[Psychopathy in childhood and adolescence]. / Psychopathie im Kindes- und Jugendalter.

Personality disorders manifest themselves in stable deviations of personality traits that especially arise in negative interactions with others. Those typical dysfunctional interactions can be observed particularly in dissocial and antisocial personality disorders: adults with severe forms of personality disorders often showed specific symptoms in childhood and adolescence. Clinical researchers therefore demand a respective diagnosis of childhood and adolescent psychopathy. There is an extensive body of research on dissocial and borderline personality disorders in children and adolescents. To date the severe form of dissocial personality disorders, psychopathy, cannot be specifically classified. The transfer of this diagnosis to childhood and adolescence is crucial: based on the assumption of persistence and the risk of stigmatisation many clinicians refuse to diagnose psychopathy at a young age. On the other hand there are positive treatment outcomes that aim at symptom reduction from a very early age. The specification of dissocial personality disorders in childhood and adolescence may encourage the development of new treatments and the de-stigmatisation as well as qualify the dogged assumption of persistence of personality disorders.

The temporal dynamics of coherent motion processing in autism spectrum disorder: evidence for a deficit in the dorsal pathway.

Individuals with autism spectrum disorder (ASD) show impairments in processing coherent motion which have been proposed to be linked to a general deficit in the dorsal visual pathway. However, few studies have investigated the neural mechanisms underlying coherent motion processing in ASD. Thus, the aim of this study was to further test the hypothesis of a dorsal pathway deficit in ASD using visual evoked potentials (VEPs). 16 children and adolescents with ASD and 12 typically developing controls were examined with VEPs elicited by a random dot kinematogram. After an initial experimental sequence, where subjects were presented randomly moving dots, a fraction of the dots moved coherently (dependent on the level of coherence, 20%, 40%, or 60% of the dots) to the left or right side. Subjects were asked to detect the direction of coherent motion via button press. On the behavioural level, no significant group differences emerged. On the neural level, coherently moving dots elicited a N200 followed by a late positive potential (P400). ASD subjects exhibited a reduced N200 amplitude compared to controls. Moreover, in the ASD group, a trend for a negative relationship between N200 amplitude and a measure of autistic pathology was revealed. The present study provides strong support of a dorsal stream deficiency in the disorder and renders alternative explanations for impaired coherent motion processing in ASD less likely. Together with findings from related research fields, our data indicate that deviances in the N200 during coherent motion perception might be fundamental to ASD.

Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia.

INTRODUCTION: Marked inter-individual variation has been observed with respect to the risk of weight gain and related metabolic disturbances during antipsychotic treatment, which in part could be explained by heritability. Such adverse effects have been proposed to occur through drug-induced mechanisms involving both the central nervous system and different peripheral tissues. METHODS: We genotyped tagSNPs in several genes ( ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAG1, PRKAG2, PRKAG3, FTO and FABP3) that regulate lipid and energy homeostasis for their possible association to antipsychotic-induced weight gain. RESULTS: In a sample of 160 patients of German origin with schizophrenia who had been monitored with respect to body weight, we found marked association between antipsychotic-related changes in BMI and 6 markers in the adiponectin gene ( ADIPOQ). DISCUSSION: These findings support previous observations (in patients' serum) that adiponectin is involved in antipsychotic-mediated metabolic adverse effects.

First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children.

Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.

Body weight gain induced by atypical antipsychotics: an extension of the monozygotic twin and sib pair study.

BACKGROUND AND OBJECTIVE: In our original study based on five monozygotic twin pairs and seven same-sex sib pairs, we previously showed that genetic factors contribute to body weight gain induced by the atypical antipsychotic clozapine. We aim to study this further by including patients treated with the atypical antipsychotics olanzapine or risperidone as well as opposite-sex sib pairs. METHODS: Twin and sib pairs were identified by a telephone screening. Measured data on weight and other clinical variables were obtained cross-sectionally and retrospectively from medical records. In seven monozygotic twin pairs and 12 sib pairs (total number of patients treated: n = 38, mean age 29.5 +/- 9.5, range 13.7-54.3 years), the similarity in BMI (kg/m(2)) change under these atypical antipsychotics (atypical Delta BMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total Delta BMI) was explored. RESULTS: For total Delta BMI we found greater similarity in antipsychotic-induced BMI change in MZ twin pairs than in sib pairs (intrapair difference) with a heritability of h(2) = 0.6, but not for atypical Delta BMI, possibly because of a genetically influenced weight plateau achieved under antipsychotic medication. CONCLUSION: The results of the present and our previous report suggest a contribution of genetic factors in antipsychotic-induced weight gain of 60-80%.

Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1 and INSIG2) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (P=0.0003-0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.

[Intelligence development in children with early-onset epilepsy with complex partial seizures]. / Intelligenzentwicklung bei im Kindesalter beginnenden Epilepsien mit komplex-fokalen Anfällen.

OBJECTIVE: Eighty-four outpatients treated for epilepsy with complex partial seizures were followed up 18 years later. RESULTS: Of these Patients, 35% showed stabile learning disabilities when they were first treated and also 18 years later. These Patients did not achieve a regular school qualification. Forty-eight percent suffered from a psychiatric disorder as classified by the ICD-10. Children with a pathological neurological result in the first examination showed poorer cognitive outcomes than Patients with only mild neurological impairment. The age of onset of the disease did not significantly predict subsequent cognitive abilities. Patients who showed complex partial seizures and generalized seizures showed poorer cognitive outcomes, as did Patients with a psychiatric disorder or psychosocial problems. DISCUSSION: The study points to the importance of a conjoint neurological and psychiatric treatment to deal with the different impairments and corresponding developmental course of the disease.

Association and linkage of allelic variants of the dopamine transporter gene in ADHD.

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

Clozapine/olanzapine-induced recurrence or deterioration of binge eating-related eating disorders.

OBJECTIVE: To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs). METHOD: Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment. RESULTS: Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [chi(2) = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3-725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine. CONCLUSION: Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.

Forty-two-years later: the outcome of childhood-onset schizophrenia.

This paper describes the long-term course of 76 patients who had been consecutively admitted to the Department of Child and Adolescent Psychiatry, Philipps University, between 1920 and 1961 with a suspected diagnosis of childhood-onset schizophrenia. By means of a consensus analysis of available data in accordance with ICD-10 criteria, the diagnosis of schizophrenia was confirmed in only 50% of the original sample (n = 38, childhood-onset schizophrenia group); whereas the rest of the sample were allotted other diagnoses (n = 38, non-schizophrenia group). A follow-up investigation was conducted, interviewing all available patients, if possible, or their first-degree relatives or doctors. In the childhood-onset schizophrenia group, age at onset (mean +/- S.D.) was 12.7 +/- 2.5 (range 5-14) years and age at follow-up was 55.0 +/- 4.8 (range 42-62) years. The outcome of this group was poor. According to the Global Assessment Scale (GAS), only 16% had a good (GAS score 71-100) and 24% had a moderate (GAS score 41-70) outcome. In the 16 childhood-onset schizophrenia patients who could be personally investigated at follow-up, 10 (62.5%) displayed severe or moderate depressive symptoms according to the BPRS depressive score. The death rate (including suicide) was significantly higher in the schizophrenia group (n = 15; 39.5%) than in the non-schizophrenia group (n = 7; 18.4%). A comparison of the life-time diagnoses of the total sample (n = 76) at follow-up with the ICD-10 diagnoses made retrospectively revealed a diagnostic stability in 69 (91%) and a change of diagnosis in 7 (9%) cases, among them 4 who were originally diagnosed as having childhood-onset schizophrenia.

No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation.

The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.

Interrelationship and familiality of dyslexia related quantitative measures.

Dyslexia is a complex gene-environment disorder with poorly understood etiology that affects about 5% of school-age children. Dyslexia occurs in all languages and is associated with a high level of social and psychological morbidity for the individual and their family; approximately 40-50% have persistent disability into adulthood. The core symptoms are word reading and spelling deficits, but several other cognitive components influence the core phenotype. A broad spectrum of dyslexia related phenotypes, including phonological decoding, phoneme awareness, orthographic processing, short-term memory, rapid naming and basic mathematical abilities, were investigated in large sample of 287 German dyslexia families. We explored the interrelationship between the component phenotypes using correlation and principal component analyses (PCA). In addition, we estimated familiality for phenotypes as well as for the factors suggested by PCA. The correlation between the component phenotypes varied between -0.1 and 0.7. The PCA resulted in three factors: a general dyslexia factor, a speed of processing factor and a mathematical abilities factor. The familiality estimates of single components and factors ranged between 0.25 and 0.63. Instead of analyzing single dyslexia-related components, multivariate analyses including factor analytic approaches may help in the identification of susceptibility genes.

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample.

Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.

Weight gain associated with clozapine, olanzapine and risperidone in children and adolescents.

The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

[The assessment of therapy outcome in child and adolescent psychiatry under naturalistic conditions--conception and implementation of the Marburg System of Quality Assurance and Therapy Evaluation]. / Die Erfassung des Therapieerfolges in der Kinder- und Jugendpsychiatrie unter naturalistischen Bedingungen.

OBJECTIVES: The objective of and concept behind the Marburg System of Quality Assurance and Therapy Evaluation (MARSYS) are presented. This a modular system with several instruments that is applicable for the evaluation of therapies with psychiatrically ill children and adolescents and can be employed in everyday routine care. METHODS: The system was tested between 1999 and 2006 in the Marburg project on therapy evaluation in inpatient care. The article presents data from a complete user population with 1,321 patients. Data reporting on the practicability of the system comprise completeness of samples, dropout rates, acceptance of the evaluation among patients and parents, and the input of time and costs. RESULTS: The results show that the system is very well suited to obtain significant findings with regard to the quality of outcome of the treatments. CONCLUSIONS: The possibilities of implementing this system are discussed with regard to the matter of costs.

Association of the melanocortin 4 receptor with feed intake and daily gain in F2 Mangalitsa x Piétrain pigs.

The melanocortin 4 receptor (MC4R) is a key factor in the regulation of energy balance and body weight. Hence it is a candidate for feed intake and energy homeostasis-related traits. Studies in humans and swine have revealed several sequence variants in the gene that are associated with some of these traits. In pigs the coding non-synonymous missense variant Asp298Asn in MC4R has been associated with feed intake, fatness and growth. Here we confirm the association of this Piétrain-derived polymorphism with feed intake and daily gain in the F2 generation of a Mangalitsa x Piétrain cross. In one Piétrain founder animal, we detected an additional non-synonymous missense variant Arg236His. Thus, the MC4R gene could be a useful marker for increased growth in the relatively slow-growing Piétrain breed.

Linkage analyses of chromosomal region 18p11-q12 in dyslexia.

Dyslexia is characterized as a significant impairment in reading and spelling ability that cannot be explained by low intelligence, low school attendance or deficits in sensory acuity. It is known to be a hereditary disorder that affects about 5% of school aged children, making it the most common of childhood learning disorders. Several susceptibility loci have been reported on chromosomes 1, 2, 3, 6, 15, and 18. The locus on chromosome 18 has been described as having the strongest influence on single word reading, phoneme awareness, and orthographic coding in the largest genome wide linkage study published to date (Fisher et al., 2002). Here we present data from 82 German families in order to investigate linkage of various dyslexia-related traits to the previously described region on chromosome 18p11-q12. Using two- and multipoint analyses, we did not find support for linkage of spelling, single word reading, phoneme awareness, orthographic coding and rapid naming to any of the 14 genotyped STR markers. Possible explanations for our non-replication include differences in study design, limited power of our study and overestimation of the effect of the chromosome 18 locus in the original study.

A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs.

Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.