Relationship between thyroid-stimulating hormone levels and risk of depression among the general population with normal free T4 levels

Accepted Manuscript Title: Relationship between Thyroid-stimulating Hormone Levels and Risk of Depression among the General Population with Normal Free T4 Levels Author: Eun Young Kim Se Hyun Kim Sang Jin Rhee Iksoo Huh Kyooseob Ha Jayoun Kim Jae Seung Chang Dae Hyun Yoon Taesung Park Yong Min Ahn PII: DOI: Reference:

S0306-4530(15)00156-0 http://dx.doi.org/doi:10.1016/j.psyneuen.2015.04.016 PNEC 2978

To appear in: Received date: Revised date: Accepted date:

30-12-2014 21-4-2015 22-4-2015

Please cite this article as: http://dx.doi.org/10.1016/j.psyneuen.2015.04.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title Relationship between Thyroid-stimulating Hormone Levels and Risk of Depression among the

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General Population with Normal Free T4 Levels

Eun Young Kim a,1

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Se Hyun Kim b,1 Sang Jin Rhee a

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Iksoo Huh c Kyooseob Ha d,e,f

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Jayoun Kim g Jae Seung Chang h

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Dae Hyun Yoon i Taesung Park c,*

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Yong Min Ahn a,e,*

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1. These authors contributed equally to this study.

Mental Health Clinic, National Cancer Center, Goyang, Republic of Korea Department of Neuropsychiatry, Dongguk University Medical School, Dongguk University International Hospital, Goyang, Republic of Korea,

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Department of Statistics, Seoul National University, Seoul, Republic of Korea Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

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Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

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Director, Seoul National Hospital, Seoul, Republic of Korea

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Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

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Department of Psychiatry and Institute of Clinical Psychopharmacology, Dongguk University

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College of Medicine, Goyang, Republic of Korea Department of Psychiatry, Seoul National University Hospital Healthcare System Gangnam Center,

*Correspondence to Dr Yong Min Ahn, M.D. Ph.D.

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Contact information for the corresponding author.

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Seoul, Republic of Korea

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Department of Psychiatry and Behavioral Science, Institute of Human Behavioral Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea

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Tel: +82 2 2072 0710; fax: +82 2 744 7241; e-mail: [email protected]

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*Co-correspondence to Prof. Taesung Park. Ph.D.

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Department of Statistics, Seoul National University, gwanak-gu, Seoul 151-747, Republic of Korea

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Tel: +82 2 880 8924; fax: +82 2 888-6693; e-mail: [email protected]

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Highlights We assessed the relationship between thyroid-stimulating hormone level and risk of depression. Relationships between thyroid function and depressive symptoms were different by gender.

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Low normal thyroid function was associated with the development of depression in females.

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Abstract Objective: This study assessed the relationship between thyroid-stimulating hormone (TSH) level and risk of depressive symptom in a population with no clinical or laboratory evidence of thyroid

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dysfunction. Methods: This retrospective cohort study included 13,017 subjects (7,913 males and 5,104 females),

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17–84 years of age, who underwent health examinations at the hospital. Subjects had a Beck Depression Inventory (BDI) total score of ≤9 and fell within the normal range of free T4 levels at

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baseline. The association between gender-specific serum TSH tertile at baseline and the development of clinically significant depressive symptom (i.e., ≥19 BDI total score) on the follow-up visit was

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evaluated using the Cox proportional hazards model, with adjustment for demographic and life style factors.

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Results: The risk of depressive symptom was increased among subjects with the highest tertile TSH level (adjusted hazard ratio [HR], 2.236; 95% confidence interval [CI], 1.443–3.466; p < 0.001) as

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compared with subjects with the lowest tertile in females, but not in males. Even among patients with

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normal TSH levels, females in the lowest-normal TSH tertile had a higher risk of depressive symptoms (adjusted HR, 2.279; 95% CI, 1.456–3.567; p < 0.001) than did those in the highest tertile.

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The TSH level as a continuous variable significantly predicted the depressive symptoms in females (adjusted HR, 1.402; 95% CI, 1.002–1.812; p = 0.027). Conclusions: Our finding suggests that suboptimal thyroid function increases vulnerability to the occurrence of depressive symptom and represents a modifiable risk factor for depression in females.

Keywords

Thyroid-stimulating hormone Subclinical thyroid function Depression

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1. Introduction There has been a long history of interest in the association between the hypothalamic– pituitary–thyroid (HPT) axis and mood disorders. Substantial literatures have documented the

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neurobiological effects of the thyroid axis in mood modulation and the role of thyroid function in the pathophysiology or treatment of mood disorders (Bauer and Whybrow, 2001). The development of

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assays for thyroid-stimulating hormone (TSH) in the early 1970s allowed for the assessment of more

subtle thyroid dysfunction (Cole et al., 2002), and many studies have documented that depression can

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be accompanied by subtle forms of hypothyroidism (Haggerty et al., 1993; Joffe and Levitt, 1992) Frank thyroid disorder is rare in depressive patients (Maes et al., 1993), whereas subclinical

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hypothyroidism (defined as normal T4 with raised TSH) is highly prevalent in depressed populations (Gold et al., 1981). Patients with subclinical hypothyroidism have a greater lifetime prevalence of

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depression (Haggerty et al., 1993), and subtle thyroid dysfunction has been suggested as a negative prognostic factor for depression (Fountoulakis et al., 2006).

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Although suboptimal thyroid function is considered a reversible cause of depression, most of

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prior researches were cross-sectional and few prospective studies have investigated the association between the development of depression and suboptimal thyroid function using large samples. A recent

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study showed that subclinical thyroid disease was not associated with incident depression in 3,932 elderly males free of overt thyroid disease (Almeida et al., 2011). A study of 2,269 middle-aged males found a weak positive effect of total T4 on incident and chronic psychiatric morbidity; however, this was consistent with chance after adjusting for alcohol, smoking and social status (Williams et al., 2009). Gender-based relationships between thyroid function and depressive symptoms may constitute an important factor, due to the difference in serum TSH levels according to gender in the general population and in depressed patients (Forman-Hoffman and Philibert, 2006), as well as differences in the prevalence of thyroid abnormalities (Flynn et al., 2004). To date, no large study has thoroughly investigated this issue with a focus on adult females. Fundamental questions remain about whether subclinical thyroid dysfunction is a risk factor for depressive symptoms and, this being the case, the question of which population is vulnerable to depression remains largely unanswered.

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We conducted a large retrospective cohort study to assess the association between thyroid function and the development of clinically significant depressive symptoms after controlling for potential confounding factors in the general population who had no clinical or laboratory evidence of

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thyroid dysfunction (free T4 values within the normal range). We present our results separately

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according to gender.

2. Methods

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2.1. Participants

This retrospective cohort study included data from 13,017 subjects, between 17–84 years of age, who

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underwent health examinations at the Seoul National University Hospital Healthcare System, Gangnam Center, Seoul, South Korea, between October 2004 and July 2012. All subjects received

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anthropometric measurements, completed self-administered questionnaires including the Beck Depression Inventory (BDI) and underwent physical examinations and laboratory tests including

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thyroid function tests. Our study included 7,913 males and 5,104 females, who completed the BDI on

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≥ two occasions during the observation period and had a BDI total score <10 on their initial visit. We excluded subjects who had abnormal free T4 levels (normal reference range, 0.7 ng/dl ≤ free T4 ≤ 1.8

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ng/dl) or diagnosis of other thyroid disease, or who were currently taking thyroid medication. This study was approved by the Institutional Review Board of the Seoul National University Hospital.

2.2. Measures

The 21-item BDI, a validated instrument for measuring the severity of depressive symptoms,

was used to determine the development of clinically significant depressive symptoms. Each BDI question was scored from 0–3 with a total score ranging from 0 - 63, with higher scores indicating greater depressive symptom severity. Scores of 0–9, 10–18, 19–29, or over 30 indicated the severity of symptoms as minimal, mild, moderate, or severe depression, respectively. This study included subjects with a total score of 0–9 on BDI to ensure absent or minimal depressive symptoms at baseline, and a BDI cutoff score of 19 indicated the development of clinically significant depressive

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symptoms as a primary outcome measure. Demographic characteristics (age, gender, and marital status), educational level, lifestyle factors, and past medical history were collected from self-administered questionnaires on the initial

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visit. Medical history was assessed for the presence or absence of hypertension, diabetes mellitus,

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stroke, cardiovascular disease, and any type of cancer.

2.3. Thyroid function

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Over the period covered by this study, thyroid function assay methodologies changed several times at Seoul National University Hospital. Serum TSH levels were measured using a commercially

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available kit (Daiichi Radioisotope Labs, Tokyo, Japan), beginning in August 1998, and the kit was replaced by the Liaison TSH kit (Diasorin, Saluggia, Italy) in February 2007. Free T4 levels were

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measured using a different commercial kit (RIA-gnostFT4; CIS Bio International, Cedex, France) beginning in March 2003. The RIA kit was eventually replaced by the Riakey TSH IRMA Kit and

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Riakey free T4 RIA Kit (Shin Jin Medics, Seoul, Korea) after April 2012. Regardless of the assay kit

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used, the reference range in Seoul National University Hospital was consistent during the study period

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(0.4–4.1 mU/L for TSH, and 0.7–1.8 ng/dl (8.9–23.2 pmol/l) for free T4)).

2.4. Statistical Analyses

We categorized patients into three groups based on the gender-specific tertiles of TSH levels.

Baseline characteristics between the groups were compared using an analysis of variance for continuous variables and chi-square tests for categorical variables. We applied Cox proportional hazards regression model to estimate the hazard of clinically significant depressive symptom according to gender-specific TSH tertiles as well as TSH levels as a continuous variable. In each model, the following possible confounding factors were used: age, BMI, marital status, educational level, smoking status, alcohol consumption, exercise frequency, and somatic illness including hypertension, diabetes mellitus, cardiovascular disease, and stroke. We also performed similar analyses after additional adjustment for menopause status and hormonal treatment only in female

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subjects to determine whether these factors would influence the associations. Finally, we performed the same analysis using samples with normal TSH levels. All p-values were two-tailed, and a p-value of 0.05 was considered statistically significant. Statistical analyses were performed using the

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Statistical Package for Social Science version 19.0 for Windows (SPSS, Inc., Chicago, IL, USA) and

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R Project for Statistical Computing software version 2.11.0.

3. Results

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3.1. Subject Characteristics

Table 1 summarizes demographic and clinical characteristics of study participants in groups

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according to the gender-specific tertiles of TSH levels at baseline (males: 0.05–1.34, 1.35–1.89, and 1.90–31.4 mU/L; females: 0.05–1.44, 1.45–2.30, and 2.31–22.0 mU/L). The mean (±SD) age of the

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study cohort was 46.9 ± 9.9 years at baseline. Subjects in the highest tertile group were older than subjects in the other groups. Subjects with higher TSH levels at baseline were less likely to be current

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smokers. Participants in all groups had similar rates of somatic illness. Pearson correlation coefficient

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between TSH levels and free T4 levels was significant (r = -0.142, p < 0.001 in males and r = -0.157, p < 0.001 in females). The mean (± SD) follow-up period was 3.2 (±1.5) years, ranging from 0.5 to

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7.6 years.

Insert Table 1

3.2. Risk of clinically significant depressive symptom and Thyroid Stimulating Hormone levels Figure 1 shows the results from Cox proportional hazards regression analyses. Clinically

significant depressive symptoms developed in 40 male and 144 female subjects. There was no association between risk of developing depressive symptoms and TSH tertile in male subjects. Conversely, in female subjects, when compared with subjects in the lowest tertile group, the risk of depressive symptoms increased among subjects in the 2nd tertile group (adjusted hazard ratio (HR), 1.795; 95% CI, 1.138–2.832; p = 0.012) and among subjects in the highest tertile group (adjusted HR, 2.236; 95% CI, 1.443–3.466; p < 0.001). The TSH level as a continuous variable also significantly

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predicted the development of depressive symptoms only in females (adjusted HR, 1.402; 95% CI, 1.002–1.812; p = 0.027). Even among patients with normal TSH levels, females in the lowest-normal TSH tertile had a higher risk of depressive symptoms (adjusted HR, 2.279; 95% CI, 1.456–3.567; p <

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0.001) than did those in the highest tertile, compared with persons in the highest tertile. In females, this significant relationship remained after more adjustment for menopause and hormonal treatment.

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Insert Figure 1

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4. Discussion

This large retrospective cohort study suggests that suboptimal HPT axis function, even

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within the normal range of thyroid hormone, is a major neuroendocrine condition predisposing females to develop depressive symptoms.

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The adjusted hazard ratio increased to 2.236 in the highest as compared with the lowest tertile of TSH levels only in females but not in men. Interestingly, in a cross-sectional analysis of

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general population, lower TSH and higher T4 levels were associated with current depression in young

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adults and elderly people (Forman-Hoffman and Philibert, 2006; Medici et al., 2014), although no association in adults aged 50 to 70 years has been reported. In several clinical studies, hyperactivity of

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the HPT axis was observed in depressive patients, and thyroxine levels decreased with treatment (Maes et al., 1993). Meanwhile, low normal thyroid function was associated with poorer treatment response and with lower rate of remission in depressive patients (Abulseoud et al., 2013; Cole et al., 2002) Collectively, previous findings are consistent with the hypothesis that hyperactivity of the HPT axis in a depressive state may represent a compensatory homeostatic response of the central nervous system to the depressive state (Whybrow and Prange, 1981) and that failure of such response, indicated by high TSH or low free T4 levels, is related to depressive recurrence as well as negative prognosis. Accordingly, our findings show that subtle thyroid dysfunction, even within the normal range, indicates a decreased capacity of compensatory thyroid response to the development of depressive symptoms. In our study, the relationship between suboptimal thyroid function and development of

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depressive symptoms was significant only in females. Overt and subclinical hypothyroidism is more common in females (Flynn et al., 2004), and the risk of developing overt hypothyroidism from subclinical thyroid dysfunction is also higher in females than males (Cooper and Biondi, 2012).

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Moreover, the thyroid reserve in response to depression can be mobilized more effectively in males than in females (Abulseoud et al., 2007). In this regard, baseline suboptimal thyroid function may

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increase vulnerability to the development of clinically significant depressive symptoms, especially in females. However, this association was not significant in males. Almeida et al. (2011) investigated the

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association between thyroid dysfunction and incident depression in 3,932 males, 69 to 87 years of age. They found that serum TSH and free T4 levels did not affect the hazard of incident depression during

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the follow-up period over 5.5 years. Williams et al. (2009) found no significant association between total T4 levels and minor psychiatric morbidity in 2,269 middle-aged males over 12.3 years. Our

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results were generally consistent in showing no association between thyroid function and risk of depression in males. On the other hand, a recent study reported that elderly people in the lowest

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normal-range TSH tertile had a higher risk of incident depressive syndromes with no sex-specific

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effect (Medici et al., 2014). However, this is not directly comparable with our study because of differences in age ranges, the depressive symptom assessment tool, and covariates.

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Our findings implicate the clinical utility of TSH levels to identify patients who are

vulnerable to depressive disorders in female. Diagnosis of subclinical hypothyroidism is currently based on laboratory tests of serum TSH determination (defined as an elevation in serum TSH above the upper limit of the reference range with normal free T4 levels) and is inevitably arbitrary in nature (Col et al., 2004). No clear evidence shows that this ‘endocrinological’ reference range of serum TSH levels can be applied to determine the relationship between thyroid function and depression and identify a high-risk population for development of depression. Similar to our study, a previous study reported that serum TSH concentrations in the highest quartile of the normal range was positively associated with recurrent depression (Berlin et al., 1999), questioning the appropriateness of the ‘endocrinological’ reference range of thyroid function in depressive patients. Our study is limited by the retrospective cohort design and the fact that past medical history

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was obtained through self-reported questionnaire. This may result in underestimation of residual confounding factors including history of thyroidectomy, use of radioactive iodine, and any type of thyroid disease or medications such as T4 supplementation which could affect TSH levels. Second,

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lack of structured diagnostic interviews for depression may limit the conclusions. Although we used a BDI cut-off point of 19 to determine clinically significant depressive symptoms, shown as valid

Finally, our results may not be generalizable to other ethnic groups.

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criteria in previous studies, under- or overestimation of depression cannot be entirely ruled out.

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Nevertheless, this is the first study to show that incident depression is associated with higher serum TSH levels in females with normal range free T4 levels using a large study sample. Our

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findings highlight the need to establish practical standard values of thyroid index to identify the risk of depression. A controlled prospective study with a longer follow-up period is necessary to establish

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a clear reference range to detect the population at risk and to assess the potential treatment benefits

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such as thyroid hormone supplementation, while considering sex differences.

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References Abulseoud, O., Sane, N., Cozzolino, A., et al., 2007. Free T4 index and clinical outcome in patients w ith depression. J. Affect. Disord. 100, 271-277.

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Abulseoud, O.A., Gitlin, M., Altshuler, L., et al., 2013. Baseline thyroid indices and the subsequent res ponse to citalopram treatment, a pilot study. Brain. Behav. 3, 89-94.

Almeida, O.P., Alfonso, H., Flicker, L., et al., 2011. Thyroid hormones and depression: the Health in

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Men study. Am. J. Geriatr. Psychiatry 19, 763-770.

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Bauer, M., Whybrow, P.C., 2001. Thyroid hormone, neural tissue and mood modulation. World J. Biol. Psychiatry 2, 59-69.

Berlin, I., Payan, C., Corruble, E., et al., 1999. Serum thyroid-stimulating-hormone concentration as an

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index of severity of major depression. Int. J. Neuropsychopharmacol. 2, 105-110.

Col, N.F., Surks, M.I., Daniels, G.H., 2004. Subclinical thyroid disease: clinical applications. JAMA 29

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1, 239-243.

Cole, D.P., Thase, M.E., Mallinger, A.G., et al., 2002. Slower treatment response in bipolar depression

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predicted by lower pretreatment thyroid function. Am. J. Psychiatry 159, 116-121.

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Cooper, D.S., Biondi, B., 2012. Subclinical thyroid disease. Lancet 379, 1142-1154. Flynn, R.W., MacDonald, T.M., Morris, A.D., et al., 2004. The thyroid epidemiology, audit, and resear

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ch study: thyroid dysfunction in the general population. J. Clin. Endocrinol. Metab. 89, 3879-3884. Forman-Hoffman, V., Philibert, R.A., 2006. Lower TSH and higher T4 levels are associated with curre nt depressive syndrome in young adults. Acta. Psychiatr. Scand. 114, 132-139. Fountoulakis, K.N., Kantartzis, S., Siamouli, M., et al., 2006. Peripheral thyroid dysfunction in depressi on. World. J. Biol. Psychiatry 7, 131-137. Gold, M.S., Pottash, A.L., Extein, I., 1981. Hypothyroidism and depression. Evidence from complete th yroid function evaluation. JAMA 245, 1919-1922. Haggerty, J.J., Jr., Stern, R.A., Mason, G.A., et al., 1993. Subclinical hypothyroidism: a modifiable risk factor for depression? Am. J. Psychiatry 150, 508-510. Joffe, R.T., Levitt, A.J., 1992. Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroe ndocrinology 17, 215-221. Maes, M., Meltzer, H.Y., Cosyns, P., et al., 1993. An evaluation of basal hypothalamic-pituitary-thyroid axis function in depression: results of a large-scaled and controlled study. Psychoneuroendocrinology 1

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8, 607-620. Medici, M., Korevaar, T.I., Schalekamp-Timmermans, S., et al., 2014. Maternal early-pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study. J.

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Clin. Endocrinol. Metab. 99, 2591-2598. Whybrow, P.C., Prange, A.J., Jr., 1981. A hypothesis of thyroid-catecholamine-receptor interaction. Its r elevance to affective illness. Arch. Gen. Psychiatry 38, 106-113.

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Williams, M.D., Harris, R., Dayan, C.M., et al., 2009. Thyroid function and the natural history of depr

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ession: findings from the Caerphilly Prospective Study (CaPS) and a meta-analysis. Clin. Endocrinol. (

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Oxf) 70, 484-492.

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Acknowledgments. This work was supported by grant A121987 from the Korea Healthcare Technology R & D Project, Ministry of Health & Welfare, Republic of Korea and by the National Research Foundation of Korea

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(NRF) grant funded by the Korea government (MSIP) (No. 2012R1A3A2026438)

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Conflict of interest Prof. Yong Min Ahn receives a research grant and served as a lecturer for Janssen, Lilly, Lundbeck

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and Otsuka. All other authors report no financial relationships with commercial interests.

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Figure 1. Cox proportional hazards regression analysis for the development of clinically significant depressive symptoms in groups according to the gender-specific tertiles of TSH levels. a

Ranges for TSH tertiles were as follows (mU/L): men: 0.05-1.34, 1.35-1.89, 1.90-31.4; women: 0.05-1.44,

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1.45-2.30, 2.31-22.0

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Role of the funding source The funding source had no role in study design; in the collection, analysis, and interpretation of data;

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in the writing of the report; or in the decision to submit the paper for publication.

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Table 1. Baseline demographic and clinical characteristics of study participants in groups according to the gender-specific tertile of TSH levels. a 2nd tertile (N=4,332)

3rd tertile (N=4,313)

Mean (SD)

Mean (SD)

Mean (SD)

46.2 (9.9)

46.9 (9.7)

47.7 (10.1)

23.4 (3.0)

23.5 (3.0)

N (%)

N (%)

Female

1,711 (39.1)

1,702 (39.3)

Currently married

3,933 (90.0)

3,949 (91.2)


118 (2.7)

73 (1.7)

87 (2.0)


512 (11.7)

501 (11.6)

499 (11.6)

College graduation

2,326 (53.2)

2,365 (54.6)

2,336 (54.2)

Post-graduate studies

1,416 (32.4)

1,393 (32.2)

1,391 (32.3)

2,168 (50.0)

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BMI (kg/m )

N (%)

1,691 (39. 2) 3,933 (91.2)

Non-smoker

2,110 (48.3)

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Education

23.5 (3.0)

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Age (years)***

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1st tertile (N=4,372)

2,215 (51.4)

Ex-smoker

1,219 (27.9)

1,256 (29.0)

1,437 (33.3)

Current smoker

1,043 (23.9)

908 (21.0)

661 (15.3)

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Cigarette smoking***

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Alcohol use

1,644 (37.6)

1,678 (38.7)

1,699 (39.4)

2/month~2/week

2,097 (48.0)

2,008 (46.4)

1,994 (46.2)

515 (11.8)

519 (12.0)

495 (11.5)

116 (2.7)

127 (2.9)

125 (2.9)

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≤1/month 3~4/week

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≥5/week Exercise

<1/week

1,415 (32.4)

1,311 (30.3)

1,322 (30.7)

1~2/week

1,394 (31.9)

1,416 (32.7)

1,341 (31.1)

3~4/week

1,117 (25.5)

1,133 (26.2)

1,154 (26.8)

≥5/week

446 (10.2)

472 (10.9)

496 (11.5)

Hypertension

687 (15.7)

676 (15.6)

718 (16.6)

Diabetes mellitus

181 (4.1)

183 (4.2)

180 (4.2)

Stroke

10 (0.2)

12 (0.3)

14 (0.3)

Cardiovascular disease

67 (1.5)

71 (1.6)

65 (1.5)

481 (28.1)

469 (27.6)

494 (29.2)

Somatic illness

Menopause b

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74 (4.3) 70 (4.1) 78 (4.6) Hormonal treatment Ranges for TSH tertiles were as follows (mU/L): men: 0.05-1.34, 1.35-1.89, 1.90-31.4; women: 0.05-1.44,

1.45-2.30, 2.31-22.0 b

Hormonal treatment includes use of oral contraceptive

*** p < 0.001

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Figure(s)

Figure 1.

3.5 3

1st tertile (reference) 2nd tertile 3rd tertile

2.5 2

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1.5 1

0.5 1

0.93

0.587

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1.795 2.236

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Female (n=5104)

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Male (n=7913)

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Adjusted Hazard ratio (95% CI)

4

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