Soc Psychiatry Psychiatr Epidemiol
DOI 10.1007/s00127-015-1043-0
ORIGINAL PAPER
Diagnosed thyroid disorders are associated with depression
and anxiety
Till Ittermann1 Henry Volzke1 Sebastian E. Baumeister1 Katja Appel2
Hans J. Grabe2
Received: 21 July 2014 / Accepted: 6 March 2015
Springer-Verlag Berlin Heidelberg 2015
Abstract
Purpose Associations between thyroid diseases and de-
pression have been described since the 1960s but there is a
lack of population-based studies investigating associations
of thyroid diseases with depression and anxiety defined by
gold-standard methods. Thus, the aim was to investigate the
association of diagnosed thyroid disorders, serum thyroid-
stimulating hormone (TSH) levels, and anti-thyroid-per-
oxidase antibodies (TPO-abs) with depression and anxiety.
Methods We used data from 2142 individuals, who par-
ticipated in the first follow-up of the Study of Health in
Pomerania (SHIP-1) and in the Life-Events and Gene-En-
vironment Interaction in Depression (LEGEND). DSM-VI
diagnoses of major depression disorder and anxiety were
defined using the Munich-Composite International Diag-
nostic Interview; the Beck depression inventory (BDI-II)
was used for the assessment of current depressive symp-
toms. Thyroid diseases were assessed by interviews and by
biomarkers and were associated with depression and
anxiety using Poisson regression adjusted for age, sex,
marital status, educational level, smoking status, BMI, and
the log-transformed time between SHIP-1 and LEGEND.
Results Untreated diagnosed hypothyroidism was
positively associated with the BDI-II-score and with
anxiety, while untreated diagnosed hyperthyroidism was
significantly related to MDD during the last 12 months.
Serum TSH levels and TPO-Abs were not significantly
& Till Ittermann
till.ittermann@uni-greifswald.de
1
Institute for Community Medicine, University Medicine
Greifswald, Greifswald, Germany
2
Institute for Psychiatry and Psychotherapy, University
Medicine Greifswald, Greifswald, Germany
associated with depression and anxiety. In sub-analyses,
distinct interactions were found between childhood mal-
treatment and thyroid disorders in modifying the asso-
ciation on depression and anxiety disorders.
Conclusions Our results substantiate evidence that diag-
nosed untreated hypothyroidism is associated with de-
pression and anxiety, and that diagnosed untreated
hyperthyroidism is associated with depression.
Keywords Thyroid
Thyroid hormone metabolism

Depression
Anxiety
Epidemiology
Introduction
Depression and anxiety disorders are highly prevalent in the
general European population. In Germany, the 12-month
prevalence of mental disorders is reported to be 32 % in West
and 28 % in East Germany [1]. A link between thyroid
hormones and depression was introduced in the late 1960s in
a clinical cohort. In depressive patients, the efficiency of
antidepressant treatment was higher after supplementation
with triiodothyronine [2], a finding that was later confirmed
in several clinical trials [35]. In contrast a casecontrol
study [6], two cross-sectional population-based studies [7,
8], and one patient study [9] did not detect an association
between hypothyroidism and depression, but in two of those
studies hyperthyroidism was associated with depression [6,
9]. Of the two population-based studies [7, 8] one was con-
ducted in men[70 years, while the other one, which was part
of the HUNT study from Norway, covered an age range of
4089 years [8]. In that study [8], depression and anxiety
symptoms were measured using the Hospital Anxiety and
Depression Scale (HADS). Limitations of the HUNT study
[8] are that no gold-standard measurement of diagnosis of
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depression and anxiety was available and that potential
confounders of the thyroid-depression association were not
considered, such as marital status and educational level.
Another limitation was a substantial non-response of 50 %.
Our group has previously demonstrated that individuals
with overt hyperthyroidism have significantly less mental
distress compared to euthyroid individuals [10]. This is in
agreement with the findings of the clinical trials [35], but
in disagreement with previous population-based research
[7, 8]. However, it is not known how strong subjective
distress is associated with depressive disorders in the
general population, so that we cannot generalize the results
of our previous study [10] to depression.
Apart from the HUNT study [8], there are no studies
which have investigated the association between thyroid
function tests and depression or anxiety disorders in the
general population. Furthermore, there is no data on the
association between thyroid function and depression using
gold-standard DSM-V diagnosis of depression and anxiety
as well as a symptomatology screener that also covers
subclinical, undiagnosed depression.
Childhood abuse and neglect are commonly regarded as
risk factors for depression and anxiety disorders [11, 12].
Thus, subjects who have been exposed to childhood mal-
treatment are supposed to carry a psychobiological vul-
nerability that lowers the resistance against psychological
but also biological stressors that poses them at risk for
mental disorders. Therefore, we follow the hypotheses that
subjects with childhood maltreatment are at increased risk
of depression and anxiety when additionally exposed to
thyroid diseases. To our knowledge, the potential effect
modification of childhood abuse and neglect on the asso-
ciation of thyroid disease with depression and anxiety has
not been examined.
Accordingly, we investigated the association of serum
thyroid-stimulating hormone (TSH) levels and self-reported
thyroid disorders with diagnosed major depression diagnosis
(MDD) based on a clinical psychiatric interview according
to DSM-IV criteria and on self-assessed depressive symp-
toms during the last 2 weeks (Beck Depression Inventory
[BDI-II] [13]) in a population-based cross-sectional study in
Northeastern Germany. We also investigated whether the
potential association between thyroid phenotypes and de-
pression is modified by childhood abuse and neglect.
Materials and methods
Study population
The Study of Health in Pomerania (SHIP) is a population-
based cohort study conducted in West Pomerania [14]. A
sample from the population aged 2079 years was drawn
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Soc Psychiatry Psychiatr Epidemiol
from population registries comprising 6267 eligible sub-
jects. For the present study, we used data from the 5-year
follow-up of baseline SHIP performed between 2002 and
2006 (SHIP-1) and from the Life-Events and Gene-En-
vironment Interaction in Depression (LEGEND) study
conducted in 2007, in which all SHIP participants were
invited. Of the 4308 participants in baseline SHIP, 3300
individuals participated in SHIP-1 and 2400 individuals
participated in LEGEND. All participants gave informed
written consent. The study followed the recommendations
of the Declaration of Helsinki and was approved by the
Ethics Committee of the University of Greifswald.
The study region was historically mild to moderate
iodine deficient [15]. In 1993, a iodine fortification pro-
gram was initiated leading to an appropriate iodine supply
on a lower recommended level during the end of the 1990s
[16]. However, due to the long-term iodine deficiency in
the past prevalence of goiter, thyroid nodules and hyper-
thyroidism are still high in West Pomerania [16].
There were no differences between subjects participat-
ing in LEGEND and those not participating regarding
thyroid measurements. Of the 3300 individuals who par-
ticipated in SHIP-1, we excluded individuals with missing
data in thyroid variables or relevant confounders (n = 52),
non-participation in LEGEND (n = 961), insufficient
quality of the interview in LEGEND (n = 128), and
missing data in depression or anxiety (n = 17). The re-
sulting 2142 individuals (1120 women) were used to ana-
lyze the association between previously diagnosed thyroid
disorders at SHIP-1 and depression or anxiety at LEGEND.
To analyze the association between serum TSH levels or
anti-thyroid-peroxidase antibodies (TPO-Ab) at SHIP-1
and depression or anxiety at LEGEND, we further ex-
cluded all individuals with previously diagnosed thyroid
disorders (n = 498).
Assessments
Information on previously diagnosed thyroid disorders
(general as well as specific diagnoses of thyroid nodules,
hyperthyroidism, and hypothyroidism), marital status,
educational level, and smoking status were taken from
computer-assisted personal interviews in SHIP-1. Marital
status was classified into the two categories ever and never
married. Education was categorized according to the Ger-
man three-level school system (low, \10 years; interme-
diate, 10 years and high, [10 years). Smoking status was
categorized into the three categories current smokers, for-
mer smokers, and never smokers. All participants were
asked to bring all medications taken 7 days prior to the
time of examination. Medication data were obtained online
using the IDOM program (online drug-database leaded
medication assessment) and categorized according to the
Soc Psychiatry Psychiatr Epidemiol
Anatomical Therapeutic Chemical (ATC) Classification
system. Thyroid medication was defined by the ATC code
H03. Height and weight were measured for the calculation
of the body mass index: BMI = weight (kg)/height2 (m2).
Blood samples were taken in SHIP-1 and analyzed in
one central laboratory. Serum TSH levels were analyzed by
an immunochemiluminescent method (Immulite 2000,
Third generation, Diagnostic Products Corporation, DPC,
Los Angeles, Il, USA). High and low TSH were defined
according to TSH reference limits established in the study
region [17]. Serum TPO-Abs were measured by an enzyme
immunoassay (VARELISA, Elias Medizintechnik GmbH,
Freiburg, Germany). The functional sensitivity of this assay
was 1 IU/ml. The TPO-Ab status was defined as follows:
normal \60 IU/ml in men and \100 IU/ml in women;
elevated [60 IU/ml in men and [100 IU/ml in women;
positive: [200 IU/ml in both sexes [16].
To evaluate MDD and anxiety diagnoses, the Munich-
Composite International Diagnostic Interview (M-CIDI)
was applied [18]. The M-CIDI is a standardized fully
structured instrument for assessing psychiatric disorders
according to DSM-IV criteria. The computerized version of
the interview was used in LEGEND by clinically experi-
enced psychologists in a face-to-face situation [19]. In our
analyses, we used the following outcomes from the
M-CIDI categorized as yes or no: global lifetime MDD,
singular episode MDD, recurrent MDD, MDD in the
12 months preceding the LEGEND examination, and
anxiety disorders (with and without specific phobias). The
BDI-II questionnaire was used to assess for current de-
pressive symptoms [13]. According to the BDI-II-sum
score, individuals were categorized into two groups (\12
and C12).
The Childhood Trauma Questionnaire (CTQ) was used
for self-report of childhood maltreatment including emo-
tional, physical, and sexual abuse [20]. It has 28 items that
are rated on a five-point Likert scale with higher scores
indicating more self-rated exposure to traumatic events. In
addition to a dimensional scoring procedure, the manual
provides threshold scores to determine the severity of
abuse and neglect (none = 0, mild = 1, moderate = 2,
and severe to extreme = 3). In independent studies, the
CTQ demonstrated good reliability and validity; addition-
ally, a factor structure reflecting the different types of
childhood trauma has been empirically confirmed [20, 21].
Based on the CTQ, we categorized childhood neglect and
abuse into two levels; 1 if an individual was abused and/or
neglect in childhood and 0 if not.
Statistical analyses
Characteristics of the study population are provided stra-
tified by previously diagnosed thyroid disorders as median
and interquartile range (continuous variables) or as abso-
lute numbers and percentages (categorical variables).
Wilcoxon and v2 tests were used to test for differences
between individuals with and without previously diagnosed
thyroid disorders. Multivariable Poisson regression models
with robust standard errors adjusted for age, sex, marital
status, educational level, smoking status, BMI, and the log-
transformed time between SHIP-1 and LEGEND ex-
amination were used to associate thyroid variables at SHIP-
1 with depression and anxiety disorders at LEGEND.
Poisson regression was used instead of logistic regression
because odds ratios from logistic regression are inflated in
comparison to relative risks from Poisson regression if the
outcome is common [22]. Analyses were repeated stratified
by childhood abuse and neglect. Fractional polynomials
were used to test for linearity of the exposureoutcome
relationship [23]. In the present analyses, we detected no
deviations from linearity, so that no transformations on the
exposure were applied. In all analyses, a p \ 0.05 was
considered as statistically significant. All analyses were
carried out by Stata 13.1 (Stata Corporation, College Sta-
tion, TX, USA).
Results
There were 498 individuals (23.3 %) with previously di-
agnosed thyroid disorders or intake of thyroid medication.
Of those, 247 individuals took thyroid medication
(49.6 %), 223 individuals had diagnosed thyroid nodules
(44.8 %), 74 had diagnosed hyperthyroidism (14.9 %), and
70 individuals had diagnosed hypothyroidism (14.1 %).
Individuals with a diagnosed thyroid disorder were older,
more often females and married, had a lower educational
level and a higher BMI than individuals without diagnosed
thyroid disorders (Table 1). Regarding depression or
anxiety disorders the two groups differed only for the BDI-
II. Of those individuals with MDD during the 12 months
prior to LEGEND 62.8 % also had a BDI-II C12. In in-
dividuals with a BDI-II C12, only 17.3 % also had a MDD
during the 12 months prior to LEGEND.
Multivariable regression analyses revealed no sig-
nificant associations between diagnosed thyroid disorders
at SHIP-1 and lifetime MDD at LEGEND, but untreated
diagnosed hyperthyroidism was positively associated with
MDD 12 months prior to LEGEND (Table 2). Diagnosed
thyroid disorders in general and diagnosed hypothyroidism
were positively associated with a BDI-II C12 when indi-
viduals taking thyroid medication were excluded. Fur-
thermore, diagnosed thyroid nodules were positively
associated with a BDI-II C12 in the population including
individuals taking thyroid medication. In individuals not
taking thyroid medication, diagnosed hypothyroidism and
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Table 1 Characteristics of the study population stratified by diagnosed thyroid disorders

No diagnosis of thyroid disorder or intake of Diagnosis of thyroid disorder or intake of p*
medication (n = 1644) medication (n = 498)

Age; years 50 (39; 61) 55 (44; 65) \0.001

Males 868 (52.8 %) 154 (30.9 %) \0.001
TSH; mIU/L 0.81 (0.55; 1.15) 0.72 (0.45; 1.10) \0.001
Increased TPO-Ab 115 (7.0 %) 76 (15.3 %) \0.001
Positive TPO-Ab 54 (3.3 %) 52 (10.4 %) \0.001
Hypoechogenicity 42 (2.6 %) 59 (12.1 %) \0.001
Ever married 1381 (84.0 %) 446 (89.6 %) 0.002
Smoking status
Never 704 (42.8 %) 212 (42.6 %) 0.967
Former 576 (35.0 %) 173 (34.7 %)
Current 364 (22.1 %) 113 (22.7 %)
Educational level
\10 years 477 (29.0 %) 177 (35.5 %) 0.010
=10 years 815 (49.6 %) 236 (47.4 %)
[10 years 352 (21.4 %) 85 (17.1 %)
Body mass index 26.9 (24.1; 30.4) 28.2 (24.9; 32.0) \0.001
Global MDD 272 (16.6 %) 91 (18.3 %) 0.368
Singular episode MDD 147 (8.9 %) 44 (8.8 %) 0.942
Recurrent MDD 125 (7.6 %) 47 (9.4 %) 0.187
MDD last 12 months 76 (4.6 %) 29 (5.8 %) 0.287
BDI-II sum-score 4 (1; 9) 5 (1; 11) \0.001
BDI-II C12 260 (16.1 %) 110 (22.3 %) 0.002
Anxiety excl. specific 105 (6.4 %) 41 (8.2 %) 0.152
phobias
Anxiety incl. specific 344 (20.9 %) 117 (23.5 %) 0.222
phobias
Anxiety last 12 months 219 (13.3 %) 79 (15.9 %) 0.151
Neglect in childhood 322 (20.6 %) 110 (23.0 %) 0.274
Abuse in childhood 125 (7.9 %) 47 (9.7 %) 0.215
Data are expressed as median and interquartile range (continuous variables) and as absolute numbers and percentages (categorical variables)
TSH thyroid-stimulating hormone, TPO-Ab anti-thyroid-peroxidase antibodies, MDD major depressive disorder, BDI-II Becks disease inventory
* Wilcoxon (continuous variables) and v2 tests (categorical variables)

diagnosed thyroid disorders in general were positively as-
sociated with anxiety disorders excluding specific phobias.
Diagnosed hypothyroidism was also associated with anxi-
ety disorders excluding specific phobias in the population
including individuals taking thyroid medication. There
were no statistically significant associations between di-
agnosed thyroid disorders and singular episode MDD (data
not shown).
In contrast to the results of diagnosed thyroid disorders,
serum TSH levels and TPO-Abs were not consistently as-
sociated with depression or anxiety disorders in multi-
variable regression analyses after exclusion of individuals
having a diagnosed thyroid disorder or taking thyroid
medication (Table 3). We detected a significantly positive
association between increased TPO-Abs in SHIP-1 and a
MDD 12 months prior to LEGEND, but this association
was not present for positive TPO-Abs.
To account for the fact that depression and anxiety were
assessed 15 years after measurement of TSH and TPO-
Abs, we excluded 70 individuals with incident thyroid
medication intake between SHIP-1 and SHIP-2, the latter
conducted 6 years following SHIP-1. Due to non-response
at SHIP-2 a further of 403 individuals were excluded for this
sensitivity analyses. In these analyses, the relative risks for
the association between TSH and depression outcomes
showed stronger inverse relationships than in the main
analyses with p values of 0.15 for global lifetime, singular
episode lifetime, and 12 months MDD and of 0.35 for a

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Table 2 Association between diagnosed thyroid disorders and depression or anxiety

Global MDD Recurrent MDD MDD last 12 months BDI-II C12 Anxiety excl. specific
phobias
RR (95 % CI) RR (95 % CI) RR (95 % CI) RR (95 % CI) RR (95 % CI)

Whole population
Diagnosed thyroid disorder 1.05 (0.791.39) 1.13 (0.771.65) 1.27 (0.782.07) 1.22 (0.941.58) 1.28 (0.861.90)
Diagnosed thyroid nodules 1.31 (0.901.89) 1.36 (0.812.28) 1.42 (0.712.86) 1.46* 1.44 (0.832.51)
(1.042.06)
Diagnosed hyperthyroidism 1.11 (0.602.06) 1.22 (0.542.74) 2.26 (0.995.10) 1.08 (0.641.84) 0.85 (0.312.34)
Diagnosed hypothyroidism 1.60 (0.982.60) 1.75 (0.863.55) 1.81 (0.724.53) 1.35 (0.822.21) 3.10** (1.685.70)
Population not taking thyroid medication
Diagnosed thyroid disorder 1.26 (0.891.79) 1.23 (0.752.02) 1.50 (0.832.70) 1.44* 1.69* (1.052.72)
(1.051.96)
Diagnosed thyroid nodules 1.22 (0.761.98) 1.24 (0.652.39) 1.22 (0.492.98) 1.46 (0.972.19) 1.84 (0.993.41)
Diagnosed hyperthyroidism 1.81 (0.814.06) 1.70 (0.535.43) 3.58* (1.349.57) 1.31 (0.602.83) 1.47 (0.405.36)
Diagnosed hypothyroidism 2.10 (0.865.11) 2.93 (0.899.63) 2.70 (0.779.43) 2.32* 3.98* (1.4810.72)
(1.284.21)
Poisson regression with robust standard errors adjusted age, sex, marital status, education, smoking status, body mass index, and the log-
transformed time between SHIP-1 and LEGEND examination; data are presented as relative risk and 95 % confidence interval
RR relative risk, MDD major depressive disorder, BDI-II Becks disease inventory
* p \ 0.05; ** p \ 0.001

Table 3 Association between laboratory thyroid measurements and depression or anxiety

Global MDD Recurrent MDD MDD last 12 months BDI-II C12 Anxiety excl. specific phobias
RR (95 % CI) RR (95 % CI) RR (95 % CI) RR (95 % CI) RR (95 % CI)

TSH; mIU/l (full range) 0.94 (0.801.11) 0.93 (0.731.17) 1.05 (0.901.21) 0.98 (0.851.13) 1.05 (0.951.17)
TSH; mIU/l (reference rangea) 0.83 (0.581.19) 0.75 (0.441.29) 0.89 (0.491.63) 0.84 (0.591.21) 1.47 (0.882.46)
Low TSHa 0.73 (0.301.81) 0.79 (0.222.92) 1.84 (0.526.47) 1.29 (0.612.73) 1.44 (0.484.35)
High TSHa 0.79 (0.371.68) 1.05 (0.452.45) 1.67 (0.664.22) 0.96 (0.491.89) 1.03 (0.412.63)
Increased TPO-Ab 1.29 (0.782.11) 1.18 (0.602.34) 2.88* (1.475.65) 0.93 (0.521.65) 1.80 (0.963.38)
Positive TPO-Ab 1.24 (0.542.84) 1.47 (0.553.92) 1.78 (0.565.74) 0.42 (0.131.34) 1.89 (0.754.81)
Poisson regression with robust standard errors adjusted age, sex, marital status, education, smoking status, body mass index, and the log-
transformed time between SHIP-1 and LEGEND examination
RR relative risk, MDD major depressive disorder, BDI-II Becks disease inventory, TSH thyroid-stimulating hormone, TPO-Ab anti-thyroid-
peroxidase antibodies
* p \ 0.05; ** p \ 0.001
a
Defined according to the TSH reference range 0.252.12 mIU/L

BDI-II C12. There was no significant association between
TSH and anxiety. Positive TPO-Abs were significantly as-
sociated with global lifetime [Relative risk (RR) = 2.14;
95 % confidence interval (CI) = 1.134.06; p = 0.020] and
global recurrent MDD (RR = 3.30; 95 % CI = 1.219.01;
p = 0.020), but not with the other outcomes.
Childhood abuse and neglect significantly moderated
three associations of thyroid characteristics with depression
and anxiety (Table 4). For three of the seven investigated
interactions, associations were stronger in individuals
without childhood abuse and neglect than in the group with
childhood abuse and neglect, while in three of the seven
investigated interactions effect sizes were comparable
among the two groups. Only for the association between
untreated diagnosed thyroid disorders and anxiety, we de-
tected a significantly stronger association among the group
of childhood abuse and neglect.
Discussion
The results of our study argue for an association between
diagnosed thyroid disorders and current depression defined
by MDD (12 months prevalence) and a BDI-II C12.

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Table 4 Significant associations stratified by childhood abuse or neglect (combined variable)

Association p for interaction# Whole population No neglect or abuse Neglect or abuse
RR (95 % CI) RR (95 % CI) RR (95 % CI)

Diagnosed thyroid disorder, exclusion of medication and 0.690 1.44* (1.051.96) 1.41 (0.952.09) 1.50 (0.902.50)
BDI-II C12
Diagnosed thyroid disorder, exclusion of medication and 0.070 1.69* (1.052.72) 1.20 (0.632.32) 3.24* (1.676.27)
anxiety
Diagnosed thyroid nodules and BDI-II C12 0.066 1.44* (1.051.96) 1.69* (1.112.59) 1.11 (0.602.06)
Diagnosed hyperthyroidism, exclusion of medication and 0.175 3.58* (1.349.57) 5.14* (1.2421.37) 1.44 (0.395.28)
MDD 12 months
Diagnosed hypothyroidism and anxiety 0.958 3.10** (1.685.70) 2.58* (1.165.74) 3.31* (1.0110.78)
Diagnosed hypothyroidism, exclusion of medication and 0.056 2.32* (1.284.21) 3.88* (1.718.82) 0.79 (0.154.26)
BDI-II C12
Diagnosed hypothyroidism, exclusion of medication and 0.623 3.98* (1.4810.72) 4.70* (1.4015.84) 3.67 (0.4529.67)
anxiety
Poisson regression with robust standard errors adjusted age, sex, marital status, education, smoking status, body mass index, and the log-
transformed time between SHIP-1 and LEGEND examination
RR relative risk, MDD major depressive disorder, BDI-II Becks disease inventory, TSH thyroid-stimulating hormone, TPO-Ab anti-thyroid-
peroxidase antibodies
#
p \ 0.1 was considered as statistically significant interaction
* p \ 0.05; ** p \ 0.001

Diagnosed hyperthyroidism was positively associated with
the MDD 12 months, while diagnosed hypothyroidism was
rather associated with a BDI-II C12. The assessment of
depression was performed 15 years after specification of
thyroid disease, which might suggest that diagnosed thyroid
disorders are precursors for depression although we did not
restrict our analyses to incident depressive episodes.
It is unclear why the two assessments of depression
differed in their association to thyroid disease. The MDD is
an approved instrument for the diagnosis of depression,
while the BDI-II considers only the magnitude of depres-
sive symptoms during a relative short time period and does
not account for adverse effects during daily routine and for
medical-, alcohol-, or drug-induced depression. The risk
for MDD (12 months prevalence) in hypothyroidism was
even higher than the risk for a BDI-II C12 but yet not
statistically significant. The same occurred for recurrent
MDD. Given the much lower prevalence of MDD
(12 months) and recurrent MDD compared to the BDI-II
C12 depression, one has to point to a lack of statistical
power to detect the association between hypothyroidism
and MDD. Therefore, we would argue that we found sup-
port for an association of MDD (12 months prevalence)
and recurrent MDD with hyper- and hypothyroidism. In
contrast, BDI-II C12 depression did not show any relevant
association with hyperthyroidism.
Implications of hypothyroidism include oxidative stress,
low appetite, fatigue, and low concentration [24], which are
also common symptoms for depression [25].
Hyperthyroidism might cause depression as a result of
thyrotoxicosis [26]. In addition to this, a population-based
study from Taiwan showed that hypo- and hyperthyroidism
might not only be a precursor for depression but can also be
a manifestation of depression [27], since incidence rates of
hypo- and hyperthyroidism were higher in patients with
depression compared to controls in that study [27]. The
association between hypothyroidism and depression might
be explained by higher rates of hypercortisolism in de-
pression [28], which might lead to changes in the HPT
axes, while the association between depression and hy-
perthyroidism might be a result of an increased frequency
of thyroid gland antibodies in depression [29]. The detected
associations were stronger for diagnosed but untreated
thyroid disorders suggesting that diagnosed thyroid disor-
ders should be treated to prevent from depressive
symptoms.
In contrast to our findings for recent depression defined
by MDD within the last 12 months or within the last
2 weeks (BDI-II), we did not detect any significant asso-
ciation between diagnosed thyroid disorders and lifetime
MDD. This result was expected, because it is not likely that
a current thyroid disease might be related to a depressive
phase, e.g., 30 years earlier.
Despite the significant associations between diagnosed
thyroid disorders and recent depression in our study, we
and two other population-based studies [7, 8] did not detect
any significant associations between serum TSH levels and
recent depression. In our study, this controversy might be

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related to the fact that biomarker analyses and assessment
of depression were conducted at different time points,
15 years apart. Thus, TSH levels might have changed
between SHIP-1 and LEGEND due to natural course or
initiation of thyroid medication, which might explain the
null associations. It is not unlikely that some individuals
with abnormal serum TSH levels at SHIP-1 started intake
of thyroid medication, because all SHIP participants were
informed about their TSH levels. A previous study reported
a significant interaction of TSH with T4 intake on de-
pression with stronger effects in individuals with T4 intake
indicating that the association between TSH and depression
might be moderated by T4 intake [30]. Thus, individuals
with low or high serum TSH levels at SHIP-1 might have
been biochemically euthyroid at LEGEND due to intake of
thyroid medication and might in consequence have more
depressive symptoms at LEGEND than at SHIP-1. Indeed,
effect sizes for the inverse association between TSH and
depression outcomes were stronger when excluding indi-
viduals with incident thyroid medication intake between
SHIP-1 and SHIP-2. However, these associations were not
statistically significant, which might be related to a di-
minished statistical power in comparison to the main ana-
lyses after 403 individuals who participated at SHIP-1 but
not at SHIP-2 had to be excluded. Thus, the stronger effect
sizes in the sensitivity analyses might argue for an asso-
ciation between low TSH and depression, but our study
population was too small to attain statistical significance.
The time period between SHIP-1 and LEGEND might
also be responsible for the lacking association between
TPO-Abs and recent depression in our study. We found a
significant positive association between increased TPO-
Abs and MDD 12 months, but that finding was neither
confirmed for positive TPO-Abs nor for a BDI-II C12, so
that the significant association might be a chance finding
due to multiple testing. Furthermore, we detected sig-
nificant associations between positive TPO-Abs and
lifetime depression when excluding individuals with
thyroid medication at SHIP-2. In line with this, a study in
583 perimenopausal women demonstrated a positive as-
sociation between increased TPO-Abs and depression
[31].
Particularly diagnosed hypothyroidism was associated
with anxiety in our study, which corresponds well with
findings from a small casecontrol study with 23 cases [32]
and a cross-sectional patient study with 254 patients [33].
In that study [33], hyperthyroid and euthyroid patients did
not differ significantly, which is in line with the results of
our study. Some other cross-sectional patient studies [34
36], however, reported significant higher prevalence of
anxiety in hyper than in euthyroidism. These studies [34
36] are limited by relatively low sample sizes, but common
symptoms of hyperthyroidism and anxiety such as
nervousness and restlessness might argue for a relationship
between hyperthyroidism and anxiety.
To the best of our knowledge, we are the first study
investigating potential moderating effects of childhood
abuse and neglect on the association between thyroid
disorders and depression and anxiety. Anxiety disorders
were somewhat more prevalent in subjects with childhood
abuse and thyroid disorders except in the condition di-
agnosed hypothyroidism, exclusion of medication and
anxiety. In contrast depressive disorders were more
prevalent in subjects without childhood abuse and neglect
and thyroid disorders. These results did support our hy-
potheses only partially as we expected subjects with
childhood abuse and neglect to be more susceptible to the
negative effects of thyroid disorders on mental health.
One explanation might be that the overall rate of de-
pression in abused and neglected subjects is much higher
than in non-abused subjects (e.g., 9.0 versus 3.6 % for
12-month depression; 27.2 versus 14.0 % for BDI-II [12).
This might have caused a ceiling effect buffering the ef-
fects of thyroid dysfunctions. In anxiety disorders, the
prevalence difference between abused and neglected
subjects and non-abused subjects was not that prominent
(9.8 versus 5.8 %).
Strengths of our study are the population-based design
allowing generalization of our results for the background
population of Western Pomerania, the large number of in-
dividuals, and the good characterization of depression and
anxiety using standardized instruments. A limitation of our
study is that thyroid function and depression were not col-
lected at the same time, which might be responsible for the
lacking associations regarding serum TSH levels and TPO-
Abs. To account for this, regression analyses were adjusted
for the time between the two examinations and sensitivity
analyses were performed by excluding individuals with
thyroid medication intake at the 6-year follow-up of SHIP-1.
In conclusion, our results substantiate evidence that di-
agnosed untreated hypothyroidism is associated with de-
pression and anxiety, and that diagnosed untreated
hyperthyroidism is associated with depression. Further
studies are warranted to investigate whether treatment
might weaken depressive symptoms and anxiety in hypo-
and hyperthyroidism.
Acknowledgments The Study of Health in Pomerania is part of the
Community Medicine Research Network of the University Medicine
Greifswald, which was funded by the German Federal Ministry for
Education and Research, the Ministry for Education, Research and
Cultural Affairs, and the Ministry for Social Affairs of the State
Mecklenburg-West Pomerania. Analyses were further supported by
the German Research Foundation (DFG VO955/10-2 and GR 1912/5-
1).
Conflict of interest On behalf of all authors, the corresponding
author states that there is no conflict of interest.
123

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