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ADHD: The state of play 

The quest to find the underlying causes of ADHD continues. What have we learnt from the latest genetic findings and what are their implications in the real world?

‘ADHD is currently and universally understood by professionals and policy makers to be biological in origin, but psychological and social in expression, in which outcomes are determined by a complex set of relationships between the individual and the environment that they experience and indeed create’. 

Background

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent diagnoses in childhood and adolescent psychiatry, with symptoms often continuing into adulthood. It is estimated that between 3 and 5% of school-age children are diagnosed and for unknown reasons, a higher rate is found in boys. Parents or schools usually take the first steps in identifying children with ADHD. Teachers are often the first professionals to notice a child’s difficulties, perhaps because they have the opportunity to compare the child’s functioning with that of other children of a similar age, or often the behaviours typical of ADHD are more visible in a school environment. The diagnostic process from recognition of suspected ADHD symptoms to actually gaining a definitive diagnosis can be long and fraught with complications.

One reason for this is because there is no biological or objective test to detect the presence of ADHD. The diagnostic assessment is usually undertaken by a psychiatrist or psychologist, in part by measuring parental and professional (e.g. teachers) views of behaviour. This process follows criteria set by international classification systems (ICD-10 and DSM-IV). Clinicians make a distinction between three subtypes of ADHD dependent on clusters of symptoms. These include, predominantly inattentive type, predominantly hyperactive type and the combined type, this is because symptoms can vary significantly between individuals. For a diagnosis to be made, a child must display at least 6 core symptoms of 18 described. These are split into two behavioural symptoms sets:

1. Inattention - including criteria such as: often makes careless mistakes, difficulty sustaining attention in play or other activities and often does not seem to listen when spoken to directly.

2. Impulsivity/hyperactivity - including criteria such as: often fidgets or squirms, often cannot stay seated, blurts out and is impatient.

These behaviours need to seriously interfere with the child’s functioning in at least two settings (for example, at home and at school, identified by parent and teacher reports), be present before the age of seven years old, persist for at least six months and not be better accounted for by another psychiatric condition, for example, schizophrenia, autism or other developmental disorder.

Co-morbidities

 Complications in diagnosing ADHD are confounded by the fact that it is often accompanied by other problems. Research has found that in a community setting, 44% of cases have at least one additional disorder present.2 This is increased in a clinical setting, with 87% of children having one additional disorder and around 67% of children having at least two.3 The most common co-morbidity is oppositional defiant disorder (ODD) or the more serious, conduct disorder (CD). These children pose significant and persistent opposition to authority figures such as parents and teachers through negative, hostile or defiant behaviours and aggression towards others, in extreme cases (conduct disorder). Anxiety, depressive symptoms and communication disorders are also frequently problematic. A large proportion of children diagnosed with autistic spectrum disorders and intellectual disability have also been found to meet criteria for ADHD. These relationships are not well-understood at the present time, but are a focus of current and future research.

 The relationship between the symptoms of ADHD, autistic spectrum disorders (ASD) and intellectual disability (ID).10

Figure 1 - The relationship between the symptoms of ADHD, autistic spectrum disorders (ASD) and intellectual disability (ID).10

 

Treatment options

There is no treatment that can cure ADHD, long-term therapies are usually required. The National Institute of Clinical Excellence (NICE) provide comprehensive guidance on the most up-to-date evidence-based approaches in the treatment of ADHD.5 Suggested treatment options include combinations of behaviour modification, life-style changes, counselling and medication. The treatment direction depends on a variety of factors, for example, the child’s age, severity of symptoms, co-existing conditions, the wishes of parents and other personal circumstances.

Medication has been found to be effective in reducing the core symptoms of ADHD in some children; however, their use is controversial for a variety of reasons. Stimulants (such as methylphenidate and dexamphetamine) are the most common drug treatment prescribed in cases of ADHD where behavioural options have not improved symptoms, and in severe cases. Stimulants work by increasing levels of neurotransmitters (dopamine and norepinephrine) in the brain. Caution is urged when using drug treatment for a variety of reasons, including:
  • questions over its long-term effectiveness
  • the inability of stimulant medication to solve secondary problems associatedwith ADHD (e.g. problems with self-esteem and peer relationships)
  • its ineffectiveness in some children
  • concerns about potential side-effects.

When medication is utilised, it is urged to be used with caution and in conjunction with psychological approaches. This combination treatment can, in some cases, reduce the dosage of medication required to achieve a positive clinical outcome.5 Examples of behavioural interventions that have strong effectiveness in ADHD include psycho-educational techniques, behaviour therapy, cognitive behaviour therapy (CBT), interpersonal psychotherapy, family therapy, school-based interventions, social skills training and parent training/education. 5

Causes

Research to date has found considerable evidence of deficits in brain function and problems with executive functioning in ADHD, known to be involved in planning and the self-regulation of emotions and behaviour. Neuro-imaging studies have detected a range of neurological abnormalities more common in those with ADHD, including differences in the:

  • frontal cortex (especially the right hemisphere) – may affect inhibitory function
  • cerebellum and basal ganglia – control the output of behaviour
  • parietal lobes – involved in directing and sustaining attention
  • neurotransmitter inefficiencies - specifically dopamine, noradrenaline and serotonin – which may affect communication between different parts of the brain responsible for memory, language, organisation and action.

ADHD has long been known to run in families, with twin studies indicating that genetics play a role in approximately 75% of cases.4 Subsequent molecular genetic studies have found a number of DNA variants to be associated with ADHD, each signifying a small contribution to its etiology,5 however, replicating findings has proven to be difficult. To highlight the complexity of the potential genetic effect on ADHD development, it is interesting to look at the gene variant that codes for a dopamine receptor (DRD4 7- repeat allele), thought to be involved in the control of attention. Researchers have found that in those with ADHD and the DRD4 7 repeat allele (compared to those without) are more likely to catch up with the development of unaffected children.6 Geneticists now understand that it is extremely unlikely that a single gene is responsible for the development and course of this complex disorder.

Twin studies have also found that between 9% and 20% of the variance in symptoms may be due to environmental factors. Research has highlighted a number of potential environmental risks including maternal alcohol intake, tobacco and heroin use, psycho-social stress during pregnancy and exposure to a range of toxins (such as lead and pesticides) early in life. There is also evidencefor increased risk from low birth weight, foetal hypoxia (lack of oxygen to the brain) and brain injuries. ADHD has also been associated with severe early psycho-social adversity. Discordant family relationships are a controversial factor that may have a bearing on the risk of ADHD development in some cases. Negative family relationships are common in those with ADHD, but whether this is a product of living with a child with these symptoms or an actual risk factor is not clear. There is also evidence of a link between additives and preservatives in children’s diets and levels of hyperactivity.5

Complex gene environment interactions are thought to be an extremely important avenue of future research. This interplay may be different for cause, course and outcomes, further complicating matters. It is becoming clear that to have any hope of truly understanding how ADHD develops, research will have to look at a myriad of genes, neural circuits and environmental factors, all interacting over time, as well as the effect various interactions have on behaviour.

What does the latest genetic research tell us?

At the end of September 2010, a study was published in the Lancet by a group of researchers from Cardiff University, who studied one type of genetic variation in a sample of children with ADHD.7 It was reported that some children with ADHD have a higher burden of large rare copy number variations (CNVs), in particular areas of their DNA. The term CNV simply describes when a large piece of DNA is duplicated or missing in the genome. CNVs are common in the general population but recently a large amount of research interest has focused on their role in the development of a range of psychiatric disorders.

Key findings

  • Copy number variations (CNVs) were found to be most common in children with ADHD and co-morbid intellectual impairment.
  •  Significantly greater CNVs were found in children with ADHD (14%) compared with children without ADHD (7%).
  • The CNVs identified have previously been implicated in autism, schizophrenia and learning disabilities indicating these conditions may share biological as well as clinical features.
  • The genetic region involved spanned 7 genes. One gene is known to play a role in the development of the brain.
  • This shared locus was on an area of chromosome 16p13, harbouring genetic duplications (rather than deletions). 7

This is the first evidence to find a direct and replicated genetic link to ADHD, providing a good indication that the future study of rare CNVs in ADHD are likely to produce further insights. This CNV is present in a limited number of individuals with ADHD (14% with the variant, 86% without). However, this is highly significant, considering the complexity of its aetiology. A range of other genetic and environmental factors are likely to be at large, these are likely to vary considerably from individual to individual.

These findings allow for the possibility that the same rare CNVs may play a role in a range of neurodevelopmental disorders. Experts say it may be that these regions are crucial to development of the brain in the womb or infancy and that disruption in this region may play a role in many psychiatric conditions.12 Recently, additional evidence of other large CNVs linking the developmental disorders has been reported. The author stated ‘we have uncovered a recurrent pathogenic CNV that confers a very high risk for autistic spectrum disorders (ASD), schizophrenia and neurodevelopmental disorders’. A significant deletion on chromosome 17 was found in both autism and schizophrenia.8

Implications for diagnosis

The fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-V) is due for publication in 2013. Autism and ADHD are not currently suggested to be diagnosed in the same individual (autism predominates), despite a significant overlap in symptoms. The usefulness of allowing these diagnoses to co-exist, and the usefulness of the 3 subtypes (inattentive, hyperactive-impulsive or combined types) are examples of the classificatory issues under debate in relation to ADHD.9 Experts involved in the continued development of the DSM, will no doubt review these latest genetic findings when making decisions about these classificatory issues.

The view of many professionals is that ‘we are dealing with multiple interacting spectra of developmental disabilities’.10 (see Figure 1). It has been suggested that the most useful way forward is to retain umbrella diagnoses for ADHD, autistic spectrum disorders and intellectual disability and to specify according to the severity and nature of any defining features. These features may include level of intellectual functioning, unusual or specific clinical traits, associated medical conditions, developmental difficulties, social issues, possible aetiologies, and any management, intervention and support implications.10 The recent genetic findings support this view and highlight the importance of clinicians to be vigilant in investigating alternative or co-existing diagnoses in children with ADHD.

Future treatment and management

Due to the varied causes and high level of co-existing difficulties that many young people with ADHD face, it is unlikely that a single cause, single treatment, or single outcome approach is going to be found. It is clear that any treatment programme needs to be tailored to individual circumstances and changing needs. Ideally, a package of treatment should be available, dependent on the child’s specific symptom set, co-morbidities and family situation. These genetic findings are in their very early stages and thus have no direct implications for treatment at the present time. Treatment options will continue to follow NICE guidelines of behaviour, medication and combined treatment approaches where necessary.5,11 Anita Thapar who headed the study stated, that knowing any genes involved would not necessarily affect current treatment methods chosen by doctors.12

 These genetic findings may work towards changing the way this controversial diagnosis is viewed by some.11 The notion ADHD is just an excuse for bad behaviour (with no biological cause) or due to ineffective parenting alone is looking highly unlikely from these findings and from our previous knowledge. It may be that the perceptions of ADHD in the future may be more aligned with our perceptions of autism, often a more socially accepted diagnosis of biological origin.

Conclusion

The complexity and incompletion of our knowledge about the causes of ADHD goes some way to explain the disagreement and controversies that surround this prevalent disorder. The exact causes are still unknown but are likely to involve the interplay between genes and environmental risk factors. This very early evidence of increased levels of large rare genetic differences (CNVs) in a small number of individuals with ADHD provides a further window of understanding into its complex etiology. These findings do not rule out the involvement of other types of genetic abnormalities or environmental factors. These are very early findings and provide an exciting avenue for further exploration. Researchers are now likely to focus on replicating these particular CNVs in other samples, take a more in-depth look at the roles of the genes involved, and how they relate to symptom presentation in ADHD and between the neurodevelopmental disorders. The difficult task of understanding gene environmental interactions will also be a major focus of further research, and how to turn any findings into novel way to treat the condition. Thus the continued investigation into the causes of ADHD is likely to provide an invaluable evidence base to inform the development of more effective treatment strategies in the future.

Glossary

Autism – A spectrum of disorders including deficits in social interaction, communication as well as a propensity for repetitive behaviour

Behaviour therapy – A form of therapy that uses learning techniques to change maladaptive behaviour, by substituting undesirable responses to stimuli with desirable ones

Co-morbidity – A medical condition that may exist simultaneously but independently with another condition, or caused by or related to another condition

Cognitive behaviour therapy (CBT) – A form of psychotherapy that aims to teach a person how to better solve emotional, behavioural and cognitive problems using a goal orientated systematic procedure

Conduct disorder – Someone with this condition will display behaviours that violate the rights of others (e.g. aggression, cruel behaviour towards people and animals, lying and stealing etc)

Developmental disorder – A disorder that disrupts normal development in childhood

Dopamine – An important neurotransmitter (chemical messenger) released in the brain

Etiology – Refers to the causes or origins of a disease

Family therapy – A form of psychotherapy used to identify family behaviours that may have an impact upon a particular disorder. This type of therapy aims to help families break those behaviour patterns to improve family functioning and inhibit undesirable behaviours

Intellectual disability – Describes lower than average intellectual functioning that is present from birth or infancy and contributes to differences in development, learning deficits and social adjustment problems

Molecular genetic studies - The branch of genetics concerned with the chemical structure, functions replication and mutations of the molecules involved in the transmission of genetic information (mainly RNA and DNA)

Neuro-imaging studies – A range of imaging techniques (e.g. PET, MRI) are used to investigate aspects of neural activity

Neurotransmitter – There are a number of chemicals in the brain that are released from nerve cells which transmit neurological information from one nerve cell to other nerve cell, muscle, organ or other tissue of the body

Oppositional defiant disorder – Children diagnosed display recurring negative, hostile, disobedient and defiant behaviour. Often co-exists with ADHD

Psychotherapy – Treatment using verbal and non-verbal communication, to relieve emotional distress and promote positive methods of coping

Psychiatry – A branch of medicine that is concerned with the diagnosis and treatment of mental, emotional and behavioural disorders

Clinical psychology – A branch of psychology that works to diagnose and treat mental disorders. Clinical psychologists cannot prescribe medication, this is undertaken by a psychiatrist

Psycho-social – A combination of psychological and social factors

Receptor – A sensory nerve ending that responds to various stimuli

Schizophrenia – A brain disease that symptoms that may include loss of personality, agitation, catatonia, confusion, psychosis, unusual behaviour and withdrawal

Serotonin – A neurotransmitter found in the brain that is responsible for stimulation of the smooth muscles, transmission of impulses between nerve cells and regulation of cyclic body processes (amongst other functions)

Social skills training – Social skills are taught to help people to be able to achieve social reinforcement and minimise social punishment

Twin studies – This type of study uses twins to determine the interplay of genetic and environmental factors on disease development. These studies are easier using identical twins (monozygotic), rather than non-identical twins (dizygotic) as they are genetically identical

References

1 Colley, B. (2010) Science and the common man. Emotional and Behavioural Difficulties. Vol 15 (3) pp 223-237

2 Szatmari, P., Offord, D. R., & Boyle, M. H. (1989a). Correlates, associated impairments and patterns of service utilization of children with attention deficit disorder: findings from the Ontario Child Health Study. J Child Psychol Psychiatry, 30(2), 205-217

3 Elia, J., Ambrosini, P., & Berrettini, W. (2008). ADHD characteristics: Concurrent co-morbidity patterns in children & adolescents. Child Adolesc Psychiatry Ment Health, 2(1), 15

4 Farone et al, (2005) What is the prevalence of adult ADHD? Results of a population screen of 966 adults, Journal of Attention Disorders, 9, 384-391

5 National Institute of Clinical Excellence (2008) Attention deficit hyperactivity disorder – diagnosis and management of ADHD in children, young people and adults. [online] Available from http://guidance.nice.org.uk/CG72 [Accessed 8 November 2010]

6 Shaw, P., Ekstrand, K., Sharp, W., Blumental, J., Lerch, J.P., Greenstein, D., Classen, L., Evans, A., Geidd, J., Rapoport, J.L. (2007) Attention deficit hyperactivity disorder is characterised by a delay in cortical maturation. Proc Natl Acad Sci, 104: 19649-19645

7 Williams, N.M., Zaharieva, I., Martin, A., Langley, K., Mantripragda, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O., Holmans, P., Owen, M, O’Donovan, M., Thapar, A. (2010) Rare chromosomal deletions and duplications in attention deficit hyperactivity disorder. The Lancet, Vol 376 (9750), pp1401-1408

8 Cell press (2010) New genetic risk factor for both autism and schizophrenia. Science daily. Available from http://www.sciencedaily.com/releases/2010/11/101104154221.htm  [November 17, 2010]

9 American Psychiatric Association (2010) Report of the DSM-V neurodevelopmental disorders work group. [Online] Available from http://www.psych.org/MainMenu/Research/DSMIV/DSMV/DSMRevisionActivities/DSMV
WorkGroupReports/NeurodevelopmentalDisordersWorkGroupReport.aspx [Accessed 17 November 2010]

10 Turk, J. (2010) Meeting the mental health needs of children and young people who have intellectual disability. [presentation]. October 2010 ed. Cerebra Annual Conference

11 Thapar, A. (2010) Genetics ADHD article [email] (Personal communication, 4 November 2010)

12 Coghlan, A., (2010) Have gene findings taken the stigma from ADHD? New Scientist [Online] Available from http://www.newscientist.com/article/dn19528-have-gene-findings-taken-the-stigma-from-adhd.html [Accessed 19 November 2010]

This information is not meant to replace the advice of any physician or qualified health professional. The information provided by Cerebra is for information purposes only and is not a substitute for medical advice or treatment for any medical condition. You should promptly seek professional medical assistance if you have concerns regarding any health issue.

 

Page last updated: 16/12/2011 16:21 
ADHD state of play 
 
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