10

The Past, Present, and Future Science of ADHD

So much work has been conducted on ADHD that one might expect some definitive answers. The biomedical sciences have made great headway into understanding the disorder, yet we still search for an elusive cause: a rogue gene, a dysfunctional brain, a poor diet, too much television, society, and, as always, bad parents.

The future science of ADHD is both guided and limited by its past. There is a tendency to follow the main hypotheses – this represents a safe funding option; therefore the future science of ADHD is as much political as it is academic.

One might consider that the search for a single cause of ADHD is futile. There may be many reasons why someone has the disorder – trauma, genes, and environment. There may be combinations of genes and other factors that conspire to cause ADHD. However, the search for the causal routes of the disorder is not futile – it just happens to be very difficult.

My intention for this book was to provide a scientific account of ADHD, and I thought that biology would provide the most parsimonious account. I still view the biological perspectives as some of the most convincing – if for no other reason than the sheer volume of work. But volume is not enough; sometimes the science is limited by its methodology and the conclusions are overstated. Critics of a biological perspective would clearly agree, but their accounts are often no better (and sometimes arguably worse). The amount of information on ADHD is impressively large, sometimes contradictory, and often controversial. The science needs to continue, but it always needs to be methodologically rigorous. We need new avenues to look at and we should not be blinkered by the pre-existing literature. New ideas and theories will come from those who think outside of the box and refuse to accept the traditional landscape of ADHD!

For all those involved in research, the future science of ADHD is as much dependent on diagnostic accuracy as it is on new technologies that can assess genetics or see differences in the brain at a higher resolution than we can today.

We have seen how the diagnosis of ADHD has evolved over the past century, and new diagnostic criteria will be released in the near future. Science is as much informed by these changes as the changes are informed by science. With the recognition of adult ADHD set to become official, we have the opportunity to study this disorder extensively and in a way that is not possible in children and adolescents. We can begin to chart a developmental trajectory in both normal and psychopathological development. Developmental psychology has provided us with detailed accounts of normal development, but the emerging subdiscipline of developmental neuroscience should allow us to investigate the mechanisms underlying the changing symptomatology of ADHD over the lifespan. In an aging population it will be interesting to see the behavioral and biological changes of those with ADHD. What will ADHD look like at the age of 70 or 80 years? Will the behaviors fade? Will the biology still be evident? Many questions remain unanswered.

Of course, one can identify differences in the biology between control groups and those with ADHD, but it is unclear how these differences translate into behavior and disorder. There are many intermediate steps bridging the gap between gene and disorder. The numerous psychological perspectives have focused primarily on executive functions bridging the gap. But other psychosocial factors should also be considered, e.g. temperament and personality.

Without a doubt, there are shortcomings in executive functioning in ADHD. What causes the deficits is another matter that needs to be resolved. To some extent, the functional imaging studies are beginning to determine what regions of the brain are active (or inactive) and how different neurocircuits interact during various cognitive tasks. Such studies need to be completed in healthy populations before they can yield useful information in patient populations, but one also has to acknowledge that the study of various disorders provides valuable insight into normal functioning.

One has to be cautious of imaging studies; they can seduce the reader into believing that there are definite regions of the brain associated with behaviors and processes. The technology gives us vivid pictures of brain differences between groups, but these pictures are only as good as the tasks that are deployed during scanning, e.g. BI tasks. Such tasks are laboratory phenomena that detect differences in ADHD groups and more besides. Much has been done with the standard neuropsychological tasks, and they have contributed enormously to the theoretical accounts of ADHD. However, it has been pointed out that new tasks are needed that are more precise and focus attention on specific and different regions [1282].

My personal view is that the majority of neuropsychological tasks may have little bearing on real-world situations. We need to make tasks with increased ecological validity and that are relevant to everyday life. This does not mean that we have to give up the scientific pursuit of such psychological investigations. Indeed, it is highly important to maintain the rigors of science, otherwise conclusions may not be justified, but a greater variety of tasks that have meaning would be illuminating. In my life I see my son’s impulsivity – his quick reactions; but I don’t see the Go/No-go task. If anything, in a more ecological setting where he is motivated he is far better than I am. To illustrate this point, whilst playing a “combat-shoot-’em-up” arcade game, similar to Call of Duty, that is popular on home consoles, I can see the advantages of different neuropsychological tasks. The game involved shooting the enemy and not your comrades within virtual worlds. The enemy outnumber comrades, as do the go to no-go trials in a laboratory task. The game therefore has a similar set of parameters as the BI task, but is far more fun. My son was able to identify and kill the enemy without killing comrades. He did this with speed and ruthless efficiency. I, on the other hand, just killed everything that came within my sights – friend or foe. This point illustrates two things: (1) a need for increased utilization of more ecological measures in which the child can engage and see the outcome; and (2) my questionable parenting skills letting my son play such games … but it was extremely enjoyable!

Little has been done to address the ecological validity of tests and tasks. Children with ADHD have been shown to perform poorly on Conners’ Continuous Performance Test, but when the same test was given in a video­game format the performance was the same as control [1283].

Furthermore, the majority of tasks that have been used in the literature are tasks of executive function and therefore most likely of the frontal lobe. What of other areas of the brain? Tasks are needed too for these other regions and the more specific areas of the frontal lobe (e.g. the orbitofrontal cortex) [1282].

We have seen how we are limited by the neuropsychological tasks, but we are even limited by the imaging techniques themselves. Neuroimaging has good spatial resolution but it is slow to react. Psychophysiological measures such as EEGs have excellent temporal resolutions but their spatial prowess is somewhat lacking. Studies are already combing the two techniques, and future studies will be sure to continue with this. Technology is moving at a rapid pace: one can envisage better techniques that will eventually be able to trace chemicals such as dopamine, which presently still requires radioactive tracers to achieve this end.

Despite the disappointment that genetics has not provided us with solid data about ADHD, we need to continue the search. However, the research needs to move away from purely characterizing an ADHD genome. It appears clear that this is unlikely to be found as many genes have only a modest effect in ADHD. The use of neuropsychological measures such as the behavioral inhibition tasks and working memory tasks offer a way of looking at genes in specific behaviors that may be a subset of the symptoms of ADHD – the endophenotype approach. A goal of the National Institutes of Mental Health in the USA was to “identify the neural and neurochemical substrates of basic cognitive processes that are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level” [1284] (p. 357). This will most likely highlight many different genes that have hitherto been overlooked in ADHD. Therefore we should not expect to see reports along the lines of a gene for ADHD. We are also unlikely to see reports in the media of the science that identifies genes involved in sustained attention or inhibitory control – far less sexy than a gene for ADHD. According to Durston et al., “imaging genetics approaches have the potential to reshape the way we think about ADHD: if multiple endophenotypes can be defined that lead to symptoms of ADHD, we will ultimately be able to define subtypes based on their biological signature” [1285] (p. 685). If this can be achieved, diagnosis will be informed further, and rather than the current one-size-fits-(nearly)-all approach, treatment can be more targeted at the individual and his or her unique symptoms.

Many are grateful for the drugs that are used to treat ADHD, but there has been little progress in the last 40 years – we are still using methylphenidate. New methods of delivery that ensure optimum levels of drug in the brain have been a vast improvement upon what existed previously, but in the main the actual drug remains the same. New drugs need to be found, and this is the business of the research and development departments within the pharmaceutical industry. Many drugs have been discovered to be effective within psychiatry by chance, but now as our understanding of the neuroanatomy, neurochemistry, and molecular genetics of ADHD is growing more sophisticated, biotechnology may be able to target the specifics of the disorder without recourse to widespread pharmacological activity. We need the precision of a scalpel not a shotgun. With higher pharmacological precision, we may be able to avoid or minimize some of the negative side-effects associated with the current pharmacological arsenal. One caveat must remain: there is always the possibility that the pharmacological cocktail that is present is just the antidote for ADHD.

How do we know the answers? This can only be achieved by research using scientific methods. The future science of ADHD will address the questions of pharmacogenetics and pharmacoimaging. Pharmacogenetics will explain what the genetic basis of a therapeutic response is. Perhaps those with a particular variant will respond well to one drug, whilst those with a different genetic variant will respond well to another. The possibility opens up for individualized therapy. Pharmacoimaging provides a more detailed opportunity to follow the effects of the drugs on the brain. Again this could lead to tailor-made therapies in the future. But studies also need to be conducted looking at the drugs’ effects over the developmental lifespan. The effects of a drug could well be different between a child and an adult with ADHD. We know the brain is developing throughout the first 25 years of life and possibly even longer. The effects of drugs need to be evaluated in this context.

In terms of treatment, we have tended to focus on psychopharmacology, but what about other treatments? Behavioral interventions and CBT are moderately successful, but do they have a similar or different neurotherapeutic rationale to the drugs? Similarities will point to common denominators, but differences may point to new regions of the brain that have not had a great deal of attention in ADHD research.

ADHD is rarely expressed on its own. Comorbidity is a real factor that needs careful consideration. The interaction of symptoms from the different disorders needs evaluating. Are the symptoms of ADHD exacerbated by affective disorders, or are affective disorders a result of ADHD? Furthermore, the symptoms of the varying comorbid disorders can overlap – the obvious example is impulsivity in both ADHD and addiction. The overlap may provide increased understanding of biological basis of these behaviors. Again similarities and differences are both important. This also brings into play how a particular endophenotype can exist for multiple disorders. The term “Impulse Control Disorder” is now frequently used in psychology, but how does impulsivity express itself as ADHD in one person and addiction in another?

Apart from the academic interest in the comorbid nature of ADHD, there is a more pragmatic use of such knowledge in terms of treatment. Again, the potential for individualized therapies targeting behaviors rather than disorders might be beneficial.

Towards a Better Understanding and Treatment of ADHD

The phrase “translational research” is used frequently in scientific communities. It is obviously important that research informs treatment – we want safe and effective drugs; but it is also vital that research informs policy. Sadly there is less evidence to support this happening. The conflict between the UK Home Office and Professor David Nutt over the dangers and legality of alcohol, nicotine, cannabis, and MDMA in 2009 is a sad testimony to the lack of translation.

On September 24, 2008 the National Institute for Health and Clinical Excellence (NICE) guidelines were released and hit the media. The NICE guidelines represent an attempt to review the evidence and make recommendations on the basis of that evidence. The media attention was not unusual, but, watching news bulletins, the take-home message was that parents need lessons in dealing with their children’s behavior. Interestingly and to their credit, the reports do not doubt the existence of ADHD, but they do put forward an anti-drug stance. They also allow for an interpretation of the headline in which parents could be to blame (e.g. parents need lessons in how to cope with their children’s unruly behavior), but also an interpretation in which parents need help with ADHD as they would if their child had diabetes or epilepsy.

The extract from the BBC website is typical.1

Parents need lessons in how to cope with their children’s unruly behaviour, new guidelines on attention deficit hyperactivity disorder (ADHD) say. …

[Parent training and education programs for preschool and school-age children] teach parents how to create a structured home environment, encourage attentiveness and concentration, and manage misbehaviour better.

Drugs remain a first option for children over five and young people with severe ADHD, say the guidelines, but only as part of a comprehensive treatment plan that includes psychological and behavioural interventions.

Dr Tim Kendall, a consultant psychiatrist from Sheffield who is joint director of the National Collaborating Centre for Mental Health and helped draw up the guidelines, said: “There is an over-reliance on medicines.”

“Quite commonly, people tend to revert to offering methylphenidate or atomoxetine. When they do that it’s not always because there’s a good balance of risk and benefits. It’s because the child has got what appears to be ADHD and that’s what’s available.

“Its easier to prescribe a drug when other options like parent training programmes are not available.”

Dr Kendall said it was important to diagnose ADHD correctly, rather than label all bad behaviour as ADHD. The symptoms of ADHD persist in all settings – both at school and at home – and cause real impairment.

Andrea Bilbow, chief executive of the ADHD charity ADDISS, welcomed the NICE recommendations but questioned how helpful the parent training programmes would be to parents.

“Parenting programmes are extremely important, but they need to be specific for ADHD.

“The ones that NICE are recommending were designed for the parents of children with conduct disorder, which is completely different from ADHD,” she said.

What Do the NICE Guidelines on ADHD Really State?

The National Institute for Health and Clinical Excellence (NICE) is an independent organization responsible for providing guidance on the promotion of good health and the prevention and treatment of ill health.

NICE comprises advisory groups made up of health professionals, those working in the NHS, patients, their carers, and the public. It provides guidelines developed using the expertise of health-care professionals, patients and carers, industry, and academia. It is a multidisciplinary group that has to look at a great deal of evidence in the form of published reports.

Healthcare professionals in the NHS are expected to follow NICE’s clinical guidelines. If a treatment is recommended, then that should be offered to the patient on the NHS. However, there are times when NICE may not support the use of a treatment. The rejection of the treatment by NICE is usually because there is not enough reliable evidence supporting its use compared to other treatments. Therefore you will not get the treatment on the NHS. This was recently highlighted in the media after NICE did not recommend the use of Aricept (donepezil) for the treatment of Alzheimer’s disease. It argued that the cost was not sufficiently justified by the effect. Thus in a cash-strapped NHS, NICE are also looking at the economics of health care. Like the consumer in the high street, they want value for money.

NICE guidelines, when they appear, are therefore critical to the health care that is available to those who have a disorder, and this now includes ADHD. NICE, under the chairmanship of Profesor Eric Taylor, has recently published its guidance for the treatment of ADHD. Its guidance extends beyond childhood and includes adult ADHD, despite the fact that it does not appear in any of the current diagnostic manuals.

The guidelines state that the treatment of ADHD should be undertaken by specialist health-care professionals with training and expertise. So that is not the school or the parents in the playground. A full clinical and psychosocial evaluation should be conducted with age-appropriate consideration, and diagnosis should not rest on rating scales (see chapter 2).

The advice the guidelines give upon diagnosis is to refer people to self-help manuals and look at the diet of those with ADHD, avoiding additives, but enhancing fatty acids (see chapter 3). They also stress that teachers should be informed and trained to deal with ADHD. In reality I cannot see much of this happening – the two groups will need to improve cross-service communication and budgets will need to be directed towards teacher training.

For preschool children, drugs are not to be used and parents are guided to parent training programs. For school-age children with moderate ADHD and their families, psychosocial interventions are recommended. Drug treatment should only be offered after non-drug options have either been refused or been unsuccessful. However, those with severe ADHD who represent the ADHD-C subtype (DSM-IV) or HKD (ICD-10) should have drug therapy as a first-line treatment – and again parent training.

The prescription of drugs for ADHD should only be initiated by the skilled health professional with expertise in the disorder. After the initial prescription, the GP can maintain prescribing and monitoring. Monitoring should consist of heart rate and blood pressure, height and weight. Other aspects such as a family history of cardiovascular disease or substance misuse should also be considered.

NICE recommends three drugs: methylphenidate, atomoxetine, and amphetamine-based products (see chapters 7 and 8). Which drug to use depends on the presenting symptoms and comorbidities. NICE continues to suggest using methylphenidate immediate release during initial titration and to determine the most effective dose. If methylphenidate is not tolerated or ineffective, the use of atomoxetine is an option. Once it is established that methylphenidate is effective and at what dose, then a switch to long-acting formulations should be considered. In adults the first-line treatment is considered to be drug therapy.

The NICE guidelines have come under some criticism from Michael Schlander. He argues that they are based on incomplete data analysis and that there is a bias in the process used [1286]. He also argues that there is an over-reliance on the economics of treatments [1287] and insufficient attention to long-term effects of treatment and the knock-on effects of ADHD for caregivers etc. [1288].

The NICE guidance on ADHD will remain intact for many years to come. Treatment has been evaluated as cost-effective and will be delivered via health service providers. This is in contrast to the change that will occur in science. Hopefully science will help illuminate more precisely the underlying causes of ADHD. There will be a continued effort to pursue such goals, with increasingly large volumes of publications hitting the press each year. This science will need to be accommodated into future guidance. There is increasing acknowledgment that research needs to translate itself from the laboratory to the clinic. Arguably, the future for those with ADHD is more positive than it was 10 years ago, but we need everyone to work together, not just health professionals, but education, social services, the pharmaceutical industry, and the media. The science of ADHD will always need to be truly multidisciplinary.

Note

1 http://news.bbc.co.uk/1/hi/health/7630926.stm.