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Discovering the individual behind the diagnosis of conduct disorder Master thesis in Medicine 30 ECTS Hannah Tolge Supervisor: Nóra Kerekes, Ph. D CELAM (Centre for Ethic Law and Mental Heath) Institute of Neuroscience and Physiology Program of Medicine Gothenburg, Sweden 2012 Abstract Background. Understanding the etiology of conduct disorder (CD) and commonalities with coexisting psychiatric complications is of essential value since children with CD have an increased risk for developing most psychiatric problems in adolescent and adulthood. Aims. The present study aims a) to compare register information to parental reports on prevalence of CD; b) to describe the distribution of CD problems and study the overlap with other neuropsychiatric and birth complications, and c) to map all coexisting neuropsychiatric and birth complications of probands, according to zygosity and gender, and to compare these with co-twins. Method. A cohort was selected from the ongoing twin-study CATSS 9/12, born between 1st of July 1992 and 31st December 2000, where at least one of the twins were screened positive for autism spectrum disorder (ASD), CD and/ or eating disorders, resulting in 2036 children. This database was further merged with the National Patient Register and the Swedish Medical Birth Register. . Results. In this enriched population, 37 % of children had conduct problems and 9 % reached CD diagnosis but only 1 % had been recognized of the Health Registers with a diagnose. The prevalence of CD was close to twice as high in boys than in girls. While the prevalence of CD declined (both genders) with rising severity, the prevalence of coexisting disorders (e.g.: oppositional defiant disorder, attention deficit hyperactivity disorder and/or ASD) were shown to markedly increase. 2 Monozygotic co-twins (both genders) and dizygotic co-twin girls showed similar number of coexisting psychiatric problems as their twin proband, while dizygotic co-twin boys had about half as much coexisting problems. The prevalence of birth complications was not correlated to severity of CD. Conclusion. This study was able to confirm the over-representation of boys over girls confined to a CD diagnosis. We have seen that the prevalence of many other co-existing psychiatric problems increases with the severity of CD. Gender specific genetic influences are suggested behind the development of CD. Key words: conduct disorder, twin-study, neurodevelopmental disorders 3 Table of contents Introduction -Background -Swedish Child and Adolescent psychiatry -Defining (diagnosing) Conduct Disorder -The risk of developing antisocial personality disorder Aims/ specific objectives Material and methods Results -Register reports and parental reports -Distribution of CD problems and prevalence of concurring complications based on the severity of CD -Prevalence of neurodevelopmental-, psychiatric problems and birth complications according to zygosity Discussion - Clinical relevance - Conclusion Appendix I DSM-IV Conduct disorder Appendix II A-TAC Conduct disorder module Appendix III Interventions for treatment of CD References 4 Introduction Background Rarely appearing inappropriate behaviors of children (lying, refusing to comply and occasionally getting involved in fights) are part of the process of growing up when occurring in an isolated manner. This normative and often short-lived noncompliance is fueled by the desire to do something autonomously and with the child’s growing self-assertion. But with active non-compliance (oppositional behavior) a child resists its caregiver in a more significant, intransigent way (Matthys and Lochman 2010). In DSM-IV the “mildest” cluster of such inappropriate behaviors define the diagnose of oppositional defiant disorder (ODD), one of three diagnoses building up the childhood disruptive behavior triad of ODD, attention deficit hyperactivity disorder (ADHD) and conduct disorder (CD). Among the three, conduct disorder represents the most serious disruptive behavior, consistently and aggressively violating age-appropriate social expectations and norms. In DSM-IV the disorders ODD and CD alone constitutes the category known as “disruptive behavior disorders“ (DBD’s). CD problems, mainly in comorbid diagnose with ADHD, are known to be associated with an increased long-term risk for antisocial personality disorder (ASPD) and criminality, substance abuse and most adult types of mental disorder in general. Previous twin-studies have suggested a strong genetic factor effect explaining the inter-individual variance in aggressive antisociality, including CD (Nadder, Rutter et al. 2002; Dick, Viken et al. 2005; Dick, Meyers 5 et al. 2010; Dick, Aliev et al. 2011), proposing that there are common genetic factors behind CD and criminality. Supporting the suspected high risk of entering criminality if diagnosed with CD, a Scandinavian (Norwegian) study of adolescent psychiatric in-patients (diagnosed with DBD’s, substance abuse disorder (SUD), or a combination of both) showed a 70% risk of having been convicted of a crime at follow up 15-33 years after admission (Kjelsberg and Dahl 1998). In all, 63% of the males had a criminality record at follow up which was more than six times the prevalence for male criminality in the general Norwegian population at that time. Crimes against property, violence and drug offences were the most commonly committed offences. The study population also showed a significantly higher disability rate (38,9 %) than the general population (5,7 %). There was a significantly higher mortality rate at follow up compared to the general population. These findings are consistent with previous studies showing that children referred for antisocial behaviour have a worse outcome than those with other symptoms at referral (Robins 1996) and with the proposed gender difference giving greater risk for males with CD of developing ASPD than girls (Offord and Bennett 1994). Preliminary results from a recent Swedish population-based epidemiological study indicate that early age at onset of criminality (defining CD) is one of the strongest predictors of persistent violence (Falk et al, in preparation). In an ongoing study mapping psychiatric conditions of young adult prisoners (aged 1825), sentenced for violent crime in the Region West of the Swedish Prison and Probation Services, it is shown that about 70 % of these perpetrators had a CD diagnose in childhood, 39 % were admitted to youth institutions and 40 % had 6 previous child- and adolescence psychiatric (CAP) contact (unpublished results from DisCat 2.0 study). Swedish Child and Adolescent psychiatry Since 1956 Swedish Child and Adolescent psychiatry (CAP) in Sweden is an independent member organization of the Swedish Society of Medicine. The upper age limit for receiving CAP care is 18 years and the modern focus predominantly lies on out-patient care, a reduction of in-patient beds by nearly 90 % have been shown from 1967-2006, in particular after 1990. The CAP research tradition includes longitudinal studies from childhood contact with CAP into juvenile delinquency. In 2007 a Swedish research team (Engqvist and Rydelius 2007) showed that every third patient leaving treatment from a CAP unit in Jämtland County (1975-1990) had entered the Register of Persons Convicted of Offences at the National Council for Crime Prevention (NCCP) some time before the end of 2003. Several other Swedish prospective and retrospective longitudinal CAP research studies have pointed out that it is school problems, behavioural disturbances and dysfunctional family situations that count for the majority of reasons for families to seek CAP care, and that problems in adulthood with drug and alcohol abuse as well as registered criminality can be retro prospectively linked back to this same panorama of childhood problems in former CAP patients. 7 Defining (diagnosing) Conduct Disorder DSM-IV In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), (APA 2000), CD is described as ”a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated”. The pattern of incorrect behaviour falls into subcategories of aggression to people and animals, destruction of property, deceitfulness or theft and serious violation of rules. For a list of the complete diagnostic criteria, see Appendix I. The disturbance must be shown to cause clinically significant impairment in social, academic or occupational functioning. For individuals aged 18 years or older, criteria for Antisocial Personality Disorder must not be met. Conduct Disorder is further subdivided into a Childhood-onset Type with the observed onset of at least one criterion prior to age 10 years, and an Adolescent-onset Type where no criteria were met prior to age 10 years. The severity of Conduct Disorder specifies as mild, moderate and severe depending on the severity of unique criteria (i.e., considerable harm to others) and/or number of all criteria met. Most children meeting criteria for Childhoodonset Type CD do also meet criteria for ODD, which is why manifestation of CD is an exclusion criterion for the ODD diagnose according to the DSM-IV. For a review see Lahey 1992 (Lahey, Loeber et al. 1992). The”developmental taxonomic theory” proposes that neurodevelopmental factors play a critical role in the ethiology of the Childhood-onset Type of CD, but that the Adolescent-onset Type develops in response to interactions with 8 deviant peers and not as a result of neurobiological factors (Moffitt 1993) . This theory have recently been challenged in a number of ways showing the same impairments regardless of subtype of CD concerning affective decision making (Fairchild, van Goozen et al. 2009), fear conditioning (Fairchild, Van Goozen et al. 2008) and facial expression recognition (Fairchild, Van Goozen et al. 2009; Fairchild, Stobbe et al. 2010). There is today substantial evidence of volumetric differences of sub cortical structures in patients with both early and late onset of CD showing reduced bilateral grey matter volume in amygdala (independent of the CD-subtype) in male adolescents regardless of age at onset, found by structural neuroimaging (MRI). The grey matter volume was reduced in the left ventral insula and in the left dorsomedial prefrontal cortex and bilaterally in the caudate nucleus as well, findings in all supporting conduct disorder to stem from a dysfunction in neural circuits involved in emotional processing (Fairchild, Passamonti et al. 2011). ICD-10 The International Classification of Diseases (ICD) represents WHO’s standard diagnostic tool for epidemiology and health management. Conduct disorders are here grouped under code F91 with sub-grouping into socialized or nonsocialized, or “confined to the family context” variants. In ICD-10 (2010) CD is defined as an enduring pattern of behavior (six months or longer) of dissocial, aggressive or defiant conduct with major violations of age-appropriate social expectations. The diagnose is based on behaviors that include ”excessive levels of fighting or bullying, cruelty to other people or animals, severe destructiveness 9 to property, fire-setting, stealing, repeated lying, truancy from school and running away from home, unusually frequent and severe temper tantrums, and disobedience.” Any marked behavior is, according to ICD-10, alone sufficient for the diagnosis - but isolated acting-outs are not. ODD and CD were formerly quite generally accepted to be different age-related conditions of the same disorder with CD more often occurring in older childhood and in adolescents (Loeber, Burke et al. 2000). Interestingly enough, in ICD-10, ODD is categorized into the conduct disorders group - although CD is today generally quite accepted being a separate and more serious disorder than ODD. A-TAC Childhood psychiatric problems may be screened for by the Autism- Tics, ADHD and other Comorbidities inventory (A-TAC), a validated parental telephone interview instrument (Larson, Anckarsater et al. 2010). The A-TAC contains 5 gate questions addressing CD, each scored as 1 point for the child if it is “true”, 0.5 point if “true in some extent”, and 0 point if it is “not true”. Consequently the most severe cases will have 5 points in A-TAC’s CD module. Clinical validation of A-TAC’s psychometric properties regarding CD (Kerekes et al, in progress) gave a 0.95 “Area Under the Curve” for the CD module and had with the suggested cutoff ≥ 2 for a CD diagnosis, good sensitivity (0.67) and excellent specificity (0.96). For a closer look at the CD related items in A-TAC, please see Appendix II. 10 The risk of developing antisocial personality disorder The presence of CD in adolescence is a prerequisite for the diagnose of ASPD (DSM-IV), but to rely on CD alone in predicting future ASPD in adulthood have shown to yield a substantial amount of false positive predictions since not all CD patients develop ASPD (Storm-Mathisen and Vaglum 1994; Maughan and Taylor 2001; Lahey, Loeber et al. 2005). ODD in early childhood and CD in adolescence may predict the possibility of future development of ASPD, but neither ADHD nor substance abuse seems to have the same potential alone (Diamantopoulou, Verhulst et al. 2010). Other authors argue that it is the adolescents’ unique mixture of internalizing (for instance anxiety and depression) and externalizing problems (acting-outs of aggression and/ or delinquent behavior) and not the CD per se, that predicts serious antisocial development (Fombonne, Wostear et al. 2001; Sourander, Jensen et al. 2007). Yet retrospective studies show that a presence of early childhood CD in ASPD patients can be up to 75% (Gelhorn, Sakai et al. 2007). A previously mentioned recent Swedish study has shown that 63% of the violent convictions are received by the 1% of the population who are persistent (accounting for three convictions or more) violent offenders. Belonging to this group is foremost predicted by male sex, any personality disorder, first violent conviction before age 19 (defining CD) and by drug-related offences (Falk et al, in progress). In conclusion, the pronounced risk for adolescents with CD of becoming a persistently violent offender, developing ASPD and/or SUD (as well as other both psychiatric and somatic problems) and the suggested strong genetic influence on the phenotype (criminality), raise the need for studies both 11 revealing the true prevalence of CD in children and mapping the frequency of possible psychiatric comorbidities. The genetic component to the development of CD (and possible contribution to an overlap of other disorders) may be investigated using twin-sampling where monozygotes (MZ) share 100% of their genes and dizygotes (DZ) (further subdivided into dizygotes of the same sex (DZss) or different sex (DZds)) on average share 50% of their genes. Prevention of the initial onset of conduct problems is an important way of hindering development of ASPD, according to Tremblay (Farrington and Coid 2003), further motivating the need of early detection. For possible medical and non-medical interventions in treating CD, see discussion. 12 Aims/ specific objectives 1. To compare information retrieved from registers to parental reports regarding the prevalence of conduct disorder in an enriched population, consisting of twin-pairs with at least one twin affected with neuropsychiatric disorders. 2. To describe the prevalence of affected children (boys and girls separate) and the overlap with other complications based on the severity of CD. 3. To describe CD probands, according to zygosity and gender, and their cotwins by the prevalence of neurodevelopmental, psychiatric problems and birth complications. 13 Material and methods The ongoing longitudinal Child and Adolescent Twin Study in Sweden (CATSS) accumulates nation-wide data on somatic and mental health problems in twins during childhood and adolescence, currently including over 20 000 children. CATSS-9/12 allows for systematic assessment of neurodevelopmental problems at a baseline of nine or twelve years age, when the parents of twins are asked to participate in a telephone interview about their children’s somatic and mental health. Children are by this way indirectly screened for childhood psychiatric problems using the Autism- Tics, ADHD and other Comorbidities inventory (A-TAC), a validated screening instrument (Larson, Anckarsater et al. 2010). Briefly, CATSS-9/12 is a twin study that targets all twins born in Sweden since the 1st of July 1992. In connection with the children’s 9th (or during the first 3 years of the CATSS-9/12 with the children’s 12th) birthdays parents have since 2004 been interviewed by lay interviewers. In the telephone interview many inventories are used; among others the A-TAC inventory covering all major clinical diagnostic criteria (according to DSM-IV) in child and adolescent psychiatry. Parents response rate has (as far as 2010) been high (80 %) with a dominance of mothers as responders (87,5 %). Questions in the survey are formulated so that they concern each twin separately and to a life span perspective. For detailed description of the CATSS, see Anckarsäter (Anckarsater, Lundstrom et al. 2011). 14 From birth cohorts between 1st of July 1992 and 31st of December 2000, a number of 1060 twin pairs were selected where at least one of the twins had been screened positive by the A-TAC for Autism Spectrum Disorders (ASD), CD and/or eating disorders (ED) (this affected twin referred to as a proband). Co-twins to the probands were by this way included regardless of being screenpositive or not. For these 1060 twin pairs register data was collected from the National Health Registers i.e. the National Patient Register (NPR) and the Swedish Medical Birth Register (MFR) yielding information on in- and (since 2001) outpatient care from private and public caregivers about any possible CD diagnose according DSM-IV or ICD-10 criteria. The database was by this way also supplemented with reports on the infants’ prenatal, delivery and neonatal care (Rosén 2003; Socialstyrelsen 2012; Socialstyrelsen 2012). The screening for CD was completed with information from parents about any possible existing CD diagnosis or about placement into Institutional Youth care. Children with brain damage or known chromosomal aberrations were excluded from the present study (57 because of brain damage, 25 with chromosomal aberrations and 2 affected with both) resulting in a working database (the studypopulation) of 2036 children: 1192 boys and 844 girls. In the study population there were 424 monozygotic (MZ), 808 same-sex dizygotic (DZss), 50 different-sex dizygotic (DZds) and 754”unknown zygotic” children. The zygosity was determined either by DNA sampling (saliva) or with a validated questionnaire having 95 % accuracy. The study population was further reduced by five children (all boys), who had more than 5 % missing data in the A-TAC, from 2036 to 2031 children: 1187 boys and 844 girls. 15 The A-TAC inventory contains scales to assess both ODD and CD. It was developed exclusively for the CATSS with originally 11 items defining [ODD+CD] joined in a single module ”conduct”. The first validation study of A-TAC (Hansson, Svanstrom Rojvall et al. 2005) showed an overall inter-rater and test-retest reliability of 1.00 and 0.93 respectively, but the ODD/CD scales at this time could not be validated due to a restricted number of affected children (small study population). Since the same was true for the next validation study (Larson, Anckarsater et al. 2010), the existing scales were supplemented with additional items while some items were removed (as they decreased Chronbach’s alpha), and finally the module was split into two new modules ”Opposition” and ”Conduct”. Later on a gate structure was established, opening for further questions if partially or fully endorsing one or several of the ”gate-items”. The ability of the ”gate scales” to identify children with significant behavior problems has been tested in the CATSS pilot study and proved successful in identifying 24 out of 25 children with significant CD problems (96,0 %) and 42 out of 43 children with significant ODD related problems (97,7 %). The Cronbach’s alphas were 0.552 and 0.841 for the final CD and ODD modules respectively. Each module has a gate-, a DSM-, and a total score corresponding to gate items, DSM-IV criteria items and to the sum of all items in the module. The high correlation between the CD module’s ”gate” and ”total” A-TAC scores was recently replicated merging A-TAC data on institutionalized adolescents with controls from the second clinical validation study of the A-TAC (Larson, Anckarsater et al. 2010). Children with any DSM-IV ODD criterion met to at least some extent (score ≥ 0,5p) were to 88 % detected by the gate scores alone. 16 With one fully met criterion or two ”to some extent” (score ≥ 1p), 96 % was detected. For CD the corresponding figures were 86 % and 96 % respectively indicating that the gate scales have very good screening properties for both conditions. With the different scales assessed as predictors in Receiver Operating Characteristics (ROC) curves (using clinical diagnoses of CD as dependent variables) excellent predictive ability for this disruptive behavior disorder was shown. In the present study the revised version of A-TAC was used including 5 gate questions addressing CD. Further selection of children after gate score variables was in the present study done by using A-TAC cut-offs of ”CD low” (gate score ≥1, representing signs of conduct problems), and ”CD high” (gate score ≥2, corresponding to a CD diagnose). These cut-offs have high specificity (0.95 and 0.98) and high to moderate sensitivity (0.84 and 0.55 respectively) and are as such recommended for screening children for CD in epidemiological studies (Kerekes et al, 2012, unpublished validation of A-TAC: FV Module O+P). Psychometric properties of A-TAC CD module is summarized in Table 1. 17 Table 1. Psychometric features of the CD module in A-TAC Children screened positive for CD (low cut-off) in the A-TAC, and/ or having a register diagnose of F91 (behavior disorders of acting out), F90.1 (hyperactive behavior disorder) (ICD-9), 312.8 (conduct disorder), 312.9 (disruptive behavior disorder) (DSM-IV) and/ or having parent reports on being placed in Youth Institutional Care for treatment or placed in some ”other care”, were selected as probands for further descriptive analyses. Children screening positive for CD high (≥2 gate score points) formed the CD diagnosis group in prevalence analyses. All personal data were unidentified, blinded for the researchers and statistically analyzed using IBM SPSS-19. 18 Results Register reports and parental reports In the study population of 2031 children, 37% (N=753) were to any extent affected by conduct problems (CD_any) of which 750 children were identified by the A-TAC (CD low cut_off). Of these 753 children 477 were boys and 276 girls. Further on, 9 % (N=177; 119 boys and 58 girls) met criteria of CD diagnosis (≥2 in the A-TAC) and 17 children scored 4 points or more, constituting the 1% of the study population (and 2% of the children above low cut_off), that are most severely affected by CD. Comparing these figures to the register reports where only seven boys and four girls were registered with diagnosed CD, a 1 % recognition rate of CD problems by registers can be concluded. Distribution of CD problems and prevalence of concurring complications based on the severity of CD As already mentioned, 119 boys and 58 girls met the criteria of CD diagnosis in this study (Figure 1). No girl reached the maximal 5 CD gate points and only one girl received 4,5p. Regarding the opposite sex, four boys scored 5p, and three received 4,5p. The declining prevalence with rising severity of CD was evident (Figure 2). 19 Figure 1: Prevalence of children scoring 2-5p in the A-TAC CD module; N=177 Figure 2: Numbers of children with CD diagnosis by gender; (N=177; 119 boys and 58 girls) 20 The overlap of epilepsy (EP) and CD problems was analyzed and showed that of 59 boys and 33 girls in the study population affected by EP (N=92; 4,5 % of the total study population), 25 boys and 9 girls also had CD problems. The prevalence of EP was equal (about 4 %) in children without any CD problems, in children with few CD points and in children with CD diagnosis (Figure 3). Figure 3: Prevalence of epilepsy in children with defined CD gate points (N=92). The prevalence of child psychiatric problems and birth complications were evaluated in relation to the severity of CD. The prevalence of co-occurring disorders of ODD, ADHD and ASD were all shown to markedly rise in adherence to the severity of CD. ODD was present in 100 % of all children scoring 3p or above in the CD gate questions of A-TAC. The prevalence of Tics, on the other hand, only discretely rose and that of ED was shown to be constant with increasing severity of CD (Figure 4) 21 Figure 4. Mental Retardation (MR) was more frequent in girls affected with CD than it was in affected boys (Table 2). The amount of birth complications in the study group was constantly high (42 %) with a close to equal gender distribution (Figure 4)(Table 2). The gender wise prevalence of concurring complications to a proposed CD diagnose (scoring 2p or above in the CD gate questions in the A-TAC) is shown in Table 2. Table 2. Prevalence of coexisting problems in probands with a “CD diagnose” 22 Prevalence of neurodevelopmental-, psychiatric problems and birth complications, according to zygosity The prevalence of coexisting complications to CD, i.e. the neurodevelopmental problems of ODD, ADHD, ASD, Tics disorder and ED, as well as the existence of mental retardation (MR) and/ or birth complications were investigated taking into account not only the severity of conduct problems, but also zygosity and gender. All probands with an A-TAC CD gate score of 3 points or more (N=59; 39 boys and 20 girls) and their co-twins were included in this part of the study. The resulting “color maps” of probands are summarized in Table 3 and for cotwins in Table 4. The sum of co-existing complications is shown in a separate column, named the “composite” variable. For convenience (and comparability between probands and co-twins), CD problems (CD_any) count as one complication in the composite scores. Table 3. MZ, DZss and DZds probands, their coexisting complications and their composite measure. 23 24 The mean value of the number of complications in each zygosity-class was calculated (the mean composite). MZ probands (N=12) on average showed five complications, including CD, while DZ probands (N=47; DZss and DZds calculated together) on average had four. Since zygosity being a proband is of little interest, though, we then calculated the mean complication rate for all probands to be four. No gender differences were shown in the mean amount of complications. The mean value of complications for the MZ co-twins was 4,5 while DZ cotwins (DZss and DZds together) on average had 2 complications, including CD if present. Table 4. MZ, DZss and DZds co-twins, their coexisting complications and their composite measure. 25 26 Finally, the presence of CD problems within twin-pairs was visualized by accounting for zygosity and gender, resulting in two genograms (Figure 5). The average point difference between MZ boys and girls were the similar just between 1 and 1.5 point differences (1.4 for boys and 1.25 for girls). For DZ however, differences increased between twins, but most obviously for boys (2.7 for boys and 1.9 for girls). Figure 5. 27 28 Discussion Main findings Twin studies make it possible to evaluate genetic and environmental components of a behavioral trait by comparing the correlations between monozygotic twin-pairs and dizygotic in terms of hereditability, shared environmental influence and non-shared environmental influences (influences that are experienced differently between members of the family). CD was two times as prevalent in boys as in girls. Male gender is a risk factor for neuropsychiatric problems (ADHD, ASD) and for aggressive behaviors (ODD, CD, ASPD) (Gillberg 2010). The paradoxical gender effect or “The Gender Paradox Hypothesis” saying that boys are more likely to be referred for treatment than girls while girls seem to be more seriously affected while referred (Eme 1992; Loeber and Keenan 1994), could though not be confirmed by our study since the girls on average scored below boys in the A-TAC module. The skewed gender prevalence of CD, more frequent in boys than in girls at this age, was though confirmed in this study as previously shown (Bongers, Koot et al. 2004). Only 6 % of the children scoring positive for a CD diagnose in our study were also found in the official registers as already being diagnosed by a psychiatrist. This low detection level could be due to the fact that children whose parents seek referral for their child may originate from better socioeconomic environments than others, making the number of unrecorded cases high, or the fact that there have been a big discrepancy in grouping definitions seen by the use of DSM-III to DSM-IV, ICD, and other different behavior rating scales. It 29 also seems reasonable to suppose that the significant overlap of childhood psychiatric disorders (also shown in this study) makes the diagnostic situation scattered and sometimes obscure. Prevalence of EP was about the same in children without any CD problems, as in children with few or very severe CD problems. Our results thereby support previous findings of no direct association between EP and aggressive behavior in children (Grunberg and Pond 1957; Caplan, Arbelle et al. 1997; Schoenfeld, Seidenberg et al. 1999; Dunn 2003). The prevalence of ED and Tics did not change with severity of CD. Very high coexistence of ODD and ADHD followed by ASD were shown. The MZ co-twins to a pronounced CD affected proband (screened >= 3p in the A-TAC) showed a mean of four comorbidities, including existing diagnostic CD as one if present. Comparing this to DZ co-twins with a mean value of two comorbidities, this suggests a pronounced shared genetic vulnerability of neuropsychiatric disorders in general. Prevalence of MR in girls affected by CD was higher than in affected boys. The rate of birth complications were high (though expected when taken into account that the study population consisted of twins) but did not seem to correlate with CD or it’s severity, being constant in the whole study population, independent from existing or not existing CD problems. 30 Clinical implications The fact that proband children in our study on average had 4-5 coexisting disorders, including CD, both disorder-specific and possible additive effects have to be considered in selecting appropriate multimodal interventions. Having a child with CD causes distress to the family aggravating family problems that in turn may worsen the CD. Several psychological techniques have been tried, including behavior modification, working with parenting techniques and tight supervision, according to Chandler (Chandler 2012), the best results being shown with ”multisystem therapy”, i.e., working on several interventions at the same time using pharmacological treatment of co morbid disorders as well as non-medical strategies (For possible interventions, see Appendix III). The longer the psychiatric problems go on in childhood and adolescence the greater the risk of developing personality disorders as adults, especially Borderline Personality Disorder and Antisocial Personality Disorder both belonging to cluster B (Kasen, Cohen et al. 1999). Limitations Register data is probably partial/ not complete. It is possible that parents only seek contact with CAP when behavior problems grow extreme. Parents may feel ashamed to seek help with aggressive children, or lack the ability or insight to do so due to their own psychiatric problems and/ or problems with drugs or criminality. 31 The analyses in this study were not controlled for socioeconomic status of the families, which has been shown to be strongly associated to aggressive behavior in children, e.i. CD (D'Onofrio, Goodnight et al. 2009), ODD and ADHD (Diamantopoulou, Verhulst et al. 2010). The study population was enriched to defined psychiatric problems (CD, ASD and ED) and the study therefore could not be used to determine the prevalence of CD and other psychiatric problems in a normal population, but the association between these yet to be studied. The parental (mainly maternal) reporting may be skewed in favour of the less affected co-twin (Simonoff, Pickles et al. 1998) or the twin-pair may show competitive effects where symptoms of one twin reduce the same in the other (Eaves, Silberg et al. 1997). For this reason it would be desirable to use reports from teachers as well. Twins do not differ significantly in prevalence of psychiatric disorders, compared to singletons (Kendler, Martin et al. 1995; Pulkkinen, Vaalamo et al. 2003), but there is some evidence for small elevations in childhood and adolescent problem behaviour prevalence in twin-pairs (Gau, Silberg et al. 1992; Levy, Hay et al. 1996). The children are evaluated at age 9 or 12 years in this study. Conduct disorder in its Adolescent form (according to DSM-IV) develops after 10 years of age, and is thereby in risk of missing out in this study whereas ODD (being a disorder of primarily early childhood) aught to be more accurately represented. The developmental continuity model of ODD/ADHD developing into CD and later ASPD (Loeber, Burke et al. 2000) was recently replicated in a large community-based sample (the Zuid-Holland-longitudinal study of Verhulst, 1985) where development of CD could be predicted by ODD or [ODD+ADHD] 32 in early childhood (Diamantopoulou, Verhulst et al. 2010). Bearing this in mind, it is possible that the children in our study not yet fully meeting the screening criteria for a CD diagnose - but for ODD - are about of developing CD, especially if charged by further comorbid disorders (ADHD, ASD, MR). Other studies have though shown that only 50 % of children with ODD as preschoolers will have any remaining psychiatiric disorder by age 8 (Lavigne, Cicchetti et al. 2001). It would be interesting to further assess and compare data from probands scoring 2 and 2,5 gate points in the A-TAC CD module, thereby encompassing all screen-positive children of a CD diagnose to the study. Further work will be done on that. Finally, when using cut-offs in epidemiological studies one must not forget the risk of categorizing individuals based on dichotomous variables alone, since behavioural studies have shown similar etiological factors behind extreme scores and the full distribution. Strength of the study This study has the advantage of presenting the results of seven psychiatric disorders, as well as the presence of birth complications, assessed in a single sample. The comparisons made are therefore not confounded with sample design or analytic differences. The most important finding of this study was that children with diagnostic CD had many other coexisting psychiatry problems as well (on average three). In addition, increasing severity of CD was linked to an increasing number of coexisting psychiatric problems. 33 All children with pronounced CD (scoring 3 p or more in the A-TAC) also screened positive for ODD. High overlap between ODD and CD is expected due to the fact that CD exists in both a Childhood onset Type and an Adolescent onset type and revisions might be done in the forthcoming DSM-V. In this study, 62 % of MZ co-twins to a proband with CD (50 % of MZ boys, 75 % of MZ girls) have CD while the prevalence of CD in DZ co-twins was 27 % (19 % of DZ boys, 44 % of DZ girls). The prevalence of CD in co-twins being doubled in MZ compared to DZ co-twins, suggests that the development of CD is coupled with strong genetic background factors. Previous twin studies have already pointed out the importance of genetic factors but emphasize the effects of common environmental effects as well (Eaves, Silberg et al. 1997; Dick, Viken et al. 2005; Ehringer, Rhee et al. 2006; Frisell, Pawitan et al. 2012). One twin-study conducted with other siblings included, showed a risk of 38 % for a brother to a proband of being diagnosed with CD, compared to 26 % for a random male (Ehringer, Rhee et al. 2006). This and our study together show not only the heritability of the conduct trait but also that the majority of the variation still is a combination of both genetics and environment. Ethical considerations The CATSS-9/12 study has ethical approval from the Karolinska Institute Ethical Review Board: Dnr 03-672 and 2010/507-31/1. 34 Acknowledgements I would like to express my gratitude to my supervisor Nóra Kerekes for her dedication and valuable input and to the staff in CELAM, especially to prof. Henrik Anckarsäter and Thomas Nilsson, for their assistance and great ideas that improved the project. And I would also want to thank all cats(s), dogs and horses in my life along with my wonderful children not at least Samuel, born during the project, for their constant well of inspiration. 35 Appendix I: DSM-IV criteria for conduct disorder In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), published by the American Psychiatric Asssociation, CD is described as ”a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated” with at least three of the following criteria present over the last 12 months and at least one present the last six months: Aggression to people and animals 1. often bullies, threatens, or intimidates others 2. often initiates physical fights 3. has used a weapon that can cause serious physical harm to others (e.g., a bat, brick, broken bottle, knife, gun) 4. has been physically cruel to people 5. has been physically cruel to animals 6. has stolen while confronting a victim (e.g., mugging, purse snatching, extortion, armed robbery) 7. has forced someone into sexual activity Destruction of property 8. has deliberately engaged in fire setting with the intention of causing serious damage 9. has deliberately destroyed others’ property (other than by fire setting) 36 Deceitfulness or theft 10. has broken into someone else’s house, building, or car 11. often lies to obtain goods or favours or to avoid obligations (i.e., ”cons” others) 12. has stolen items of nontrivial value without confronting a victim (e.g., shoplifting, but without breaking and entering; forgery) Serious violations of rules 13. often stays out at night despite parental prohibitions, beginning before age 13 years 14. has run away from home overnight at least twice while living in parental or parental surrogate home (or once without returning for a lengthy period) 15. often truant from school, beginning before age 13 years The disturbance must be shown to cause clinically significant impairment in social, academic or occupational functioning. For individuals aged 18 years or older, criteria for Antisocial Personality Disorder must not be met. Conduct Disorder is further subdivided into a Childhood-onset Type with the observed onset of at least one criterion prior to age 10 years, and an Adolescent-onset Type where no criteria were met prior to age 10 years. 37 Appendix II: A-TAC: Items regarding symptoms of conduct disorder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ppendix III: Interventions for treatment of CD Medical interventions Medical intervention should be considered if treatable comorbidities are present (ADHD, depression, psychosis, tic disorders or seizures), if non-medical interventions have proved unsuccessful and when the CD symptoms are very severe (Chandler 2012). Studies have shown that treating ADHD/CD with stimulants reduces the symptoms of both conditions (Klein, Abikoff et al. 1997). The drugs of choice should be proven safe in children and given in an initially low dose, slowly increasing while closely monitoring for possible side effects. Usually atypical antipsychotics are tried first (risperidone, olanzapine, quetiapine), with possible side effects of weight gain, drug induced Parkinsons, elevated serum cholesterol, diabetes or tardive dyskinesia. Risperidon has been demonstrated to be superior to placebo in ameliorating aggression in children with CD (Findling, McNamara et al. 2000), and in children with subaverage IQ and severe forms of aggression (Buitelaar, van der Gaag et al. 2001). In clinical practice atypical antipsychotics are often combined with psychostimulants (Findling, Newcorn et al. 2007). The second drugs of choice are older mood stabilizers (valproic acid, Lithium) initially used for bipolar illness but also tried in people violent from brain damage, personality disorders or ODD/CD (Chandler 2012). Of the two Lithium has been tested the most, its side effects are possible weight gain, acne, nausea and kidney damage. It has known antiaggressive properties shown in adolescents and children with CD (Campbell, Small et al. 1984; Malone, Delaney et al. 2000). Valproic acid is an anticonvulsant drug found to have great effect on treating rapid cycling bipolar 39 illness in adults. It has been tested to some extent for the same indication in children and could be of interest when the CD child has a strong family history of bipolar illnesss (Chandler 2012), since it has also shown to be an efficacious treatment for mood lability and explosive temper in children with DBD’s (Donovan, Stewart et al. 2000). The third line of drugs includes Clonidine (originally a cardiovascular drug, an adrenergic agonist), according to Chandler (Chandler 2012) used to treat Tics, severe ADHD and sometimes autism with hyperactivity). Clonidine and psychostimulants in combination have shown to reduce conduct symptoms but not hyperactivity symptoms in children with ADHD/CD (Hazell and Stuart 2003). Occasionally (when all other fails) new mood stabilizers (lamotrigine, gabapentin, toprimate) might be of interest - of which there unfortunately are no good studies showing that they actually work (Chandler 2012). Non-medical interventions The caregivers will need some help in fostering the child with CD. If social security networks fail (grandparents, friends, cousins e.t.c), respite foster care or hospitalization might be necessary and useful. The child must not learn that violence or intimidation works, which is the case with parents or teachers that are afraid. It has been discussed that children with CD frequently have learning disorders, may have grown up in abusive homes and most of them lack social skills to get along with peers (Chandler 2012). Addressing these problems with individually designed psycho-educative treatment and counseling may help the child to in time ”outgrow” the CD. 40 The CD child needs structure, supervision and involvement all around the clock. Candler suggests fulltime parenting (no job) or foster care, residental care or hospitalization and argues that the most impressive changes are shown under such circumstances (Chandler 2012). The combined use of behavioral parent training and child training programs enhancing cognitive problem-solving skills have shown more effective than programs providing intervention only to the child with disruptive behavior (Kazdin, Esveldt-Dawson et al. 1987; Kazdin, Siegel et al. 1992). In the US “The Incredible Years Training Series”, originally developed as a parent training program for the treatment of DBD’s in childhood (WebsterStratton 2001; Webster-Stratton and Taylor 2001; Webster-Stratton 2002; Kazdin and Weisz 2003), today also includes the “Dinosaur School” and a teacher component for strengthening home-school connections, improving the teachers’ management and discipline skills and reinforcement of socialemotional skills in the classroom. The Incredible Years intervention have shown to produce significant reductions in conduct problems shown at home and in school and increases in social problem-solving skills, compared to waiting-list controls (Webster-Stratton, Reid et al. 2001). Multicomponent programs are many such as “Dinosaur School” training program for children and teachers (Webster-Stratton and Hammond 1997; Webster-Stratton, Reid et al. 2004), Fast Track (Conduct Problems Prevention Research Group, 1992), Family Check-Up (Shaw, Dishion et al. 2006), PSSTPMT (Kazdin, Siegel et al. 1992), Coping Power program (Lochman and Wells 2002), and LIFT (Snyder, Reid et al. 2002). In early adolescence multisystemic therapy (MST) can be used, implemented with chronic and violent juvenile 41 offenders, being an individualized intervention focusing on the interaction between the adolescent and the multiple environmental systems influencing the antisocial behavior, such as peers, family, community and school (Henggeler, Melton et al. 1992). CBT therapy have recently shown to be effective for adults with ADHD (Weiss, Murray et al. 2012), with or without stimulant therapy, but similar psychological treatments of ADHD in childhood have only added a small margin of benefits over medication alone (MTA 1999). The reason for that might be the adults’ greater insight into their individual problems with ADHD and as such being more receptive learning new coping strategies. 42 Populärvetenskaplig sammanfattning (svenska) Uppförandestörning (Conduct Disorder; CD) är en beteendestörning hos barn och ungdomar som kännetecknas av betydande brott mot sociala normer och regler; aggressivt beteende mot människor och djur, skadegörelse samt stöld och/ eller trotsande av föräldrars/ lärares regler (skolk och rymning från hemmet). Barn med CD har ökad risk för att utveckla missbruk, kriminellt beteende och att drabbas av olika vuxenpsykiatriska problem, oftast antisocial personlighetsstörning (ASPD). I tidigare studier har man sett att så mycket som 75 % av alla vuxna som har ASPD, även hade uppförandestörning i tonåren. Nyligen har en annan studie visat att 1 % av den svenska befolkningen står för 63 % av alla domar som gäller våldsbrott, och att CD i barndomen är en stark riskfaktor för att tillhöra den gruppen. Därför är det viktigt att samla in så mycket information som man kan om barn med CD och deras familjer. I den här studien samlades information in om 9/12 åriga barns (tvillingars) psykiska hälsa, från Nationella Hälsoregistret, från föräldrarna, samt med hjälp av ett strukturerat och validerat screening instrument. Sammanställd data analyserades och förekomsten av psykiatriska problem (så som trotssyndrom, uppmärksamhetsstörning/ hyperaktivitet (ADHD), Autism, Tics, svåra inlärningssvårigheter och ätstörningar) hos barn med CD bestämdes, samt även frekvenserna av dessa och av CD hos tvilling-syskonen till dessa barn. Resultaten visar att endast 1 % av barn i 9/12- års ålder med CD problem har fångats upp av sjukvården. CD drabbar dubbelt så många pojkar som flickor. 43 Det var vanligare att båda syskonen i ett enäggstvillingpar var drabbade av CD, än vad det var i de syskonpar som var tvåäggstvillingar. Dessutom har enäggstvillingar i genomsnitt lika många psykiatriska problem var, vilket inte sågs vad det gäller tvåäggstvillingar. Sammanfattningsvis: CD är kopplat med många andra psykiatriska problem hos barn och deras syskon. En stark genetisk faktor antas ligga bakom utvecklingen av CD. Den kliniska relevansen av studien ligger i att den visar betydelsen av noggrann psykiatrisk utredning av barn med beteendeproblem. 44 References Anckarsater, H., S. Lundstrom, et al. (2011). "The Child and Adolescent Twin Study in Sweden (CATSS)." Twin Res Hum Genet 14(6): 495-‐508. Bongers, I. L., H. M. Koot, et al. (2004). "Developmental trajectories of externalizing behaviors in childhood and adolescence." 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