Journal of Affective Disorders 121 (2010) 184188

Contents lists available at ScienceDirect

Journal of Affective Disorders

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Brief report

Severe affective and behavioral dysregulation in youth is associated with increased serum TSH
Martin Holtmann a,b,, Eftichia Duketis b, Kirstin Goth b, Luise Poustka a, Sven Boelte a,b
a b

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

a r t i c l e

i n f o

a b s t r a c t
Background: The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identied as the Child Behavior Checklist Dysregulation Prole (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of n = 114 psychiatric children and adolescents with and without the CBCL-DP. Method: A CBCL-DP score was generated based on the composite of the crucial CBCL syndrome scales (A/D, AP, AB). Participants with a CBCL-DP score 2.5 SDs above average constituted the CBCL-DP subgroup (n = 53). Those with CBCL-DP scores of 1 SD or less above average percentile were regarded as controls (n = 61). Groups were compared regarding serum levels of TSH, fT3 and fT4. Results: In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels. Conclusions: This is the rst study to demonstrate associations between CBCL-DP and subclinical hypothyroidism. Future research should address the long-term outcome of CBCL-DP with coexisting hypothyroidism, the potential benets of supplementation with thyroid hormone, and the association between severe dysregulation and the bipolar spectrum. 2009 Elsevier B.V. All rights reserved.

Article history: Received 20 February 2009 Received in revised form 8 June 2009 Accepted 9 June 2009 Available online 28 June 2009 Keywords: Child Behavior Checklist (CBCL) Dysregulation Thyroid TSH Bipolar

1. Introduction The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized (Bauer et al., 2008). Indices of thyroid hypofunction have been suggested as endophenotypes related to the development and trajectory of BD. Even though most patients with BD do not have overt thyroid disease, it seems possible that relative abnormalities in thyroid function could modulate the phenotypic expression of their condition. In individuals with BD, an elevated prevalence of

Corresponding author. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Postbox 12 21 20, D 68072 Mannheim, J5, 68159 Mannheim, Germany. Tel.: +49 621/1703 4521 or 4522; fax: +49 621/1703 4505. E-mail address: martin.holtmann@zi-mannheim.de (M. Holtmann). 0165-0327/$ see front matter 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.06.009

hypothyroidism and of autoimmune thyroiditis compared to the general population and psychiatric controls have been observed. This increase is likely to be independent of lithium treatment (Kupka et al., 2002a). Although within the normal range, a higher concentration of the thyroid stimulating hormone (TSH) was associated with poorer treatment response during the depressed phase of BD (Cole et al., 2002). In addition, subclinical thyroid hypofunction during lithium treatment is associated with a higher risk for depressive relapse and more manic episodes (Frye et al., 1999, 2009). Rapid-cycling BD was associated with a latent hypofunction of the hypothalamicpituitary-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 (Post et al., 1997; Kupka et al., 2002b). Autoimmune thyroiditis is more frequent in unaffected offsprings of people with BD and in non BD cotwins of siblings with BD than in controls (Hillegers

M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184188

185

et al., 2007; Vonk et al., 2007). This suggests that autoimmune thyroid dysfunction seems to be related to the genetic vulnerability to develop BD rather than to the specic pathogenesis itself. Evidence on abnormalities in thyroid function of children and adolescents affected by bipolar spectrum disorders is scarce and until now focused on lithium-induced hypothyroidism (Gracious et al., 2004). There is an ongoing debate in child and adolescent psychiatry, whether youth presenting with severe affective and behavioral dysregulation, including irritability, aggression, affective storms, hyperarousal and altered mood, should be classied as bipolar. Some authors have suggested to consider such chronic, non-episodic affective and behavioral dysregulation as a broad phenotype of BD; as opposed to the classical narrow bipolar phenotype with clearly demarcated affective episodes (Leibenluft et al., 2003). Severe affective and behavioral dysregulation in youth is captured by a recently identied and well ensured prole on the Child Behavior Checklist (CBCL-dysregulation prole, CBCLDP; Biederman et al.,1995; Holtmann et al., 2007; Hudziak et al., 2005; Mick et al., 2003). The CBCL is one of the best-studied, empirically derived parent checklists to measure general child and adolescent psychopathology. It has excellent psychometric properties, and a large body of research demonstrates its reliability and validity in both clinical and nonclinical populations (Achenbach, 1991). The CBCL-DP is characterized by deviance on the Anxious/Depressed, Attention Problems, and Aggressive Behavior syndrome scales. The prole is well ensured by replication studies and meta-analysis (Mick et al., 2003), and has been conrmed to be highly heritable and stable across ages (Hudziak et al., 2005). The precise relation of CBCLDP and the bipolar spectrum is not yet completely understood (Holtmann et al., 2008; Volk and Todd, 2007). There is increasing consensus that the CBCL-DP prole appears to be an indicator of overall psychopathology, symptom severity, functional impairment, and disordered self-regulation, rather than being indicative of any one particular diagnosis (Meyer et al., 2009). Two longitudinal studies presented recently suggest that the majority of children with CBCL-DP do not do well in adulthood, and about one third of them shows a transition to BD in young adulthood (Biederman et al., 2009; Meyer et al., 2009). The purpose of this study was to investigate whether children and adolescents with severe affective and behavioral dysregulation as assessed by the CBCL-DP show similar alterations of thyroid function as previously reported from adult patients with a core BD phenotype, their unaffected siblings and offsprings. Therefore, two child and adolescent psychiatric samples exhibiting severe and normal levels of behavioral dysregulation, respectively, were compared with regard to serum TSH, fT3, fT4. In addition, the number of subjects with hypothyroidism in both groups was 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 were established by experienced child and adolescent psychiatrists in weekly consensus conferences according to the diagnostic guidelines of the German society for child and adolescent psychiatry (DGKJP, 2007). In these meetings, all materials obtained throughout the diagnostic and therapeutic process via semistructured parent and child interviews administered by experienced clinicians (German version of the Clinical Assessment-Scale for Child and Adolescent Psychopathology, CASCAPD; Dpfner et al., 1999), teacher report, rating scales, psychological assessment, and behavior observation are reviewed. The internal consistency (Cronbach's ) of the CASCAP-D is .90 for externalizing symptom scales (aggressive, delinquent, hyperkinetic and impulsive symptoms), .74 for internalizing symptom scales (anxious and depressed symptoms), and .80 for eating disorders. Discriminant and convergent validity have been shown in previous studies in n = 597 German children and adolescents (Dpfner et al., 1999). Diagnoses were considered positive only when the consensus committee determined that diagnostic criteria according to the ICD-10 were unequivocally met. However, no -coefcients were computed between interviews and consensus diagnoses. A waiver for human subjects was obtained for this retrospective study from the local medical ethics committee. 2.2. Subgroups For all participants, parents or caregivers completed the German consensus version of the Child Behavior Checklist (Arbeitsgruppe Deutsche CBCL, 1998). Reliability, factorial validity and discriminant validity of this adaptation have been conrmed (Schmeck et al., 2001). The CBCL queries about the child's behavior in the past six months. The CBCL has eight narrow-band syndrome scales: Withdrawn, Somatic Complaints, Anxious/Depressed, Social Problems, Thought Problems, Attention Problems, Delinquent Behavior, and Aggressive Behavior. Raw score are transformed into age and gender corrected T-norms (mean 50, SD= 10). In 27 subjects (24.6%), no information was available who completed the CBCL; 62.7% of the checklists were completed by mothers and 12.7% were lled out by fathers. Following the method of Hudziak et al. (2005), we dened the CBCL-DP score as the composite Tscore of the three CBCL subscales Attention Problems, Aggressive Behavior, and Anxious/Depressed. Children with a CBCL-DP score in the denite clinical range (exceeding 225, i.e. 2.5 SDs above average) constituted the subgroup with pronounced dysregulation (CBCL-DP; n = 53). Children with CBCL-DP scores below 180 (1 SD above average or less) were regarded as psychiatric controls without dysregulation (n = 61). Faraone et al. (2005) suggested to use this composite of the crucial CBCL syndrome scales as a quantitative trait for research studies and provided sensitivity and specicity values for DSM-IV dened bipolar disorder at various cut-points. According to their receiver operating curve analysis, the cut-point of 225 has a specicity of 97% and a negative predictive power of 99% to predict a current diagnosis of BD. Similar dimensional approaches contrasting groups with very high and low CBCDP scores have been used in a study on serotonergic dysfunction in CBCL-DP (Zepf et al., 2008), and in a longitudinal analysis on the predictive value of CBCL-DP (Biederman et al., 2009).

186

M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184188 Table 2 Indices of thyroid function in CBCL-DP subjects and controls. CBCL-DP n = 53 TSH (mIU/l) fT3 fT4 2.59 1.15 3.84 0.57 1.46 1.20 Controls n = 61 2.08 1.10 3.59 0.80 1.31 0.56 F = 4.31 F = 1.57 F = 0.63 P .040 .214 .428

Diagnoses comprised a broad spectrum of child psychiatric disorders in both groups. No patient was diagnosed with BD. CBCL-DP children were signicantly younger than controls (t = 2.65, p = .009). Gender was comparably distributed between the two groups (Chi2 = .35, p = .555). At admission, no patient received drugs potentially inhibiting thyroid function, such as lithium, carbamazepine, propanolol, quetiapine, and iodide. Distribution of age, gender and ICD-10 diagnoses for both groups are displayed in Table 1. 2.3. Thyroid function tests The thyroid panel used in this study included TSH, free thyroxine (fT4; normal range 0.91.6 mg/dl), and free triiodothyronine (fT3; normal range 2.35.6 pg/ml). The assays were performed by the clinical laboratory at the University of Frankfurt Medical Center by the electro-chemoluminescence-immunoassay (ECLIA) method (Roche Elecsys). In children, the HPA-axis undergoes progressive maturation 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 are established, we decided to follow recommendations of the National Academy of Clinical Biochemistry (NACB): individuals with a serum TSH above 2.5 mIU/l and normal serum fT4 were regarded as suffering from subclinical hypothyroidism (Baloch et al., 2003). 2.4. Statistics In accordance with published evidence (Penny et al., 1983; Verheecke, 1997), fT3 concentration was inversely correlated with age (r = .33, p b .01). In addition, fT3 levels were higher in females (t = 3.31, p b .01). Therefore, groups were

compared regarding serum levels of TSH, fT3 and fT4, using ANCOVAs covarying for age. Sex was included as another between-group factor. Pearson's correlation was computed between serum TSH and the CBCL-DP score. Effect sizes are expressed by partial eta squared (partial 2) [b .06 = low, .06 to .14 middle, N .14 = high]. Given the N of this study and alpha (5%), the test-power (1-beta) for detecting signicant group mean differences between the samples using a general linear model was .18 for a small, .75 for a medium and .99 for a large effect. 3. Results Serum TSH was higher in CBCL-DP (2.591.15 mIU/l) than in controls (2.08 1.10 mIU/l; F =4.31, p =.040, partial 2 =.038). There was also a group difference in the number of subjects with subclinical hypothyroidism: 45.3% of CBCL-DP patients (24/53), but only 23.0% of controls (14/61) had serum TSH levels above 2.5 mIU/l (Chi2 =6.37; p =.012; OR=2.78, 95% CI: 1.256.17). 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 were moderately correlated (r =.25, p b .01) (Table 2). 4. Discussion The present study investigated whether children and adolescents with severe behavioral dysregulation as operationalized by the CBCL-DP show similar signs of altered thyroid function as previously reported from samples with or at risk for BD. In fact, serum TSH was elevated in dysregulated patients, and subclinical hypothyroidism was more frequent among CBCL-DP patients than among psychiatric controls. The effect of the association was rather small but proved to be stable even if after controlling for age effects. Due to the retrospective design of our study the etiology of the observed hypothyroidism is unclear. Adaptive changes in hormone secretion as a result of group differences in the nutritional status (with a higher number of controls diagnosed with anorexia nervosa) are an unlikely explanation for the differences in thyroid function: groups did not differ in weight (F = 2.46, p = .123), and no correlation was found between weight and TSH levels (r = .087, p = .528). The high number of children with conduct disorder (CD) in the CBCL-DP group does not provide an explanation for the altered 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 differences between TSH levels (F = 1.48, p = .226). Autoimmune thyroiditis is a major cause of hidden thyroid failure. However, antibodies to the thyroid, such as thyroperoxidase antibodies (TPO-Abs), were not assessed in our study. In addition, no TRH stimulation test was delivered.

Table 1 Age, sex distribution, and diagnoses in CBCL-DP and controls. CBCL-DP (n = 53) Age (mean SD) Sex (male:female) ICD-10 Diagnosis (n) F32/F33 Depressive disorders F40/F41 Phobia/Anxiety disorders F42 Obsessive compulsive disorder F43 Adjustment disorders F50 Eating disorders F60 Personality disorders F84 Pervasive developm. disorders F90.0 Hyperkinetic disorder F90.1 Hyperkinetic conduct disorder F91 Conduct disorder F92 Disorders of conduct & emotions F93 Anxiety disorder of childhood F94 Attachment disorders F98 Enuresis/Enkopresis Other 11.2 3.7 29:24 2 2 1 1 1 1 7 15 10 9 1 1 2 CON (n = 61) 13.0 3.3 30:31 6 5 3 2 10 2 3 5 3 7 1 3 3 8 T = 2.65 2 = .35 p .009 .555

M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184188

187

Given the close thyroid-serotonin system interaction (Bauer et al., 2002), it could be speculated that the altered thyroid function is at least in part linked to the previously reported serotonergic dysfunction in CBCL-DP (Zepf et al., 2008). Against this background, thyroid dysregulation may be regarded as a compensatory mechanism for diminished central serotonergic activity (Duval et al., 1999). There is an ongoing controversy as to whether subclinical hypothyroidism is associated with cognitive impairment, e.g. working memory dysfunction (Zhu et al., 2006). Evidence is accumulating that even a mild decrement of the thyroid reserve does have adverse effects on psychomotor speed, visual-spatial and verbal skills, memory, and the health-related quality of life of affected individuals (Alvarez-Pedrerol et al., 2007; Gulseren et al., 2006; Col et al., 2004; for review, see Bauer et al., 2008). No systematic neuropsychological data were available for the present sample. In a previous study we observed a reduced cognitive performance in CBCL-DP children with attentiondecit/hyperactivity disorder (ADHD) compared to children with ADHD alone (Zepf et al., 2008). However, thyroid function was not determined in that sample. Future studies should therefore examine neuropsychological function in CBCL-DP in relation to thyroid abnormalities. Clinical implications of our ndings are not yet clear. Increasing evidence suggests that adjunctive treatment with supraphysiological doses of thyroid hormones may be a safe and effective strategy for adult patients with rapid cycling or treatment resistant BD, bipolar II and BD not otherwise specied, leading to meaningful improvements of scores on both depressive and manic symptom rating scales, fewer relapses and shorter hospitalizations (for review, see Bauer et al., 2008; Kelly and Lieberman, 2009). Taking into consideration the putative consequences of hidden hypothyroidism on the development and course of BD, future studies need to determine whether a rationale emerges for an early treatment with thyroid hormones in children and adolescents with severe dysregulation and a subclinical thyroid failure. A limitation of our study is the retrospective, cross-sectional design and the associated lack of follow-up data. In addition, no structured 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 psychometric properties (Achenbach, 1991). Secondly, the behavioral phenotype assessed by the CBCL-DP seems well ensured by replication studies and meta-analysis (Mick et al., 2003), and has been conrmed to be highly heritable and stable across ages (Hudziak et al., 2005). 5. Conclusions Taken together, our results show thyroid hypofunction in a higher number of children with severe affective and behavioral dysregulation (CBCL-DP) than in psychiatric controls without dysregulation. These ndings need replication in larger samples; therefore, treatment and prevention implications are not yet clear. Previous studies have shown a not yet fully understood association of the bipolar spectrum and CBCL-DP. This relation has been evidenced in overlapping clinical symptoms (increased suicidality, decreased need for sleep, hypersexuality; Holtmann et al., 2008; Volk and Todd, 2007), and a frequent transition from CBCL-DP to classical bipolar disorder (Meyer et al., 2009).

However, it is unclear whether the observed pattern of thyroid dysfunction in CBCL-DP that has previously been reported from samples with rapid cycling BD, unaffected cotwins of bipolar siblings and bipolar offspring endorses the notion of an association of CBCL-DP and broad phenotype BD. Thyroid hypofunction has been linked to anxiety and attention disorders and therefore does not appear to be specic to BD (AlvarezPedrerol et al., 2007; Gulseren et al., 2006). An association between early onset BD and thyroid dysfunction has yet to be established. In addition, it is unclear whether ndings from adult BD can be extended to children and adolescents, given that there are as yet very limited data establishing continuity between childhood and adult forms of BD (Geller et al., 2008). Future research should address the long-term outcome of CBCL-DP with coexisting hypothyroidism, and study the potential benets of supplementation with thyroid hormone in this group of seriously disturbed children and adolescents.
Role of funding source There was no funding of the study. Conict of interest MH is member of Advisory Boards of Lilly, Novartis, and Bristol Myers Squibb, and serves on the speaker bureaus of Lilly and Astra Zeneca. The other authors have no nancial relationships to disclose.

Acknowledgements Nothing declared. References

Achenbach, T.M., 1991. Manual for the Child Behavior Checklist/4-18 and 1991 Prole. University of Vermont, Burlington. Alvarez-Pedrerol, M., Ribas-Fit, N., Torrent, M., Julvez, J., Ferrer, C., Sunyer, J., 2007. TSH concentration within the normal range is associated with cognitive function and ADHD symptoms in healthy preschoolers. Clin. Endocrinol. (Oxf.) 66 (6), 890898. Arbeitsgruppe Deutsche CBCL, 1998. [CBCL/4-18: Parent questionnaire on the behavior of children and adolescents]. 2nd edn. Koeln: Arbeitsgruppe Kinder-, Jugend- und Familiendiagnostik. Azorin, J.M., Kaladjian, A., Adida, M., Hantouche, E.G., Hameg, A., Lancrenon, S., Akiskal, H.S., 2008. Factors associated with rapid cycling in bipolar I manic patients: ndings from a French national study. CNS Spectr. 13 (9), 780787. Baloch, Z., Carayon, P., Conte-Devolx, B., Demers, L.M., Feldt-Rasmussen, U., Henry, J.F., LiVosli, V.A., Niccoli-Sire, P., John, R., Ruf, J., Smyth, P.P., Spencer, C.A., Stockigt, J.R., Guidelines Committee, National Academy of Clinical Biochemistry, 2003. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13, 3126. Bartela, L., Pellegrini, L., Meschi, M., Antonangeli, L., Bogazzi, F., Dell'Osso, L., Pinchera, A., Placidiet, G.F., 1990. Evaluation of thyroid function in patients with rapid-cycling bipolar disorder. Psychiatry Res. 34, 1317. Bauer, M., Whybrow, P.C., 1990. Rapid cycling bipolar affective disorder, I: association with grade I hypothyroidism. Arch. Gen. Psychiatry 47, 427432. Bauer, M., Heinz, A., Whybrow, P.C., 2002. Thyroid hormones, serotonin and mood: of synergy and signicance in the adult brain. Mol. Psychiatry 7 (2), 140156. Bauer, M., Goetz, T., Glenn, T., Whybrow, P.C., 2008. The thyroidbrain interaction in thyroid disorders and mood disorders. J. Neuroendocrinol. 20 (10), 11011114. Biederman, J., Wozniak, J., Kiely, K., Ablon, S., Faraone, S., Mick, E., Mundy, E., Kraus, I., 1995. CBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD. J. Am. Acad. Child Adolesc. Psych. 34, 464471. Biederman, J., Petty, C.R., Monuteaux, M.C., Evans, M., Parcell, T., Faraone, S.V., Wozniak, J., 2009. The child behavior checklist-pediatric bipolar disorder prole predicts a subsequent diagnosis of bipolar disorder and associated impairments in ADHD youth growing up: a longitudinal analysis. J. Clin. Psychiatry 2009 Apr 21.

188

M. Holtmann et al. / Journal of Affective Disorders 121 (2010) 184188 Holtmann, M., Blte, S., Goth, K., Poustka, F., 2008. CBCL-pediatric bipolar disorder phenotype: severe ADHD or bipolar disorder? J. Neural Transm. 115, 155161. Hudziak, J.J., Althoff, R.R., Derks, E.M., Faraone, S.V., Boomsma, D.I., 2005. Prevalence and genetic architecture of Child Behavior Checklist-juvenile bipolar disorder. Biol. Psychiatry 58, 562568. Kelly, T., Lieberman, D.Z., 2009. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J. Affect. Disord. 116 (3), 222226. Kupka, R.W., Breunis, M.N., Knijff, E., Ruwhof, C., Nolen, W.A., Drexhage, H.A., 2002a. Immune activation, steroid resistancy and bipolar disorder. Bipolar Disord. 4 (Suppl 1), 7374. Kupka, R.W., Nolen, W.A., Post, R.M., McElroy, S.L., Altshuler, L.L., Denicoff, K.D., 2002b. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol. Psychiatry 51, 305311. Leibenluft, E., Charney, D.S., Towbin, K.E., Bhangoo, R.K., Pine, D.S., 2003. Dening clinical phenotypes of juvenile mania. Am. J. Psychiatry 160 (3), 430437. Meyer, S.E., Carlson, G.A., Youngstrom, E., Ronsaville, D.S., Martinez, P.E., Gold, P.W., Hakak, R., Radke-Yarrow, M., 2009. Long-term outcomes of youth who manifested the CBCL-Pediatric Bipolar Disorder phenotype during childhood and/or adolescence. J. Affect. Disord. 113, 227235. Mick, E., Biederman, J., Pandina, G., Faraone, S.V., 2003. A preliminary metaanalysis of the child behavior checklist in pediatric bipolar disorder. Biol. Psychiatry 53, 10211027. Penny, R., Spencer, C.A., Frasier, S.D., Nicoloff, J.T., 1983. Thyroid stimulating hormone (TSH) and thyroglobulin (Tg) levels decrease with chronological age in children and adolescents. J. Clin. Endocrinol. Metab. 56, 177180. Post, R.M., Kramlinger, K.G., Joffe, R.T., Roy-Byrne, P.P., Rosoff, A., Frye, M.A., Huggins, T., 1997. Rapid cycling bipolar affective disorder: lack of relation to hypothyroidism. Psychiatry Res. 72 (1), 17. Schmeck, K., Poustka, F., Dopfner, M., Pluck, J., Berner, W., Lehmkuhl, G., Fegert, J.M., Lenz, K., Huss, M., Lehmkuhl, U., 2001. Discriminant validity of the child behaviour checklist CBCL-4/18 in German samples. Eur. Child Adolesc. Psychiatry 10, 240247. Verheecke, P., 1997. Free triiodothyronine concentration in serum of 1050 euthyroid children is inversely related to their age. Clin. Chem. 43, 963967. Volk, H.E., Todd, R.D., 2007. Does the child behavior checklist juvenile bipolar disorder phenotype identify bipolar disorder? Biol. Psychiatry 62 (2), 115120. Vonk, R., van der Schot, A.C., Kahn, R.S., Nolen, W.A., Drexhage, H.A., 2007. Is autoimmune thyroiditis part of the genetic vulnerability (or an endophenotype) for bipolar disorder? Biol. Psychiatry 62 (2), 135140. Zepf, F.D., Wckel, L., Poustka, F., Holtmann, M., 2008. Diminished 5-HT functioning in CBCL Pediatric Bipolar Disorder proled ADHD patients vs. normal ADHD: susceptibility to rapid tryptophan depletion inuences reaction time performance. Hum. Psychopharmacol. 23 (4), 291299. Zhu, D.F., Wang, Z.X., Zhang, D.R., Pan, Z.L., He, S., Hu, X.P., Chen, X.C., Zhou, J.N., 2006. fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. Brain 129, 29232930.

Col, N.F., Surks, M.I., Daniels, G.H., 2004. Subclinical thyroid disease: clinical applications. JAMA 291 (2), 239243. Cole, D.P., Thase, M.E., Mallinger, A.G., Soares, J.C., Luther, J.F., Kupfer, D.J., Frank, E., 2002. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am. J. Psychiatry 159, 116121. Cowdry, R.W., Wehr, T.A., Zis, A.P., Goodwin, F.K., 1983. Thyroid abnormalities associated with rapid-cycling bipolar illness. Arch. Gen. Psychiatry 40 (4), 414420. DGKJP (Deutsche Gesellschaft fr Kinder- und Jugendpsychiatrie und Psychotherapie) (ed.), 2007. [Guidelines for diagnostics and therapy of psychiatric disorders in infancy, childhood and adolescence. Chapter Hyperkinetic Disorders (F90)]. 3rd, revised edition. Koeln: Deutscher Aerzteverlag. Dpfner, M., Berner, W., Flechtner, H., Lehmkuhl, G., Steinhausen, H.C., 1999. Clinical Assessment Scale for Child and Adolescent Psychopathology, CASCAP-D. Hogrefe, Gttingen. Duval, F., Mokrani, M.C., Bailey, P., Correa, H., Diep, T.S., Crocq, M.A., Macher, J.P., 1999. Thyroid axis activity and serotonin function in major depressive episode. Psychoneuroendocrinology 24 (7), 695712. Faraone, S.V., Perlis, R.H., Doyle, A.E., Smoller, J.W., Goralnick, J.J., Holmgren, M.A., Sklar, P., 2005. Molecular genetics of attention-decit/hyperactivity disorder. Biol. Psychiatry 57, 13131323. Fisher, D.A., Nelson, J.C., Carlton, E., Wilcox, R.B., 2000. Maturation of human hypothalamic-pituitary-thyroid function and control. Thyroid 10, 229234. Frye, M.A., Denicoff, K.D., Bryan, A.L., Smith-Jackson, E.E., Ali, S.O., Luckenbaugh, D., Leverich, G.S., Post, R.M., 1999. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am. J. Psychiatr. 156, 19091914. Frye, M.A., Yatham, L., Ketter, T.A., Goldberg, J., Suppes, T., Calabrese, J.R., Bowden, C.L., Bourne, E., Bahn, R.S., Adams, B., 2009. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr. Scand. 120, 1013. Geller, B., Tillman, R., Bolhofner, K., Zimerman, B., 2008. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch. Gen. Psychiatry 65 (10), 11251133. Gracious, B.L., Findling, R.L., Seman, C., Youngstrom, E.A., Demeter, C.A., Calabrese, J.R., 2004. Elevated thyrotropin in bipolar youths prescribed both lithium and divalproex sodium. J. Am. Acad. Child Adolesc. Psych. 43 (2), 215220. Gulseren, S., Gulseren, L., Hekimsoy, Z., Cetinay, P., Ozen, C., Tokatlioglu, B., 2006. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch. Med. Res. 37 (1), 133139. Gyulai, L., Bauer, M., Bauer, M.S., Garca-Espaa, F., Cnaan, A., Whybrow, P.C., 2003. Thyroid hypofunction in patients with rapid-cycling bipolar disorder after lithium challenge. Biol. Psychiatry 53 (10), 899905. Hillegers, M.H., Reichart, C.G., Wals, M., Verhulst, F.C., Ormel, J., Nolen, W.A., Drexhage, H.A., 2007. Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents. Eur. Neuropsychopharmacol. 17 (67), 394399. Holtmann, M., Blte, S., Goth, K., Dpfner, M., Plck, J., Huss, M., Fegert, J.M., Lehmkuhl, G., Schmeck, K., Poustka, F., 2007. Prevalence of the CBCLpediatric bipolar disorder phenotype in a German general population sample. Bipolar Disord. 9, 895900.