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Mapping susceptibility genes for attention deficit hyperactivity disorder

This collaborative MRC-funded project led by Philip Asherson and Eric Taylor, more details at:
Inst. of Psychiatry K.C.L

This collaborative MRC-funded project led by Philip Asherson and Eric Taylor brings together expertise from both within the Centre and the MRC Child Psychiatry Unit (Ian Craig, Thalia Eley, Robert Plomin, and Emily Simonoff (the School of Medicine). The aim of this project is to identify genes conferring susceptibility to attention deficit hyperactivity disorder (ADHD) in children. It is now generally accepted that allelic association studies are the most powerful method for detecting genes of small effect in complex disorders and a systematic genome screen for association and candidate gene association studies will be performed. Adaptation of DNA pooling techniques will make it possible to perform a rapid preliminary genome wide screen. Proband assessments will allow a polydiagnostic approach to be gathered on parental phenotypes, siblings and environmental variables, enabling gene-environment interactions to be studied once genetic risk factors are isolated.

Hyperactivity

Eric Taylor has carried out research on the assessment and classification of attention deficit and hyperactivity which has now led to a refinement of the diagnosis (Taylor 1998, Swanson and others 1998). Explicit behavioural criteria define a disorder in which high rates of neurological problems are found.

Prevalence in different countries

Hyperactivity occurs all over the world; when explicit behavioural criteria are used the rates are very similar. Different diagnoses (eg ADHD and hyperkinetic disorder) mark different levels of severity.

Rubia and others (1998) have clarified the nature of this brain basis of Attention Deficit/Hyperactivity Disorder (ADHD) with a pioneering study using the new technique of functional magnetic resonance imaging to investigate how children with ADHD cope with situations in which they are required to withhold responses - in effect, to stop and think rather than being impulsive. The results have shown marked underactivity of the brain in ADHD - especially in an area involving the frontal lobes and basal ganglia, which normally works to inhibit inappropriate responses, and is underfunctioning in young people with ADHD.

Functional magnetic resonance imaging has been applied to measure brain activity while the person is doing a test involving stopping or delaying a response. An area of the frontal part of the brain is underactive in young people with attention deficit disorders.

Our long-term investment in a longitudinal study programme is now starting to deliver very clinically relevant information. Our previous work found that hyperactivity is a substantial risk factor for the development of psychopathology in late adolescence. Michael Rutter and colleagues (1997) have now found a set of factors in children with ADHD that predict who will grow out of their problems and who will have continuing difficulties in adolescence and early adult life. For example, good acceptance by families and low levels of hostility from other people are associated with a better outcome in young adult life. This helps clinicians to be more accurate in giving prognoses to the families of affected children, and it also helps them to set the right targets for therapy e.g. cognitive behavioural therapy. A preliminary trial of the reduction of hostile and critical expressed emotion by family members has shown that a programme of education and advice can indeed achieve the desired end and that the children's level of hyperactivity also falls.

A diagram illustrating possible treatments.

Taylor and others (1998) have conducted a programme of controlled treatment trials (medication, diet and psychotherapies) which has led them to formulate proposals for routine treatment that are the basis of a consensus European guidelines document. The resulting principles and details of treatment for the disorder - both psychological and pharmacological - have been taught to multidisciplinary professional groups throughout the country, and this process has contributed to rapid changes in practice by the NHS, with many more children now having their disorder recognised and treated than was the case even three years ago.

Conduct disorder

Conduct disorders - persistent patterns of aggressive, antisocial, and defiant maladjustment - are the most prevalent form of child psychological disorder and the commonest problems referred to child mental health clinics. They have also been notorious for the extent to which they are refractory to conventional treatment.

Innovative treatments are therefore being introduced and assessed through our child mental health clinics. Stephen Scott (1998) has shown with a controlled trial that parent training in groups using video technology is an effective treatment for conduct problems in childhood. This is potentially of great importance for health service practice and for preventive work with young offenders. The treatment technique is being taught to clinicians in selected NHS centres elsewhere, and we plan expansion of trials on this form of cost-effective intervention.

We have also been able to report progress on understanding the basic causes of conduct disorder (Eaves and others 1997). Our collaborative twin studies have shown that there are genetic as well as environmental effects on the way that antisocial behaviour develops, and Michael Rutter and Robert Plomin (1997) in the Social, Genetic & Developmental Psychiatry Research Centre (SGDPRC) have developed a theory about how these factors interact. This longer-term research is intended to lead to better understanding about how to treat those individuals who do not respond to the promising therapies that we are now evaluating in our trials programme.

Cognitive deficits in developmental disorders

The Wellcome Trust has funded a study (Francesca Happé with Claire Hughes) to examine the relationship between executive function and social cognition. This will be investigated by comparing boys with autism and boys with ADHD, with the prediction that these groups may share deficits in some executive functions but will differ in their social cognitive capacities and cognitive style. This work is planned to lead to future functional imaging studies of normal and abnormal development and to QTL research.

Francesca Happé, in collaboration with Uta Frith at University College London, is also examining specific cognitive mechanisms assumed to be critical to the development of theory of mind. Dysfunction in this mechanism is hypothesised to play a role in the causation of autism.

Hyperactivity

Attention Deficit/Hyperactivity Disorder has become a much more widely accepted concept, diagnosed with increasing frequency, in the light of the evidence that it is not just a component part of the spectrum of disadvantage and conduct disorder. We are continuing follow-up studies of boys and girls who were originally selected from the general population because of hyperactive and/or antisocial behaviour. Genetic factors are important in the origins of the disorder, but some maintaining factors are psychosocial: we are exploring the interactions of neuropsychological abnormalities and environmental risk and protective factors.

Eric Taylor, Katja Rubia and Phillip Asherson have therefore set up a combination of structural and functional magnetic resonance imaging studies with DNA studies of candidate genes. A cooperation between a consortium of clinics in London and Southampton has been set up, that will enable enough cases to be systematically scanned so that susceptibility genes can be mapped across the genome.

Conduct disorder

As described above, we are concentrating both on defining the risk and protective factors and on evaluating the results of promising interventions with random-allocation controlled trials. The emphasis has been on short-term and focussed therapies, especially those that can be delivered into communities on a group basis or an affordable individual contact with a therapist. This is in part because the conduct and oppositional disorders are very common indeed; only a proportion are ever referred to mental health services and even then they make up the most numerous category of problems at most clinics. Consideration of cost-effectiveness is therefore important. Furthermore, the positive results already obtained in some of out trials contrast with the negative results of evaluations of longer-term and less focussed therapy. Our current work is therefore building on the encouraging results already obtained and examining the possibilities of early identification and treatment in a variety of community settings.

This insight into the way that individuals' constitutions come to alter their environments is potentially relevant to the longer-term prevention of the complications of conduct disorder. We are taking this further with a genetic twin study based partly on a follow-up study of twin pairs in which one or both twins attended The Maudsley Hospital, and partly on a population-based sample of over 1400 twin pairs, aged 8 to 16, carried out as a collaborative study with Professor Lindon Eaves of the University of Virginia and others. Genetic factors appear to account for just over a third of the population variance in conduct disturbance, measured dimensionally. The pattern of genetic and environmental influences on aggressive behaviour differs from that applied to other forms of conduct disorder. It looks as though genetic influences are stronger on antisocial behaviour in adult life than they are in childhood. Family factors are strong in childhood and can potentially be modified through psychological treatment.

Forward Look

The research of this IRG will be focussed on themes of direct relevance to the work of the NHS - disorders with high impact in childhood, including the disorders that lead to antisocial behaviour, childhood depression, and those that result from abnormal development of the brain or from severe psychosocial trauma; the development of clinical trial methodology and results for child and adolescent psychiatry; and the establishment of methods and findings for analysing the operation of the child mental health services.

Disruptive and antisocial behaviours

The various forms of antisocial and disruptive behaviour disorders impose high costs on individuals and society. We are planning a programme of investigations to include: Analysis of the use of different types of service by children with ADHD; and economic costing of the impact of the disorders on society and the costs of treatment The identification of treatment goals and targets needs to be based on a better understanding of how and why the disorders develop. We shall therefore pursue a programme of research, in collaboration with the Centre for Social Genetic and Developmental Research, to identify the main influences on development, both biological and psychosocial Biological research will aim to uncover the causes of ADHD, based on neuropsychological and brain imaging studies of what goes wrong when attention is impaired; molecular and behaviour genetic analyses of the inherited contribution to the disorder; and study of children with relevant neurological abnormalities such as perinatal brain damage Psychosocial analyses will focus on longitudinal studies, to clarify the contributions made to ADHD and conduct disorder by social adversity and alterations of relationships A randomised controlled trial, in conjunction with educationalists, of home and school interventions for the prevention of conduct disorder in 5-year-old children.

Neurodevelopmental problems

Some child psychiatric problems are now considered to be based on altered brain function. However, clinical practice still identifies far fewer cases than research has indicated should be detected. Our research will therefore focus on:

Improving the methods of diagnosis:

in hyperkinetic disorder, where schemes of clinical identification from the ages of four to 16 will be worked out and tested, based on predicting carefully diagnosed cases with objective measures and empirical cut-offs in autism, where the nature of the broader phenotype will be worked out with a program of neuropsychological and genetic study and an analysis of the reasons for the links between autism and intellectual retardation in cerebral palsy, where the types of psychological problem encountered will be charted in a population survey of hemiplegia.

Clarifying the causes of developmental disorders through:

a molecular genetic study of autism a study of brain-behaviour relationships in hemiplegia examining the spectrum of problems in children who have been exposed to very severe deprivation in childhood molecular genetic techniques will also be used, in collaboration with the Social, Genetic and Developmental Psychiatry Research Centre, to clarify the inherited as well as the environmental contributions to the major disorders of affect (anxiety and depression) in childhood and to ADHD.

Inst. of Psychiatry K.C.L

Our thanks to Kathy West for bringing this to our attention

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Attention Deficit Disorder Online Information




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