ADHD Program

Attention-Deficit/Hyperactivity Syndrome:
Molecular Pathogenesis and Endophenotypes in the Course of Treatment

Director:
Prof. Dr. K.P. Lesch

Molecular Psychiatry
Department of Psychiatry, Psychosomatics and Psychotherapy
University of Würzburg
Füchsleinstr. 15
97080 Würzburg

Phone:   +49-931-201 77600
Fax:        +49-931-201 77620
E-mail: kplesch@mail.uni-wuerzburg.de

Office:
Ms. J. Stilla

Telefon: +49-931-201 77600
Fax:        +49-931-201 77620
E-mail: judith.nicol@mail.uni-wuerzburg.de

Coordinator:
Prof. Dr. A. Warnke

Department of Child and Adolescent Psychiatry
University of Würzburg
Füchsleinstr. 15
97080 Würzburg

Phone: +49-931-201 78000
Fax: +49-931-201 78040
E-mail: rung@kjp.uni-wuerzburg.de

Summary

The molecular pathogenesis of Attention-Deficit/Hyperactivity Syndrome (ADHD) and the significance of its endophenotypes and comorbid disorders, such as substance abuse, affective disorders, and antisocial personality disorders, for the course of illness is both clinically and health politically a highly relevant but largely unsolved problem. The Clinical Research Group (KFO 125), as a joint facility of the Departments of Child and Adolescent Psychiatry and Psychotherapy (KJPP) and Adult Psychiatry and Psychotherapy (EPP), deals with the interdependent relationships between the molecular and functional-structural mechanisms of the pathogenesis of ADHD and its significance for its long-term course using interdisciplinary and translational research strategies.

The primary goals are as follows:

•     By joining preclinical and clinically oriented research groups, who work on ADHD-specific molecular mechanisms of nerve cell function as well as molecular genetic and developmental biological essentials of brain function, and on structural-functional basis of the complex behavior of ADHD, predictors and differential strategies for therapy during the long-term course of illness will be developed.

•     Evolutionary conserved ADHD-relevant principles of structure and function of the brain as well as syndrome-typical behavior (e.g. hyperactivity, attention-deficit, impulsivity, aggression, substance use) will be defined by comparative investigations of different species (humans, nonhuman primates, mice).

•     The preexisting areas of convergence between the fields of neuropsychology, psychobiology as well as child and adolescent psychiatry and adult psychiatry will strengthen the connections between the individual disciplines by establishing new research groups, who will investigate common topics. In that, new opportunities for the study of the molecular foundations in the etiopathogenesis and long-term course of ADHD will be developed.

The basis for the pursuit of these goals is the interdisciplinary composition of KFO 125 and its integration into the research structures of the University of Wuerzburg (e.g. SFB 581, GRK 1156, GRK 1263, GSLS, IZKF) as well as into a wide spectrum of national (e.g. BMBF Multicenter Study: Therapy of ADHD, National Network ADHS, MPI of Molecular Genetics) and international collaborations (e.g. EU Newmood Network, NIMH, NHGRI, NIDA, NIAAA, Tgen Research Institute). This resulted in a specific and long-term configuration of competence at Clinical Institute of the University of Wuerzburg with focus on future-oriented translational research of etiopathogenetic mechanisms and novel therapeutic options of ADHD.

Overview

Attention-deficit/hyperactivity disorder (ADHD; MIM 143465) is the most common behavioral disorder in childhood with a prevalence of 3-6% and with substantial heritability which is likely due to multiple genes of small effect size. Long-term studies demonstrated persistence into adulthood with lifetime prevalence estimated at approximately 4%. Epidemiological studies suggested high co-morbidity with other psychiatric disorders, lifetime prevalence rates of anxiety disorders in adult ADHD approach 50%. Affective disorders and alcohol/drug dependence also display a substantial prevalence. The co-morbidity with antisocial personality disorders was reported to be increased in several clinical cohorts. The burden of disease has been estimated by accounts of social and economic problems as well as impaired academic achievement and work performance. While prenatal and parental risk factors may be important mediators of influences on the risk, a great deal of the association between these variables and ADHD appears to be indirect. Particularly, disruptive family environment may harm offspring development.

Family, adoption, and twin studies revealed that ADHD is a highly heritable disorder (h²: 70-80%) with a multifactorial pattern of inheritance. Genom-wide linkage analyses identified several susceptibility loci, for example on chromosome 4q13.2, 16p13, and 17p11. Faraone and colleagues listed eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratios across studies: the dopamine receptor D4 (DRD4), dopamine receptor D5 (DRD5), dopamine transporter (DAT), and dopamine b-hydroxylase (DBH), serotonin 1B receptor (HTR1B), serotonin transporter (5HTT) and synaptosomal-associated protein 25 (SNAP-25) genes. Moreover, complex interactions are to be expected between environmental factors and multiple genes each with a small to moderate influence on different traits.

A complex multigenetic etiology with contribution of genes influencing different neuronal functions and intermediate phenotypes are thought to form the genetic basis of ADHD and several brain areas, neurocircuits, and transmitter systems have been implicated. Pharmacological and functional neuroimaging studies in humans and animal models have consistently linked the prefrontal/anterior cingulate cortex and various connected association cortices to the modulation of attention-, cognition- and motor response-related processes as well as the cortico-limbic circuitry to emotion regulation and are in line with the clinically observed alleviation of symptoms of ADHD by compounds interacting with monoaminergic systems. Dysregulation in synaptic transmission of the dopamine (DA) and serotonin (5HT), but also of the noradrenegic and cholinergic, system is implicated in both the pathophysiology of ADHD and the therapeutic mechanism of action of widely-used stimulants such as methylphenidate (Ritalin™). DAT knockout mice display increased locomotor activity which is reversed by MPH-induced increases serotonergic transmission. In contrast, hyperlocomotion is attenuated by 5-HT enhancing compounds in these mice. Investigations have therefore been concentrating on genes which moderate synaptic transmission and association with ADHD was detected especially for key modulators of the dopaminergic and serotonergic system, such as DRD4, DAT, and 5HTT as well as tryptophan hydroxylase 2 (TPH2).

Although the neurobiological foundation of the clinical entity of ADHD is evident, data from studies on pathomechanism-phenotype correlations are inconsistent. There are several obvious limitations of the DSM-IV diagnostic criteria to describe an adequate phenotype of adult ADHD. For example, age, development, and gender-related modifications of the symptomatology are not taken into account. The criteria refer to the behavior of children and have to be transferred to the behavior of adults without standardized instructions. There is currently substantial debate as to whether the most common category, ADHD-combined, (ADHD-C; inattention and hyperactivity/impulsivity) and ADHD-inattentive (ADHD-I; inattention only) constitute subtypes of the same disorder or are two different disorders. Moreover, it has to be kept in mind that the diagnostic criteria of DSM-IV are based on a categorical model, which is not compatible with the genetic model of quantitative trait loci (QTLs) and is unlikely to reflect neurobiological mechanisms.

A promising alternative research strategy for complex disorders, such as ADHD, are neurobiological construct-based endophenotypes or intermediate, quantifiable traits, that lie in the pathway from genes to behavior predicting an individual's disease risk. Impaired behavioral inhibition is a core deficit of ADHD and four linked executive neuropsychological functions, working memory, self-regulation of affect-motivation-arousal, internalization of speech, and reconstitution (behavioral analysis and synthesis), appear to depend on it for their effective execution. The lack of behavioral inhibition might be associated with orbitofrontal hypoarousal. Based on this concept locomotor hyperactivity, high response variability/ inconsistency in performance, deficit in response inhibition, and impairment of working memory have been proposed as candidate endophenotypes of ADHD.

Locomotor hyperactivity is one of the most prominent clinical symptoms of adult ADHD. Hypo- and hyperdopaminergic models are supported by findings of alterations in DAT density in ADHD patients, the efficiency of psychostimulants (which increase the levels of catecholamines at synapses) in reversing hyperactivity, and dysfunction of the striatum. However, this endophenotype is confounded by aggression and oppositionality. High response variability/inconsistency in performance with subsequent deficits in the perception and reproduction of time intervals are also prevalent features of ADHD. Response inhibition is another endophenotype of ADHD and is the source to obtain a larger, delayed reward, instead of a small, immediate. In that, response inhibition is integral to virtually all behavioral regulation and executive function that allow one to generate voluntary controlled and actively guided behaviors. Working memory is a non-unitary system of processes and mechanisms that allow task-relevant information to be maintained temporarily (for a few seconds) in an active state for further processing or recall, in the service of complex cognition, including novel or familiar skilled tasks. Deficiencies in working memory are linked to delay aversion, executive dysfunction, inattention and phonemic-awareness deficits in ADHD.

Concepts and Goals

By integrating the concepts of molecular genetics, neurobiology, and cognitive psychology, the psychiatric neurosciences have witnessed remarkable progress in the understanding of the relationship between neurodevelopment, neural function, and behavior related to ADHD. In this context particularly animal models such as the mouse or the nonhuman primate contributed important insight. On the other hand improvement of methodological tools in psychology and psychiatry permitted the accumulation of new information on the psychobiological basis of behavior and its alteration in ADHD. The human genome project and the sequencing of mouse and rhesus macaque genomes shifted the focus also to investigations of gene function in biologically founded psychiatry. This development will allow better understanding of both the molecular and cellular foundation of ADHD and the relevance of genetic variation for disease-related behavior such as hyperactivity, attentional and cognitive deficits, emotional dysregulation, and drug use. Finally, the design of novel therapeutic strategies requires the interdisciplinary cooperation of basic research and clinical medicine. But how can the available pieces of our knowledge of ADHD be integrated?

What is particularly lacking is how these diverse fragments of knowledge are connected, not only phenomenologically but also mechanistically. The Clinical Research Group on ADHD has been aspiring to change this situation. Primary goals were and continue to be 1) to join preclinical and clinically oriented research groups, who work on ADHD-specific molecular mechanisms of nerve cell function as well as molecular genetic and developmental biological essentials of brain function, and on structural-functional basis of the complex behavior of ADHD as well as on the development of predictors and differential strategies for therapy during the long-term course of ADHD; 2) to define evolutionary conserved ADHD-relevant principles of structure and function of the brain as well as syndrome-typical behavior (e.g. hyperactivity, attention-deficit, impulsivity, aggression, substance use) by comparative investigations of different species (humans, nonhuman primates, mice); and 3) to take advantage of the preexisting areas of convergence between the fields of neuropsychology, psychobiology as well as child and adolescent psychiatry and adult psychiatry and to strengthen the connections between the individual disciplines by establishing new research groups, who will investigate common topics. Taken together, this is bound to create new opportunities for the study of the molecular foundations in the etiopathogenesis and long-term course of ADHD. With the establishment of the Clinical Research Group as a competence center for research on ADHD the initial goal has been accomplished.

Participating Scientists

Name	Department	Institute	SP
Ms. A. Conzelmann	Neuropsychology	Department of Psychology I	7
Ms. C. Bähne	Neurophysiology	Department of Psychiatry and Psychotherapy	8
Dr. A. Biller	Neuroradiology	Department of Neuroradiology	6
Ms. Dr. A. Boreatti-Hümmer	Psychiatry	Department of Psychiatry and Psychotherapy	1
Ms. Dr. A. Dempfle	Biostatistics	Institute of Epidemiology and Biostatistics	9
Prof. Dr. A.J. Fallgatter	Neurophysiology	Department of Psychiatry and Psychotherapy	6, 8
Prof. Dr. M. Gerlach	Clinical Neurochemistry	Department of Child and Adolescent Psychiatry and Psychotherapy	5
Ms. Dr. E. Grünblatt	Clinical Neurochemistry	Department of Psychiatry and Psychotherapy	5
Dr. M. Herrmann	Neuroimaging	Department of Psychiatry and Psychotherapy	10
G. Homola	Neuroradiology	Department of Neuroradiology	6
Dr. C. Jacob	Psychiatry	Department of Psychiatry and Psychotherapy	2
Ms. T. Huter	Neuroimaging	Department of Psychiatry and Psychotherapy	10
Prof. Dr. A. Karschin	Physiology	Physiological Institute	4
Prof. Dr. K.P. Lesch	Molecular Psychobiology	Department of Psychiatry and Psychotherapy	3, 4, 9, 10
Ms. PD Dr. C. Mehler-Wex	Child and Adolescent Psychiatry	Department of Child and Adolescent Psychiatry and Psychotherapy	1
Dr. R.F. Mucha	Neuropsychology	Department of Psychology I	7
Prof. Dr. P. Pauli	Neuropsychology	Department of Psychology I	7
Dr. A. Reif	Molecular Psychobiology	Department of Psychiatry and Psychotherapy	4
Dr. T. Renner	Child and Adolescent Psychiatry	Department of Child and Adolescent Psychiatry and Psychotherapy	3
Ms. M. Richter	Neurophysiology	Department of Psychiatry and Psychotherapy	8
C. Röser	Molecular Psychobiology	Department of Psychiatry and Psychotherapy	3
Dr. M. Romanos	Child and Adolescent Psychiatry	Department of Child and Adolescent Psychiatry and Psychotherapy	1
Ms. Dr. J. Romanos	Psychiatry	Department of Psychiatry and Psychotherapy	2
M. Schecklmann	Neurophysiology	Department of Psychiatry and Psychotherapy	8
Prof. Dr. H. Schäfer	Biostatistics	Institute of Epidemiology and Biostatistics	9
Prof. Dr. A. Schmidtke	Psychology	Department of Psychiatry and Psychotherapy	2
Ms. Dr. A. Schmitt	Neurobiological Laboratory	Department of Psychiatry and Psychotherapy	5
Prof. Dr. L. Solymosi	Neuroradiology	Department of Neuroradiology	6
Ms. Dr. S. Walitza	Child and Adolescent Psychiatry	Department of Child and Adolescent Psychiatry and Psychotherapy	3
Prof. Dr. A. Warnke	Child and Adolescent Psychiatry	Department of Child and Adolescent Psychiatry and Psychotherapy	1, 9, 10
Dr. P. Weyers	Psychology	Department of Psychology I	7
Dr. T. Wultsch	Molecular Psychobiology	Department of Psychiatry and Psychotherapy	4

SP	Title	Applicants
1	Persistence and longitudinal development of attention-deficit/ hyperactivity disorder in consideration of family genetic determinants	Prof. Dr. A. Warnke Ms. PD Dr. C. Mehler-Wex
2	Long-term follow-up study of attention-deficit/hyperactivity disorder across the life span	Dr. C. Jacob Prof. Dr. A. Schmidtke
3	Functional molecular genetics: genotype - phenotype correlation and linkage analysis in attention deficit/hyperactivity disorder	Prof. Dr. K.P. Lesch Ms. Dr. S. Walitza
4	Behavioral and pharmacological characterization of animal models for attention-deficit hyperactivity disorder	Dr. A. Reif Prof. Dr. A. Karschin Prof. Dr. K.P. Lesch
5	Molecular and cellular characterization of molecular models of attention-deficit/hyperactivity disorder	Ms. Dr. E. Grünblatt Ms. Dr. A. Schmitt Prof. Dr. M. Gerlach
6	Segregation of putative endophenotypes of the attention-deficit/hyperactivity disorder via functional magnetic resonance imaging (fMRI)	Prof. Dr. L. Solymosi Dr. A. J. Fallgatter
7	Emotional-motivational deficits in attention-deficit/hyperactivity disorder	Prof. Dr. P. Pauli Dr. P. Weyers Dr. R. Mucha
8	Electrophysiological correlates of putative endophenotypes of attention-deficit/hyperactivity disorder	Prof. Dr. A.J. Fallgatter
9	Genetic-epidemiological and biostatistical methods for clinical research on attention-deficit/hyperactivity disorder	Prof. Dr. H. Schäfer
10 JRG	Genetic modulation of functional brain activity of attention- deficit/hyperactivity disorder-related working memory processes	Prof. Dr. K.P. Lesch Prof. Dr. A. Warnke

Prof. Dr. K.P. Lesch

Prof. Dr. A. Schmidtke