Impact of autism-associated genetic variants in interaction with environmental factors on ADHD comorbidities: an exploratory pilot study.

Attention-deficit/hyperactivity disorder (ADHD) is determined by genetic and environmental factors, and shares genetic risk with ASD. Functional single-nucleotide polymorphisms of the metabotropic glutamatergic signaling pathway are reported to increase the risk for ASD. The aim of this pilot study was to explore the main effects of respective ASD variants as well as their interaction effects with well-replicated ADHD environmental risk factors on the risk for ADHD, ADHD symptom severities, and comorbidities. We included 318 children with ADHD, aged 5-13 years, and their parents (N = 164 trios, N = 113 duos, N = 41 singletons). Interaction of ASD risk variants CYFIP1-rs7170637, CYFIP1-rs3693, CAMK4-rs25925, and GRM1-rs6923492 with prenatal biological and lifetime psychosocial risk factors was explored in a subsample with complete environmental risk factors (N = 139 trios, N = 83 duos, two singletons) by transmission disequilibrium test and stepwise regression analyses. We identified nominally significant (alpha < 0.05) GxE interactions of acute life events with CYFIP1-rs3693 on ADHD diagnosis (p = 0.004; fdr = 0.096) but no significant association of any single marker. Further results suggest that the risk for comorbid disruptive disorders was significantly modulated by GxE interactions between familial risk factors and CAMK4-rs25925 (p = 0.001; fdr = 0.018) and prenatal alcohol exposure with CYFIP1-rs3693 (p = 0.003; fdr = 0.027); both findings survived correction for multiple testing (fdr value < 0.05). Nominal significant GxE interactions moderating the risk for anxiety disorders have also been identified, but did not pass multiple testing corrections. This pilot study suggests that common ASD variants of the glutamatergic system interact with prenatal and lifetime psychosocial risk factors influencing the risk for ADHD common comorbidities and thus warrants replication in larger samples.

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits.

Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.

Child and adolescent psychiatry: which knowledge and skills do primary care physicians need to have? A survey in general practitioners and paediatricians.

Primary care physicians (PCPs) play a key role in the initial assessment and management of children and adolescents with mental health problems. However, it is unclear whether current medical education curricula sufficiently equip PCPs for this task. The aim of this study was to investigate, which child and adolescent psychiatry (CAP)-related skills and knowledge PCPs say they require in their daily practice. A questionnaire was generated, employing a modified two-step Delphi approach. Besides socio-demographic items, the questionnaire contained 17 CAP-related knowledge items and 13 CAP-related skills items, which had to be rated by importance in daily practice. The questionnaire was distributed to 348 office-based paediatricians and 500 general practitioners (GPs) in Germany. The overall return rate was 51.3% (435/848). Regarding CAP-related knowledge, both paediatricians and GPs rated somatoform disorders and obesity as highly important for daily practice. Moreover, paediatricians also deemed regulatory disorders during infancy (e.g. crying, sleep disorders) as important, while GPs assessed knowledge on paediatric depression as relevant. For paediatricians and GPs, the most relevant CAP-related skills were communicating with children and adolescents and their parents. Additionally, paediatricians rated differentiating between non-pathologic and clinically relevant behaviour problems very relevant, while GPs considered basic psychotherapeutic skills essential. The CAP-related knowledge and skills perceived relevant for doctors in primary care differ from the majority of current medical school CAP curricula, which cover mainly typical, epitomic CAP disorders and are predominantly knowledge-oriented. Therefore, medical education in CAP should be amended to reflect the needs of PCPs to improve healthcare for children and adolescents with mental health problems.

[Suicide and suicide tendencies in adolescent detainees]. / Suizid und Suizidalität unter adoleszenten Häftlingen.

Following accidents, suicide is the second leading cause of death in adolescence. This stage of life has the most suicide attempts of all age groups. In addition to mentally ill juveniles, adolescent delinquents represent a high-risk group for suicidal behavior and completed suicide. In particular, the population of detainees, an extreme form of juvenile delinquency, have a 16- to 18-fold higher risk of suicidal behavior and suicide compared to the general population. Because the composition of juvenile detainees differs greatly from that of detained adults, age-specific scientific approaches and prevention programs are needed. This task cannot be addressed by juvenile detention staff alone, but rather demands close cooperation between adolescent psychiatrists, psychologists, prison medical staff, legal experts and prison officers to use the opportunity for suicide prevention in juvenile detention facilities.

[Maintaining a comprehensive provision of inpatient child and adolescent mental health services in the years to come-a German perspective]. / Wie kann auch zukünftig eine gute stationäre Versorgung im Fachgebiet Kinder- und Jugendpsychiatrie gewährleistet werden? Ein Diskussionsbeitrag aus deutscher Perspektive.

BACKGROUND: A considerable number of child and adolescent psychiatry inpatient units in Germany suffer from a significant shortage of doctors, which endangers the current system of nation-wide availability of high-quality child and adolescent inpatient services. METHODS: Drawing on recent data, this article pictures the status quo of child and adolescent psychiatry inpatient services in Germany. The authors then discuss the pros and cons of different suggestions of how to cope with the doctor shortage crisis in child and adolescent psychiatry. RESULTS: The following options for action are suggested: reduction of service provision across the board, shift from personnel-intensive inpatient towards home-based treatment, trans-sectoral cooperation by means of tele-psychiatry, delegation of clinical responsibilities to psychologists, limiting ward physicians' tasks to mere medical care of patients, improvement of working conditions in inpatient units, recruitment of doctors from abroad, and increased recruiting efforts at medical school level. From the authors' viewpoint, the latter option offers the best chance of lasting success; however, this requires a long-term, nationwide approach and considerable efforts of all departments involved.

Who wants to become a child psychiatrist? Lessons for future recruitment strategies from a student survey at seven German medical schools.

OBJECTIVE: The objective of this survey was to investigate undergraduate German medical students' attitudes toward child and adolescent psychiatry (CAP) and to describe the characteristics of students considering CAP as a possible career choice. METHODS: The authors conducted a cross-sectional, multicenter survey of medical students (at the time of their first CAP lecture) at seven German medical schools. The students completed an anonymous self-report questionnaire, asking about their attitude toward CAP and their view of CAP as a possible career choice. RESULTS: Of the 574 students, 42.9% had "high" or "very high" interest in CAP, and 59.4% rated CAP basic knowledge as "highly" or "very highly" relevant for their prospective work as physicians. CAP was a possible career choice for 25.4%. The most frequently mentioned reasons for choosing CAP were interesting clinical cases (65.8%), helping ill children (52.1%), and close patient-physician contact (50.7%). The most frequently mentioned reasons against this decision were a definite decision for another subspecialty (54.8%), expected difficulties in working with parents and family members (35.3%), and an expected high emotional burden (29.6%). In addition to the highly significant correlation with general interest in CAP, students with previous experience in general psychiatry and CAP clinical courses, as well as female students and students with relatives or acquaintances with CAP-related disorders, showed the highest interest in CAP as a possible career choice. CONCLUSION: The majority of the students surveyed showed a positive attitude toward CAP and considered CAP basic knowledge to be relevant for their future work. When designing recruitment strategies, it may be helpful to consider that CAP exposure early in the curriculum might be decisive and that students with previous clinical courses in this field, as well as female students, showed the highest interest in CAP as a possible career choice.

[Suicide in children and adolescents - a 13-year study with 78 cases]. / Suizide im Kindes- und Jugendalter.

OBJECTIVE: Updated and regional data about the circumstances of death and the psychosocial backgrounds of suicides can be helpful for improving suicide-preventive strategies in childhood and adolescence. METHOD: All known cases of completed suicide in the period from 1996 to 2008 in persons ≤ 21 years of age from the Institute of Forensic Medicine, Frankfurt/Main were analysed in a retrospective study. We included 78 cases and matched them with a comparative sample of 1,797 adult suicides of persons > 21 years of age. RESULTS: Within the chosen period there was a 44 % decrease in incidence of suicide in the group of ≤ 21-year-olds. The fraction of incarcerated persons in this group was 8.0 % compared to 2.56 % in the adult group. Differences from suicide in adulthood were also demonstrated in terms of suicide-related substance abuse (less detection of alcohol, more frequent detection of illicit drugs) and choice of methods (more deaths by being hit by a train). CONCLUSIONS: Incarcerated adolescents are an important risk group for suicidal tendency and need increased, well-directed preventive measures. Clinical adolescent psychiatry should pay special attention to the indications in this study of an age-dependent association of drug use in suicide.

[What do medical students expect of lectures in child and adolescent psychiatry?]. / Was erwarten medizinstudierende von vorlesungen in der kinder- und jugendpsychiatrie?

OBJECTIVE: In child and adolescent psychiatry (CAP) lectures are the most common teaching format for medical students. Besides conveying basic knowledge and skills related to the medical management of children and adolescents with mental health problems, lectures also play a decisive role in the recruitment of future residents for this discipline. Thus, knowledge of the expectations of medical students of lectures is a crucial factor. METHOD: 1,029 medical students at ten German medical schools were surveyed with a questionnaire in a cross-sectional design. RESULTS: Items perceived as most important were knowledge of disorders (73 %), medical skills in handling children and adolescents (61 %), and differential diagnosis of normal and abnormal child behaviour in children and adolescents (59 %). 71 % set a high value on patient presentation, while 41 % expressed ethical concerns about presenting mentally ill minors in lectures. CONCLUSIONS: The expectations of medical students toward CAP lectures are mainly related to the transfer of specialty-related knowledge and generic skills. The important area of teaching attitudes could best be covered via patient presentations, which are desired by most students. However, ethical concerns over patient presentation also need to be discussed with students.

Genome-wide association study in German patients with attention deficit/hyperactivity disorder.

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

Suicide after reception into prison: A case-control study examining differences in early and late events.

OBJECTIVE: Prisoners constitute a high-risk group for suicide, with suicide rates about 5 to 8 times higher than in the general population. The first weeks of imprisonment are a particularly vulnerable time, but there is limited knowledge about the risk factors for either early or late suicide events. METHODS: Based on a national total sample of prison suicides in Germany between 2005 and 2017, suicides within the first 2 (4 and 8) weeks after reception into prison were matched by age and penalty length with cases that occurred later. Factors that potentially influence the timing of suicide were investigated. RESULTS: The study has shown that 16.7% (31.5%) of all 390 suicides in German prisons occurred within the first two weeks (two months) of imprisonment. Factors that facilitate adaptation to the prison environment (e.g. prior prison experience) were negatively associated with early suicide events. Factors that hindered the adaptation process (e.g. withdrawal from illicit drugs) were observed more frequently in early suicide events than in late ones. These factors are active at different times of imprisonment. CONCLUSION: At reception, particular attention should be paid to the following factors associated with early suicide events: widowed marital status, lack of prison experience, and drug dependency.

Phenotypic and measurement influences on heritability estimates in childhood ADHD.

Twin studies described a strongly heritable component of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. However, findings varied considerably between studies. In addition, ADHD presents with a high rate of comorbid disorders and associated psychopathology. Therefore, this literature review reports findings from population-based twin studies regarding the influence of subtypes, assessment instruments, rater effects, sex differences, and comorbidity rates on ADHD heritability estimates. In addition, genetic effects on the persistence of ADHD are discussed. By reviewing relevant factors influencing heritability estimates more homogeneous subtypes relevant for molecular genetic studies can be elicited. A systematic search of population-based twin studies in ADHD was performed, using the databases PubMed and PsycInfo. Results of family studies were added in case insufficient or contradictory findings were obtained in twin studies. Heritability estimates were strongly influenced by rater effects and assessment instruments. Inattentive and hyperactive-impulsive symptoms were likely influenced by common as well as specific genetic risk factors. Besides persistent ADHD, ADHD accompanied by symptoms of conduct or antisocial personality disorder might be another strongly genetically determined subtype, however, family environmental risk factors have also been established for this pattern of comorbidity.

Murderers or thieves at risk? Offence-related suicide rates in adolescent and adult prison populations.

PURPOSE: Prisoners have a higher risk of suicide compared to non-incarcerated individuals. One aim of suicide prevention for prisoners is to identify risk factors in order to put stronger support mechanisms in place for the more vulnerable detainees. This study investigates the suicide risk (SR) in offence-related sub-populations in a representative German sample and differentiates between SR for adolescent and adult prisoners. METHODS: Conducting a national study with data from public German records on the entire prison population from 2000 to 2016 and suicide numbers in German prisons in the same period, SR was calculated for the total male prison population as well as for both subgroups, adolescent and adult male prisoners. RESULTS: In the study period, male prisoners spent 959.584 life years (LY) in German criminal detention. Among those, 524 prisoners died of suicide. SR was higher for detainees imprisoned for an offence resulting in extensive physical harm for another person, e.g. homicide (suicide rate = 134,8 suicides per 100.000 LY; OR = 2,47; CI95%: 1,98-3,08), bodily injury (suicide rate = 87,3; OR = 1,60; CI95%: 1,29-1,99), and sexual offences (suicide rate = 84,2; OR = 1,54; CI95%: 1,18-2,01) compared with the SR of the total prison population (suicide rate = 54.6). Age differences between offence-related SR were found for theft, with adolescents (suicide rate = 69,3; OR = 1,25; CI95%: 0,85-1,84) showing higher SR than adults (suicide rate = 38,2; OR = 0,7; CI95%: 0,54-0,92). CONCLUSION: The index offence of detainees is associated with SR and age-related differences exist. Suicide prevention in prisons should take both into account to determine populations at risk.

Male suicide rates in German prisons and the role of citizenship.

PURPOSE: Prisoners are at a particularly high risk of suicide. In contrast to other psychosocial risk factors it remains unclear to what degree the risk of suicide differs between prisoners with local citizenship and foreigners. In order to provide more detailed information for suicide prevention in prisons, this study aims to compare suicide rates (SR) between these populations in German criminal custody. METHODS: Based on a German national database of completed suicide in custody, suicides by prisoners were analysed and compared with epidemiological data of the prison population and the general population, stratified for German and foreign citizenship. Data analysis was adjusted for differences in the age distribution of both populations by calculating standard mortality ratios (SMR) for suicide. RESULTS: SR were higher in prisoners with German citizenship than those with foreign citizenship (SR = 76.5 vs. SR = 42.8, P<0.01). This association was not specific to the prison population, as the higher SR in citizens compared to non-citizens (SR = 19.3 vs. SR = 9.0, P<0.01) were also found in the general population. The association between prison suicide and citizenship was comparable in juvenile and adult prisoners, indicating its relevance to both the juvenile and adult detention systems. CONCLUSION: Imprisonment is associated with a substantially increased risk of suicide in both German and non-German citizens, a finding which needs to be taken into consideration by the justice system. The lower suicide risk in non-German citizens is independent of whether or not they are in custody.

Classifying Autism Spectrum Disorders by ADI-R: Subtypes or Severity Gradient?

To reduce phenotypic heterogeneity of Autism spectrum disorders (ASD) and add to the current diagnostic discussion this study aimed at identifying clinically meaningful ASD subgroups. Cluster analyses were used to describe empirically derived groups based on the Autism Diagnostic Interview-revised (ADI-R) in a large sample of n = 463 individuals with ASD aged 3-21. Three clusters were observed. Most severely affected individuals regarding all core symptoms were allocated to cluster 2. Cluster 3 comprised moderate symptom severity of social communication impairments (SCI) and less stereotyped repetitive behavior (RRB). Minor SCI and relatively more RRB characterized cluster 1. This study offers support for both, a symptom profile, and a gradient model of ASD within the spectrum due to the sample included.

Antipsychotic prescription in children and adolescents: an analysis of data from a German statutory health insurance company from 2005 to 2012.

BACKGROUND: Despite sparse documentation of their long-term therapeutic effects and side effects, antipsychotic drugs have come to be prescribed more frequently for children and adolescents in recent years, both in the USA and in Europe. No current data are available about antipsychotic prescriptions for this age group in Germany. METHODS: Data from the largest statutory health insurance fund in Germany (BARMER GEK) were studied to identify antipsychotic prescriptions for children and adolescents (age 0-19 years) from 2005 to 2012 and analyze them with respect to age, sex, drug prescribed, prescribing medical specialty, and any observable secular trends. RESULTS: The percentage of children and adolescents receiving a prescription for an antipsychotic drug rose from 0.23% in 2005 to 0.32% in 2012. In particular, atypical antipsychotic drugs were prescribed more frequently over time (from 0.10% in 2005 to 0.24% in 2012). The rise in antipsychotic prescriptions was particularly marked among 10- to 14-year-olds (from 0.24% to 0.43%) and among 15- to 19-year-olds (from 0.34% to 0.54%). The prescribing physicians were mostly either child and adolescent psychiatrists or pediatricians; the most commonly prescribed drugs were risperidone and pipamperone. Risperidone was most commonly prescribed for patients with hyperkinetic disorders and conduct disorders. CONCLUSION: In Germany as in other industrialized countries, antipsychotic drugs have come to be prescribed more frequently for children and adolescents in ecent years. The German figures, while still lower than those from North America, are in the middle range of figures from European countries. The causes of the increase should be critically examined; if appropriate, the introduction of prescribing guidelines of a more restrictive nature could be considered.

Altered gene expression in the prefrontal cortex of young rats induced by the ADHD drug atomoxetine.

Atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, is a non-stimulant approved for the treatment of attention deficit/hyperactivity disorder (ADHD). Little is known about the molecular basis for its therapeutic effect. The objective of this animal study was to determine alterations in gene expression patterns in the prefrontal cortex after long-term administration of atomoxetine. Rats were treated for 21 days during childhood and early adolescent stages of development with a once-daily oral application of 0.05 g/kg atomoxetine, which resulted in plasma levels similar to those described in children. A whole genome RNA-microarray of rat prefrontal cortical gene expression after administration of atomoxetine versus sterile water revealed an mRNA increase in 114 genes (≥2-fold) while 11 genes were down-regulated (≤0.5-fold). By applying quantitative real-time PCR (qRT-PCR) and Western Blot we confirmed a significant increase in the expression of GABA A receptor subunits as well as ubiquinol-cytochrome c reductase complex core protein 2 (Uqcrc2). SNAP-25 (synaptosomal-associated protein of 25 kDa), which is an ADHD candidate gene and an important vesicle protein involved in axonal growth, synaptic plasticity and regulation of neurotransmitter release was also significantly upregulated on RNA- and protein level after atomoxetine treatment. In summary, we could show that long-term treatment with the ADHD drug atomoxetine induces the regulation of several genes in the prefrontal cortex of young rats. Especially the increased expression of SNAP-25 and GABA-A receptor subunits may indicate additional active therapeutic mechanisms for atomoxetine.

Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations.

Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut(0) and mut(-)) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut(-) defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut(0) defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut(-) defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype.