H.-C. Steinhausen

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder : association signals in DRD4, DAT1 and 16 other genes

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Conduct Disorder and ADHD: Evaluation of Conduct Problems as a Categorical and Quantitative Trait in the International Multicentre ADHD Genetics Study

Attention‐deficit/hyperactivity disorder (ADHD) is typically characterized by inattention, excessive motor activity, impulsivity, and distractibility. Individuals with ADHD have significant impairment in family and peer relations, academic functioning, and show high co‐morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse, and pervasive developmental disorder (PDD). Family studies suggest that ADHD + CD represents a specific subtype of the ADHD disorder with familial risk factors only partly overlapping with those of ADHD alone. We performed a hypothesis‐free analysis of the GAIN–ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family‐Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 autosomal markers. This study is part of a series of exploratory analyses to identify candidate genes that may be important in ADHD and ADHD‐related traits, such as conduct problems. We did not find genome‐wide statistical significance (P < 5 × 10−7) for any of the tested markers and the three conduct problem traits. Fifty‐four markers reached strong GWA signals (P < 10−5). We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding of the etiology of ADHD + CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis‐free study design and were able to identify a number of biologically interesting markers and genes for follow‐up studies.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband–sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, ∼95 cM) and Dutch (LOD>1, ∼100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

Evaluation of treatment and intermediate and long-term outcome of adolescent eating disorders

BACKGROUND A cohort of 60 adolescent eating-disordered patients that was consecutively admitted between 1979 and 1988 to a child and adolescent psychiatric university department in Berlin, Germany was followed up at a mean of 5-0 years and for a second time at a mean of 11.5 years. METHODS Each patient was personally interviewed and findings dealing with eating disorder symptoms and psychosocial functioning were rated on four-point scales. In addition, the duration of both in-patient and out-patient treatment and the Body Mass Index (BMI) were recorded. RESULTS Patients were in treatment for a mean of 33 % of the initial 5-year follow-up period, but this has dropped to a mean of 17% of the entire 11-year follow-up period. No predictors of treatment duration were found. The mortality rate was 8.3% at the second follow-up. The distribution of abnormal BMIs ( < 17.5) reflected a trend of improvement with increasing duration of follow-up. In comparison to the 5-year follow-up, fewer patients suffered from symptoms of the full clinical picture of an eating disorder at the 11-year follow-up. Among the surviving patients 80% recovered during the long-term course. There were few specific predictors of three different outcome criteria. CONCLUSION This outcome study of adolescent eating disorders provides further evidence that the long-term course of the disorders in terms of the eating pathology is better than can be expected after a few years. Very little can be said with regard to individual prognosis.

ADHD and DAT1: further evidence of paternal over-transmission of risk alleles and haplotype

We [Hawi et al. (2005); Am J Hum Genet 77:958–965] reported paternal over‐transmission of risk alleles in some ADHD‐associated genes. This was particularly clear in the case of the DAT1 3′‐UTR VNTR. In the current investigation, we analyzed three new sample comprising of 1,248 ADHD nuclear families to examine the allelic over‐transmission of DAT1 in ADHD. The IMAGE sample, the largest of the three‐replication samples, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3′‐UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over‐transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller samples although neither is independently significant. Although the mechanism driving the paternal over‐transmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon.

The Zurich long-term outcome study of child and adolescent psychiatric disorders in males

BACKGROUND Within the framework of developmental psychopathology the outcome of male former child and adolescent psychiatric patients at age 36 or 38 was studied in order to add to the limited knowledge in this field. METHODS A total of 269 former child psychiatric patients of male sex and a control group of more than 2700 men, who were all born in 1952, were compared with regard to mortality, delinquency and adult psychiatric disorders. The study was based on case-file data from assessments conducted with the child and adolescent psychiatric patients and on adults, derived from either federal registers (mortality, delinquency) or army health records and records of the psychiatric facilities of the canton. The study is based on lifetime prevalence rates. RESULTS The two samples did not differ with regard to mortality rates. Delinquency tended to be more prevalent and psychiatric disorders were significantly more prevalent among the former child psychiatric patients. Close to 10% of the latter group showed major delinquency, one-quarter was psychiatrically disturbed and 30% displayed one of these two indicators or maladjustment at least once during the follow-up period. A correspondence in pattern of varying between child and adult psychiatric spectrum disorders was observed. Whereas the type of child and adolescent psychiatric disorders did not predict adult maladjustment, there was some indication that deprived environments, broken homes and parental psychiatric disorders during childhood increased the likelihood of poor adult outcome. CONCLUSIONS This study clearly underlines the long-term negative effects of child and adolescent mental abnormalities in males.

The validity and reliability of the diagnosis of hyperkinetic disorders in the Danish Psychiatric Central Research Registry

OBJECTIVE To validate the diagnosis of hyperkinetic disorders (HD) in the Danish Psychiatric Central Research Registry (DPCRR) for children and adolescents aged 4 to 15 given in the years 1995 to 2005. METHOD From a total of 4568 participants, a representative random subsample of n=387 patients were used to validate the diagnosis. Patient files were systematically scored for the presence of ICD-10 criteria for HD and oppositional defiant disorder/conduct disorder (ODD/CD; F91). Further to this, an inter-rater reliability study was also conducted, whereby two experienced child and adolescent psychiatrists who were blind to patients discharge diagnoses, rated a random subsample of n=101 participants. RESULTS Information was available for 372 out of 387 patients. Out of n=372 available files, n=324 (86.8%) were evaluated to fulfil diagnostic criteria for HD. Due to missing information it was not possible to reach a conclusion for 5.1% of the cases, 3.8% of the diagnoses were registration errors, and in 4.3% of the files the diagnosis had to be rejected. Inter-rater agreement was high (κ=0.83, z=10.9, P<.001). The validity of hyperkinetic disorders, unspecified (F90.9) was lower and comorbid CD/ODD were under-diagnosed in the sample. All participants fulfilling HD criteria also fulfilled DSM-5-criteria for ADHD. CONCLUSION The risk of misclassification of patients with HD in the DPCRR is relatively low, with the exception of the diagnosis of hyperkinetic disorders, unspecified (F90.9).

[Long-acting medications for the treatment of hyperkinetic disorders - a systematic review and European treatment guideline. Part 1: overview and recommendations].

Langwirksame Medikamente zur Behandlung der hyperkinetischen St?rungen. Teil 1: ?bersicht und EmpfehlungenA panel of experts from several European countries has accomplished a systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorders, on the basis of which practical recommendations for the application of these medications have been developed. The current article outlines results of this analysis, comparing the effect sizes and numbers-needed to-treat for extended-release stimulant preparations and atomoxetine (ATX). It is concluded (1) that long-acting preparations should be licensed and used. (2) However, they should not completely replace short-acting medications, in view of costs as well as the greater flexibility of dosing. Individual choices of therapy are necessary. (3) Both ATX and retarded-release stimulants should be available.Zusammenfassung: Ein Expertengremium aus mehreren europaischen Landern hat samtliche verfugbaren veroffentlichten und unveroffentlichten Studienergebnisse zum Einsatz von langwirksamen Medikamenten bei ADHS und hyperkinetischer Storung analysiert und auf dieser Grundlage Empfehlungen zur praktischen Anwendung dieser Arzneimittel entwickelt: Auf der Grundlage der Analyse wurde gefolgert: (1) Langwirksame Praparate sollten zugelassen sein und eingesetzt werden; (2) Sie sollen kurzwirksame Arzneimittel (aus Kostengrunden und wegen der hoheren Flexibilitat der Dosierung) nicht vollstandig ersetzen. Individuelle Therapieoptionen sind erforderlich. (3) Sowohl ATX als auch Stimulanzien mit retardierter Freisetzung sollten zur Verfugung stehen. Zusatzlich werden ausfuhrliche Empfehlungen gegeben, nach welchen Kriterien ein spezifisches Praparat fur den individuellen Patienten ausgewahlt werden sollte.A panel of experts from several European countries has accomplished a systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder. Based on this analysis detailed recommendations about the use of these drugs in practice have been developed: (1) Long-acting preparations should be licensed and used; (2) They should not completely replace short-acting drugs (which will be the initial treatment for many children in view of cost and the greater flexibility of dosing). Individual clinical choices are necessary. (3) Both ATX and extended-release stimulants should be available. In addition, detailed recommendations will be made with regard to the criteria to be applied in choosing a preparation for the individual patient.

[Long-acting medications for the treatment of hyperkinetic disorders - a systematic review and European treatment guidelines. Part 2: a quantitative evaluation of long-acting medications]

A panel of experts from several European countries has accomplished a systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorders, on the basis of which practical recommendations for the application of these medications have been developed. The current article outlines results of this analysis, comparing the effect sizes and numbers-needed to-treat for extended-release stimulant preparations and atomoxetine (ATX). It is concluded (1) that long-acting preparations should be licensed and used. (2) However, they should not completely replace short-acting medications, in view of costs as well as the greater flexibility of dosing. Individual choices of therapy are necessary. (3) Both ATX and retarded-release stimulants should be available.Langwirksame Medikamente zur Behandlung der hyperkinetischen Storungen. Teil 2: Ein quantitativer Vergleich der langwirksamen Praparate

PW01-59 - Effects of an internet based assessment of child and adolescent psychopathology (DAWBA) on clinical decision making

Objectives The main objective was to examine agreement between the internet based Development and Well-Being Assessment (DAWBA) generated diagnoses and clinical diagnoses. Second, we aimed to explore how disclosure of the DAWBA-diagnosis before clinical decision making influenced the clinicians diagnosis. Third, whether there were differences of influence for different categories of disorders. Last, we examined how the use of DAWBA information affected identification of co-morbidities. Methods 315 patients from outpatient clinics were randomised into two groups. In 177 cases the clinician was informed about DAWBA diagnosis, in 155 cases the clinican was blind to DAWBA information. DAWBA is an internet based package of questionnaires and rating techniques designed to generate psychiatric ICD10 or DSM IV diagnoses for 5- 17 year old children and adolescents. Information from parents, teachers and self-reports are brought together by a computer programme that predicts likely diagnoses. An expert rater decides on the diagnosis by synopsis of these different inputs. Results DAWBA diagnoses and clinical diagnosis without information from DAWBA showed acceptable agreement with Cohens kappa 0,26 for emotional disorders, kappa of 0,29 for hyperactive disorders and kappa of 0.31 for disruptive disorders. There was a significant effect on clinical diagnoses for emotional disorders for disclosure of DAWBA (kappa of 0.26 without DAWBA information versus kappa of 0,52 with information, Fishers z of p There was no significant effect of information about DAWBA-diagnosis considering comorbidities. Conclusions DAWBA showed the most pronounced effect on clinical diagnoses for emotional disorders in children and adolescents.