Psychiatry Research 225 (2015) 212–214

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Brief report

Thyroid functioning in patients with bipolar disorder

with mixed features
In Hee Shim a, Young Sup Woo b, Dong Sik Bae c, Won-Myong Bahk b,n
a
Department of Psychiatry, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea
b
Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
c
Department of Surgery, Thyroid Center, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea

art ic l e i nf o a b s t r a c t

Article history: We compared the prevalence of thyroid dysfunction in patients with bipolar disorder with and without
Received 24 July 2014 mixed features by measuring of thyroid function test. We reviewed the medical charts between 2005
Received in revised form and 2013. These results did not show a significant difference in the association between thyroid
4 November 2014
dysfunction and the mixed features.
Accepted 12 November 2014
& 2014 Elsevier Ireland Ltd. All rights reserved.
Available online 21 November 2014

Keywords:
Bipolar disorder
Mixed features
Thyroid functioning

1. Introduction and triidothyronine (T3) among those with no primary thyroid

The association between impairment in the thyroid gland and
affective disorders has been well documented. Thyroid hormones
have a major effect on behavior, modulating the phenotypic
expression of affective disorders. A polymorphism in the deiodi-
nase and transporter genes may be an important contributor to
the psychiatric symptoms associated with hypothyroidism, such as
depression, cognitive dysfunction, and mania or hypomania
(Sathya et al., 2009; Bunevicius and Prange, 2010; Chakrabarti,
2011). It has been proposed that hyperthyroidism or thyrotoxicosis
is related to forms of anxiety or mood lability, such as mania, as
mediated by adrenergic hyperactivity (Bunevicius et al., 2005;
Bunevicius and Prange, 2010).
However, the association between overt or subclinical thyroid
abnormalities and bipolar disorder with mixed features has not yet
been fully clarified. Differences between individuals with mixed
and non-mixed features of bipolar disorder with regard to the
results of serum thyroid function tests have not been confirmed,
although thyroid axis dysfunction may be more common in
patients with mixed episodes than in those with manic episodes
(Joffe et al., 1994; Chang et al., 1998; Cassidy et al., 2002).
We compared the prevalence of abnormal thyroid status in
those with and without mixed features by measuring the levels of
thyroid stimulating hormone (TSH), free serum thyroxine (fT4),
n
Corresponding author. Tel.: þ 82 2 3779 1250; fax: þ 82 2 780 6577.
E-mail address: wmbahk@catholic.ac.kr (W.-M. Bahk).
disease.
2. Methods
We reviewed the medical charts of patients admitted to Yeouido St. Mary's Hospital,
College of Medicine, The Catholic University of Korea in Seoul, Korea between 2005 and
2013 who met DSM-IV-TR criteria for bipolar disorder. All patients hospitalized at this
institution were diagnosed using clinical interviews, and diagnoses of an Axis I disorder
were made by a board-certified psychiatrist in accordance with the DSM-IV-TR criteria.
Patients with a severe comorbid medical or neurological condition, with another major
psychiatric disorder as a principle diagnosis, or with a history of substance use disorder
were excluded. If a subject experienced more than one hospitalization during the study
period, data from only the last admission were analyzed. Patients were monitored for
opposite-polarity symptoms to identify mixed features. Two independent physicians (W.
Y.S. and B.W.M.), who were not informed of the purpose of the study, independently
evaluated the medical records for opposite-polarity symptoms.
Levels of fT4, T3, and TSH were measured within 48 h of hospitalization, between
06:00 and 08:00. Patients with a history of primary thyroid disease were excluded. The
charts of 307 subjects diagnosed with bipolar disorder were analyzed at baseline; 17
cases were excluded based on the aforementioned criteria, and 24 cases were excluded
based on insufficient data from the thyroid function test. Thus, 266 patients were
enrolled in the present study and categorized into two groups, “without mixed features”
and “with mixed features,” according to a re-evaluation using DSM-5 criteria. Previous
treatment with lithium was recorded. Thyroid function tests were measured by
chemiluminescence immunoassay (CLIA) and immuno-radiometric assay (IRMA). Nor-
mal ranges for these assays were: 0.89–1.76 ng/dL for fT4, 0.60–1.81 ng/mL for T3, and
0.55–4.78 uIU/mL for TSH on the CLIA and 0.780–1.940 ng/dL for fT4, 0.800–2.000 ng/
mL for T3, and 0.300–4.000 mIU/L for TSH on the IRMA. We classified patients as having
normal thyroid status, hypothyroidism (overt hypothyroidism or subclinical hypothyr-
oidism), and hyperthyroidism (overt hyperthyroidism or subclinical hyperthyroidism)
according to the thyroid function test. We compared thyroid dysfunctions, such as
hypothyroidism and hyperthyroidism, between the groups with and without mixed

http://dx.doi.org/10.1016/j.psychres.2014.11.020
0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
 I.H. Shim et al. / Psychiatry Research 225 (2015) 212–214
features. Statistical analyses consisted of chi-square tests for comparisons of categorical
variables and independent t-tests or Mann–Whitney tests for continuous variables.
Logistic regression analyses of categorical variables were used to adjust for age. A p-
valueo0.05 was considered significant.
3. Results
3.1. Prevalence of thyroid status among those with and without
mixed features
Data on the prevalence of thyroid status, as determined by the
TSH, fT4, and T3 levels within 48 h of hospitalization, are pre-
sented in Fig. 1. Thyroid function tests were performed on 266
subjects, 208 in the without-mixed-features group and 58 in the
with-mixed-features group, which were formed by re-evaluating
inpatients who had been diagnosed with bipolar disorder with
regard to the DSM-5 specifier. Patients with mixed features had a
significantly younger age (25.0 79.1 vs. 43.9 713.4 years;
p o0.001) compared with patients without mixed features. How-
ever, no significant differences were observed between patients
with and without mixed features regarding sex (34.5% vs. 43.8%,
p ¼0.206) or use of lithium (27.6% vs. 32.2%, p ¼0.277). No
significant correlation was observed for any thyroid status
between the groups with and without mixed features after
adjusting for age (normal, 89.7% vs. 91.8%; subclinical, or overt
hypothyroidism, 5.2% vs. 2.9%; and subclinical or overt hyperthyr-
oidism, 5.2% vs. 5.3%; p ¼0.724). Additionally, there were no
significant between-group differences in thyroid status among
bipolar patients with manic/hypomanic (normal: 81.5% vs. 91.6%,
respectively; subclinical or overt hypothyroidism: 11.1% vs. 2.5%,
respectively; and subclinical or overt hyperthyroidism: 7.4% vs.
5.9%; p ¼0.827) and depressive (normal: 89.9% vs. 100%; subclini-
cal or overt hypothyroidism: 5.6% vs. 0%, respectively; and sub-
clinical or overt hyperthyroidism: 4.5% vs. 0%; p ¼0.999) episodes.
4. Discussion
The aim of the present study was to investigate the association
between thyroid dysfunction and bipolar disorder with mixed
features, as thyroid dysfunction is one of the potential mechanisms
underpinning these symptoms. We compared the prevalence of
abnormal thyroid status, as determined by thyroid function tests,
among patients with no primary thyroid disease or no thyroid
supplementation according to the presence of mixed features.
Interestingly, no differences in the prevalence of thyroid status, as
determined by thyroid function tests, were noted between these
groups. These findings are in contrast to previous results indicating
that thyroid axis dysfunction is more common in bipolar patients
100%
98%
5.3 % 5.2 %
96%
94%
2.9 %
92% 5.2 %
90%
88% 91.8 %
89. 7 %
86%
84%
without mixed features (N=208) with mixed features (N=58)
normal hypothyroidism hyperthyroidism
Fig. 1. Thyroid status according to levels of thyroid stimulating hormone (TSH),
free thyroxine (fT4), and triiodothyronine (T3) in groups with and without mixed
features.
213
with mixed than in those with manic episodes (Zarate et al., 1997;
Chang et al., 1998). Several potential hypotheses associated with
these negative results are inconsistent with past reports. Indeed, the
presence of mixed features may be uncommon in patients with
thyroid dysfunction, even though both hyperthyroidism and
hypothyroidism are related to changes in mood. Some studies have
reported no association between thyroid disease or thyroid hormone
levels and mixed states (Joffe et al., 1994; Cassidy et al., 2002).
Evidence of an association between thyroid dysfunction and mixed
features remains inconsistent and inadequate. Additionally, as it has
been argued that abnormal thyroid function test results in psychiatric
patients, including those with acute psychiatric illnesses, may reflect
a manifestation of secondary effects on systemic illness and stress
states, interpretations connecting existing hypothalamic–pituitary–
thyroid (HPT) dysfunction with mixed features must be made care-
fully (Dickerman and Barnhill, 2012). However, accumulating evi-
dence that HPT axis dysfunction is related to the pathophysiology
and clinical course of bipolar disorder may suggest a connection
between such dysfunction and the presence of mixed features, and
this may involve affective instability and an unfavorable illness
course (Chakrabarti, 2011; Swann et al., 2013). Thus, HPT dysfunction
remains a potential mechanism in patients with mixed features,
although the role of thyroid hormones in the pathophysiology of
mixed features remains to be clarified. These negative results may be
because the present study compared laboratory measurements of
peripheral thyroid functioning, which may not adequately character-
ize central thyroid metabolism (Bauer et al., 2008). Additionally, the
use of medications such as anticonvulsants in a naturalistic setting
may have affected the laboratory measurements, even though we
controlled for the effect of lithium and excluded samples from
subjects with any history of substance abuse. In terms of the thyroid
indices themselves, it may be more informative to consider the actual
mean7S.D. values. Unfortunately, in the present study, these values
were measured using two different methods (CLIA and IRMA) so they
could not be directly compared.
Several limitations of the present study should be considered. First,
this was a retrospective study, and it is possible that reviewer bias
affected the diagnostic classification. Second, the small sample size in
this study may have undermined our ability to detect a true effect.
Third, several characteristics of the present study may have biased the
null hypothesis. Although substance use disorders that could have
contributed to the mood symptoms or thyroid function tests of the
subjects were excluded in the present study, a large amount of
evidence suggests that there is a relationship between substance use
disorders and the presence of mixed features in bipolar disorder
patients. Thus, this exclusion may have produced an atypical (possibly
less severe) population of mixed-state patients.
Taken together, the results of our study did not show a
significant difference in the association between abnormality in
thyroid functioning and the presence of mixed features. Despite
the literature documenting various thyroid gland dysfunctions in
patients with mixed features, the role of thyroid hormones in the
pathophysiology of mixed features remains to be clarified.
Contributers
Author In Hee Shim and Dong sik Bae designed the study and
wrote the protocol. All authors managed the literature searches,
summaries of previous related work. Author In Hee Shim undertook
the statistical analysis and wrote the first draft of the manuscript. All
authors contributed to and have approved the final manuscript.
Conflict interests
No conflict of interest declared.
214 I.H. Shim et al. / Psychiatry Research 225 (2015) 212–214
Acknowledgment
The authors had no conflicts of interest in conducting this study
or preparing the manuscript.
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