Developing bipolar disorder. A study among children of patients with bipolar disorder Hillegers, Manon Hubertine Johanna

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1 University of Groningen Developing bipolar disorder. A study among children of patients with bipolar disorder Hillegers, Manon Hubertine Johanna IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Hillegers, M. H. J. (2007). Developing bipolar disorder. A study among children of patients with bipolar disorder s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

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3 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents. Published in: European Neuropharmacology, 2006 Nov 28 (Epub ahead of print)

4 94 chapter 6 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents. Manon H.J. Hillegers, Catrien G. Reichart, Marjolein Wals, Frank C. Verhulst, Johan Ormel, Willem A. Nolen and Hemmo A. Drexhage ABSTRACT Background: Studies are inconsistent as to whether patients with bipolar disorder are more frequently affected by autoimmune thyroiditis. Aim: To study the prevalence of autoimmune thyroiditis in offspring of bipolar patients. Method: In children (age years) of bipolar parents were evaluated psychiatrically using the K-SADS-PL and blood was drawn to determine thyroperoxidase antibodies (TPO-Abs) and serum TSH. Blood samples of high school students (aged years, n=77) and young adults (aged yrs, n=52) were used as comparisons. At follow-up the offspring were psychiatrically evaluated and tested for TPO-Abs and TSH twice (14 months and 55 months after enrollment). Results: TPO-Abs were predominantly found in female bipolar offspring, who had a significantly higher prevalence of positive TPO-Ab titers (9 out of 57 female offspring subjects) as compared to the female high school and young adult comparisons (4 out of 103 female control subjects). In TPO-Ab positive offspring (n=11) a raised prevalence of 55% of thyroid failure (i.e. a raised serum TSH or l-thyroxine treatment) was evident. TPO-Ab positive offspring did not show a raised prevalence of mood disorders (or any psychopathology) as compared to the TPO-Ab negative offspring. Conclusion: Our study suggests that bipolar offspring are more vulnerable to develop thyroid autoimmunity independently from the vulnerability to develop psychiatric disorders. Keywords: immunology, thyroid autoimmunity, prevalence, bipolar disorder, offspring.

5 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents 95 INTRODUCTION The core feature of bipolar disorder is a pathological disturbance in mood (affect) ranging from extreme elation or mania to severe depression. Typically it is an episodic illness, usually with full recovery between episodes (Craddock et al., 1999). Family and twin studies have established the importance of genetic factors in the etiology of bipolar disorder with a lifetime risk of 40-70% for monozygotic twins and of 5-10% for first degree relatives of a bipolar proband as compared to % for unrelated persons (Craddock et al., 1999). Environmental factors are involved as well, because the concordance for monozygotic twins is not a 100%. The precise interaction between the genetic vulnerability and environmental factors is, however, not clear. Many studies among adults have searched for a relationship between bipolar disorder and biological factors. Thyroid indices have been suggested as state and/or trait markers related to the development of bipolar disorder and indeed changes in the hypothalamic-pituitary-thyroid axis (HPT-axis) are present in patients with mood disorders (Kirkegaard and Faber, 1998). Autoimmune thyroiditis is a major cause of thyroid failure, and is marked by the presence of antibodies to the thyroid. Mild forms of autoimmune thyroiditis with a clinically euthyroid state are not uncommon: antithyroid antibodies occur in 5-15% of the normal population, predominantly in women and older people. Studies are inconsistent as to whether thyroid antibodies are elevated in bipolar disorder (Kupka et al., 2000; Haggerty et al., 1990; Haggerty et al., 1997; Wilson, et al., 1991; Rapaport 1994). In a recent study on a large sample of outpatients with bipolar disorder we found the prevalence of autoimmune thyroiditis (as evidenced by a higher prevalence of antithyroid antibodies) and of thyroid failure (as evidenced by a raised serum TSH) higher than in the general population and disease controls (Kupka et al., 2002). Autoimmune thyroiditis was not associated with lithium exposure. Also there were no differences in the prevalence rates of autoimmune thyroiditis between euthymic bipolar patients and bipolar patients in a manic or depressive episode. Hence we considered thyroid autoimmunity more likely to be a trait marker of bipolar disorder than a state marker of an episode (Kupka et al., 2002) and these findings thus raised the question whether thyroid autoimmunity is related to the disease itself or to the vulnerability for bipolar disorder.

6 96 chapter 6 To study this problem we collected blood samples of adolescent offspring of parents with a bipolar disorder ( bipolar offspring ) and examined the presence of antibodies to thyroperoxidase (TPO-Abs, one of the antithyroid antibodies and the best serum marker of autoimmune thyroiditis). All cases were studied for serum TSH. The study is part of an ongoing prospective study among bipolar offspring in the Netherlands (Wals et al., 2001; Reichart et al., 2004; Hillegers et al., 2005). In this cohort we found an increased prevalence of mood disorders, which is in line with findings from other studies among bipolar offspring (Lapalme et al., 1997; Chang et al., 2000; DelBello et al., 2001). Since normative data of TPO-Ab prevalence in adolescents and young adults are scarce (Kabelitz et al., 2003; Kordonouri et al., 2002) we additionally composed a comparison group of 77 healthy high school students, aged years, and one of 52 young female adults, aged years of age. SUBJECTS AND METHODS Sample The study presented here is part of an ongoing prospective study among adolescent bipolar offspring in The Netherlands. The Medical Ethical Review Committee of the University Medical Center Utrecht approved the study. Written informed consent from both parents and their offspring was obtained after a complete description of the study was given to all participants. The study design, recruitment procedure and study population have been described in detail by Wals et al., In brief, 86 bipolar parents and their spouses and 140 offspring aged 12 to 21 years were examined between November 1997 and March 1999 (Time 1). Fourteen months after the first assessment, 132 subjects, aged years, were available for reassessment (Time 2) (Reichart et al., 2004). At that time 7 girls and 1 boy from altogether 6 families had dropped out; but 2 siblings of these families were still participating resulting in 82 families still in the study at Time 2. At the third measurement (Time 3), 41 months (SD=5.2) after Time 2, 129 subjects (mean age 20.8 years, SD=2.7, range years) belonging to 80 families were still participating (Hillegers et al., 2005). There was at least one blood sample available of 126 offspring subjects (57 females and 69 males). Of the 80 participating families at third measurement 32 (40%) had a bipolar father and 48 (60%) a bipolar mother. High school students (n=77, aged years) and female young adults (n= 52, aged years) were respectively enrolled through a high school in the south west of the

7 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents 97 Netherlands and via enrolling laboratory, medical staff and medical students via our departments. The inclusion criteria for the comparison groups (high school students and young adults) were: using no medication (except oral contraceptives), no major psychiatric disorders themselves and no first degree family members with a history of major psychiatric disorders such as psychosis, mood disorders and anxiety disorders. All gave a written informed consent. In order to participate, control subjects and bipolar offspring had to be in self-proclaimed good health and filled in a brief questionnaire regarding the inclusion criteria described above. All were free of any obvious medical illness for at least two weeks prior to the blood withdrawal, including acute infections and allergic reactions. Psychopathology During the first two measurements (Time 1, Time 2), diagnoses according to DSM- IV criteria were assessed using the Kiddie Schedule of Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 1997). At the third measurement (Time 3), the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I) (First et al., 1996) was used to determine current (last month) and past (as of Time 2) psychiatric diagnoses according to DSM-IV. Lifetime DSM-IV diagnoses at Time 3 were based on the psychiatric interviews that took place during all three measurements (Time 1, 2 and 3) adding up the incidence of psychopathology between Time 2 and Time 3 to the incidence of psychopathology between Time 1 and Time 2 and the lifetime Time 1 diagnoses. Immunological evaluation Sample Preparation: Blood samples of the offspring subjects were collected during all three measurements, with a mean of 14 months between Time 1 and Time 2 and 41 months between Time 2 and Time 3. There was at least one blood sample available of 126 offspring subjects (57 females and 69 males). One single blood drawn was available of both comparisons groups; 77 high school students (51 females and 26 males) and 52 female young adults. These blood samples were collected in a heparinized syringe. All the results herein were obtained from the same vena puncture for each subject. Serum samples were frozen, stored, and later assessed in one laboratory (Dept. of Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands).

8 98 chapter 6 Thyroid parameter Assay: The TPO-Ab level was measured by an ELISA (Immulite assay, DPC, Breda, The Netherlands), according to the methods indicated by the manufacturer. A level of 25 U/ml or higher was considered as positive for the presence of TPO-Abs, while TPO-Abs can be measured reliably in the Immulite assay from 10 U/ml onwards (according to the manufacturer). The normal range for TSH (measured by Immulite assay, DPC) was mu/l and for FT pmol/l (inhouse assay, courtesy of R. Docter, Rotterdam). We considered thyroid failure present if a patient had a TSH exceeding 4.0 mu/l and/or was treated with thyroid hormone for previously diagnosed primary hypothyroidism. All assays were carried out blind to the subjects medical status. Statistical Analysis Statistical analyses were performed with use of a standard statistical software package (SPSS 11.0). The prevalence of autoimmune thyroiditis (TPO-Abs positive 25 U/ml) between various groups was analyzed as a dichotomized variable (positive/negative) with a Chi-square test. RESULTS Table 1: The prevalence and percentages of TPO-Abs in the offspring group and healthy control group. TPO-Ab positive TPO-Ab negative p ALL Bipolar offspring (n=126) 11 (8.7%) 115 P=0.05 Healthy controls* (n=129) 4 (3.1%) 125 FEMALES Bipolar offspring (n=57) 9 (15.8%) 48 P=0.008 Healthy controls* (n=103) 4 (3.9%) 99 Healthy controls*: high-school subjects and female young adults subjects together.

9 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents 99 This follow-up study demonstrated an autoimmune thyroiditis (as evidenced by being or becoming positive for TPO-Abs i.e. > 25 U/ml) in 11 out of the in total 126 (57 females and 69 males) (8.7 %) bipolar offspring subjects aged 12-21, studied (Table 1). Two out of 77 (51 females and 26 males) (2.6%) of the healthy high school students aged 12-19, and 2 out of the 52 (3.8%) of the female young adults, aged 20-35, were positive for TPO- Abs. This difference was marginally significant (Chi-square analysis p=0.05). Nine of these 11 TPO-Abs positive bipolar offspring subjects and all of the 4 TPO- Abs positive controls) were females. Table I shows the prevalence of TPO-Abs positive cases in the female offspring (n= 57) as compared to all female controls (n=103). The difference, i.e. a prevalence of 15.8% versus 3.9% (offspring versus controls) was significant (Chi-square analysis p=0.008). Table 2 gives a short summary of each of the TPO-Ab positive offspring. Firstly it can be seen from this table (but particularly also from Figure 2) that the prevalence of mood disorders (or any psychopathology) was not raised in the TPO-Ab positive cases as compared to the TPO-Ab negative cases. In fact 6 out of the 11 TPO-Ab positive offspring (55%) were without any psychopathology. It must be noted here that in the entire offspring (n=129) group 41% was without any psychopathology at Time 3, while the lifetime prevalence of bipolar disorder was 10%, of unipolar disorders 30% and of other disorders 19%, the latter consisting of anxiety disorders, disruptive behavioral disorders, substance abuse disorders, attention deficit hyperactive disorders, enuresis, encopresis, pervasive developmental disorder, tic and eating disorders. Table 2 further shows that with regard to the actual thyroid status of the TPO-Ab positive offspring 6 out of the 11 TPO-Ab positive cases (55%) had a raised TSH (i.e. > 4 mu/l) or were on levo-thyroxine treatment. In the 115 TPO-Abs negative subjects of the offspring group 12% showed (sub-clinical) a raised TSH. None of the control adolescents showed sub-clinical hypothyroidism.

10 100 chapter 6 Table 2: Description and details of 11 TPO-Abs positive bipolar offspring subjects Subject Gender Age (yr) Bipolar parent Other parent Mood disorder Age of onset Age of TPO abs (yr) TPO-abs (IU/ml) TSH (mu/ml) Ft4 (pmol/l) Medication Social Functioning Female (F) Male (M) Father (F) Mother (M) Mood dis. (MD) Healthy (H) Present (P) Absent (A) first appearance Highest level OC: oral contraceptive AD:antidepressant Case 1 F 22 F MD A OC University graduate Case 2 F 22 F H A OC University graduate Case 3 F 24 F H A 19 > Stabile life, married, has plans to emigrate to Sweden. Case 4 F 22 M H A unstable family, follows higher education successfully Case 5 M 23 M H P, 20 yrs Functions reasonably well as a university graduate Case 6 M 21 M MD P, 13 yrs l-thyroxine 21 yrs Fatigue and heart palpitations disappeared with l-thyr. Case 7 F 21 M MD P, 21 yrs OC Professional ballerina Case 8 F 25 M MD P, 10 yrs BPD 24 yrs AD, l-thyroxine Received a bachelor degree in Social sciences, refuses psychiatric treatment Case 9 F 16 M MD P OC Highschool student, frequent sinusitis, functions moderate Case 10 F 19 F H A OC University graduate, functions well. Case 11 F 16 M H A Higschool student, Developed recently DM Type I

11 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents 101 Figure 1: The distribution of psychopathology over two groups: 11 TPO-Ab positives com pared to 115 TPO-Ab negatives. TPO-Ab positives other disorder (1) bipolar disorder (1) TPO-Ab negatives other disorder (22) bipolar disorder (12) unipolar disorder (4) no disorder (5) unipolar disorder (33) no disorder (48) Psychopathology according to DSM-IV criteria is divided in: no disorder, bipolar disorder, unipolar disorder, other disorder (anxiety disorders, disruptive behavioral disorders, substance abuse disorders, attention deficit hyperactive disorders, enuresis, encopresis, pervasive developmental disorder, tic and eating disorders) DISCUSSION This study suggests that offspring of bipolar parents not only inherit the vulnerability to develop mood disorders (at Time 3: 40% of the bipolar offspring subjects developed a lifetime mood disorder) but also probably the vulnerability to develop autoimmune thyroiditis. Offspring (and particularly female offspring) of a bipolar parent had a higher prevalence of autoimmune thyroiditis, i.e. a TPO-Ab titer > 25 U/ml, of 8.7% (versus 2.6 and 3.2% in the two healthy comparison groups). However, various points of concern need to be raised: a) Although the low prevalence of autoimmune thyroiditis in our control groups is in line with data in the literature on younger healthy subjects, so far few data of thyroid autoimmunity in large cohorts of adolescents and young adults are available. Previous population studies have found a prevalence of 5-15% in the general population depending on age and gender with the higher prevalence in females and aged individuals (Rapaport & McLachlan, 1996). In contrast, the prevalence in young adults was % and in children and adolescents 3.4 % (male to female ration 1:2.7) (Kabelitz et al., 2003). The age of our control population (aged years) is compared to the general population samples young, as is our offspring group. This might be an explanation for

12 102 chapter 6 the low prevalence of autoimmune thyroiditis in both groups as compared to the general population. Moreover, the general population samples include mostly more subjects of older age (which have a higher prevalence of TPO- Abs) as compared to our control population (aged years) and offspring population (aged years). b) Although our study is to our knowledge one of the largest offspring studies carried out, the sample size is still too limited for a reliable figure on the exact prevalence of autoimmune thyroiditis in the various groups; in our experience over 250 subjects in each group should be studied for a reliable and statistically testable prevalence figure. c) Another flaw of the study is that with regard to the high school students and young adult controls we were allowed to obtain one blood drawing only. Therefore, we have no follow-up data for these groups. Also the information about psychopathology and family history with mood disorders in both control groups is not as reliable as in the offspring group. d) Unfortunately we did not have the opportunity and funds to collect blood samples of both the parents of the offspring in order to determine their TPO- Ab level. A possible explanation for the higher prevalence of autoimmune thyroiditis in the offspring group is the parental thyroid autoimmune status (which is likely raised in the bipolar parent). In the previous mentioned study (Kabelitz et al., 2003) there was a trend towards a more frequent family history of thyroid disease in TPO-Ab positive, but otherwise healthy children and adolescents, but without statistical significance. To solve above described concerns our cohort of offspring (as well as the control groups) need to be expanded and followed longer. It is also necessary to collect blood samples of both parents (preferably in follow-up) to investigate the heritability of autoimmune thyroiditis in this setting. The increased prevalence of autoimmune thyroiditis in the offspring was independent from the presence of mood disorders or of any other psychiatric disorder, at least during the time of follow-up. Of course, it is also possible that in time and with the development of more psychopathology in our bipolar offspring subjects autoimmune thyroiditis and bipolar disorder become associated. Alternatively however, our findings suggest that the vulnerabilities to develop autoimmune thyroiditis are independent from each other. Thus, our data on the high prevalence of thyroid

13 Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents 103 autoimmunity in bipolar patients and their offspring (in the latter not associated to any psychopathology) underscore the systemic character of bipolar disorder and suggest common inheritable molecular aberrancies in both brain and immune cells involved in the development of these disorders or may be even combined syndrome. The so far different penetrance of mood disturbances and autoimmune thyroiditis is likely due to the co-effect of other inheritable influences and/or the effect of exposure to different eliciting environmental factors in line with the view that bipolar disorder and autoimmune thyroiditis are etiologically complex syndromes. The outcomes of our study on the offspring of bipolar patients if confirmed by others might also have implications for the clinic. The general idea that autoimmune thyroiditis in children and adolescents is usually benign and without severe clinical symptoms cannot be substantiated with our data (see Table 2). One may consider testing not only bipolar patients for TPO-Abs and serum(s)-tsh, but also their offspring. In general around 30-40% of TPO-Ab positive individuals have a raised s-tsh as evidence for a sub-clinical compensated thyroid failure (Hak et al., 2000). In this cohort the prevalence of raised s-tsh is elevated even in the TPO-Abs negative subjects (12%). Such mild decrement of the thyroid reserve often accompanies the early phases of thyroid autoimmunity. This hidden thyroid failure becomes more important when the thyroid needs to perform optimally, such as in states when there is a heightened risk for atherosclerosis. Hidden thyroid failure raises the chance for myocardial infarction (Hak et al., 2000) and during pregnancy hidden thyroid failure raises the chance for spontaneous abortion (Muller et al., 2001). Evidence is also accumulating that even autoimmune thyroiditis characterized by positive TPO-Abs only and in the absence of a raised serum TSH as a biochemical sign of hidden thyroid failure, does have adverse consequences for the well being of affected individuals (Col et al., 2004). A Dutch study (Kuijpens et al., 2001) provided an argument for TPO-Abs screening in pregnant women; women with TPO-Abs during early pregnancy in the absence of a present or previous episode of depression have a threefold-increased risk of developing a subsequent outburst of post-partum autoimmune thyroiditis with a concomitant depression. Knowledge of the TPO-Abs status of a young woman might help the clinician to identify those who are at risk of such thyroid related depression at an early stage after parturition. If one also takes into consideration the putative consequences of such hidden hypothyroidism for the severity of a mood disorder, a rationale emerges

14 104 chapter 6 for an early treatment of the here-described TPO-Ab positive offspring with levothyroxine, a safe and effective treatment. If we would find during follow-up of this high-risk cohort that those bipolar offspring subjects with raised TPO-abs titers are at an increased risk for developing mood disorders, consequences in early treatment are righteous.

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16 106 chapter 6 Disorders 1994; 32(3): Rapaport B, McLachlan M. Thyroid peroxidase antibodies. In: JB Peter and Y Schoenfeld editors, Autoantibodies Amsterdam, Elsevier 1996: pp , Reichart CG, Wals M, Hillegers MHJ, Ormel J, Nolen WA, Verhulst FC. Psychopathology in the adolescent offspring of bipolar parents. Journal of Affective Disorders 2004; Vol 78(1): Wals M, Hillegers MHJ, Reichart CG, Ormel J, Nolen WA, Verhulst FC. Prevalence of psychopathology in children of a bipolar parent. Journal of the American Academy of Child & Adolescent Psychiatry 2001; Vol 40(9): Wilson R, McKillop JH, Crocket GT, Pearson C, Jenkins C, Burns F et al. The effect of lithium therapy on parameters thought to be involved in the development of autoimmune thyroid disease. Clinical Endocrinology 1991; 34(5):

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