 diabetes. Findings from the Finnish D2D Survey. Diabetes Care. 2011;34:71–76. doi: 10.2337/dc10-1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Vanhala M, Jokelainen J, Keinänen-Kiukaanniemi S, Kumpusalo E, Koponen H. Depressive symptoms predispose females to metabolic syndrome: a 7-years follow-up study. Acta Psychiatric Scand. 2009;119:137–142. doi: 10.1111/j.1600-0447.2008.01283.x. [DOI] [PubMed] [Google Scholar]
- 9.Carlé A, Laurberg P, Pedersen IB, et al. Epidemiology of subtypes of hypothyroidism in Denmark. Eur J Endocrinol. 2006;154:21–28. doi: 10.1530/eje.1.02068. [DOI] [PubMed] [Google Scholar]
- 10.Pop VJ, Maartens LH, Leusink G, et al. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab. 1998;83:3194–3197. doi: 10.1210/jcem.83.9.5131. [DOI] [PubMed] [Google Scholar]
- 11.Kirim S, Keskek SO, Koksal F, Haydardedeoglu FE, Bozkirli E, Toledano Y. Depression in patients with euthyroid chronic autoimmune thyroiditis. Endocr J. 2012;59:705–708. doi: 10.1507/endocrj.ej12-0035. [DOI] [PubMed] [Google Scholar]
- 12.Wekking EM, Appelhof BC, Fliers E, et al. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol. 2005;153:747–753. doi: 10.1530/eje.1.02025. [DOI] [PubMed] [Google Scholar]
- 13.Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, psychological symptoms, mood, and cognition in l-thyroxine-treated hypothyroid subjects. Thyroid. 2007;17:249–258. doi: 10.1089/thy.2006.0252. [DOI] [PubMed] [Google Scholar]
- 14.Medici M, Direk N, Visser E, et al. Thyroid function within the normal range and the risk of depression: a population-based cohort study. J Clin Endocrinol Metab. 2014;99:1213–1219. doi: 10.1210/jc.2013-3589. [DOI] [PubMed] [Google Scholar]
- 15.Laake JP, Stahl D, Amiel SA, et al. The association between depressive symptoms and systemic inflammation in people with type 2 diabetes: findings from the South London Diabetes Study. Diabetes Care. 2014;37:2186–2192. doi: 10.2337/dc13-2522. [DOI] [PubMed] [Google Scholar]