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Doc. 9456

7 May 2002

Controlling the diagnosis and treatment of hyperactive children in Europe

Report

Social, Health and Family Affairs Committee

Rapporteur: Mr Ovidiu Brînzan, Romania, Socialist Group

Summary

Following a trend set in the USA, increasing numbers of children in certain Council of Europe member States are being diagnosed as suffering from “attention deficit/hyperactivity disorder” (ADHD), and similar behavioural conditions and treated by means of central nervous system stimulants such as amphetamines and methylphenidate, listed in Schedule II of the 1971 United Nations Convention on Psychotropic Substances because their liability to abuse constitutes a substantial risk to public health and they have little to moderate therapeutic usefulness.

Although their precise causes are unknown, the validity of such disorders as ADHD, defined in terms of persistent and severe behavioural symptoms centred on inattention, hyperactivity and impulsiveness, is widely recognised by professional medical, psychological and scientific organisations, including the World Health Organisation. The consensus view is that these behaviourally defined disorders can significantly impair the social, educational and psychological development of some children, resulting in poor self-esteem and emotional and social problems and severely hampering attainment of their educational potential.

However, there is controversy surrounding ADHD, not only as to whether it may validly be described as an abnormality or disease, but above all as to whether it is justified to treat such cases with central nervous system stimulants, which have been shown to be effective in reducing the symptoms, but whose long-term effects are uncertain and which cannot effect a cure.

The Parliamentary Assembly is therefore invited to recommend, among other things, that the Committee of Ministers instruct the European Health Committee to investigate this question in consultation with the appropriate bodies, identify best practice in the diagnosis and treatment of such children fully reflecting their rights and interests, and draft a recommendation to the governments of the member states designed more strictly to regulate diagnosis and treatment on the basis of the precautionary principle and the ethical standards corresponding to the values of the Council of Europe.

I.        Draft recommendation

1.       The Parliamentary Assembly is concerned that increasing numbers of children in certain Council of Europe member states are being diagnosed as suffering from “attention deficit/hyperactivity disorder” (ADHD), “hyperkinetic disorder” or related behavioural conditions and treated by means of central nervous system stimulants such as amphetamines or methylphenidate, which are controlled drugs listed in Schedule II of the 1971 United Nations Convention on Psychotropic Substances because they have been judged by the World Health Organisation to be liable to abuse, to constitute a substantial risk to public health, and to have little to moderate therapeutic usefulness.

2.       This issue is of particular concern to the Council of Europe as a human rights organisation which aims, among other things, to protect the rights of children and to seek European responses to social and health problems including drug use. The Parliamentary Assembly underlines, in accordance with the United Nations Convention on the Rights of the Child, that in all actions concerning children, the best interests of the child must be a primary consideration. Moreover, children have the right to the highest standard of health and medical care attainable, and to protection from the illicit use of drugs.

3.       Although their precise causes are unknown, the validity of ADHD and hyperkinetic disorders, defined in terms of persistent and severe behavioural symptoms centred on inattention, hyperactivity and impulsiveness and resulting in functional impairment, is widely recognised by professional medical, psychological and scientific organisations, including the World Health Organisation. However, the Assembly is concerned that two different sets of criteria are applied in diagnosing these disorders: one adopted by the American Psychiatric Association and used worldwide, the other, more stringent, by the World Health Organisation. The Assembly considers that the basis for these different standards should be examined with a view to clarifying and harmonising the criteria governing diagnosis and treatment.

4.       The consensus view is that these behaviourally defined disorders can significantly impair the social, educational and psychological development of some children, resulting in poor self-esteem and emotional and social problems and severely hampering attainment of their educational potential. The symptoms of ADHD may continue into adolescence and adulthood, and may be accompanied by continuing emotional and social problems, resulting in unemployment, criminality and substance abuse. The toll on those suffering from these disorders, as well as on their families and on society cannot be measured precisely but may be considerable.

5.       Controversy surrounding ADHD hinges not only on whether it may validly be described as an abnormality or disease, but above all on whether it is justified to treat such cases with central nervous system stimulants, which some psychiatric studies have shown to be effective in reducing the symptoms of those diagnosed, allowing them to focus more on what they are doing and reducing their hyperactivity, but whose long-term effects are uncertain and which cannot effect a cure.

6.       The Parliamentary Assembly, emphasising that the precautionary principle should prevail where doubt exists in regard to the long-term effects of medicaments and aware that behavioural disorders of childhood and adolescence, like all mental and behavioural disorders are known to stem from a complex interaction of biological, psychological and social factors, believes that stricter control should be exercised over the diagnosis and treatment of these disorders. The Assembly also considers that more research should be conducted into the impact of proper tutoring and educational solutions for children exhibiting ADHD symptoms, into the behavioural effects of such medical problems as allergies or toxic reactions, and into alternative forms of treatment such as diet.

7.       The Parliamentary Assembly has been disappointed that to date the pharmaceutical industry has not always acted in a way which takes into account the values and principles of the Council of Europe; it wishes to ensure that in future the medical and scientific community and the pharmaceutical industry act in the best interests of society in general, and urges the Committee of Ministers to monitor the situation.

8.       Therefore, the Parliamentary Assembly recommends that the Committee of Ministers:

i.       instruct the European Health Committee, in consultation with the Pompidou Group, the European Committee for Social Cohesion, the Steering Committee on Bioethics and the Steering Committee on Education, and in close cooperation with the appropriate international organisations:

a.       to make a study of the diagnosis and treatment in Europe of children showing symptoms of attention deficit/hyperactivity and similar disorders;

b.       to identify best practice fully reflecting the rights and interests of such children; and

c.       to draft a recommendation to the governments of the member states designed to regulate more strictly the diagnosis and treatment of children showing symptoms of attention deficit/hyperactivity and similar disorders based on the precautionary principle and on the ethical standards corresponding to the values and principles of the Council of Europe;

ii.       to invite the Pompidou Group, in cooperation with the appropriate international organisations, to strengthen guidelines on the promotion of psychotropic drugs;

iii.       invite the governments of the member states:

a.       to monitor more closely the diagnosis and treatment of children showing symptoms of attention deficit/hyperactivity and similar disorders;

b.       to co-ordinate and step up research into the prevalence, causes, diagnosis and treatment (in particular alternative treatments such as diet) of these disorders and in particular into the long-term effects of the psychostimulants prescribed for treatment as well as into the possible social, educational and cultural factors involved;

c.       to produce information material designed for parents of hyperactive children explaining what possibilities exist for improving their condition;

iv.       invite the World Health Organisation, in cooperation with the American Psychiatric Association, to re-examine the basis of their diagnostic criteria respectively for hyperkinetic disorder and ADHD with a view to clarifying and harmonising the criteria governing diagnosis and treatment.

II.       Explanatory memorandum by Mr Brînzan

Introduction

1.       Following a trend set in the USA, increasing numbers of children in certain Council of Europe member States are being diagnosed as suffering from “attention deficit/hyperactivity disorder” (ADHD), “hyperkinetic disorder” or related behavioural conditions and treated by means of central nervous system stimulants such as amphetamines or methylphenidate (better known by its trade name Ritalin). These controlled drugs are listed in Schedule II of the 1971 United Nations Convention on Psychotropic Substances because their “liability to abuse constitutes a substantial risk to public health” and they “have little to moderate therapeutic usefulness”.¹

2.       The International Narcotics Control Board (INCB), a United Nations agency, is increasingly concerned about the rapid increase in the use of such psychostimulants for the purposes of medical treatment over the last decade, primarily in the United States but also in several mainly Western European countries.²

3.       This issue is of particular concern to the Council of Europe as a human rights organisation which aims, among other things, to protect the rights of children, to examine social and health issues including drug use, and to make recommendations to governments.

4.       On 16 May 2000 the Parliamentary Assembly’s Bureau referred this question to the Social, Health and Family Affairs Committee on the basis of a Motion for an Order presented by Mr Gustafsson and others (Doc. 8727), which called for “a study and investigation into this subject so that possible legal measures can be taken to curtail the abuse of psychiatric drugs by children”.

5.       Five months earlier, on 8-10 December 1999, the Council of Europe’s Co-operation Group to Combat Drug Abuse and Illicit Trafficking in Drugs (Pompidou Group), together with the World Health Organisation (WHO) had organised a Seminar on Attention deficit/hyperkinetic disorders: their diagnosis and treatment with stimulants, which produced a preliminary evaluation of the situation in Europe.³ This seminar was organised on the recommendation of the Joint Pompidou Group/International Narcotics Control Board (INCB) Conference on the Control of Psychotropic Substances in Europe, held in Strasbourg on 7-9 December 1998.

6.       Following up the Pompidou Group/WHO seminar, the Social, Health and Family Affairs Committee’s Sub-Committees on Children and on Health organised a joint hearing on 23 November 2001 on the diagnosis and treatment of hyperactive children, to which some of the same experts who had attended the seminar were invited to testify. The Rapporteur would like to take this opportunity to thank all the experts who testified at the hearing.

7.       As that hearing demonstrated, the whole subject is highly controversial. Most psychiatric experts recognise that some children suffer from ADHD as a diagnosable behavioural disorder characterised by such symptoms as inattentiveness, hyperactivity and impulsiveness, resulting in problems with learning and socialisation, and that this disorder responds well (paradoxically) to treatment with certain stimulant drugs.

8.       Other observers claim that the disorder “has no known cause, no scientific basis, and was literally voted into existence by the American Psychiatric Association in 1987, leading to millions of children the world over being erroneously prescribed powerful and potentially addictive drugs like Ritalin”.⁴

9.       The critics intimate, moreover, that such drugs may be responsible for some of the recent highly publicised outbursts of violence, including killings, committed by American teenagers taking psychiatric drugs known to cause violent reactions.

10.       Yet others, while accepting the need to address the problem of hyperactive, inattentive and impulsive children, believe that there is no need to treat them with drugs. It may suffice to alter the child’s diet. It may even suffice to alter the way in which the child is being educated and brought up.

11.       Whatever the case, as this report will seek to show, it seems there is sufficient reason to recommend, if only on the precautionary principle, that member states’ medical authorities should closely monitor and regulate the diagnosis and treatment of this disorder.

What is attention deficit/hyperactivity disorder (ADHD)?

12.       ADHD is widely recognised as a behavioural disorder that is defined by a set of diagnostic criteria in the fourth edition (1994) of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association (see Appendix 1). The essential behavioural characteristics are inattention (for which nine symptoms are listed, e.g. disorganisation, distractibility) and hyperactivity (six symptoms, e.g. inability to sit still, excessive talking) linked with impulsivity (three symptoms, e.g. frequent interruption of others). The diagnosis may specify which type of behaviour predominates (“combined” for all three, “predominantly inattentive”, or “predominantly hyperactive-impulsive”). For a positive diagnosis, at least six symptoms have to be present in either the “inattention” category or the “hyperactivity-impulsivity” category, or in each for the combined type. Moreover, the signs must have persisted for at least six months, must be inappropriate to the developmental level of the child, must be associated with impairment in social or academic functioning (at least in part before the age of seven and in two or more environments (usually home and school), and must not be attributable to some other mental disorder such as schizophrenia, depression or anxiety.

13.       The World Health Organisation (WHO), in the tenth edition of its International Classification of Diseases (ICD-10), defines diagnostic criteria very similar to, but somewhat more strict than, the combined type of ADHD under the label “Hyperkinetic disorder” (HKD) (see Appendix 1). This classification is more widely used in Europe.⁵

14.       In as many as 65 per cent of cases, ADHD occurs together with other (co-morbid) psychiatric disorders, some of which are also defined in DSM-IV according to behavioural criteria. For example, it is estimated that about 40 per cent meet the criteria for “oppositional defiant disorder” (ODD, characterised by a pattern of persistent and abnormally negativistic, hostile and defiant behaviour), and 20 per cent for “conduct disorder” (CD, characterised by a repetitive and persistent pattern of behaviour that violates the rights of others or major age-appropriate societal norms). Other problems that may occur at the same time as ADHD are obsessive behaviour, motor dysfunction, speech impediments, language problems, depression, anxiety neurosis, tics, Tourette’s syndrome, etc. Co-morbidity obviously complicates and aggravates the whole situation and makes the diagnostic process more difficult.

Prevalence estimates

15.       According to the National Institutes of Health (NIH) in the United States, ADHD “is the most commonly diagnosed behavioral disorder of childhood, estimated to affect 3 to 5 percent of school-age children...although the reported rate in some other countries is much lower.”⁶ Nevertheless, the figure for England and Wales is around 5 per cent, while approximately one per cent meet the diagnostic criteria for the more severe HKD.⁷ ADHD affects about 2 per cent of adolescents and one per cent of adults. It affects boys more often than girls by a factor of between four and nine.⁸ The Rapporteur attempted to gain a more accurate picture of the situation in Council of Europe countries by means of a questionnaire to governmental and other authorities in the majority of member States, but was unable to do so on the basis of the four replies received (Finland, Luxembourg, Slovenia and the United Kingdom). Nevertheless, the figures reported are consistent with the above estimates. The Rapporteur takes this opportunity to thank those who responded to the questionnaire.

Causes

16.       Although the National Institutes of Health (NIH) in the United States in their 1998 Consensus statement on ADHD admitted that “our knowledge about the cause or causes of ADHD remains largely speculative”⁹, and the National Institute for Clinical Excellence in the United Kingdom concedes that “there is still controversy over the causes and diagnostic validity of ADHD”¹⁰, E. Taylor, Professor of Child and Adolescent Psychiatry at the University of London told the Parliamentary Assembly’s Sub-Committees on Children and Health on 23 November 2001 that:

“The causes have recently been clarified by extensive research, with major contributions from European centres. There is a strong genetic contribution (evidence from many twin studies is of 80-90% heritability), and there is definitive evidence of association with inherited variants of genes controlling aspects of dopamine neurotransmission, and also abnormalities of structure and function in regions of frontal lobes and basal ganglia. This alteration of neurological function leads to alteration of psychological functions, so that children fail adequately to suppress inappropriate responses. The results include a cascade of failures in various kinds of cognitive performance.

Most children with hyperkinetic disorder (the severe form of the problem) show other evidence of neurodevelopmental problems, eg in language, or motor coordination, or psychological tests of impulse control. No single problem is present in all affected children, but most show at least one; and these are included in clinical assessment.”

17.       Professor Taylor’s evidence was strongly corroborated by Professor Dr. A. Rothenberger, Director of Child and Adolescent Psychiatry at the University of Göttingen, who said that “facts from family investigations, molecular genetics, neurochemistry, brain imaging, neurophysiology and drug studies show there is a clear and disorder-specific cluster of neurobiological abnormalities in well diagnosed ADHD”.

18.       In his testimony to the Sub-Committees on Children and Health on the same occasion, Dr F. Baughman, speaking as “a neurologist, not a psychiatrist” and as such “medically and legally responsible for the diagnosis and treatment of actual abnormalities/diseases of the brain”, inveighed against the evidence:

“Throughout the eighties and nineties, I witnessed the exploding ADHD epidemic. Just as it was my duty to my every patient to diagnose actual disease when it was present, it was equally my duty to make clear to them that they had no disease, when that was the case—when no abnormality could be found. That was the case with every child and adult referred with a diagnosis of ADHD. Moreover, it was my duty to know the scientific literature concerning every real, neurological disease, and every purported neurological disease as well. Neither could I find validation of ADHD in the medical/scientific literature. Finally, I am a neurologist who has discovered and reported real neurological and genetic diseases. By contrast, in 40 years of pseudo-scientific research, ‘biological psychiatry,’ has yet to validate a single psychiatric condition/diagnosis as an abnormality/disease, or as anything ‘neurological,’ ‘biological,’ ‘chemically-imbalanced’ or ‘genetic.’ Out of deference to the almighty, psychiatric-pharmaceutical cartel, other neurologists and neurological associations neglect to speak of these false representations of emotional and behavioral patterns as “brain diseases” due to “chemical imbalances of the brain.”

19.       Some evidence has been adduced for a relationship of ADHD with diet. Following up earlier research, Dr L.M.J. Pelsser of the Research Centre for Hyperactivity and ADHD in Middelburg, the Netherlands, found that 62 per cent of children diagnosed with ADHD showed significant improvements in behaviour as a result of a change of diet over a period of three weeks. Such research shows that it is possible to speak of a food-dependent form of ADHD. The food test also eliminated any symptoms of co-morbid conditions in those children who tested successfully.¹¹

20.       To argue about the causes of ADHD in terms of “genetic”, “biological”, and “neuro-chemical” factors in opposition to social and environmental factors may seem somewhat sterile. As the World Health Organisation points out in its World Health Report 2001: Mental Health: New Understanding, New Hope:

“The artificial separation of biological from psychological and social factors has been a formidable obstacle to a true understanding of mental and behavioural disorders. In reality, these disorders are similar to many physical illnesses in that they are the result of a complex interaction of all these factors.

For years, scientists have argued over the relative importance of genetics versus environment in the development of mental and behavioural disorders. Modern scientific evidence indicates that mental and behavioural disorders are the result of genetics plus environment or, in other words, the interaction of biology with psychological and social factors. The brain does not simply reflect the deterministic unfolding of complex genetic programmes, nor is human behaviour the mere result of environmental determinism. Prenatally and throughout life, genes and environment are involved in a set of inextricable interactions. These interactions are crucial to the development and course of mental and behavioural disorders.”¹²

21.       To decide what is normal and what is abnormal in terms of behavioural disorders, and to assess the risks associated with such disorders, is the task of expert diagnosticians.

Diagnosis and prognosis

22.       Since for the time being the precise causes of ADHD and HKD are not known it has to be admitted that there can be no objectively and universally valid biological test, such as a blood test, for establishing a diagnosis, nor is primary prevention possible. Thus diagnosis can only be made starting with observation and using well-tried diagnostic interview methods. These are necessarily subjective and may produce different results depending on who conducts the test. Nevertheless, it must also be said that a similar situation prevails with regard to other psychiatric and neurological conditions, including schizophrenia, depression, dementia and Parkinson’s disease.

23.       Given that lack of attention, overactivity and impulsiveness are common features of most children’s behaviour, what is the cut-off point between normality and abnormality? J. Buitelaar and A. Bergsma, of the Department of Child Psychiatry at the University Hospital Utrecht, give the following answer:

“Any decision about this is to a certain extent arbitrary, but is guided by diagnostic criteria that are derived from statistical information about the seriousness of the situation. There are indications on severity, duration, and impairment of functioning. Only in serious cases can a diagnosis be made. But clearly, there is room for disagreement here, as can be seen from the fact that the criteria for the ICD-10 hyperkinetic disorder are more stringent than the criteria for ADHD. However, this problem is not unique to child psychiatry. The borderline between normal and high blood pressure or normal body weight and overweight is just as arbitrary. In these cases, researchers also had to draw the line based on statistical information on what degree of high blood pressure or overweight in general leads to adverse consequences in health, such as heart failure. In a similar vein, the cut-off point for ADHD (six out of nine criteria in DSM-IV) has been established because of the general relationship between the number of criteria endorsed and the risk of serious impairment of functioning at home, in school, and in relationships with peers.”¹³

24.       As stated by E. Taylor, Professor of Child and Adolescent Psychiatry at the University of London, in testimony to the Parliamentary Assembly’s Sub-Committees on Children and Health on 23 November 2001:

“The longitudinal course of the disorder has been studied through epidemiological surveys. They make it clear that childhood hyperactivity is a strong risk for later mental health problems; about 40% have a diagnosed mental health problem after 10 years if treatment has not been given. Psychological factors – especially, rejection by family members and peers - influence whether or not the risk is translated into actual disorder. As with other medical conditions such as blood pressure, the level of problem that should be recognised and treated is set at the level that constitutes a harmful influence – specifically, that predicts later mental health problems. The level of symptoms that constitutes a risk may vary with cultural expectations and other qualities of the child and family; and symptoms are sometimes secondary to other problems such as brain damage or severe psychosocial deprivation.”

25.       Moreover, according to the National Institute for Clinical Excellence in the United Kingdom,

“The consequences of severe ADHD for children, their families and for society can be very serious. Children can develop poor self-esteem, emotional and social problems and their educational attainment is frequently severely impaired. The pressure on families can be extreme. The signs of ADHD may persist into adolescence and adulthood, and may be associated with continuing emotional and social problems, unemployment, criminality and substance misuse.”¹⁴

26.       What do the critics say? As U.S. neurologist Dr F. Baughman, ardent campaigner against the diagnosis and treatment of ADHD with drugs, told the Assembly’s Sub-Committees on Children and Health on 23 November 2001:

“The first duty of all physicians, with the notable exception of psychiatrists, is to determine whether a disease/abnormality is present, or not present. A third to a half of all persons who visit their physician have complaints/symptoms (subjective), but no abnormality/disease (objective). ... The fundamental issue before us, and before all countries of the developed world is whether or not ADHD is a bona fide, diagnosable disease or not. If not, if the children are normal, as I know them to be, they are not medical patients and no medical treatment is necessary, or justified. Rather, their unmet needs lie, as in generations-past, with their parents, teachers, and with their communities....It would be a fraud for any physician to call ADHD or any psychiatric condition an actual disease. ...there is no such thing as a psychiatric/psychological disease.”

27.       Whatever the case, the World Health Organisation is clearly alarmed by the potential for misdiagnosis of ADHD/hyperkinetic disorder, pointing out in its World Health Report 2001: Mental Health: New Understanding, New Hope:

“All too often, hyperkinetic disorders are diagnosed even though the patient does not meet the objective diagnostic criteria. Failure to make an appropriate diagnosis leads to difficulties in establishing the patient's response to therapeutic interventions. Hyperkinetic symptoms can be seen in a range of disorders for which there are specific treatments that are more appropriate than the treatment for hyperkinetic disorder. For instance, some children and adolescents with symptoms of hyperkinetic disorder are suffering from psychosis, or may be manifesting obsessivecompulsive disorder. Others may have specific learning disorders. Still others may be within the normal range of behaviour but are seen in environments with a reduced tolerance for the behaviours that are reported. Some children manifest hyperkinetic symptoms as a response to acute stress in the school or home. A thorough diagnostic process is thus essential, for which specialist help is often needed.”¹⁵

28.       What should such a thorough diagnostic process consist of? As J. Buitelaar and A. Bergsma explain:

“Over the last years, both the American Academy of Child and Adolescent Psychiatry and the European Society for Child and Adolescent Psychiatry have published clinical guidelines for the assessment and treatment of children with ADHD. ... These guidelines specify the essentials of a thorough and balanced evaluation that should include a parent interview, a developmental history, information from the school, an interview with and observation of the child, a medical evaluation and an assessment of family context and parenting skills. Treatment plans should be designed not only to affect the core symptoms of ADHD, but also to direct comorbid problems such as disobedience, aggression, learning disabilities and social

problems. Usually, multi-model interventions are indicated, among which psycho-educational approaches, parent training, and medication are the most important ones.”¹⁶

29.       One is entitled to ask whether those in everyday contact with children demonstrating hyperactive, inattentive and impulsive behaviour, that is to say their parents and teachers, may not be tempted to accept too easily, for the sake of peace and quiet, that such children need to be treated with medication for a psychiatric disorder. If perhaps they were given more loving and focused attention in the family, if education were perhaps more child-centred and better able to make provision for the level and rate of progress of each individual, if discipline both at home and at school were more consistently and justly exercised, if children were provided with a more structured environment and more constructive, including physical, activities which more readily held their interest and attention, then perhaps they would demonstrate less hyperactivity, inattention and impulsive behaviour. This may be particularly true in borderline cases. Moreover, if a child showing five of the characteristic symptoms of ADHD does not qualify for a positive diagnosis then is it really acceptable to diagnose as ADHD a child demonstrating six?

Treatment

30.       As might be expected, controversy about the treatment of ADHD, particularly in so far as it involves Schedule II controlled drugs, is if anything even more intense than about its causes and diagnostic validity. Essentially, the critics of treatment with medication assert that there is no justification for prescribing drugs if there is no disease and that all drugs are poisonous in some degree. They argue that psycho-stimulants, favoured for the treatment of ADHD, can be addictive, are subject to abuse and diversion, and may lead to abuse of other substances. Such drugs can have adverse side effects, including loss of appetite, nervous and cardiovascular system problems and even death,¹⁷ and have long-term effects that are little known. Finally, in the best case drugs can only alleviate the symptoms, not effect a cure.

31.       The International Narcotics Control Board, a United Nations agency, has expressed concern about the use of amphetamine and methylphenidate (pemoline is also used) for the treatment of ADHD in every one of its annual reports since 1995. Although the USA has accounted in most years for about 85-90 per cent of global consumption of methylphenidate, in 2000 this figure dropped to 70 per cent because of the large increase in consumption in the rest of the world, and also because in the United States use of amphetamines has surpassed the use of methylphenidate, accounting for more than half the stimulants prescribed for the treatment of ADHD. The highest rates of methylphenidate consumption in Europe in 2000 were in Switzerland, Iceland, the Netherlands, the United Kingdom, Norway, Germany, Belgium, and Luxembourg (see Appendix 2).¹⁸

32.       There are other forms of treatment and intervention, ranging from psychotherapy and behaviour therapy to school-based intervention, counselling, parent training, and change of diet. Indeed, these may be applied alone, in combination, or together with medication.

33.       As to the comparative effectiveness of the various forms of treatment, Professor E. Taylor of London University, in his testimony to the Parliamentary Assembly’s Sub-Committees on Children and Health on 23 November 2001, gave the following assessment:

“A recent major trial (the MTA study)¹⁹ has compared medication with the best available psychological treatments, and has concluded that medication is more effective. Nevertheless,

most European practitioners consider that the most effective treatment (medication) is best reserved, as a first line of therapy, for the most severe and handicapping problems.

Consensus guidelines recommend that less severe problems should first of all be managed by psychological methods including education and behaviour therapy; and that medication should then be considered for cases that have not responded. This view is considerably more cautious than conventional US practice, which emphasises medication as the first line of treatment. The “European” view is based on randomised controlled trial evidence for a significant effect of psychological therapy and on the greater frequency of adverse effects such as loss of appetite when the treatment is medication. Even so, stimulants are generally considered to be acceptably safe -especially because any adverse effects that may be induced stop quickly when the drug is discontinued, making harm to the child very improbable.”

34.       Nevertheless, the National Institute for Clinical Excellence in the United Kingdom points out that “the MTA researchers have warned that there were some features of the study design that could have favoured medication over behavioural treatment.”²⁰ It adds that “common side effects of methylphenidate are relatively mild and short-lived, and that more severe side-effects are very rare”, but that this conclusion is “based on treatment and follow-up of less than one year” and that “none of the studies included assessment of longer-term side effects or the risk of addiction or abuse with methylphenidate.”²¹

35.       The question whether addiction can be triggered by treatment of ADHD with stimulants over the long term was the subject of a study presented by Dr M. Huss, a researcher in child and adolescent psychiatry at the Humboldt University in Berlin, to the Parliamentary Assembly’s Sub-Committees on Children and Health on 23 November 2001. The study was undertaken as a result of a sharp increase in stimulant prescription in Germany, particularly since 1996. While it was difficult to determine the causal links due to the complexity of factors that influenced addiction, the study had nevertheless shown that methylphenidate treatment did not have a strong effect on addictive behaviour. The preliminary results had even shown that the non-treated control group had an increased risk of substance use disorder. Such puzzling results could perhaps be explained by the stimulant treatment’s effect in improving school performance and preventing school failure, thus reducing the risk of drug addiction. Furthermore, stimulant medication influenced the reward system in the brain, which had links to addictive behaviour. ²²

36.       Further insight into how methylphenidate (trade name Ritalin) works in the brain stems from research conducted on 11 healthy adult males, using brain scans by positron emission tomography, at the Brookhaven National Laboratory in the United States.²³ This showed that the substance, used in that country for more than 40 years to treat ADHD, significantly increases levels of dopamine in the brain, thereby stimulating attention and motivational circuits that enhance ability to focus and complete tasks.

37.       The results showed that brain dopamine levels increased significantly approximately 60 minutes following ingestion of the drug. This would seem likely to increase a sense of motivation and purpose, and to make the tasks that children are performing seem more exciting, raising their level of interest and their ability to focus on the task.

38.       Apparently methylphenidate also works to suppress "background" firing of neurons not associated with task performance, allowing the brain to transmit a clearer signal. Random activation of other cells can be distracting, and children with ADHD are easily distracted. Methylphenidate suppresses the background firing and accentuates the specific activation, basically increasing the signal-to-noise ratio and increasing a child's ability to focus.

39.       Dr N. Volkow, director of the study, is following up this research with a study of subjects suffering from ADHD, on the hypothesis that ADHD sufferers have decreased function of dopamine circuits and are therefore easily distracted, and that the effect of methylphenidate should be to normalize these levels, allowing them to focus and pay attention.

40.       The findings also have important implications for another research area - understanding why methylphenidate, which is chemically quite similar to highly addictive cocaine, is not addictive when taken in pill form. One thing in common with all drugs of abuse is that they increase dopamine levels. Since oral doses of methylphenidate do not produce a "high," the Brookhaven researchers did not expect to see a significant increase in dopamine levels. Since they did see a significant increase, Dr Volkow postulates that another factor is at work.

"We've found that for drugs of abuse to be effective, they must get into the brain very quickly, and for that reason, when injected, Ritalin can become addictive. However, when Ritalin is given in pill form it takes at least 60 minutes to raise dopamine levels in the brain. So, it is the speed at which you increase dopamine that appears to be a key element in the addiction process."²⁴

Controlling the promotion and diversion of stimulants used for treatment of ADHD

41.       In his testimony to the Parliamentary Assembly’s Sub-Committees on Children and Health on 23 November 2001, Mr T. Yoshida of the World Health Organisation confirmed that consumption of methylphenidate had increased rapidly in recent years, particularly in the United States and Canada (see Appendix 2). This phenomenon needed explanation given that ADHD is not a new disorder, even though diagnosis appears to have risen rapidly, and that methylphenidate is not a new drug. One explanation could be the active promotion of the drug by pharmaceutical companies that began in the early 1990s. For example, two leaflets had been prepared targetting parents and teachers. These emphasised the link between ADHD and learning disabilities, described very broad diagnostic criteria, and recommended drug treatment without mentioning the possibility of other treatments. They also emphasised drug efficacy, stating that treatment by medication made the child “normal” by correcting for neurochemical imbalance. They also emphasised the safety of the drug and argued against the prescription of periods off medicine as practised by some doctors in order to reduce the risk of long-term side effects. US pharmaceutical companies spent an estimated 2.6 billion US dollars in 2000 on direct-to-consumer advertising for prescription drugs.

42.       Such practices clearly contravene WHO’s Ethical Criteria for Medicinal Drug Promotion, which state, among other things, that “to fight drug addiction and dependency, scheduled narcotic and psychotropic drugs should not be advertised to the general public.” More generally, scientific and educational activities should not be deliberately used for promotional purposes. WHO defines drug promotion to include all informational and persuasive activities undertaken by manufacturers and distributors, the effect of which is to induce the prescription, supply, purchase and/or use of medicinal drugs. In contrast to advertising, which is regulated in most countries, promotion without indication of substance name is generally not regulated. The distinction between advertising and promotion creates space for disguised promotion.

43.       Since methylphenidate is a scheduled psychotropic substance subject to international control, several diversion control measures are applicable to the distribution of this drug : licensing of handlers; international trade and export/import permits; safe storage; prescription requirements; and record-keeping obligations. However, these diversion control measures may become less effective when consumption levels increase rapidly as has been the case in recent years. It is therefore important to ensure that diagnosis and treatment is kept as far as possible in the hands of specialists.

Conclusions

44.       The validity of ADHD and hyperkinetic disorders, defined in terms of persistent behavioural symptoms centred on inattention, hyperactivity and impulsiveness resulting in functional impairment, is widely recognised by professional medical, psychological and scientific organisations, as attested to by their consensus statements and guidelines, many of which have been cited in this report.

45.       The consensus view is that these behaviourally defined disorders can significantly impair the development of some children, resulting in poor self-esteem and emotional and social problems and severely hampering attainment of their educational potential. The symptoms of ADHD may continue into adolescence and adulthood, and may be accompanied by continuing emotional and social problems, resulting in unemployment, criminality and substance abuse. The toll on those suffering from these disorders, as well as on their families and on society cannot of course be measured precisely but may be considerable.

46.       The controversy surrounding ADHD hinges on whether it may validly be described as an abnormality or disease, and whether it is justified to treat such cases with psycho-stimulants, which have been shown to be effective in altering the behaviour of those diagnosed, allowing them to focus more on what they are doing and reducing their hyperactivity, but whose long-term effects are uncertain. Indeed, the drugs of choice used in treatment are controlled drugs listed in Schedule II of the 1971 United Nations Convention on Psychotropic Substances because they have been judged by the World Health Organisation to be liable to abuse, to constitute a substantial risk to public health, and to have little to moderate therapeutic usefulness.

47.       The fact is that consumption of these drugs has increased considerably in recent years, and in view of their controlled status, it is legitimate to ask why. In so far as the increase is connected with an increase in the number of prescriptions written to treat ADHD, the World Health Organisation as well as the International Narcotics Control Board have sounded the alarm about the appropriateness of such diagnoses in many instances and also about the connection between such prescriptions and drug promotion by the pharmaceutical companies.

48.       The precautionary principle should prevail where doubt exists in regard to the long-term effects of medicaments, stricter control should be exercised over the diagnosis and treatment of these disorders and more research should be conducted into alternative forms of treatment such as diet.

49.       The Parliamentary Assembly should be concerned to ensure that the medical and scientific community, as well as the pharmaceutical industry, are acting in the best interests of society, of patients, and in particular of children and in accordance with ethical standards corresponding to the values and principles of the Council of Europe.

50.       Hence it seems entirely appropriate for the Parliamentary Assembly to recommend to the governments of the member States, many of which are certainly aware of the problem, that they monitor the question more closely, that they co-ordinate and step up research into the prevalence, diagnosis and treatment (in particular alternative treatment) of these disorders and in particular into the long-term effects of the prescribed substances as well as into the possible social and cultural factors involved.

51.       Moreover, it would seem appropriate to recommend that the Committee of Ministers of the Council of Europe should instruct the European Health Committee, in consultation with the Pompidou Group, the European Committee for Social Cohesion, and the Steering Committees on Bioethics and for Education, and in close cooperation with the appropriate international organisations, to work out safeguards and guidelines to be addressed to the governments of the member States.

Reporting committee: Social, Health and Family Affairs Committee

Reference to committee: Doc 8727 and Reference No. 2511 of 16 May 2000

Draft recommendation unanimously adopted by the committee on 25 April 2002.

Members of the committee: Mrs Ragnarsdóttir (Chairman), Mr Hegyi, Mrs Gatterer, Mr Christodoulides (Vice-Chairmen), MM. Alís Font, Arnau, Mrs Belohorská, Mr Berzinš, Mrs Biga-Friganović, Mr Bilovol, Mrs Björnemalm, Mrs Bolognesi (alternate: Mr Oliverio), MM. Brînzan, Brunhart, Cerrahoğlu, Cesário, Cox, Dees, Dhaille, Evin, Floros, Flynn, Ms Gamzatova, MM. Giertych, Glesener, Goldberg, Gönül, Gregory (alternate: Mr Kiely), Gusenbauer (alternate: Mrs Schicker), Gustafsson, Haack (alternate: Mrs Onur), Herrera, Høie, Hörster (alternate: Mr Hornung), Ms Jäger, Mrs Jirousová, Baroness Knight, MM. Kontogiannopoulos, Lomakin-Rumiantsev, Ms Lotz (alternate: Mrs Rupprecht), Ms Luhtanen, MM. Makhachev, Małachowski, Manukyan, Mrs Markovska (alternate: Mr Polložhani), MM. Marmazov, Marty (alternate: Mr Schmied), Mattei, Mrs Milotinova, MM. Mladenov, Monfils (alternate: Mr Timmermans), Ms Nowiak (alternate: Mr Wikiński), MM. Olekas, Ouzký (alternate: Ms Palečková), Padilla, Podobnik, Popa, Poroshenko, Poty, Provera, Rigoni, Rizzi, Seyidov, Mrs Shakhtakhtinskaya, MM. Slutsky, Surján, Telek, Ms Tevdoradze, Mrs Troncho, MM. Truu, Tudor, Vella, Mrs Vermot-Mangold, MM. Vesselbo, Vis, Vos, Mrs Zafferani, Mr Zidu.

NB : The names of those members present at the meeting are printed in italics.

Secretaries to the committee: Mr. Newman, Ms Meunier and Ms Karanjac

Appendix 1

Diagnostic criteria for ADHD listed in the fourth edition (1994) of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association

“A. Either (1) or (2)

(1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:

(a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities

(b) often has difficulty sustaining attention in tasks or play activities

(c) often does not seem to listen when spoken to directly

(d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)

(e) often has difficulty organizing tasks and activities

(f) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort ( such as schoolwork or homework)

(g) often loses things necessary for tasks or activities (e.g. toys, school assignments, pencils, books, or tools)

(h) is often easily distracted by extraneous stimuli

(i) is often forgetful in daily activities

(2) six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:

Hyperactivity

(a) often fidgets with hands and feet or squirms in seat

(b) often leaves seat in classroom or in other situations in which remaining seated is expected

(c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness)

(d) often has difficulty playing or engaging in leisure activities quietly

(e) is often "on the go" or often acts as if "driven by a motor"

(f) often talks excessively

Impulsivity

(g) often blurts out answers before questions have been completed

(h) often has difficulty awaiting turn

(i) often interrupts or intrudes on others (e.g. butts into conversations or games)

B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years.

C. Some impairment from the symptoms is present in two or more settings (e.g. at school [or work] and at home).

D. There must be clear evidence of clinically significant impairment in social, academic, or occupational funtioning.

E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).”²⁵

There are three sub-types of ADHD: (i) the Combined Type, where both Criteria A1 and A2 are met for the past 6 months; (ii) the Predominantly Inattentive Type, where Criterion A1 is met but Criterion A2 is not met for the past 6 months; and (iii) the Predominantly Hyperactive-Impulsive Type, where Criterion A2 is met but Criterion A1 is not met for the past 6 months.²⁶

Diagnostic criteria for “Hyperkinetic disorder” (HKD) listed in the tenth edition of the International Classification of Diseases (ICD-10) published by the World Health Organisation (WHO)

“A. Demonstrate abnormality of attention and activity at HOME, for the age and developmental level of the child, as evidenced by at least three of the following attention problems:

1. short duration to spontaneous activities

2. often leaving play activities unfinished

3. over-frequent changes between activities

4. undue lack of persistence at tasks set by adults

5. unduly high distractibility during study, e.g. homework or reading assignment

6. and by at least two of the following activity problems: continuous motor restlessness (running, jumping etc.)

7. markedly excessive fidgeting or wriggling during spontaneous activities

8. markedly excessive activity in situations expecting relative stillness, e.g. mealtimes, travel, visiting, church

9. difficulty in remaining seated when required

B. Demonstrate abnormality of attention and activity at SCHOOL or NURSERY (if applicable), for the age and developmental level of the child, as evidenced by at least two of the following attention problems:

1. undue lack of persistence at tasks

2. unduly high distractibility, i.e. often orientating towards extrinsic stimuli

3. over frequent changes between activities when choice is allowed

4. excessively short duration of play activities

5. and by at least two of the following activity problems: continuous and excessive motor restlessness (running, jumping etc.) in school

6. markedly excessive fidgeting and wriggling in structured situation

7. excessive levels of off-task activity during tasks

8. unduly often out of seat when required to be sitting

C. Directly observed abnormality of attention or activity. This must be excessive for the child's age and developmental level. The evidence may be any of the following:

1. direct observation of the criteria in A or B above, i.e. not solely the report of parent and/or teacher

2. observation of abnormal levels of motor activity, or off-task behaviour, or lack of persistence in activities, in a setting outside home or school (e.g., clinic or laboratory)

3. significant impairment of performance on psychometric test of attention

D. Does not meet criteria for pervasive developmental disorder, mania, depressive or anxiety disorder.

E. Onset before the AGE OF 6 YEARS.

F. Duration of AT LEAST 6 MONTHS.

G. IQ above 50.

Note: The research diagnosis of Hyperkinetic disorder requires the definite presence of abnormal levels of inattention and restlessness that are pervasive across situations and persistent over time, that can be demonstrated by direct observation, and that are not caused by other disorders such as autism or affective disorders...”²⁷

Appendix 2

Consumption of methylphenidate in Council of Europe member States, Canada and the USA, 1991-2000 (Defined daily doses per 1 000 inhabitants per day)*
	1991	1992	1993	1994	1995	1996	1997	1998	1999	2000
Albania	0	0	0	0	0	0	0	0	0	0
Andorra	0,012	0,002	0,002	0,01	0,005		0,017	0,052	0,099	0,115
Armenia	0	0	0	0	0	0	0	0	0	0
Austria	0,002	0,003	0,003	0,004	0,008	0,004	0,008	0,019	0,029	0,046
Azerbaijan	0	0	0	0	0	0	0	0	0	0
Belgium	0,036	0,077	0,107	0,096	0,112	0,154	0,201	0,29	0,402	0,472
Bulgaria	0	0	0	0	0	0	0	0	0	0
Canada	0,441	0,663	0,67	1,352	1,296	1,912	1,751	2,618	1,727	4,497
Croatia	0	0	0	0	0	0	0	0	0	0
Cyprus	0,011		0,011		0,011	0,013	0,01	0,031	0,054	0,058
Czech Republic					0,012	0,015	0,016	0,051	0,012	0,032
Denmark	0,045	0,049	0,051	0,057	0,07	0,084	0,097	0,114	0,143	0,186
Estonia	0	0	0	0	0	0	0	0	0	0,011
Finland	0,001	0,001	0,002	0,002	0,003	0,003	0,004	0,009	0,016	0,037
France	0,001	0,002	0,003	0,003	0,006	0,01	0,012	0,015	0,021	0,026
Georgia	0	0	0	0	0	0	0	0	0	0
Germany	0,023	0,028	0,038	0,049	0,067	0,106	0,135	0,204	0,27	0,563
Greece	0,001	0,001	0,002	0,001		0,002	0,002	0,001	0,003	0,003
Hungary	0,043	0,005	0,001	0,195	0,012	0,086	0,023	0,023	0,033	0,038
Iceland	0,103	0,102	0,083	0,136	0,16	0,43	0,51	0,783	1,214	2,287
Ireland	0,017	0,017	0,017	0,017	0,276	0,046	0,149	0,136		0,261
Italy	0	0	0	0	0	0	0	0	0	0
Latvia	0	0	0	0	0	0	0	0	0	0,006
Liechtenstein
Lithuania								0,001	0,001	0,002
Luxembourg	0,012	0,023	0,029	0,038	0,041		0,1	0,138		0,282
Malta	0	0	0	0,001	0	0,014	0,013	0,05	0,092	0,064
Moldova	0	0	0	0	0	0	0	0	0	0
Netherlands	0,02	0,046	0,09	0,044	0,114	0,223	0,306	0,477	0,905	0,988
Norway	0,178	0,202	0,21	0,237	0,252	0,236	0,407	0,578	0,312	0,745
Poland	0	0	0	0	0	0	0	0	0	0
Portugal	0,002		0,001	0,003	0,001	0,002	0,005	0,004	0,01	0,012
Romania	0	0	0	0	0	0	0	0	0	0
Russian Federation	0	0	0	0	0	0	0	0	0	0
San Marino
Slovak Republic	0	0	0	0	0	0	0	0	0	0
Slovenia	0	0	0	0	0	0	0,022	0,04	0,042	0,033
Spain	0,052	0,057	0,102	0,077	0,109	0,155	0,187	0,279	0,135	0,241
Sweden	0,012	0,014	0,014	0,016	0,02	0,025	0,031	0,042	0,055	0,096
Switzerland	0,059	0,139	0,7	0,271	0,8		0,453	1,907	0,764	2,789
"The former Yug Rep of Macedonia"	0	0	0	0	0	0	0	0	0	0
Turkey	0	0	0	0	0	0	0,001	0,004	0,009	0,016
Ukraine	0	0	0	0	0	0	0	0	0	0
United Kingdom	0,006	0,007	0,006	0,808	0,546	0,081	0,274	0,635	0,548	0,987
United States	1,087	1,49	1,927	2,423	3,165	3,444	3,385	3,692	4,32	3,692
* Source: International Narcotics Control Board (INCB).
The defined daily dose (DDD) is a technical unit of measurement.
These data are calculated on the basis of statistics on manufacture and trade provided by Governments. In countries
that do not manufacture and export methylphenidate, quantities declared as imported are considered to be destined
for consumption. Non consumption is always expressed by a zero. Whenever no data are given for any specific year
for a country, data have been judged to be incorrect due to statistical and/or reporting errors.

¹ World Health Organisation Technical Report Series, No. 437, 1970.

² Cf. in particular INCB Annual Reports since 1995.

³ Council of Europe, Pompidou Group, Attention deficit/hyperkinetic disorders: their diagnosis and treatment with stimulants, Council of Europe Publishing, March 2000, ISBN 92-871-4240-8.

⁴ Doc. 8727, Ending the misdiagnosis of children, Motion for an order presented by Mr Gustafsson and others.

⁵ In Sweden the condition is known as “deficits in attention, motor control and perception” (DAMP) and is also subject to controversy (testimony of Professor E. Kärfve to the Sub-Committees on Children and Health, 23 November 2001.

⁶ Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder. National Institutes of Health (NIH) Consensus Statement Online 1998 Nov 16-18; 16(2): 1-37. http://odp.od.nih.gov/consensus/cons/110/110_statement.htm

⁷ Guidance on the Use of Methylphenidate (Ritalin, Equasym) for Attention Deficit/Hyperactivity Disorder (ADHD) in childhood, National Institute for Clinical Excellence, London, October 2000. http://www.nice.org.uk/Docref.asp?d=11653

⁸ Jan Buitelaar, Ad Bergsma, “Sociocultural factors and the treatment of ADHD” in Council of Europe, op. cit., p. 21

⁹ NIH, op. cit.

¹⁰ National Institute for Clinical Excellence, op. cit., para.2.4.

¹¹ Mrs M. de Boer, testifying on behalf of Dr. Pelsser before the Parliamentary Assembly’s Sub-Committees on Children and Health, 23 November 2001. Cf. also J. Breakey, “The role of diet and behaviour in childhood”, in J. Paediatr. Child Health (1997) 33, 190-194.

¹² WHO, World Health Report 2001: Mental Health: New Understanding, New Hope, chapter 1, p. 10, http://www.who.int/whr

¹³ J. Buitelaar, A. Bergsma, “Sociocultural factors and the treatment of ADHD” in Council of Europe, op.cit., p.35.

¹⁴ National Institute for Clinical Excellence, op. cit., para. 2.5.

¹⁵ WHO, World Health Report 2001, chapter 3, p. 72.

¹⁶ J. Buitelaar, A. Bergsma, in Council of Europe, op. cit., p. 25.

¹⁷ The US Food and Drug Administration’s MedWatch programme registered 186 deaths in the US attributed to methylphenidate for the decade 1990-2000.

¹⁸ Reports of the International Narcotics control Board at http://www.incb.org.

¹⁹ Multimodal Treatment Study of Children with ADHD, a collaborative conducted under the auspices of the U.S. National Institute of Mental Health; cf. Archives of General Psychiatry, December 1999.

²⁰ National Institute for Clinical Excellence, op. cit., para. 4.5.2.

²¹ ibid., para. 4.7.

²² Results of earlier research conflicted: of the two major epidemiological studies conducted , one showed more drug addiction in ADHD children taking methylphenidate over the long-term than in those not taking it (Journal of Learning Disabilities, 1998;31:533-544), the other showed the opposite (Pediatrics, 1999;104:e20) (as cited in Vastag, loc.cit.)

²³ Nora D. Volkow et al., “Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain” in The Journal of Neuroscience, 2001, 21:RC121:1-5 at http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr011501a.html . See also Brian Vastag, “Pay attention: Ritalin acts much like cocaine” in Journals of the American Medical Association, Vol. 286, No. 8, August 22/29, 2001 at http://jama.ama-assn.org/issues/v286n8/ffull/jmn0822-1.html

²⁴ Brookhaven National Laboratory News Release, 16.1.2001. http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr011501a.html

²⁵ Diagnostic and Statistical Manual of mental Disorders – Fourth Edition (DSM-IV), American Psychiatric Association, Washington, D.C., 1994

²⁶ Ibid.

²⁷ International Classification of Diseases (10th Ed.) (ICD-10). World Health Organisation, Geneva, 1990