Journal of Affective Disorders 121 (2010) 184–188

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Journal of Affective Disorders

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Brief report

Severe affective and behavioral dysregulation in youth is associated withincreased serum TSH

Martin Holtmann a,b,⁎, Eftichia Duketis b, Kirstin Goth b, Luise Poustka a, Sven Boelte a,b

a Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germanyb Department of Child and Adolescent Psychiatry and Psychotherapy, Goethe-University, Frankfurt/Main, Germany

a r t i c l e i n f o

⁎ Corresponding author. Department of Child andand Psychotherapy, Central Institute of Mental Health68072 Mannheim, J5, 68159 Mannheim, Germany. Telor 4522; fax: +49 621/1703 4505.

E-mail address: martin.holtmann@zi-mannheim.d

0165-0327/$ – see front matter © 2009 Elsevier B.V.doi:10.1016/j.jad.2009.06.009

a b s t r a c t

Article history:Received 20 February 2009Received in revised form 8 June 2009Accepted 9 June 2009Available online 28 June 2009

Background: The relationship of bipolar disorder (BD) and altered thyroid function is increasinglyrecognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed(A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has beenidentified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has beenlinked to BD. This study tested for differences in thyroid function within a sample of n=114psychiatric children and adolescents with and without the CBCL-DP.Method: A CBCL-DP score was generated based on the composite of the crucial CBCL syndromescales (A/D, AP, AB). Participants with a CBCL-DP score ≥2.5 SDs above average constituted theCBCL-DP subgroup (n=53). Those with CBCL-DP scores of 1 SD or less above average percentilewere regarded as controls (n=61). Groupswere compared regarding serum levels of TSH, fT3 andfT4.Results: In participants showing the CBCL-DP, basal serum TSHwas elevated compared to controls.More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences wereobserved for serum fT3 and fT4 levels.Conclusions: This is the first study to demonstrate associations between CBCL-DP and subclinicalhypothyroidism. Future research should address the long-term outcome of CBCL-DP withcoexisting hypothyroidism, the potential benefits of supplementationwith thyroid hormone, andthe association between severe dysregulation and the bipolar spectrum.

© 2009 Elsevier B.V. All rights reserved.

Keywords:Child Behavior Checklist (CBCL)DysregulationThyroidTSHBipolar

1. Introduction

The relationship of bipolar disorder (BD) and altered thyroidfunction is increasingly recognized (Bauer et al., 2008). Indicesof thyroid hypofunction have been suggested as endopheno-types related to the development and trajectory of BD. Eventhough most patients with BD do not have overt thyroiddisease, it seems possible that relative abnormalities in thyroidfunction could modulate the phenotypic expression of theircondition. In individuals with BD, an elevated prevalence of

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hypothyroidism and of autoimmune thyroiditis compared tothe general population and psychiatric controls have beenobserved. This increase is likely to be independent of lithiumtreatment (Kupka et al., 2002a). Although within the normalrange, a higher concentration of the thyroid stimulating hor-mone (TSH) was associated with poorer treatment responseduring thedepressedphaseof BD(Cole et al., 2002). In addition,subclinical thyroid hypofunction during lithium treatment isassociated with a higher risk for depressive relapse and moremanic episodes (Frye et al., 1999, 2009). Rapid-cycling BD wasassociated with a latent hypofunction of the hypothalamic-pituitary-thyroid system in several studies (Azorin et al., 2008;Bauer and Whybrow, 1990; Bartela et al., 1990; Cowdry et al.,1983; Gyulai et al., 2003),while others found the contrary (Postet al., 1997; Kupka et al., 2002b). Autoimmune thyroiditis ismore frequent in unaffected offsprings of peoplewith BDand innon BD cotwins of siblings with BD than in controls (Hillegers

185M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184–188

et al., 2007; Vonk et al., 2007). This suggests that autoimmunethyroid dysfunction seems to be related to the geneticvulnerability to develop BD rather than to the specificpathogenesis itself.

Evidence on abnormalities in thyroid function of childrenand adolescents affected by bipolar spectrum disorders isscarce and until now focused on lithium-induced hypothyr-oidism (Gracious et al., 2004).

There is an ongoing debate in child and adolescentpsychiatry, whether youth presenting with severe affectiveand behavioral dysregulation, including irritability, aggres-sion, “affective storms”, hyperarousal and altered mood,should be classified as bipolar. Some authors have suggestedto consider such chronic, non-episodic affective and behav-ioral dysregulation as a broad phenotype of BD; as opposed tothe classical narrow bipolar phenotype with clearly demar-cated affective episodes (Leibenluft et al., 2003).

Severe affective and behavioral dysregulation in youth iscapturedbya recently identifiedandwell ensuredprofile on theChild Behavior Checklist (“CBCL-dysregulation profile”, CBCL-DP; Biedermanet al.,1995;Holtmannet al., 2007;Hudziaket al.,2005; Mick et al., 2003). The CBCL is one of the best-studied,empirically derived parent checklists to measure general childand adolescent psychopathology. It has excellent psychometricproperties, and a large body of research demonstrates itsreliability and validity in both clinical and nonclinical popula-tions (Achenbach, 1991). The CBCL-DP is characterized bydeviance on the Anxious/Depressed, Attention Problems, andAggressive Behavior syndrome scales. The profile is wellensured by replication studies and meta-analysis (Mick et al.,2003), and has been confirmed to behighly heritable and stableacross ages (Hudziak et al., 2005). The precise relation of CBCL-DP and the bipolar spectrum is not yet completely understood(Holtmann et al., 2008; Volk and Todd, 2007). There isincreasing consensus that the CBCL-DP profile appears to bean indicator of overall psychopathology, symptom severity,functional impairment, and disordered self-regulation, ratherthan being indicative of any one particular diagnosis (Meyeret al., 2009). Two longitudinal studies presented recentlysuggest that the majority of children with CBCL-DP do not dowell in adulthood, and about one third of them shows atransition to BD in young adulthood (Biederman et al., 2009;Meyer et al., 2009).

The purpose of this study was to investigate whetherchildren and adolescents with severe affective and behavioraldysregulation as assessed by the CBCL-DP show similaralterations of thyroid function as previously reported fromadult patients with a core BD phenotype, their unaffectedsiblings and offsprings. Therefore, two child and adolescentpsychiatric samples exhibiting severe and normal levels ofbehavioral dysregulation, respectively, were compared withregard to serum TSH, fT3, fT4. In addition, the number ofsubjectswith hypothyroidism in both groupswas determined.

2. Methods

2.1. Sample

We studied a clinical sample of 114 children and adolescents(55 girls and 59 boys), aged 4.0 to 17.7 years (mean 12.2±3.6 years), who were referred to out- and inpatient child

psychiatric care. Clinical discharge ICD-10 diagnoses wereestablished by experienced child and adolescent psychiatristsin weekly consensus conferences according to the diagnosticguidelines of the German society for child and adolescentpsychiatry (DGKJP, 2007). In these meetings, all materialsobtained throughout the diagnostic and therapeutic process viasemistructured parent and child interviews administered byexperienced clinicians (German version of the Clinical Assess-ment-Scale forChild andAdolescentPsychopathology, CASCAP-D; Döpfner et al., 1999), teacher report, rating scales, psycho-logical assessment, and behavior observation are reviewed. Theinternal consistency (Cronbach's α) of the CASCAP-D is .90 forexternalizing symptom scales (aggressive, delinquent, hyper-kinetic and impulsive symptoms), .74 for internalizing symp-tom scales (anxious and depressed symptoms), and .80 foreating disorders. Discriminant and convergent validity havebeen shown in previous studies in n=597 German childrenand adolescents (Döpfner et al., 1999).

Diagnoses were considered positive only when theconsensus committee determined that diagnostic criteriaaccording to the ICD-10 were unequivocally met. However, noκ-coefficients were computed between interviews and con-sensus diagnoses.

A waiver for human subjects was obtained for this retro-spective study from the local medical ethics committee.

2.2. Subgroups

For all participants, parents or caregivers completed theGerman consensus version of the Child Behavior Checklist(Arbeitsgruppe Deutsche CBCL, 1998). Reliability, factorialvalidity and discriminant validity of this adaptation have beenconfirmed (Schmeck et al., 2001). The CBCL queries about thechild's behavior in the past six months. The CBCL has eightnarrow-band syndrome scales: Withdrawn, Somatic Com-plaints, Anxious/Depressed, Social Problems, Thought Pro-blems, Attention Problems, Delinquent Behavior, andAggressive Behavior. Raw score are transformed into age andgender corrected T-norms (mean 50, SD=10). In 27 subjects(24.6%), no informationwas availablewhocompleted the CBCL;62.7% of the checklists were completed by mothers and 12.7%were filled out by fathers. Following the method of Hudziaket al. (2005), we defined the CBCL-DP score as the composite T-score of the three CBCL subscales Attention Problems, Aggres-sive Behavior, andAnxious/Depressed. Childrenwith a CBCL-DPscore in the definite clinical range (exceeding 225, i.e. 2.5 SDsabove average) constituted the subgroup with pronounceddysregulation (CBCL-DP;n=53). ChildrenwithCBCL-DP scoresbelow 180 (1 SD above average or less) were regarded aspsychiatric controls without dysregulation (n=61). Faraoneet al. (2005) suggested to use this composite of the crucial CBCLsyndrome scales as a quantitative trait for research studies andprovided sensitivity and specificity values for DSM-IV definedbipolar disorder at various cut-points. According to theirreceiver operating curve analysis, the cut-point of 225 has aspecificity of 97% and a negative predictive power of 99% topredict a current diagnosis of BD. Similar dimensionalapproaches contrasting groups with very high and low CBC-DP scores have been used in a study on serotonergic dysfunc-tion inCBCL-DP(Zepf et al., 2008), and in a longitudinal analysison the predictive value of CBCL-DP (Biederman et al., 2009).

Table 2Indices of thyroid function in CBCL-DP subjects and controls.

CBCL-DPn=53

Controlsn=61

P

TSH (mIU/l) 2.59±1.15 2.08±1.10 F=4.31 .040fT3 3.84±0.57 3.59±0.80 F=1.57 .214fT4 1.46±1.20 1.31±0.56 F=0.63 .428

186 M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184–188

Diagnoses comprised a broad spectrum of child psychia-tric disorders in both groups. No patient was diagnosed withBD. CBCL-DP children were significantly younger than con-trols (t=2.65, p=.009). Gender was comparably distributedbetween the two groups (Chi2=.35, p=.555). At admission,no patient received drugs potentially inhibiting thyroidfunction, such as lithium, carbamazepine, propanolol, que-tiapine, and iodide. Distribution of age, gender and ICD-10diagnoses for both groups are displayed in Table 1.

2.3. Thyroid function tests

The thyroid panel used in this study included TSH, freethyroxine (fT4; normal range 0.9–1.6 mg/dl), and freetriiodothyronine (fT3; normal range 2.3–5.6 pg/ml). Theassays were performed by the clinical laboratory at theUniversity of Frankfurt Medical Center by the electro-chemo-luminescence-immunoassay (ECLIA) method (RocheElecsys). In children, the HPA-axis undergoes progressivematuration and modulation (Fisher et al., 2000). As a result,higher TSH concentrations are typically seen in children.Since no age-adjusted reference ranges for thyroid indices areestablished, we decided to follow recommendations of theNational Academy of Clinical Biochemistry (NACB): indivi-duals with a serum TSH above 2.5 mIU/l and normal serumfT4 were regarded as suffering from subclinical hypothyroid-ism (Baloch et al., 2003).

2.4. Statistics

In accordance with published evidence (Penny et al., 1983;Verheecke, 1997), fT3 concentration was inversely correlatedwith age (r=− .33, pb .01). In addition, fT3 levels werehigher in females (t=3.31, pb .01). Therefore, groups were

Table 1Age, sex distribution, and diagnoses in CBCL-DP and controls.

CBCL-DP(n=53)

CON(n=61)

p

Age (mean±SD) 11.2±3.7 13.0±3.3 T=2.65 .009Sex (male:female) 29:24 30:31 χ2=.35 .555ICD-10 Diagnosis (n)F32/F33 Depressive disorders 2 6F40/F41 Phobia/Anxietydisorders

– 5

F42 Obsessive compulsivedisorder

2 3

F43 Adjustment disorders 1 2F50 Eating disorders 1 10F60 Personality disorders 1 2F84 Pervasive developm.disorders

1 3

F90.0 Hyperkinetic disorder 7 5F90.1 Hyperkinetic conductdisorder

15 3

F91 Conduct disorder 10 7F92 Disorders of conduct &emotions

9 1

F93 Anxiety disorder ofchildhood

1 3

F94 Attachment disorders 1 –

F98 Enuresis/Enkopresis 2 3Other – 8

compared regarding serum levels of TSH, fT3 and fT4, usingANCOVAs covarying for age. Sex was included as anotherbetween-group factor. Pearson's correlation was computedbetween serum TSH and the CBCL-DP score. Effect sizes areexpressed by partial eta squared (partial η2) [b .06=low, .06to .14middle, N .14=high]. Given theN of this study and alpha(5%), the test-power (1-beta) for detecting significant groupmean differences between the samples using a general linearmodel was .18 for a small, .75 for a medium and .99 for a largeeffect.

3. Results

SerumTSHwashigher in CBCL-DP (2.59±1.15mIU/l) than incontrols (2.08±1.10 mIU/l; F=4.31, p=.040, partial η2=.038).Therewas also a group difference in the number of subjectswithsubclinical hypothyroidism: 45.3% of CBCL-DP patients (24/53),but only 23.0% of controls (14/61) had serum TSH levels above2.5 mIU/l (Chi2=6.37; p=.012; OR=2.78, 95% CI: 1.25–6.17).No differences were observed for fT3 (F=1.57, p=.214) and fT4(F=0.63, p=.428). Serum TSH and the CBCL-DP score weremoderately correlated (r=.25, pb .01) (Table 2).

4. Discussion

The present study investigated whether children andadolescents with severe behavioral dysregulation as oper-ationalized by the CBCL-DP show similar signs of alteredthyroid function as previously reported from samples with orat risk for BD. In fact, serum TSH was elevated in dysregulatedpatients, and subclinical hypothyroidism was more frequentamong CBCL-DP patients than among psychiatric controls.The effect of the associationwas rather small but proved to bestable even if after controlling for age effects.

Due to the retrospective design of our study the etiologyof the observed hypothyroidism is unclear. Adaptive changesin hormone secretion as a result of group differences in thenutritional status (with a higher number of controls diagnosedwith anorexia nervosa) are an unlikely explanation for thedifferences in thyroid function: groups did not differ in weight(F=2.46, p=.123), and no correlation was found betweenweight and TSH levels (r=.087, p=.528).

The high number of childrenwith conduct disorder (CD) inthe CBCL-DP group does not provide an explanation for thealtered thyroid function: contrasting all 35 subjects with CD(including ICD-10 categories for hyperkinetic CD, F90.1, and CD,F91) with the remaining 79 subjects, there were no differencesbetween TSH levels (F=1.48, p=.226).

Autoimmune thyroiditis is a major cause of “hidden thyroidfailure”. However, antibodies to the thyroid, such as thyroper-oxidase antibodies (TPO-Abs), were not assessed in our study.In addition, no TRH stimulation test was delivered.

187M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184–188

Given the close thyroid-serotonin system interaction(Bauer et al., 2002), it could be speculated that the alteredthyroid function is at least in part linked to the previouslyreported serotonergic dysfunction in CBCL-DP (Zepf et al.,2008). Against this background, thyroid dysregulationmay beregarded as a compensatory mechanism for diminishedcentral serotonergic activity (Duval et al., 1999).

There is an ongoing controversy as to whether subclinicalhypothyroidism is associated with cognitive impairment, e.g.working memory dysfunction (Zhu et al., 2006). Evidence isaccumulating that even amild decrementof the thyroid reservedoes have adverse effects on psychomotor speed, visual-spatialand verbal skills, memory, and the health-related quality of lifeof affected individuals (Alvarez-Pedrerol et al., 2007; Gulserenet al., 2006; Col et al., 2004; for review, see Bauer et al., 2008).No systematic neuropsychological data were available for thepresent sample. In a previous study we observed a reducedcognitive performance in CBCL-DP children with attention-deficit/hyperactivity disorder (ADHD) compared to childrenwith ADHD alone (Zepf et al., 2008). However, thyroid functionwas not determined in that sample. Future studies shouldtherefore examine neuropsychological function in CBCL-DP inrelation to thyroid abnormalities.

Clinical implications of our findings are not yet clear.Increasing evidence suggests that adjunctive treatment withsupraphysiological doses of thyroid hormones may be a safeand effective strategy for adult patients with rapid cycling ortreatment resistant BD, bipolar II and BD not otherwisespecified, leading to meaningful improvements of scores onboth depressive and manic symptom rating scales, fewerrelapses and shorter hospitalizations (for review, see Baueret al., 2008; Kelly and Lieberman, 2009). Taking into considera-tion the putative consequences of hidden hypothyroidism onthe development and course of BD, future studies need todetermine whether a rationale emerges for an early treatmentwith thyroid hormones in children and adolescentswith severedysregulation and a subclinical thyroid failure.

A limitation of our study is the retrospective, cross-sectionaldesign and the associated lack of follow-up data. In addition, nostructured interviews were used to establish ICD-10 diagnoses.The main strength of this study is the use of a well-normed,standardized parental questionnaire with excellent psycho-metric properties (Achenbach, 1991). Secondly, the behavioralphenotype assessed by the CBCL-DP seems well ensured byreplication studies and meta-analysis (Mick et al., 2003), andhas been confirmed tobehighly heritable and stable across ages(Hudziak et al., 2005).

5. Conclusions

Taken together, our results show thyroid hypofunction in ahigher number of children with severe affective and behavioraldysregulation (CBCL-DP) than in psychiatric controls withoutdysregulation. Thesefindingsneed replication in larger samples;therefore, treatment and prevention implications are not yetclear. Previous studies have shown a not yet fully understoodassociation of the bipolar spectrum and CBCL-DP. This relationhasbeenevidenced inoverlappingclinical symptoms(increasedsuicidality, decreased need for sleep, hypersexuality; Holtmannet al., 2008; Volk and Todd, 2007), and a frequent transitionfrom CBCL-DP to classical bipolar disorder (Meyer et al., 2009).

However, it is unclear whether the observed pattern of thyroiddysfunction in CBCL-DP that has previously been reported fromsamples with rapid cycling BD, unaffected cotwins of bipolarsiblings and bipolar offspring endorses the notion of anassociation of CBCL-DP and broad phenotype BD. Thyroidhypofunction has been linked to anxiety and attention disordersand therefore does not appear to be specific to BD (Alvarez-Pedrerol et al., 2007; Gulseren et al., 2006). An associationbetween early onset BD and thyroid dysfunction has yet to beestablished. In addition, it is unclear whether findings fromadult BD can be extended to children andadolescents, given thatthere are as yet very limited data establishing continuitybetween childhood and adult forms of BD (Geller et al., 2008).

Future research should address the long-term outcome ofCBCL-DP with coexisting hypothyroidism, and study thepotential benefits of supplementation with thyroid hormonein this group of seriously disturbed children and adolescents.

Role of funding sourceThere was no funding of the study.

Conflict of interestMH is member of Advisory Boards of Lilly, Novartis, and Bristol Myers

Squibb, and serves on the speaker bureaus of Lilly and Astra Zeneca. Theother authors have no financial relationships to disclose.

Acknowledgements

Nothing declared.

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