Brief report

Thyroid functioning in patients with bipolar disorderwith 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 Koreab Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Koreac Department of Surgery, Thyroid Center, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea

a r t i c l e i n f o

Article history:Received 24 July 2014Received in revised form4 November 2014Accepted 12 November 2014Available online 21 November 2014

Keywords:Bipolar disorderMixed featuresThyroid functioning

a b s t r a c t

We compared the prevalence of thyroid dysfunction in patients with bipolar disorder with and withoutmixed features by measuring of thyroid function test. We reviewed the medical charts between 2005and 2013. These results did not show a significant difference in the association between thyroiddysfunction and the mixed features.

& 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

The association between impairment in the thyroid gland andaffective disorders has been well documented. Thyroid hormoneshave a major effect on behavior, modulating the phenotypicexpression of affective disorders. A polymorphism in the deiodi-nase and transporter genes may be an important contributor tothe psychiatric symptoms associated with hypothyroidism, such asdepression, cognitive dysfunction, and mania or hypomania(Sathya et al., 2009; Bunevicius and Prange, 2010; Chakrabarti,2011). It has been proposed that hyperthyroidism or thyrotoxicosisis related to forms of anxiety or mood lability, such as mania, asmediated by adrenergic hyperactivity (Bunevicius et al., 2005;Bunevicius and Prange, 2010).

However, the association between overt or subclinical thyroidabnormalities and bipolar disorder with mixed features has not yetbeen fully clarified. Differences between individuals with mixedand non-mixed features of bipolar disorder with regard to theresults of serum thyroid function tests have not been confirmed,although thyroid axis dysfunction may be more common inpatients 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 inthose with and without mixed features by measuring the levels ofthyroid stimulating hormone (TSH), free serum thyroxine (fT4),

and triidothyronine (T3) among those with no primary thyroiddisease.

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 and2013 who met DSM-IV-TR criteria for bipolar disorder. All patients hospitalized at thisinstitution were diagnosed using clinical interviews, and diagnoses of an Axis I disorderwere 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 majorpsychiatric disorder as a principle diagnosis, or with a history of substance use disorderwere excluded. If a subject experienced more than one hospitalization during the studyperiod, data from only the last admission were analyzed. Patients were monitored foropposite-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, independentlyevaluated the medical records for opposite-polarity symptoms.

Levels of fT4, T3, and TSH were measured within 48 h of hospitalization, between06:00 and 08:00. Patients with a history of primary thyroid disease were excluded. Thecharts of 307 subjects diagnosed with bipolar disorder were analyzed at baseline; 17cases were excluded based on the aforementioned criteria, and 24 cases were excludedbased on insufficient data from the thyroid function test. Thus, 266 patients wereenrolled 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. Previoustreatment with lithium was recorded. Thyroid function tests were measured bychemiluminescence 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, and0.55–4.78 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 havingnormal 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 ashypothyroidism and hyperthyroidism, between the groups with and without mixed

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Psychiatry Research

http://dx.doi.org/10.1016/j.psychres.2014.11.0200165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.

n Corresponding author. Tel.: þ82 2 3779 1250; fax: þ82 2 780 6577.E-mail address: wmbahk@catholic.ac.kr (W.-M. Bahk).

Psychiatry Research 225 (2015) 212–214

features. Statistical analyses consisted of chi-square tests for comparisons of categoricalvariables 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 withoutmixed features

Data on the prevalence of thyroid status, as determined by theTSH, fT4, and T3 levels within 48 h of hospitalization, are pre-sented in Fig. 1. Thyroid function tests were performed on 266subjects, 208 in the without-mixed-features group and 58 in thewith-mixed-features group, which were formed by re-evaluatinginpatients who had been diagnosed with bipolar disorder withregard to the DSM-5 specifier. Patients with mixed features had asignificantly younger age (25.079.1 vs. 43.9713.4 years;po0.001) compared with patients without mixed features. How-ever, no significant differences were observed between patientswith and without mixed features regarding sex (34.5% vs. 43.8%,p¼0.206) or use of lithium (27.6% vs. 32.2%, p¼0.277). Nosignificant correlation was observed for any thyroid statusbetween the groups with and without mixed features afteradjusting for age (normal, 89.7% vs. 91.8%; subclinical, or overthypothyroidism, 5.2% vs. 2.9%; and subclinical or overt hyperthyr-oidism, 5.2% vs. 5.3%; p¼0.724). Additionally, there were nosignificant between-group differences in thyroid status amongbipolar 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%; p¼0.827) 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%; p¼0.999) episodes.

4. Discussion

The aim of the present study was to investigate the associationbetween thyroid dysfunction and bipolar disorder with mixedfeatures, as thyroid dysfunction is one of the potential mechanismsunderpinning these symptoms. We compared the prevalence ofabnormal thyroid status, as determined by thyroid function tests,among patients with no primary thyroid disease or no thyroidsupplementation according to the presence of mixed features.

Interestingly, no differences in the prevalence of thyroid status, asdetermined by thyroid function tests, were noted between thesegroups. These findings are in contrast to previous results indicatingthat thyroid axis dysfunction is more common in bipolar patients

with mixed than in those with manic episodes (Zarate et al., 1997;Chang et al., 1998). Several potential hypotheses associated withthese negative results are inconsistent with past reports. Indeed, thepresence of mixed features may be uncommon in patients withthyroid dysfunction, even though both hyperthyroidism andhypothyroidism are related to changes in mood. Some studies havereported no association between thyroid disease or thyroid hormonelevels and mixed states (Joffe et al., 1994; Cassidy et al., 2002).Evidence of an association between thyroid dysfunction and mixedfeatures remains inconsistent and inadequate. Additionally, as it hasbeen argued that abnormal thyroid function test results in psychiatricpatients, including those with acute psychiatric illnesses, may reflecta manifestation of secondary effects on systemic illness and stressstates, 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 pathophysiologyand clinical course of bipolar disorder may suggest a connectionbetween such dysfunction and the presence of mixed features, andthis may involve affective instability and an unfavorable illnesscourse (Chakrabarti, 2011; Swann et al., 2013). Thus, HPT dysfunctionremains a potential mechanism in patients with mixed features,although the role of thyroid hormones in the pathophysiology ofmixed features remains to be clarified. These negative results may bebecause the present study compared laboratory measurements ofperipheral thyroid functioning, which may not adequately character-ize central thyroid metabolism (Bauer et al., 2008). Additionally, theuse of medications such as anticonvulsants in a naturalistic settingmay have affected the laboratory measurements, even though wecontrolled for the effect of lithium and excluded samples fromsubjects with any history of substance abuse. In terms of the thyroidindices themselves, it may be more informative to consider the actualmean7S.D. values. Unfortunately, in the present study, these valueswere measured using two different methods (CLIA and IRMA) so theycould 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 biasaffected the diagnostic classification. Second, the small sample size inthis study may have undermined our ability to detect a true effect.Third, several characteristics of the present study may have biased thenull hypothesis. Although substance use disorders that could havecontributed to the mood symptoms or thyroid function tests of thesubjects were excluded in the present study, a large amount ofevidence suggests that there is a relationship between substance usedisorders and the presence of mixed features in bipolar disorderpatients. Thus, this exclusion may have produced an atypical (possiblyless severe) population of mixed-state patients.

Taken together, the results of our study did not show asignificant difference in the association between abnormality inthyroid functioning and the presence of mixed features. Despitethe literature documenting various thyroid gland dysfunctions inpatients with mixed features, the role of thyroid hormones in thepathophysiology of mixed features remains to be clarified.

Contributers

Author In Hee Shim and Dong sik Bae designed the study andwrote the protocol. All authors managed the literature searches,summaries of previous related work. Author In Hee Shim undertookthe statistical analysis and wrote the first draft of the manuscript. Allauthors contributed to and have approved the final manuscript.

Conflict interests

No conflict of interest declared.

91.8 %89. 7 %

2.9 %5.2 %

5.3 % 5.2 %

84%

86%

88%

90%

92%

94%

96%

98%

100%

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 mixedfeatures.

I.H. Shim et al. / Psychiatry Research 225 (2015) 212–214 213

Acknowledgment

The authors had no conflicts of interest in conducting this studyor preparing the manuscript.

References

Bauer, M., Goetz, T., Glenn, T., Whybrow, P.C., 2008. The thyroid-brain interaction inthyroid disorders and mood disorders. Journal of Neuroendocrinology 20,1101–1114.

Bunevicius, R., Prange Jr., A.J., 2010. Thyroid disease and mental disorders: causeand effect or only comorbidity? Current Opinion in Psychiatry 23, 363–368.

Bunevicius, R., Velickiene, D., Prange Jr., A.J., 2005. Mood and anxiety disorders inwomen with treated hyperthyroidism and ophthalmopathy caused by Graves'disease. General Hospital Psychiatry 27, 133–139.

Cassidy, F., Ahearn, E.P., Carroll, B.J., 2002. Thyroid function in mixed and puremanic episodes. Bipolar Disorders 4, 393–397.

Chakrabarti, S., 2011. Thyroid functions and bipolar affective disorder. Journal ofThyroid Research 2011, 306367.

Chang, K.D., Keck Jr., P.E., Stanton, S.P., McElroy, S.L., Strakowski, S.M., Geracioti Jr., T.D.,1998. Differences in thyroid function between bipolar manic and mixed states.Biological Psychiatry 43, 730–733.

Dickerman, A.L., Barnhill, J.W., 2012. Abnormal thyroid function tests in psychiatricpatients: a red herring? American Journal of Psychiatry 169, 127–133.

Joffe, R.T., Young, L.T., Cooke, R.G., Robb, J., 1994. The thyroid and mixed affectivestates. Acta Psychiatrica Scandinavica 90, 131–132.

Sathya, A., Radhika, R., Mahadevan, S., Sriram, U., 2009. Mania as a presentation ofprimary hypothyroidism. Singapore Medical Journal 50, e65–e67.

Swann, A.C., Lafer, B., Perugi, G., Frye, M.A., Bauer, M., Bahk, W.M., Scott, J., Ha, K.,Suppes, T., 2013. Bipolar mixed states: an international society for bipolardisorders task force report of symptom structure, course of illness, anddiagnosis. American Journal of Psychiatry 170, 31–42.

Zarate, C.A., Tohen, M., Zarate, S.B., 1997. Thyroid function tests in first-episodebipolar disorder manic and mixed types. Biological Psychiatry 42, 302–304.

I.H. Shim et al. / Psychiatry Research 225 (2015) 212–214214