Katja Becker

Molecular genetics of attention-deficit/hyperactivity disorder: an overview

As heritability is high in attention-deficit/hyperactivity disorder (ADHD), genetic factors must play a significant role in the development and course of this disorder. In recent years a large number of studies on different candidate genes for ADHD have been published, most have focused on genes involved in the dopaminergic neurotransmission system, such as DRD4, DRD5, DAT1/SLC6A3, DBH, DDC. Genes associated with the noradrenergic (such as NET1/SLC6A2, ADRA2A, ADRA2C) and serotonergic systems (such as 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2) have also received considerable interest. Additional candidate genes related to neurotransmission and neuronal plasticity that have been studied less intensively include SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF. This review article provides an overview of these candidate gene studies, and summarizes findings from recently published genome-wide association studies (GWAS). GWAS is a relatively new tool that enables the identification of new ADHD genes in a hypothesis-free manner. Although these latter studies could be improved and need to be replicated they are starting to implicate processes like neuronal migration and cell adhesion and cell division as potentially important in the aetiology of ADHD and have suggested several new directions for future ADHD genetics studies.

Impact of age at first drink on vulnerability to alcohol-related problems: Testing the marker hypothesis in a prospective study of young adults

There is ample evidence that the early initiation of alcohol use is a risk factor for the development of later alcohol-related problems. The purpose of the current study was to examine whether this association can be explained by indicators of a common underlying susceptibility or whether age at drinking onset may be considered as an independent predictor of later drinking behavior, suggesting a potential causal relationship. Participants were drawn from a prospective cohort study of the long-term outcomes of early risk factors followed up from birth onwards. Structured interviews were administered to 304 participants to assess age at first drink and current drinking behavior. Data on risk factors, including early family adversity, parental alcohol use, childhood psychopathology and stressful life events, were repeatedly collected during childhood using standardized parent interviews. In addition, information on genotype was considered. Results confirmed previous work demonstrating that hazardous alcohol consumption is related to early-adolescent drinking onset. A younger age of first drink was significantly predicted by 5-HTTLPR genotype and the degree of preceding externalizing symptoms, and both factors were related to increased consumption or harmful alcohol use at age 19. However, even after controlling for these potential explanatory factors, earlier age at drinking onset remained a strong predictor of heavy alcohol consumption in young adulthood. The present longitudinal study adds to the current literature indicating that the early onset - adult hazardous drinking association cannot solely be attributed to shared genetic and psychopathologic risk factors as examined in this study.

The interaction between the dopamine transporter gene and age at onset in relation to tobacco and alcohol use among 19-year-olds.

Recent evidence suggests that heterogeneity in the age at onset could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with alcohol and nicotine consumption. The aim of this study was to examine interactions between two DAT1 polymorphisms and different initiation ages with regard to alcohol and tobacco consumption levels and dependence. Two hundred and ninety‐one young adults (135 males, 156 females) participating in the Mannheim Study of Children at Risk were genotyped for the 40‐bp variable number of tandem repeats (VNTR) and rs27072 polymorphisms of DAT1. Age at initiation was assessed at age 15 and 19 years. Information about current alcohol and tobacco consumption was obtained at age 19 years using self‐report measures and structured interviews. Results suggest that age at onset of intensive consumption moderated the association of the DAT1 gene with early adult substance use and dependence, revealing a DAT1 effect only among individuals homozygous for the 10r allele of the 40‐bp VNTR who had started daily smoking or being intoxicated early in life. Equally, carriers of the T allele of the rs27072 polymorphism reporting an early age at first intoxication showed higher current alcohol consumption at age 19 years. In contrast, no interaction between rs27072 and the age at first cigarette with regard to later smoking was observed. These findings provide evidence that the DAT1 gene interacts with an early heavy or regular drug exposure of the maturing adolescent brain to predict substance (ab)use in young adulthood. Further studies are required to confirm these findings.

The impact of individual and methodological factors in the variability of response to methylphenidate in ADHD pharmacogenetic studies from four different continents

Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention‐deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: (a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta‐regression analysis; (b) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies vs. randomized controlled trials) was significantly associated with heterogeneity of results (P = 0.001). At the individual level, age (P < 0.001), comorbid oppositional defiant disorder (P < 0.001), and pre‐treatment scores (P < 0.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed.

Treating nonsuicidal self-injury (NSSI) in adolescents: consensus based German guidelines

BackgroundNonsuicidal self-injury (NSSI) is a frequent and clinically relevant phenomenon in adolescence. Within Europe, Germany has one of the highest prevalence rates in youth with lifetime prevalence ranging between 25 and 35%. However, treatment guidelines for NSSI are not yet available.MethodsConsensus based clinical guidelines were created by a working group consisting of members of eleven medical, psychological or psychotherapeutic professional national associations, and two members of patient self-help and prevention groups. The guidelines were developed in consecutive expert meetings and literature searches and agreed on in a final consensus conference.ResultsGiven that evidence on both the psychotherapeutic and psychopharmacological treatment of NSSI is limited, a consensus based approach was chosen. The consensus indicated that due to the accumulating evidence on the efficacy of psychotherapeutic approaches, core elements of psychotherapy should be provided in treatment of NSSI. A specific psychopharmacological therapy of NSSI cannot be recommended. In addition, the guidelines provide recommendations for surgical intervention of NSSI.ConclusionsIn accordance with the heterogeneous level of evidence, recommendations for the clinical management of NSSI in adolescence were made during a consensus conference after reviewing available literature. There is still a lack of knowledge on prevention as well as clinical interventions, which needs to be addressed by further clinically relevant studies.

Maternal Responsiveness as a Predictor of Self-Regulation Development and Attention-Deficit/Hyperactivity Symptoms Across Preschool Ages

Preschool-age “hot” executive function capacity (i.e. reward-related effortful control) represents an early kind of self-regulation that is involved in social adjustment development as well as the development of subtypes of attention-deficit/hyperactivity disorder (ADHD). Early self-regulation development might be malleable by responsive parenting. We analyzed whether maternal responsiveness/sensitivity predicts reward-related control (RRC) development within the preschool period, and whether RRC mediates a negative link between maternal responsiveness and ADHD symptoms. A sample of 125 preschoolers and their families were seen at the ages of 4 and 5 years. Maternal responsiveness/sensitivity was assessed via home observations, RRC by neuropsychological tasks, and ADHD symptoms by a structured clinical parent interview. Maternal responsiveness/sensitivity predicted RRC development. The negative link between maternal responsiveness/sensitivity at 4 years and ADHD symptoms at 5 years was mediated by RRC performance at 5 years. Preschoolers showing ADHD symptoms combined with low RRC capacity in particular might benefit from responsive/sensitive parenting.

Hair cortisol concentration in preschoolers with attention-deficit/hyperactivity symptoms—Roles of gender and family adversity

OBJECTIVE Previous studies on the association between hypothalamic-pituitary-adrenal axis (HPAA) activity and ADHD yielded inconsistent findings, particularly in younger children. This might be due to the heterogeneity of the disorder, making moderator effects of variables probable, which circumscribe more homogenous subgroups. There have been indications of moderator effects on this association by gender of child and exposure to family adversity. Moreover, difficulties in capturing long-term basal HPAA activity in younger children might have contributed to the inconsistencies. We therefore analyzed moderator effects of gender and family adversity while using the hair cortisol concentration (HCC) to assess integrated long-term HPAA. METHODS The community-based sample consisted of 122 4-5-year-old preschoolers (71 screened positive for elevated ADHD symptoms). ADHD symptoms were measured by a clinical parent interview and parent and teacher questionnaires. HCC in the most proximal 3-cm scalp hair segment was analyzed using luminescence immunoassay. An extended family adversity index was used. RESULTS Hierarchical linear regression analyses yielded an interaction effect (p<.05) between ADHD symptom groups and gender on HCC, indicating a low HCC in boys with elevated ADHD symptoms. Further exploratory analyses revealed that this interaction effect was most pronounced under the condition of family adversity. The results held after controlling for oppositional, anxiety, and depressive symptoms. CONCLUSION Low HCC might indicate a specific pathogenic mechanism in boys with elevated ADHD symptoms. This mechanism might further involve an exposure to family adversity. However, the results need to be cross-validated before definitive conclusions can be drawn.

Multiple causal pathways in attention-deficit/hyperactivity disorder – Do emerging executive and motivational deviations precede symptom development?

ABSTRACT The multiple causal pathways model on the etiology of attention-deficit/hyperactivity disorder (ADHD) is well established. However, developmental implications of the model are not yet sufficiently analyzed. The model implies that critical neural and neuropsychological deviations from normative development precede secondarily developing ADHD symptoms. Cognitive, “cool” inhibitory control (CIC) and reward-related, “hot” functions (RRF) are regarded as neuropsychological basic deficits that indicate independent causal pathways. Both functions involve top-down control networks that undergo major normative developmental changes in the preschool period. We formalized the following assumptions in a path model: (a) CIC and RRF predict change in ADHD symptoms in the preschool period, (b) the reverse is not true, and (c) CIC and RRF independently contribute to this prediction. A community-based sample of 125 (71 boys) preschoolers was assessed at at age 4 and 5 years. At each assessment wave, CIC and RRF were measured by a battery of age-appropriate valid tasks. ADHD symptoms were measured by a clinical parent interview. Evaluation of model fit using manifest maximum likelihood parameter estimation clearly supported the hypothesized path model while controlling for gender of child and maternal education level. Thus, regarding the basic deficits of CIC and RRF, the results add evidence on the developmental implications of the multiple causal pathways model. Our findings point to the potential significance of these early emerging characteristics as indicators of risk and as targets for preventive interventions.

[Structural quality in inpatient and daycare child and adolescent psychiatry- indicators for planning future staff ratios for the era following the Psychiatry Personnel Act].

The German Psychiatry Personnel Act, which went into effect in 1990, has led to a decrease in the number of child and adolescent psychiatry inpatient beds, to a decrease in the length of stay, and to an increase in inpatient psychotherapy. Today, this act is outdated~ for a number of reasons, such as changes in the morbidity of the population, the rising number of emergencies, and new professional standards such as documentation. In addition, new legal provisions and conventions (like the UN Convention on the Rights of the Child) necessitate a complete reevaluation. Child and adolescent psychiatry needs a normative act to enable the necessary implementation. Many different rationales are available to support the debate.

Low hair cortisol concentration and emerging attention-deficit/hyperactivity symptoms in preschool age

Previous research demonstrated hypoactivity of the HPA axis in children with attention-deficit/hyperactivity disorder (ADHD) or externalizing symptoms. We analyzed the predictive association between the long-term HPA axis activity and increasing symptoms of ADHD in the preschool period. The sample consisted of n = 125 4-year-old children and their families (including n = 64 children with elevated ADHD symptoms). ADHD symptoms were assessed by a structured clinical interview with the mother and by parent- and teacher-report questionnaires. The long-term HPA axis activity was assessed by the hair cortisol concentration (HCC) (over a 3-month period). After controlling for potential confounders, low HCC predicted an increase in ADHD symptoms between the age of 4 and 5 years. Exploration of gender effects revealed that cross-sectional and predictive associations were significant in boys but not in girls. Low HCC might thus be regarded as an early marker of a possibly gender-related developmental pathway to ADHD.