Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Bipolar disorder risk alleles in children with ADHD.

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

Evaluation of the LIM homeobox genes LHX6 and LHX8 as candidates for Tourette syndrome.

The etiology and pathophysiology of Tourette Syndrome (TS) remain poorly understood. Multiple lines of evidence suggest that a complex genetic background and the cortico-striato-thalamo-cortical circuit are involved. The role of Lhx6 and Lhx8 in the development of the striatal interneurons, prompted us to investigate them as novel candidate genes for TS. We performed a comparative study of the expression of Lhx6 and Lhx8 and investigated genetic association with TS using two samples of trios (TSGeneSEE and German sample - 222 families). We show that Lhx6 and Lhx8 expression in the forebrain is evolutionarily conserved, underlining their possible importance in TS-related pathophysiological pathways. Our tagging-single nucleotide polymorphism (tSNP)-based association analysis was negative for association with LHX8. However, we found positive association with LHX6 in the TSGeneSEE sample (corrected P-value = 0.006 for three-site haplotype around SNP rs3808901) but no association in the sample of German families. Interestingly, the SNP allele that was identified to be significantly associated in the TSGeneSEE dataset, showed an opposite trend of transmission in the German dataset. Our analysis of the correlation of the LHX6 region with individual ancestry within Europe, revealed the fact that this particular SNP demonstrates a high degree of population differentiation and is correlated with the North to South axis of European genetic variation. Our results indicate that further study of the LHX6 gene in relation to the TS phenotype is warranted and suggest the intriguing hypothesis that different genetic factors may contribute to the etiology of TS in different populations, even within Europe.

[Early onset psychosis: rationale and concept of a cognitive-behavioral intervention]. / Jugendliche mit psychotischen Störungen: Rationale und Konzept einer kognitiv-verhaltenstherapeutischen Intervention.

Early onset psychoses (EOP, age of onset between age 14 and 18 years) are known to be associated with a poorer outcome than adult onset psychoses, both in terms of psychotic symptoms and social remission. For adult patients with psychosis, numerous cognitive-behavioral interventions have proven their effectiveness in recent years. This contrasts with a dearth of findings for EOP, even though it can be considered as a variant of adult onset psychosis. Thus, we have developed a cognitive-behavioral therapy intervention that was specifically adapted to the characteristics and needs of young people suffering from psychosis. The concept of the intervention is outlined in the present article. Acceptability and feasibility of the intervention are currently undergoing evaluation in a randomised, controlled pilot study.

[Depressive disorders in children and adolescents]. / Depressive Störungen im Kindes- und Jugendalter.

Depressive disorders in children and adolescents are widespread, cause a strong impairment in everyday life and are of great risk for further development. This paper gives an overview on the symptomatology, epidemiology, comorbid disorders and the further course of the disorder. Etiologic factors are presented and empiric studies concerning the treatment of depressive disorders in children and adolescents are summarized. Based on the empirical evidence and clinical experience suggestions for the treatment are provided.

No increase in long-term risk for nicotine use disorders after treatment with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD): evidence from a non-randomised retrospective study.

OBJECTIVE: To evaluate long-term effects of methylphenidate (MPH) treatment in ADHD children on the development of nicotine use disorders (SUD-N). METHODS: Multisite retrospective non-randomised longitudinal study with 215 ADHD children (diagnosis at 9.2 years of age; reassessment for SUD-N at 21.9 years of age) strictly parallel allocated to MPH treated (n = 106) and drug naive (n = 109) children. RESULTS: There was no difference between the groups with respect to frequency (84% MPH; 89% non-MPH; chi(2) = 1.6; p = 0.21) and age of onset for first cigarette smoking (log rank 1.68; p = 0.19). Continuous smoking was reached by 51% (MPH) and 61% (non-MPH) of the patients. Survival analyses revealed a small and nominally significant delay in age of onset for continuous smoking in the MPH-group (log rank = 3.85; p = 0.049). Nicotine dependency was reached by 20% (MPH) and 27% (non-MPH). Age of onset does not differ between groups (log rank = 2.24; p = 0.13). DISCUSSION: Limited evidence due to the non-randomised nature of the study is given that MPH does not induce SUD-N. The data suggests there may be a beneficial effect of MPH on delay of onset for continuous nicotine consumption in ADHD patients.

Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder.

INTRODUCTION: Aggression is frequently observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to assess the efficacy with regard to oppositional and aggressive behavior of a new long-acting methylphenidate preparation (Medikinet retard, MPH-MR), with equal portions of the immediate-release and the sustained-release active substance, and especially to look at correlations between either teacher or parent assessment of aggression and ADHD sub-symptomatology. METHODS: Eighty five children and adolescents (6-16 years) were investigated in a double-blind, randomized, clinical trial over 5 weeks under a treatment with MPH-MR using symptom checklists for ADHD, oppositional-defiant and conduct disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). RESULTS: A total of 64.9% of the children showed oppositional defiant disorder/conduct disorder (ODD/CD) symptoms. A statistically significant effect was found in the group treated with MPH (verum-group). On the basis of Cohen's criteria, high effects were found for aggressive symptoms in school (d = 1.0), but not in the afternoon (d = 0.4). There were also lower effect sizes for more severe aggressive symptoms. We found characteristic correlations between ODD/CD symptoms and the ADHD subscale hyperactivity/impulsivity compared to the subscale inattention. CONCLUSIONS: Long-acting MPH is effective in the treatment of oppositional-defiant and aggressive behavior, especially concerning milder symptoms. The expected correlation between impulsivity and aggressiveness could be confirmed.

[Attention deficit hyperactivity disorders in children and adolescents: diagnostic and therapeutic guidelines]. / Hyperkinetische Störung/ADHS erkennen und behandeln. Hilfe für den Zappelphilipp.

The treatment of attention deficit hyperactivity disorders (ADHD) requires extensive diagnosis. Check lists and questionnaires may be helpful. Comorbidities are common and must be clarified. ADHD should be treated over a longer period of time. A multimodal treatment concept is recommended in which the administration of psychostimulants is combined with educational and behavioural therapeutic measures.

What do we know about the serotonergic genetic heterogeneity in attention-deficit/hyperactivity and autistic disorders?

BACKGROUND: Shared candidate gene regions point to a link between autistic disorders and attention-deficit/hyperactivity disorder (ADHD). Although they represent nosologically different diagnoses, the disorders do show some shared symptoms, above all inattention. For both disorders, the association with the serotonergic system is a focus of current research. SAMPLING AND METHODS: The current work provides an overview of serotonergic mechanisms in ADHD and autistic disorders as well as the resulting pharmacogenetic approaches. RESULTS: No uniform picture emerges either for ADHD or for autistic disorders. In pharmacogenetic terms, there are some isolated studies on associations between serotonergic mechanisms and pharmacotherapy. For the area of autism, such studies are still lacking. CONCLUSIONS: The presented serotonergic mechanisms show relationships of this polymorphism to ADHD and autistic disorders, but they do not result in a uniform picture. The overlaps can best be explained by a dimensional classification approach. As yet, only a small number of studies on attentional disorders in autism and ADHD using shared samples have been carried out. With regard to diagnostics and therapy, analyses on the etiology of the attentional disorder of ADHD and autism are required.

[Autism and ADHD - are there common traits?]. / Autismus und ADHS - Gibt es Gemeinsamkeiten?

INTRODUCTION: Genetic, neuropsychological and psychopathological findings refer to a connection of autism and attention deficit/hyperactivity disorder (ADHD). Although the disorders represent different nosological diagnoses they partly include similar symptoms like hyperactivity, impulsivity and attention deficit disorder. METHODS: This paper gives an overview of genetic, morphological, neurophysiological and -psychological studies concerning ADHD and autism. In addition, results concerning pharmacotherapy and the development of both disorders in adulthood are described. RESULTS: With regard to genetics, common candidate regions are discussed. Under a morphological perspective, results on the one hand point out identical brain regions or functional systems but on the other hand underline that these regions are not equally affected. The morphological results could not be replicated on a neuropsychological basis. So far findings of studies which involved combined ADHD- and autistic samples lead to controversal results. CONCLUSION: At present, there exist only few studies which include the issue of attention disorders in autism and ADHD in a same sample. With regard to diagnosis and therapeutical interventions, further research concerning the etiology of both disorders is necessary.

[Assessing psychopathic personality disorders for legal procedures for using a version for adolescents of Hare's revised checklist]. / Erfassung von Persönlichkeitsdimensionen der Psychopathy nach Hare bei der strafrechtlichen Begutachtung von Jugendlichen. Eine retrospektive Untersuchung zur Anwendbarkeit der Psychopathy-Checkliste als Version für Jugendliche.

In accordance with Robert Hare's concept, the term psychopathy was operationalized in 1985 when the revised form of the psychopathy checklist (PCL-R) was published. Since then, the PCL-R has been used internationally. For several years in North America and now even in England and the Netherlands, personality traits of psychopathy have also been studied in children and juveniles. Based on the PCL-R, a checklist for adolescents (PCL-YV) was developed that takes the special conditions of adolescents into account. The goal of this paper was to test the applicability of the PCL-YV retrospectively in a sample of forensic psychiatric evaluations of delinquent juveniles that were assigned to the Clinic for Child and Adolescent Psychiatry at the University of Cologne, Germany. Based on results collected with the PCL-YV, data on groups of low- and medium-scoring juveniles were classified which partially differed significantly in relation to sociodemographic and anamnestic data. Furthermore, factor analyses showed a three-factor model solution. Associations with legal issues such as the question of criminal responsibility could not be found. In summary, the results indicate the applicability of the PCL-YV for adolescents but show the difficulties of retrospective design without conducting PCL interviews.

The principle of regulation in biology--from bone to eating behavior.

Cell physiology and molecular biology typically follow a reductionistic approach in science. In the last decade, molecular principles and pathogenetic factors involved in the development of many diseases have been successfully discovered. Therefore, early biological concepts based on systemic and cybernetic thoughts have been largely overshadowed by these more recent molecular and pathogenetic factors. This review highlights discoveries on bone development and hypothalamic controlled feeding and eating behavior with a cybernetic and systemic perspective. Interestingly, ancient ideas on bone development and hypothalamic function are still reasonable considerations to embed new molecular discoveries into a systemic concept of principles organizing nature.

[The effectiveness of atomoxetine in children, adolescents, and adults with ADHD. A systematic overview]. / Wirksamkeit von Atomoxetin bei Kindern, Jugendlichen und Erwachsenen mit ADHS. Eine systematische Ubersicht.

This paper gives an overview of the pharmacology, efficacy, duration, tolerance, and side effects of atomoxetine for children, adolescents, and adults. A systematic analysis of the published clinical studies and poster abstracts was conducted. Atomoxetine is the first selective inhibitor of the noradrenaline transporter that was approved by the FDA in the US as a nonstimulant for the treatment of ADHD in children, adolescents, and adults. In clinical studies, its efficacy was studied in 4,000 patients. Compared with placebo, atomoxetine proved to be superior with respect to reducing impulsiveness, hyperactivity, and inattention. There are indications that its efficacy is comparable to that of methylphenidate. In general, atomoxetine was well tolerated. The most frequently reported adverse events were decrease of appetite, abdominal problems, tiredness, and vertigo. These were classified as mild and found mostly at the beginning of treatment. The existing results indicate that atomoxetine is promising for the treatment of ADHD in children, adolescents, and adults.

[The psychopathy-concept and its psychometric evaluation in childhood, adolescence and adulthood]. / Das Psychopathy-Konzept und seine psychometrische Erfassung im Kindes-, Jugend- und Erwachsenenalter.

The psychopathy concept in accordance with Robert Hare was operationalized in 1985 when the revised form of the Psychopathy Checklist (PCL-R) was published. Since then, the PCL-R has been used internationally in prognosis and therapy research. In North America, personality traits of psychopathy have also been studied in children and juveniles for several years by now. On the basis of the PCL-R, a checklist for adolescents (PCL-YV) was developed that takes the special conditions of adolescents into account. In juveniles with a high score research with the PCL-YV demonstrated a lack of empathy, impulsivity and social adjustment disorder. Furthermore, researchers found associations between the number and severity of violent offences, early drug abuse and earlier recidivism, i. e. repeated criminality. The biological determinants of these dimensions are discussed as well as associated questions about recent specific therapy concepts and diagnostic aspects of psychopathy in juveniles.

A cybernetic approach to osteoporosis in anorexia nervosa.

A group of 25 female individuals, who had been admitted to the University Hospital with the diagnosis of anorexia nervosa (AN) 3 to 10 years before, was seen for a follow-up visit in the hospital. These women got a psychiatric exploration to detect a present eating disorder. Moreover, parameters of the muskuloskeletal interaction were determined on the non-dominant forearm. Bone mineral content (BMC) of the radius was measured by pQCT and maximal grip force was evaluated by the use of a dynamometer. Eating disorders were present in 12 females. The mean of BMC standard deviation (SD) score was significantly reduced in comparison with reference values. Furthermore, the mean of BMC SD score was also significantly lower than the mean of grip force in SD score. These results gave the suggestion that the adaptation of bone mass to biomechanical forces is disturbed in AN. The linear regression analyses between the parameters grip force and BMC were compared between the study and the reference group. The comparison delivered a significantly lower constant in the regression equation of the study group. This result can be interpreted on the background of the mechanostat theory. The affection with an eating disorder decreases the set point in the feedback loop of bone modeling. The results offer for the first time the possibility to analyse osteoporosis in anorexic females under the paradigm of muskuloskeletal interaction.

[Pharmacological treatment in adults with attention deficit hyperactivity disorder]. / Die medikamentöse Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung im Erwachsenenalter.

Treatment in adults with attention deficit hyperactivity disorder predominantly relies on pharmacotherapeutic approaches especially with psychostimulants. Empirical studies indicate that their clinical effectiveness may be as high as in children and adolescents, especially in higher dosages. However, due to the high prevalence of comorbidities, e.g. depression, psychopharmacological treatment requires an extended use of other substance groups, especially antidepressants. An optimal treatment response necessitates the choice of an adequate substance depending on the leading clinical symptoms and a procedure of an individual titration of different dosages. This article reviews the current empirical results in the pharmacological treatment of ADHD in adults and provides possible treatment strategies for clinical practice.

[School truancy. A heterogeneous disturbing picture]. / Schulverweigerung. Ein heterogenes Störungsbild.

School truancy is not a diagnostic entity. It is rather a conglomeration of symptoms with various causal factors. With a prevalence of about 5% of all children attending school, three typical groups of anxious school truants can be differentiated: children with separation anxiety, with simple and social phobia as well as anxious and/or depressive symptoms. Anxious truants show depressive symptoms and separation anxiety significantly above chance, while school truancy is closely associated with social disorders, depression and oppositional behaviour and mostly occurs in boys. Psychosocial risk factors such as contact problems with peers, familial and school problems often play an important part. The increased comorbidity as well as various associated stress factors demand multiple behaviour and psychological diagnostics. Sophisticated therapeutic measures should regard this and focus on cognitive behaviour therapy as well as educative and supportive interventions.