Publications by authors named "Marcel Romanos"

150 Publications

Toward a Dimensional Assessment of Externalizing Disorders in Children: Reliability and Validity of a Semi-Structured Parent Interview.

Front Psychol 2020 24;11:1840. Epub 2020 Jul 24.

School of Child and Adolescent Cognitive Behavior Therapy (AKiP), Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.

Objective: This study assesses the reliability and validity of the DSM-5-based, semi-structured (ILF-EXTERNAL).

Method: Participant data were drawn from the ongoing ESCAschool intervention study. The ILF-EXTERNAL was evaluated in a clinical sample of 474 children and adolescents (aged 6-12 years, 92 females) with symptoms of attention-deficit/hyperactivity disorder (ADHD). To obtain interrater reliability, the one-way random-effects, absolute agreement models of the intraclass correlation (ICC) for single ICC(1,1) and average measurements ICC(1,3) were computed between the interviewers and two independent raters for 45 randomly selected interviews involving ten interviewers. Overall agreement on DSM-5 diagnoses was assessed using Fleiss' kappa. Further analyses evaluated internal consistencies, item-total correlations as well as correlations between symptom severity and the degree of functional impairment. Additionally, parents completed the German version of the (CBCL) and two DSM-5-based parent questionnaires for the assessment of ADHD symptoms and symptoms of disruptive behavior disorders (FBB-ADHS; FBB-SSV), which were used to evaluate convergent and divergent validity.

Results: ICC coefficients demonstrated very good to excellent interrater reliability on the item and scale level of the ILF-EXTERNAL [scale level: ICC(1,1) = 0.83-0.95; ICC(1,3) = 0.94-0.98]. Overall kappa agreement on DSM-5 diagnoses was substantial to almost perfect for most disorders (0.38 ≤ κ ≤ 0.94). With some exceptions, internal consistencies (0.60 ≤ α ≤ 0.86) and item-total correlations (0.21 ≤ ≤ 0.71) were generally satisfactory to good. Furthermore, higher symptom severity was associated with a higher degree of functional impairment. The evaluation of convergent validity revealed positive results regarding clinical judgment and parent ratings (FBB-ADHS; FBB-SSV). Correlations between the ILF-EXTERNAL scales and the CBCL were moderate to high. Finally, the ILF-EXTERNAL scales were significantly more strongly associated with the CBCL than with the , indicating divergent validity.

Conclusion: In clinically referred, school-age children, the ILF-EXTERNAL demonstrates sound psychometric properties. The ILF-EXTERNAL is a promising clinical interview and contributes to high-quality diagnostics of externalizing disorders in children and adolescents.
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http://dx.doi.org/10.3389/fpsyg.2020.01840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396521PMC
July 2020

[Anxiety and Depression in Transition - Desiderata for Improved Care and Research: Results of the Joint Task Force Transition of DGPPN and DGKJP].

Z Kinder Jugendpsychiatr Psychother 2020 Nov 3;48(6):429-433. Epub 2020 Jul 3.

Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum Freiburg.

Anxiety and Depression in Transition - Desiderata for Improved Care and Research: Results of the Joint Task Force Transition of DGPPN and DGKJP Affective disorders (e. g., anxiety, depression) frequently begin during adolescence. Yet therapeutic approaches during adolescence differ in some respects from those employed during adulthood. During the transition from adolescence to adulthood, there is a high risk of discontinuation of therapeutic treatment, which may consequently affect integration in employment. There is a need for age-specific therapeutic strategies that address the relevant issues of adolescents as well as the presently unmet needs in research and treatment for this specific population.
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http://dx.doi.org/10.1024/1422-4917/a000739DOI Listing
November 2020

An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes.

J Neural Transm (Vienna) 2020 11 29;127(11):1527-1537. Epub 2020 May 29.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel Platz 1, 97080, Würzburg, Germany.

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.
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http://dx.doi.org/10.1007/s00702-020-02206-xDOI Listing
November 2020

Depression and anxiety with exposure to ozone and particulate matter: An epidemiological claims data analysis.

Int J Hyg Environ Health 2020 07 19;228:113562. Epub 2020 May 19.

Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, Ludwig Maximilian University of Munich; Comprehensive Pneumology Center (CPC) Munich, Member DZL, German Center for Lung Research, Munich, Germany; Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. Electronic address:

Background: Depression and anxiety have complex etiologies and are associated with a significant burden of disease. Although air pollution has been hypothesized as a possible risk factor of these disorders, the associations are still under-investigated. We aimed to analyze associations between long-term exposure to ambient ozone and particulate matter with diameter <10 μm (PM) and diagnoses of depression and anxiety in a general population.

Methods: We utilized data from a large statutory health insurance company from Saxony, Germany. Information on outpatient clinical diagnoses of depression and anxiety was available for the years 2005-2014. We assigned ambient ozone and PM estimates to residential districts of 1.13 million individuals aged 16 and older. Depression and anxiety were defined as diagnoses counts. Associations with depression and anxiety were assessed using adjusted generalized estimating equations models.

Results: In the ten-year study period, the observed prevalences of depression and anxiety were 7.40% and 3.82%, respectively. In the two-pollutant model, 10 more days with a maximum 8-h average ozone concentration exceeding 120 μg/m³ resulted in a relative risk (RR) of 1.010 with 95% confidence interval (CI) (1.005, 1.014) for depression and an RR of 1.007 (95% CI (1.000, 1.014)) for anxiety. The effect estimates of PM for depression and anxiety were 1.180 (95% CI (1.160, 1.201)) and 1.176 (95% CI (1.148, 1.205)) per 10 μg/m³ increase in PM concentration, respectively. Age, sex, and access to healthcare of the individual were also associated with the diagnosis of the disorders. The associations were consistent across one- and two-pollutant models.

Conclusions: Our findings indicate that increased levels of ambient ozone and PM may elevate the risk of a depression or anxiety diagnosis in the general population. However, given the lack of data on individual air pollutant exposure and socioeconomic status, our results should be interpreted with caution. Further well-designed epidemiological studies should replicate our findings.
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http://dx.doi.org/10.1016/j.ijheh.2020.113562DOI Listing
July 2020

ADHD in school-age children is related to infant exposure to systemic H1-antihistamines.

Allergy 2020 11 12;75(11):2956-2957. Epub 2020 Jun 12.

Center for Evidence-Based Healthcare, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

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http://dx.doi.org/10.1111/all.14411DOI Listing
November 2020

Distribution of transcripts of the GFOD gene family members gfod1 and gfod2 in the zebrafish central nervous system.

Gene Expr Patterns 2020 06 18;36:119111. Epub 2020 Mar 18.

Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany. Electronic address:

The glucose-fructose oxidoreductase domain containing gene family (GFOD) is small and contains only two members in human (GFOD1 and GFOD2). Information about its function is scarce. As the name implies the proteins contain an enzyme-defining domain, however, if this is functional and has enzymatic activity remains to be shown. A single nucleotide polymorphism situated in an intron of GFOD1 was found to be associated with inattentive symptomology in patients with attention-deficit/hyperactivity disorder. Further, in a large schizophrenia genome-wide association study the GFOD2 locus was found to be associated with the psychiatric condition. Until now, however, it is unclear what specific functions are associated with the two GFOD-family members, if they might be involved in neurodevelopment and how this may relate to the development of psychiatric disorders. In order to gain first insights into the hypothesis that GFOD-family members are involved in brain development and/or function we performed RNA in situ hybridization on zebrafish (Danio rerio) tissues at different developmental stages. We found that both family members are expressed in the central nervous system at embryonic, larvae and adult stages. We were able to define subtle differences of expression of the two gfod genes and we showed that a subset of GABAergic neurons express gfod1. Taken together, we conclude that both gfod gene family members are expressed in overlapping as well as in distinct regions in the zebrafish central nervous system. Our data suggest that gfod1 and gfod2 are relevant both for the developing and adult zebrafish brain. This study paves the way for further functional analyses of this yet unexplored gene family.
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http://dx.doi.org/10.1016/j.gep.2020.119111DOI Listing
June 2020

Individualised stepwise adaptive treatment for 3-6-year-old preschool children impaired by attention-deficit/hyperactivity disorder (ESCApreschool): study protocol of an adaptive intervention study including two randomised controlled trials within the consortium ESCAlife.

Trials 2020 Jan 9;21(1):56. Epub 2020 Jan 9.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Medical Faculty of the University of Cologne, Cologne, Germany.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a psychosocially impairing and cost-intensive mental disorder, with first symptoms occurring in early childhood. It can usually be diagnosed reliably at preschool age. Early detection of children with ADHD symptoms and an early, age-appropriate treatment are needed in order to reduce symptoms, prevent secondary problems and enable a better school start. Despite existing ADHD treatment research and guideline recommendations for the treatment of ADHD in preschool children, there is still a need to optimise individualised treatment strategies in order to improve outcomes. Therefore, the ESCApreschool study (Evidence-Based, Stepped Care of ADHD in Preschool Children aged 3 years and 0 months to 6 years and 11 months of age (3;0 to 6;11 years) addresses the treatment of 3-6-year-old preschool children with elevated ADHD symptoms within a large multicentre trial. The study aims to investigate the efficacy of an individualised stepwise-intensifying treatment programme.

Methods: The target sample size of ESCApreschool is 200 children (boys and girls) aged 3;0 to 6;11 years with an ADHD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a diagnosis of oppositional defiant disorder (ODD) plus additional substantial ADHD symptoms. The first step of the adaptive, stepped care design used in ESCApreschool consists of a telephone-assisted self-help (TASH) intervention for parents. Participants are randomised to either the TASH group or a waiting control group. The treatment in step 2 depends on the outcome of step 1: TASH responders without significant residual ADHD/ODD symptoms receive booster sessions of TASH. Partial or non-responders of step 1 are randomised again to either parent management and preschool teacher training or treatment as usual.

Discussion: The ESCApreschool trial aims to improve knowledge about individualised treatment strategies for preschool children with ADHD following an adaptive stepped care approach, and to provide a scientific basis for individualised medicine for preschool children with ADHD in routine clinical care.

Trial Registration: The trial was registered at the German Clinical Trials Register (DRKS) as a Current Controlled Trial under DRKS00008971 on 1 October 2015. This manuscript is based on protocol version 3 (14 October 2016).
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http://dx.doi.org/10.1186/s13063-019-3872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953462PMC
January 2020

Anxiety risk SNPs on chromosome 2 modulate arousal in children in a fear generalization paradigm.

Eur Child Adolesc Psychiatry 2020 Sep 21;29(9):1301-1310. Epub 2019 Dec 21.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Alterations in fear learning/generalization are considered to be relevant mechanisms engendering the development of anxiety disorders being the most prevalent mental disorders. Although anxiety disorders almost exclusively have their first onset in childhood and adolescence, etiological research focuses on adult individuals. In this study, we evaluated findings of a recent meta-analysis of genome-wide association studies in adult anxiety disorders with significant associations of four single nucleotide polymorphisms (SNPs) in a large cohort of 347 healthy children (8-12 years) characterized for dimensional anxiety. We investigated the modulation of anxiety parameters by these SNPs in a discriminative fear conditioning and generalization paradigm in the to-date largest sample of children. Results extended findings of the meta-analysis showing a genomic locus on 2p21 to modulate anxious personality traits and arousal ratings. These SNPs might, thus, serve as susceptibility markers for a shared risk across pathological anxiety, presumably mediated by alterations in arousal.
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http://dx.doi.org/10.1007/s00787-019-01458-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497385PMC
September 2020

High-resolution chromosomal microarray analysis for copy-number variations in high-functioning autism reveals large aberration typical for intellectual disability.

J Neural Transm (Vienna) 2020 01 14;127(1):81-94. Epub 2019 Dec 14.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.

Copy-number variants (CNVs), in particular rare, small and large ones (< 1% frequency) and those encompassing brain-related genes, have been shown to be associated with neurodevelopmental disorders like autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID). However, the vast majority of CNV findings lack specificity with respect to autistic or developmental-delay phenotypes. Therefore, the aim of the study was to investigate the size and frequency of CNVs in high-functioning ASD (HFA) without ID compared with a random population sample and with published findings in ASD and ID. To investigate the role of CNVs for the "core symptoms" of high-functioning autism, we included in the present exploratory study only patients with HFA without ID. The aim was to test whether HFA have similar large rare (> 1 Mb) CNVs as reported in ASD and ID. We performed high-resolution chromosomal microarray analysis in 108 children and adolescents with HFA without ID. There was no significant difference in the overall number of rare CNVs compared to 124 random population samples. However, patients with HFA carried significantly more frequently CNVs containing brain-related genes. Surprisingly, six HFA patients carried very large CNVs known to be typically present in ID. Our findings provide new evidence that not only small, but also large CNVs affecting several key genes contribute to the genetic etiology/risk of HFA without affecting their intellectual ability.
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http://dx.doi.org/10.1007/s00702-019-02114-9DOI Listing
January 2020

Transcript Analysis of Zebrafish GLUT3 Genes, and , Define Overlapping as Well as Distinct Expression Domains in the Zebrafish () Central Nervous System.

Front Mol Neurosci 2019 27;12:199. Epub 2019 Aug 27.

Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function . GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington's and Alzheimer's diseases. Furthermore, was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish () has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, and . Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The transcripts are present in overlapping as well as distinct regions compared to . Double hybridizations were used to demonstrate that is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish and expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.
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http://dx.doi.org/10.3389/fnmol.2019.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718831PMC
August 2019

Serotonergic influence on depressive symptoms and trait anxiety is mediated by negative life events and frontal activation in children and adolescents.

Eur Child Adolesc Psychiatry 2020 May 17;29(5):691-706. Epub 2019 Aug 17.

Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5-HTTLPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents (N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/L + S/L + LL + LL genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only LL genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.
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http://dx.doi.org/10.1007/s00787-019-01389-3DOI Listing
May 2020

No Association of Variants of the NPY-System With Obsessive-Compulsive Disorder in Children and Adolescents.

Front Mol Neurosci 2019 3;12:112. Epub 2019 May 3.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

Obsessive-compulsive disorder (OCD) causes severe distress and is therefore counted by the World Health Organisation (WHO) as one of the 10 most impairing illnesses. There is evidence for a strong genetic underpinning especially in early onset OCD (eoOCD). Though several genes involved in neurotransmission have been reported as candidates, there is still a need to identify new pathways. In this study, we focussed on genetic variants of the Neuropeptide Y (NPY) system. NPY is one of the most abundant neuropeptides in the human brain with emerging evidence of capacity to modulate stress response, which is of high relevance in OCD. We focussed on tag-SNPs of and its receptor gene in a family-based approach. The sample comprised 86 patients (children and adolescents) with eoOCD with both their biological parents. However, this first study on genetic variants of the NPY-system could not confirm the association between the investigated SNPs and eoOCD. Based on the small sample size results have to be interpreted as preliminary and should be replicated in larger samples. However, also in an additional GWAS analysis in a large sample, we could not observe an associations between NPY and OCD. Overall, these preliminary results point to a minor role of NPY on the stress response of OCD.
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http://dx.doi.org/10.3389/fnmol.2019.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511743PMC
May 2019

KCNJ6 variants modulate reward-related brain processes and impact executive functions in attention-deficit/hyperactivity disorder.

Am J Med Genet B Neuropsychiatr Genet 2020 07 17;183(5):247-257. Epub 2019 May 17.

Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.

KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)-relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, on reporter gene expression was explored in cultured cells. The KCNJ6 variants were then tested for association with ADHD and personality traits in a family-based sample (165 affected children) and an adult case-control sample (450 patients, 426 controls). Furthermore, the genotypic influence on performance in an n-back task and a cued continuous performance test (cCPT) was investigated by electroencephalography recordings. Finally, rs6517442 function was assessed by a reward anticipation paradigm using functional magnetic resonance imaging. Different haplotypes of rs7275707 and rs6517442 significantly influenced KCNJ6 gene expression proving their functional relevance on the molecular level. In the family-based children sample rs7275707 was associated with ADHD (p = .038). Moreover, rs7275707 showed association with the personality trait of Reward Dependence (p = .031). In the ADHD group, both rs7275707 and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopamine-related brain processes in ADHD risk.
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http://dx.doi.org/10.1002/ajmg.b.32734DOI Listing
July 2020

Mean Heart Rate and Parameters of Heart Rate Variability in Depressive Children and the Effects of Antidepressant Medication.

Z Kinder Jugendpsychiatr Psychother 2019 May 11;47(3):253-260. Epub 2019 Apr 11.

1 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.

Researchers have repeatedly discovered an association between depression and autonomic cardiac dysregulation in adults. However, corresponding data concerning minors are still rare. For this exploratory, cross-sectional study, we included = 43 minors (age range 9-17 years). The subjects were depressive subjects with or without antidepressant medication ( = 23) or healthy control children (HC) ( = 20). We assessed several indices of cardiac functioning using long-term electrocardiogram data (mean heart rate, HR, and several parameters of heart rate variability, HRV). We hypothesized that increased HR and reduced HRV are associated with depressive disorders. Furthermore, we assessed the impact of age, sex, and antidepressant medication on HR and HRV. When sex and age were controlled for, HR was significantly increased in depressive minors compared to HC. However, our preliminary data suggest that this might not be the case in medicated patients, and there were no differences between groups regarding HRV parameters. There was no significant correlation in the whole sample between severity of depression and both HR and HRV. In the subsample of patients with depression, antidepressant medication was associated with lower HR and higher indices of HRV. The data indicate an association between depression and altered autonomic cardiac regulation, which can already manifests in minors.
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http://dx.doi.org/10.1024/1422-4917/a000672DOI Listing
May 2019

Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder.

Atten Defic Hyperact Disord 2019 Mar 29;11(1):107-111. Epub 2019 Mar 29.

Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Tübingen, Tübingen, Germany.

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, p = 1 p = 1) and rs356219 (OR 1.28; p = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, p = 0.020), which survived Bonferroni correction (p = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, p = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.
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http://dx.doi.org/10.1007/s12402-019-00286-8DOI Listing
March 2019

Association study and a systematic meta-analysis of the VNTR polymorphism in the 3'-UTR of dopamine transporter gene and attention-deficit hyperactivity disorder.

J Neural Transm (Vienna) 2019 04 28;126(4):517-529. Epub 2019 Mar 28.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.

Attention-deficit hyperactivity disorder (ADHD) has been postulated to associate with dopaminergic dysfunction, including the dopamine transporter (DAT1). Several meta-analyses showed small but significant association between the 10-repeat allele in the DAT1 gene in 3'-untranslated region variant number tandem repeat polymorphism and child and adolescent ADHD, whereas in adult ADHD the 9-repeat allele was suggested to confer as risk allele. Interestingly, recent evidence indicated that the long-allele variants (10 repeats and longer) might confer to lower expression of the transporter in comparison to the short-allele. Therefore, we assessed here the association in samples consisting of families with child and adolescent ADHD as well as a case-control sample, using either the 10- versus 9-repeat or the long- versus short-allele approach. Following, we conducted a systematic review and meta-analysis, including family and case-control studies, using the two aforementioned approaches as well as stratifying to age and ethnicity. The first approach (10-repeat) resulted in nominal significant association in child and adolescent ADHD (OR 1.1050 p = 0.0128), that became significant stratifying to European population (OR 1.1301 p = 0.0085). The second approach (long-allele) resulted in significant association with the whole ADHD population (OR 1.1046 p = 0.0048), followed by significant association for child and adolescent ADHD (OR 1.1602 p = 0.0006) and in Caucasian and in European child and adolescent ADHD (OR 1.1310 p = 0.0114; OR 1.1661 p = 0.0061; respectively). We were not able to confirm the association reported in adults using both approaches. In conclusion, we found further indication for a possible DAT1 gene involvement; however, further studies should be conducted with stringent phenotyping to reduce heterogeneity, a limitation observed in most included studies.
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http://dx.doi.org/10.1007/s00702-019-01998-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456487PMC
April 2019

On the Role and Significance of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy (CAPPP) Within the Planned National Health Centers.

Z Kinder Jugendpsychiatr Psychother 2019 Mar;47(2):103e-110e

5 Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim of the University of Heidelberg.

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http://dx.doi.org/10.1024/1422-4917/a000658DOI Listing
March 2019

Zur Rolle und Bedeutung der Kinder- und Jugendpsychiatrie, -psychosomatik und -psychotherapie (KJPPP) in den geplanten nationalen Gesundheitszentren.

Z Kinder Jugendpsychiatr Psychother 2019 Mar 7;47(2):103-110. Epub 2019 Feb 7.

5 Klinik Psychiatrie und Psychotherapie des Kindes- und Jugendalters , Zentralinstitut für Seelische Gesundheit (ZI), Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim.

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http://dx.doi.org/10.1024/1422-4917/a000649DOI Listing
March 2019

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Transl Psychiatry 2019 02 4;9(1):75. Epub 2019 Feb 4.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Preclinical studies point to a pivotal role of the orexin 1 (OX) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10), particularly in the female subsample (p = 9.8 × 10). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
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http://dx.doi.org/10.1038/s41398-019-0415-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361931PMC
February 2019

The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis.

Am J Med Genet B Neuropsychiatr Genet 2019 09 25;180(6):365-376. Epub 2018 Nov 25.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.

Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.
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http://dx.doi.org/10.1002/ajmg.b.32695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767385PMC
September 2019

[Polypharmacy of psychotropic drugs in child and adolescent psychiatry in Germany - rather the rule than the exception].

Z Kinder Jugendpsychiatr Psychother 2019 May 13;47(3):193-202. Epub 2018 Nov 13.

1 Zentrum für Psychische Gesundheit (ZEP), Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg, Würzburg.

Polypharmacy of psychotropic drugs in child and adolescent psychiatry in Germany - rather the rule than the exception Polypharmacy increases the risk of interactions and enhances the chance of adverse drug reactions (ADRs). Hence, child and adolescent psychiatrists generally try to avoid polypharmacy with psychotropic drugs. However, only little data regarding the frequency of polypharmacy in child and adolescent psychiatry are available. This study analyzes clinical data on polypharmacy and the possible association with a higher risk of ADRs in Germany, with a focus on antidepressants and antipsychotics. We investigated a total of 940 datasets from descriptive studies on therapeutic drug monitoring (TDM) of pediatric patients treated with different psychotropic drugs. The frequency of polypharmacy ranged up to 45.6 % (escitalopram) and 72.1 % (olanzapine). In 17.4 % of the cases, polypharmacy consisted of four or more psycho-/neuropharmacological substances. No increased incidence of ADRs was reported with polypharmacy of antipsychotics compared to monotherapy. Polypharmacy with sertraline was associated with a higher number of ADRs. There is a high prevalence of polypharmacy with psychotropic drugs in child and adolescent psychiatry in Germany. Conclusions concerning individual drugs should be drawn with care since the subsample sizes were relatively small. However, our results do provide an indication of the prevalence of polypharmacy, although the validity of the data is limited. There is an urgent need to analyze data from larger and more homogeneous groups under more controlled conditions.
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http://dx.doi.org/10.1024/1422-4917/a000632DOI Listing
May 2019

Fractal Analysis of BOLD Time Series in a Network Associated With Waiting Impulsivity.

Front Physiol 2018 4;9:1378. Epub 2018 Oct 4.

Center of Mental Health, Department of Child and Adolescent Psychiatry, University of Wuerzburg, Wuerzburg, Germany.

Fractal phenomena can be found in numerous scientific areas including neuroscience. Fractals are structures, in which the whole has the same shape as its parts. A specific structure known as (also called fractal or 1/f noise) is one key fractal manifestation, exhibits both stability and adaptability, and can be addressed via the Hurst exponent (). FMRI studies using on regional fMRI time courses used fractality as an important characteristic to unravel neural networks from artificial noise. In this fMRI-study, we examined 103 healthy male students at rest and while performing the 5-choice serial reaction time task. We addressed fractality in a network associated with waiting impulsivity using the adaptive fractal analysis (AFA) approach to determine . We revealed the fractal nature of the impulsivity network. Furthermore, fractality was influenced by individual impulsivity in terms of decreasing fractality with higher impulsivity in regions of top-down control (left middle frontal gyrus) as well as reward processing (nucleus accumbens and anterior cingulate cortex). We conclude that fractality as determined via is a promising marker to quantify deviations in network functions at an early stage and, thus, to be able to inform preventive interventions before the manifestation of a disorder.
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http://dx.doi.org/10.3389/fphys.2018.01378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180197PMC
October 2018

Cognitive-behavioral therapy effects on alerting network activity and effective connectivity in panic disorder.

Eur Arch Psychiatry Clin Neurosci 2019 Aug 4;269(5):587-598. Epub 2018 Oct 4.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, 97080, Wuerzburg, Germany.

Given the particular relevance of arousal and alerting in panic disorder (PD), here the alerting network was investigated (1) contrasting patients with PD and healthy controls, (2) as a function of anxiety sensitivity constituting a dimensional measure of panic-related anxiety, and (3) as a possible correlate of treatment response. Using functional magnetic resonance imaging (fMRI), 45 out-patients with PD (f = 34) and 51 matched healthy controls were investigated for brain activation patterns and effective connectivity (Dynamic Causal Modeling, DCM) while performing the Attention Network Task (ANT). Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). Forty patients and 48 controls were re-scanned after a 6 weeks cognitive-behavioral treatment (CBT) or an equivalent waiting time, respectively. In the alerting condition, patients showed decreased activation in fronto-parietal pathways including the middle frontal gyrus and the superior parietal lobule (MFG, SPL). In addition, ASI scores were negatively correlated with connectivity emerging from the SPL, the SFB and the LC and going to the MFG in patients but not in healthy controls. CBT resulted in an increase in middle frontal and parietal activation along with increased connectivity going from the MFG to the SPL. This change in connectivity was positively correlated with reduction in ASI scores. There were no changes in controls. The present findings point to a pathological disintegration of the MFG in a fronto-parietal pathway in the alerting network in PD which was observed to be reversible by a successful CBT intervention.
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http://dx.doi.org/10.1007/s00406-018-0945-8DOI Listing
August 2019

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

Mol Psychiatry 2020 09 16;25(9):2047-2057. Epub 2018 Aug 16.

Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Center of Mental Health, University of Würzburg, Würzburg, Germany.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.
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http://dx.doi.org/10.1038/s41380-018-0210-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473839PMC
September 2020

Outdoor air pollution, greenspace, and incidence of ADHD: A semi-individual study.

Sci Total Environ 2018 Nov 21;642:1362-1368. Epub 2018 Jun 21.

Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Allergy and Lung Health Unit School of Population and Global Health, University of Melbourne, Melbourne, Australia.

Background: Attention deficit hyperactivity disorder (ADHD) is a frequently occurring neurodevelopmental disorder, symptoms of which first appear in early childhood. Etiology of ADHD is not well understood. We investigated whether outdoor air pollution and greenspace affect ADHD incidence in children residing in Saxony.

Methods: 66,823 children, all beneficiaries of the statutory health insurance company AOK PLUS and born between 2000 and 2004, were followed until 2014. We considered any child with at least one ICD-10-GM F90 diagnosis by a child/adolescent psychiatrist, neuropaediatrician, or psychotherapist an ADHD case. Children's home addresses were known up to their four-digit postal code area. Population-weighted mean values of particulate matter with diameter of < 10 μm (PM), nitrogen dioxide (NO), and MODIS Normalized Difference Vegetation Index (NDVI) were calculated for 186 postal code areas. Associations with each exposure were assessed by two-level adjusted Poisson regression models.

Results: 2044 children (3.06%) were diagnosed with ADHD within the observation period. An increase of PM and NO by 10 μg/m raised the relative risk of ADHD by a factor of 1.97 [95% CI: 1.35-2.86] and 1.32 [1.10-1.58], respectively. A 0.1-unit increase in NDVI decreased the relative risk of ADHD by a factor of 0.82 [0.68-0.98]. Better access to child/adolescent psychiatrists was the most important confounder that increased ADHD risk across all models.

Conclusion: Our results provide some evidence that air pollution might affect ADHD. Future studies with more detailed address information and better control for confounders, in particular socioeconomic status and parental psychopathology, should replicate the observed associations.
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http://dx.doi.org/10.1016/j.scitotenv.2018.06.167DOI Listing
November 2018

Analysis of shared heritability in common disorders of the brain.

Science 2018 06;360(6395)

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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http://dx.doi.org/10.1126/science.aap8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097237PMC
June 2018

Ambient ozone exposure and mental health: A systematic review of epidemiological studies.

Environ Res 2018 08 1;165:459-472. Epub 2018 May 1.

Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Electronic address:

Background: An increasing number of studies have suggested adverse effects of air pollution on mental health. Given the potentially negative impacts of ozone exposure on the immune and nervous system driven from animal experiments, ozone might also affect mental health. However, no systematic synthesis of the relevant literature has been conducted yet. This paper reviews the studies that assessed the link between ozone exposure and mental health thus far.

Methods: We followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). PubMed, Web of Science, and EMBASE were systematically searched for epidemiological studies on ambient ozone exposure and mental or behavioral disorders according to the International Classification of Disease. The period was from January 1st, 1960 to December 14st, 2017. We evaluated the risk of bias by the Office of Health Assessment and Translation (OHAT) Approach and Navigation Guide for each included study.

Results: The keyword search yielded 567 results. 31 papers met the selection criteria and were included in the review. We found only inconclusive evidence that ozone affects autism spectrum disorders, impairment of cognitive functions and dementia, depression, and suicide. The large heterogeneity of study designs, outcome definitions and study quality in general prevented us from conducting meta-analyses.

Conclusions: Current evidence for an association between ambient ozone exposure and mental health outcomes is inconclusive and further high quality studies are needed to assess any potential links given the strong biologic plausibility.
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http://dx.doi.org/10.1016/j.envres.2018.04.015DOI Listing
August 2018

Individualised short-term therapy for adolescents impaired by attention-deficit/hyperactivity disorder despite previous routine care treatment (ESCAadol)-Study protocol of a randomised controlled trial within the consortium ESCAlife.

Trials 2018 Apr 27;19(1):254. Epub 2018 Apr 27.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Center of Mental Health, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.

Background: Despite the high persistence rate of attention-deficit/hyperactivity disorder (ADHD) throughout the lifespan, there is a considerable gap in knowledge regarding effective treatment strategies for adolescents with ADHD. This group in particular often shows substantial psychosocial impairment, low compliance and insufficient response to psychopharmacological interventions. Effective and feasible treatments should further consider the developmental shift in ADHD symptoms, comorbidity and psychosocial adversity as well as family dysfunction. Thus, individualised interventions for adolescent ADHD should comprise a multimodal treatment strategy. The randomised controlled ESCAadol study addresses the needs of this patient group and compares the outcome of short-term cognitive behavioural therapy with parent-based telephone-assisted self-help.

Methods/design: In step 1, 160 adolescents aged 12 to 17 years with a diagnosis of ADHD will undergo a treatment as usual (TAU) observation phase of 1 month. In step 2, those still severely affected are randomised to the intervention group with an Individualised Modular Treatment Programme (IMTP) or a telephone-assisted self-help programme for parents (TASH) as an active control condition. The IMTP was specifically designed for the needs of adolescent ADHD. It comprises 10 sessions of individual cognitive behavioural therapy with the adolescents and/or the parents, for which participants choose three out of 10 available focus modules (e.g. organisational skills and planning, emotion regulation, problem solving and stress management, dysfunctional family communication). TASH combines a bibliotherapeutic component with 10 counselling sessions for the parents via telephone. Primary outcome is the change in ADHD symptoms in a clinician-rated diagnostic interview. Outcomes are assessed at inclusion into the study, after the TAU phase, after the intervention phase and after a further 12-week follow-up period. The primary statistical analysis will be by intention-to-treat, using linear regression models. Additionally, we will analyse psychometric and biological predictors and moderators of treatment response.

Discussion: ESCAadol compares two short-term non-pharmacological interventions as cost-efficient and feasible treatment options for adolescent ADHD, addressing the specific needs and obstacles to treatment success in this group. We aim to contribute to personalised medicine for adolescent ADHD intended to be implemented in routine clinical care.

Trial Registration: German Clinical Trials Register (DRKS), Current Controlled Trial DRKS00008974, http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00008974 ; http://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008974 ; Registered on 28 December 2015.
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http://dx.doi.org/10.1186/s13063-018-2635-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921777PMC
April 2018
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