Psychiatry Research 225 (2015) 212–214

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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 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 b

art ic l e i nf o

a b s t r a c t

Article history: Received 24 July 2014 Received in revised form 4 November 2014 Accepted 12 November 2014 Available online 21 November 2014

We compared the prevalence of thyroid dysfunction in patients with bipolar disorder with and without mixed features by measuring of thyroid function test. We reviewed the medical charts between 2005 and 2013. These results did not show a significant difference in the association between thyroid dysfunction and the mixed features. & 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Bipolar disorder Mixed features Thyroid functioning

1. Introduction 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 deiodinase 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: [email protected] (W.-M. Bahk).

http://dx.doi.org/10.1016/j.psychres.2014.11.020 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.

and triidothyronine (T3) among those with no primary thyroid 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). Normal 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 hypothyroidism), 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

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 pvalueo0.05 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 presented 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. However, 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 hyperthyroidism, 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%; subclinical or overt hypothyroidism: 5.6% vs. 0%, respectively; and subclinical 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%

5.2 %

5.3 %

96% 94%

2.9 % 5.2 %

92% 90% 88%

91.8 % 89. 7 %

86% 84%

without mixed features (N=208) normal

hypothyroidism

with mixed features (N=58)

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 carefully (Dickerman and Barnhill, 2012). However, accumulating evidence 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 characterize 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.

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.

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Conflict interests No conflict of interest declared.

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Acknowledgment The authors had no conflicts of interest in conducting this study or preparing the manuscript. References Bauer, M., Goetz, T., Glenn, T., Whybrow, P.C., 2008. The thyroid-brain interaction in thyroid disorders and mood disorders. Journal of Neuroendocrinology 20, 1101–1114. Bunevicius, R., Prange Jr., A.J., 2010. Thyroid disease and mental disorders: cause and effect or only comorbidity? Current Opinion in Psychiatry 23, 363–368. Bunevicius, R., Velickiene, D., Prange Jr., A.J., 2005. Mood and anxiety disorders in women 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 pure manic episodes. Bipolar Disorders 4, 393–397.

Chakrabarti, S., 2011. Thyroid functions and bipolar affective disorder. Journal of Thyroid 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 psychiatric patients: 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 affective states. Acta Psychiatrica Scandinavica 90, 131–132. Sathya, A., Radhika, R., Mahadevan, S., Sriram, U., 2009. Mania as a presentation of primary 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 bipolar disorders task force report of symptom structure, course of illness, and diagnosis. American Journal of Psychiatry 170, 31–42. Zarate, C.A., Tohen, M., Zarate, S.B., 1997. Thyroid function tests in first-episode bipolar disorder manic and mixed types. Biological Psychiatry 42, 302–304.

Thyroid functioning in patients with bipolar disorder with mixed features.

We compared the prevalence of thyroid dysfunction in patients with bipolar disorder with and without mixed features by measuring of thyroid function t...
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