Attention-deficit Hyperkinetic Disorders in Childhood and Adolescence

Attention-deficit hyperkinetic disorders in childhood and adolescence - technical UK based article.

Topics covered:

  • Introduction
  • History
    • Evolution of the concept
    • Evolution in nomenclature
    • Evolution in clinical practice
  • Clinical features
  • Classification
    • Impairment
    • Comorbidity
    • Subtypes
  • Diagnosis and differential diagnosis
    • Assessment of children
    • Assessment of adolescents and adults
  • Epidemiology
  • Aetiology
    • Cognitive and neural basis of AD-HKD
    • Neurobiological and psychosocial risk factors
    • Genetic factors
  • Course and prognosis
  • Treatment
    • Prevalence of medication use
    • Neurobiology of the medications used to treat AD-HKD
    • Pharmacology of stimulant medication
    • Therapeutic effects of stimulants
    • Variation among stimulants
    • Limitations of stimulant medication
    • Non-stimulant medications
    • Behavioural treatment
    • Multimodal treatment
  • Management
    • General principles
    • Initiating treatment with medication
    • Monitoring side-effects
  • Prevention
  • Conclusions 
  • References

Introduction

The syndrome of restless, inattentive, and impulsive child behaviour known as attention-deficit hyperactivity disorder ( ADHD) in North America and hyperkinetic disorder (HD) in Europe is a common mental health problem.This disorder is a source of considerable adversity for those affected and their families. Persons affected by this disorder in childhood are at risk for learning, behavioural, and social problems and also for the development of serious impairments such as academic failure, substance abuse, and criminality in adolescence and adulthood. Consequently, the disorder places a substantial demand on mental health, educational, and judicial services. 

This disorder reflects the interplay of biological, psychological, and social factors. Biological factors such as genetic risk are clearly implicated in the neuropathology of ADHD and HD. However, social influences are significant determinants of the impairment associated with the disorder, the prognosis for individual children, and attitudes toward the cause of the disorder and its therapy. Psychological processes, particularly deficits in attention and information-processing, mediate the link between the underlying neuropathology and the behavioural manifestations of the disorder. Consequently, the disorder is informative for the study of child psychopathology in general.

Important differences exist between the diagnostic traditions of North America and Europe. We examine them specifically in this article, along with the characteristics they share (signalled by our use of the term ‘AD-HKD'). The purpose of this article is to review our current understanding of the causes, natural history, and treatment of AD-HKD in the context of its social and historical development.

History

Evolution of the concept

Although the frequency of the diagnosis of AD-HKD has certainly increased rapidly in the second half of the twentieth century, the discovery of AD-HKD is not recent. Excessively hyperactive, inattentive, and impulsive children have been described in the medical literature since the late nineteenth century. (1,2) In the early years of the twentieth century, the syndrome was clearly described, along with its various cardinal manifestations, such as soft neurological signs, minor congenital anomalies, and inattentiveness, and labelled a ‘defect in moral control'. (3,4) According to the prevailing social Darwinian theory, moral control was the latest and greatest achievement of evolution, and, as a consequence, was considered particularly susceptible to loss as a result of various brain insults. Only persons with a genetic predisposition to AD-HKD were thought to develop the disorder. The adverse environmental and social circumstances that were characteristic of the situations of many affected persons were considered consequences rather than causes of the disorder. (2)

In many respects, theories of AD-HKD have changed little over the decades. These theories have continued to reflect the belief that the syndrome is a consequence of an interaction between subtle hereditary and acquired traumatic or toxic processes acting on the nervous system during fetal or early child development to cause minimal brain damage or dysfunction. (5)

As knowledge of brain function grew during the century, concepts of the fundamental behavioural and neuropathological deficit of AD-HKD changed. Initial theories emphasized hyperactivity and abnormal arousal arising from the dysfunction of the thalamus. Later theories focused on the deficient attention that results from the dysfunction of the frontal circuits involved in cognition. Current theory favours the role of deficient inhibitory control—the delaying mechanism involved in the timing, initiation, and interruption of action—and neuropathology in the frontal and related regions of the brain. (6)

Evolution in nomenclature

Since the earliest descriptions of moral deficit, various labels have been applied to the syndrome, each reflecting the prevailing theories of its aetiology, opinions of its cardinal features, and beliefs about the role of subtle, rather than obvious, neuropathological causes of the disorder.

When the syndrome first appeared in the modern classification schemas, the disorder was known as the hyperkinetic child syndrome (7) or hyperkinetic reaction of childhood (8) in North America. In Europe and many other countries where the International Classification of Diseases (9) is used, the disorder was known as the hyperkinetic disorder. These labels reflected the existing emphasis on hyperactivity as the cardinal manifestation of the syndrome. (10) The name of the disorder was changed to attention-deficit disorder in the third edition of the Diagnostic and Statistical Manual in 1980 (11) to reflect the prevailing opinion, especially in North America, that cognitive deficit rather than overactivity lay at the heart of the disorder. (12) Nevertheless, a distinction between those with and those without hyperactivity was retained. In 1987, DSM-IIIR changed the name of the disorder to attention-deficit hyperactivity disorder and combined all symptoms into one unidimensional category, reflecting the then current view that inattention, restlessness, and impulsiveness were related and equivalent markers of the disorder.

This change in criteria embodied in DSM-IIIR resulted in a loss of the distinction between children who had AD-HKD with hyperactivity and those without. Since clinicians and researchers thought that this distinction was clinically relevant and scientifically valid, in 1994 (13) the symptoms were divided once again into inattentive and hyperactive–impulsive clusters.

Evolution in clinical practice

Clinical practice in North America and the United Kingdom diverged markedly in the 1940s. In North America, the presence of the behavioural manifestations of the syndrome alone was considered sufficient for the diagnosis of minimal brain damage or dysfunction. (14) Coexisting disorders such as conduct disorder and mental retardation (learning disability) were thought to be manifestations of the syndrome. (15) In the United Kingdom, clinicians required evidence of documented neuropathology, such as a history of head injury or seizure disorder, (16) significant behavioural disturbance in multiple settings (pervasive hyperactivity), and the absence of significant comorbid psychopathology, including conduct disorder. In many European countries, clinicians emphasized the need for evidence of neurological dysfunction, along with deficits in attention and motor control. (17)

These differences in diagnostic practice have had a profound impact on estimates of the prevalence of the disorder and its treatment, initiating a debate about the overinclusiveness of the diagnosis that continues today. (18) In the United Kingdom, for example, HD was diagnosed in only 0.001 per cent of children during the 1960s, (19) whereas in North America, ADHD was thought to apply to between 5 and 10 per cent of children. (20) Revisions of both North American (DSM-IV) (13) and European (ICD-10) (21) criteria have resulted in a much more unified set of diagnostic criteria, although differences remain (see below for discussion and Table 1). The DSM 5 was published in May 2013. See below for information about ADHD in the DSM 5.

The most important development in the history of the treatment of AD-HKD occurred in 1937: Bradley's chance discovery (22) of the beneficial effect of dextroamphetamine on attention and behaviour among children with behavioural problems. The growing awareness of the positive effects of medication, coupled with the waning influence of psychoanalytical theory and practice, resulted in a marked increase in the popularity of the diagnosis.

Table 1 Diagnostic criteria:

DSM-IV Criteria for ADHD

I. Either A or B:

A. Six or more of the following symptoms of inattention have been present for at least 6 months to a point that is inappropriate for developmental level:

Inattention
  1. Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities.
  2. Often has trouble keeping attention on tasks or play activities.
  3. Often does not seem to listen when spoken to directly.
  4. 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).
  5. Often has trouble organizing activities.
  6. Often avoids, dislikes, or doesn't want to do things that take a lot of mental effort for a long period of time (such as schoolwork or homework).
  7. Often loses things needed for tasks and activities (e.g. toys, school assignments, pencils, books, or tools).
  8. Is often easily distracted.
  9. Is often forgetful in daily activities.

B. Six or more of the following symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level:

Hyperactivity
  1. Often fidgets with hands or feet or squirms in seat when sitting still is expected.
  2. Often gets up from seat when remaining in seat is expected.
  3. Often excessively runs about or climbs when and where it is not appropriate (adolescents or adults may feel very restless).
  4. Often has trouble playing or doing leisure activities quietly.
  5. Is often "on the go" or often acts as if "driven by a motor".
  6. Often talks excessively.
Impulsivity
  1. Often blurts out answers before questions have been finished.
  2. Often has trouble waiting one's turn.
  3. Often interrupts or intrudes on others (e.g., butts into conversations or games).

II. Some symptoms that cause impairment were present before age 7 years.

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

IV. There must be clear evidence of clinically significant impairment in social, school, or work functioning.

V. The symptoms do not happen only during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder.

The symptoms are not better accounted for by another mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).

Based on these criteria, three types of ADHD are identified:

  1. IA. ADHD, Combined Type: if both criteria IA and IB are met for the past 6 months
  2. IB. ADHD, Predominantly Inattentive Type: if criterion IA is met but criterion IB is not met for the past six months
  3. IC. ADHD, Predominantly Hyperactive-Impulsive Type: if Criterion IB is met but Criterion IA is not met for the past six months.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.

ICD-10 criteria: attention deficit/hyperactivity disorder

F90 Hyperkinetic disorders

G1 Inattention

At least six of the following symptoms of attention have persisted for at least six months, to a degree that is maladaptive and inconsistent with the developmental level of the child:

  1. often fails to give close attention to details, or makes careless errors in school work, work or other activities;
  2. often fails to sustain attention in tasks or play activities;
  3. often appears not to listen to what is being said to him or her;
  4. often fails to follow through on instructions or to finish school work, chores, or duties in the workplace (not because of oppositional behaviour or failure to understand instructions);
  5. is often impaired in organising tasks and activities;
  6. often avoids or strongly dislikes tasks, such as homework, that require sustained mental effort;
  7. often loses things necessary for certain tasks and activities, such as school assignments, pencils, books, toys or tools;
  8. is often easily distracted by external stimuli;
  9. is often forgetful in the course of daily activities.
G2 Hyperactivity

At least three of the following symptoms of hyperactivity have persisted for at least six months, to a degree that is maladaptive and inconsistent with the developmental level of the child:

  1. often fidgets with hands or feet or squirms on seat;
  2. leaves seat in classroom or in other situations in which remaining seated is expected;
  3. often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, only feelings of restlessness may be present);
  4. is often unduly noisy in playing or has difficulty in engaging quietly in leisure activities;
  5. exhibits a persistent pattern of excessive motor activity that is not substantially modified by social context or demands.
G3 Impulsivity

At least one of the following symptoms of impulsivity has persisted for at least six months, to a degree that is maladaptive and inconsistent with the developmental level of the child: (1) often blurts out answers before questions have been completed; (2) often fails to wait in lines or await turns in games or group situations; (3) often interrupts or intrudes on others (eg butts into others’ conversations or games); (4) often talks excessively without appropriate response to social constraints.

G4

Onset of the disorder is no later than the age of seven years.

G5

Pervasiveness The criteria should be met for more than a single situation, eg the combination of inattention and hyperactivity should be present both at home and at school, or at both school and another setting where children are observed, such as a clinic. (Evidence for cross-situationality will ordinarily require information from more than one source; parental reports about classroom behaviour, for instance, are unlikely to be sufficient.)

G6

The symptoms in G1 and G3 cause clinically significant distress or impairment in social, academic, or occupational functioning.

G7

The disorder does not meet the criteria for pervasive developmental disorders (F84.-), manic episode (F30.-), depressive episode (F32.-), or anxiety disorders (F41.-).

Comment

Many authorities also recognise conditions that are sub-threshold for hyperkinetic disorder. Children who meet criteria in other ways but do not show abnormalities of hyperactivity/impulsiveness, may be recognised as showing attention deficit; conversely, children who fall short of criteria for attention problems but meet criteria in other respects may be recognised as showing activity disorder. In the same way, children who meet criteria for only one situation (eg only the home or only the classroom) may be regarded as showing a home-specific or classroom-specific disorder. These conditions are not yet included in the main classification because of insufficient empirical predictive validation, and because many children with sub-threshold disorders show other syndromes (such as Oppositional Defiant Disorder, F91.3) and should be classified in the appropriate category.

Above: Table 1 Diagnostic criteria: DSM IV and ICD 10 

DSM 5 update 

The DSM 5 was published in May 2013. Here is a summary of the changes:

The definition of attention-deficit/hyperactivity disorder (ADHD) has been updated in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to more accurately characterize the experience of affected adults.

This revision is based on nearly two decades of research showing that ADHD, although a disorder that begins in childhood, can continue through adulthood for some people. Previous editions of DSM did not provide appropriate guidance to clinicians in diagnosing adults with the condition. By adapting criteria for adults, DSM-5 aims to ensure that children with ADHD can continue to get care throughout their lives if needed.

Changes to the Disorder

ADHD is characterized by a pattern of behavior, present in multiple settings (e.g., school and home), that can result in performance issues in social, educational, or work settings.

As in DSM-IV, symptoms will be divided into two categories of inattention and hyperactivity and impulsivity that include behaviors like failure to pay close attention to details, difficulty organizing tasks and activities, excessive talking, fidgeting, or an inability to remain seated in appropriate situations.

Children must have at least six symptoms from either (or both) the inattention group of criteria and the hyperactivity and impulsivity criteria, while older adolescents and adults (over age 17 years) must present with five.

While the criteria have not changed from DSM-IV, examples have been included to illustrate the types of behavior children, older adolescents, and adults with ADHD might exhibit.

The descriptions will help clinicians better identify typical ADHD symptoms at each stage of patients’ lives.

Using DSM-5, several of the individual’s ADHD symptoms must be present prior to age 12 years, compared to 7 years as the age of onset in DSM-IV. This change is supported by substantial research published since 1994 that found no clinical differences between children identified by 7 years versus later in terms of course, severity, outcome, or treatment response.

DSM-5 includes no exclusion criteria for people with autism spectrum disorder, since symptoms of both disorders co-occur. However, ADHD symptoms must not occur exclusively during the course of schizophrenia or another psychotic disorder and must not be better explained by another mental disorder, such as a depressive or bipolar disorder, anxiety disorder, dissociative disorder, personality disorder, or substance intoxication or withdrawal.

Care Beyond Childhood

The ADHD diagnosis in previous editions of DSM was written to help clinicians identify the disorder in children. Almost two decades of research conclusively show that a significant number of individuals diagnosed with ADHD as children continue to experience the disorder as adults. Evidence of this came from studies in which individuals were tracked for years or even decades after their initial childhood diagnosis.

The results showed that ADHD does not fade at a specific age. Studies also showed that the DSM-IV criteria worked as well for adults as they did for children but that a lower threshold of symptoms (five instead of six) was sufficient for a reliable diagnosis.

Clinical features of AD-HKD

The cardinal features of AD-HKD are excessive and impairing levels of activity, inattention, and impulsiveness. Children with AD-HKD have great difficulty remaining seated when required to in structured situations such as in the classroom or at the dinner table. They are more active than their peers in unstructured situations such as in the playground. They fail to pay attention to instructions in academic and social situations. They have serious difficulty withholding a response of any kind until the appropriate moment, interrupting an inappropriate course of action once initiated, and adjusting incorrect or maladaptive responses. These characteristics are not simply the subjective impressions of adults, but can be confirmed reliably with a range of objective measures (23) and rating scales completed by observers. (24,25)

AD-HKD behaviours are highly context dependent; the extent of disagreement among raters, such as mothers, fathers, and teachers, indicates that observers are influenced by their own particular perspectives on child behaviour and their opportunities for interaction with particular children. (25) Also, ratings of the severity of AD-HKD symptoms are influenced by contrast effects, which result in the exaggeration of existing differences between persons (namely, twin contrast affects), and by the presence of concurrent psychopathology. For example, the inattentiveness or irritability of the depressed person or the aggressiveness of a person with conduct disorder may result in an exaggerated perception of AD-HKD symptoms. (26,27)

Classification

There are two broad perspectives on the classification of AD-HKD—the dimensional and the categorical approaches. According to the dimensional approach, the constituent behaviours of AD-HKD vary widely in the general population; persons are, therefore, more or less impaired. (28) Accordingly, AD-HKD is best viewed as the extreme of these behaviours, rather than as a discrete entity; affected persons are qualitatively distinct from unaffected persons. The categorical approach embodied in the current diagnostic classification schemas argues that AD-HKD is qualitatively, as well as quantitatively, distinct. The matter of which approach is correct is not easily resolved. It is likely that certain aspects of the syndrome are captured best by the categorical approach, while others are better characterized by the dimensional, or qualitative, perspective.

Even from the categorical perspective, the European approach to the definition and classification of AD-HKD disorders differs from that of North America. The most recent editions of DSM and ICD classifications reflect an effort to bring the definitions of ADHD and HD closer together. DSM-IV and ICD-10 have adopted almost identical criteria for the identification of inattentive, hyperactive, and impulsive symptoms (Table 1). However, significant differences between the two nosological systems are still evident in their diagnostic algorithms (the number of criteria in each domain required for a diagnosis), the role of inattentiveness, the definition of pervasiveness across situations, and the role of comorbidity.

According to DSM-IV, the diagnosis of ADHD requires the presence of six inattentive or six hyperactive–impulsive symptoms, or both. Three different subtypes of ADHD are permitted: predominantly inattentive (the presence of six or more symptoms of disordered attention and fewer than six symptoms of hyperactivity–impulsivity), predominantly hyperactive–impulsive (the presence of six or more symptoms of hyperactivity–impulsivity and fewer than six symptoms of inattention), and combined (the presence of six or more inattentive and six or more hyperactive–impulsive symptoms). To establish a diagnosis of HD based on ICD-10, at least six inattentive, three hyperactive, and one impulsive symptom must be present. The diagnosis cannot be made in the absence of the symptoms of inattentiveness.

ICD-10 is also more rigorous about cross-situational pervasiveness, requiring that all necessary criteria be present, both at home and at school (or other situations). DSM-IV is more lenient; it demands evidence that criteria be met in at least one situation and that impairment be present in another, without stipulation of the number of symptoms present or their severity in this second situation.

The consequence of the differences in ICD and DSM operational definitions and decision rules is that patients with a diagnosis of HD (as defined by ICD-10) are more severely impaired than those with a diagnosis of ADHD (as defined by DSM-IV). (18,29)

Perhaps the most salient difference between DSM-IV and ICD-10 classifications is the approach to the diagnosis when more than one disorder coexists with AD-HKD. DSM-IV recognizes all diagnoses that are present, except for schizophrenia, autism, and pervasive developmental disorder. In contrast, ICD-10, in general, discourages multiple diagnoses. In the presence of internalizing disorders such as anxiety and mood disorders, ICD-10 does not recommend the HD diagnosis. The only exception occurs when both HD and conduct disorder coexist. ICD-10 labels this combination the diagnostic subtype hyperkinetic conduct disorder. This new subcategory may deal with the tendency of clinicians in the United Kingdom and Europe to prefer the diagnosis of conduct disorder to HD when both disorders are evident. (30)

Impairment

AD-HKD is associated with serious social, academic, and psychological difficulties at each stage of development. The quality of the social relationships of children with AD-HKD with their siblings, peers, parents, and other adults is poor as a result of their verbal and physical aggressiveness, inattention to social cues, and bias toward attributing hostile motives to others. (31) As a result, children with AD-HKD are rejected by others and treated in a controlling and negative fashion by their peers, teachers, and parents. (32,33) Their families experience considerable stress, feelings of incompetence, and marital discord because of these behavioural problems. These children's parents tend to use coercive parenting strategies. Children with AD-HKD are more likely than their unaffected peers to live in families whose lives are disrupted by poverty, marital separation, and parental psychopathology. (34,35 and 36)

AD-HKD is associated with deficits in various cognitive skills: planning, sustaining attention, maintaining performance, identifying and adjusting to errors, judging the passage of time, and inhibiting inappropriate responses (see Table 2). Their sleep is poor; for example, they tend to have sleep-related breathing disorders, periodic limb movements, and habitual snoring. (37) Frequently, these children feel demoralized and incompetent. Compared with their normally developing peers, children with AD-HKD get lower marks, fail more grades at school, are more poorly organized, and more often have a diagnosis of a mental retardation. (38,39)

Table 2 Common impairments associated with AD-HKD
Cognitive deficits in planning, sustained attention, peception of time and inhibition
Disorganization
Verbal aggression
Hostile-attribution bias
Social rejection
Poor sleep
Demoralization
Anxiety
Learning disability and academic underachievement
Poor occupational outcome
Poor driving practices
Increased risk of accidents

Adolescents and adults with AD-HKD show many of the same features as their younger counterparts, although they are less restless. They are more likely to drop out of school with lower marks and to have lower paid and lower status occupations than their non-AD-HKD peers and siblings. Their self-esteem is low. Persons with AD-HKD are more likely to exhibit poor driving practices and to have a substance abuse disorder. There is evidence that they may be more likely to attempt suicide or die accidentally. (More information about the effects of AD-HKD on the lives of adolescents and adults is given elsewhere. (38,40)

Comorbidity

Frequently, children with AD-HKD meet the criteria for more than one concurrent psychiatric disorder—a phenomenon known as comorbidity. In samples of children with AD-HKD, approximately 35 per cent meet the criteria for oppositional defiant disorder, 25 per cent for conduct disorder, 15 per cent for depressive disorder, and 25 per cent for anxiety disorder. (41) In fact, over 50 per cent of children with AD-HKD meet the criteria for two comorbid conditions. (42) A mental retardation occurs in about 12 to 25 per cent, and language impairment in about 5 per cent of children with AD-HKD. (43)

Subtypes

Various subtypes of AD-HKD have been distinguished, based on phenomenology, pervasiveness of symptoms, and patterns of comorbidity. Subgrouping based on the children's response to treatment is less well established, but is suggested by the existence of children who do not respond favourably to methylphenidate (44) and the apparent role of the genes involved in the dopaminergic and noradrenergic systems. (45)

Some subtypes appear in the current classification schemas. For example, DSM distinguishes among inattentive, hyperactive–impulsive, and combined (both inattentive and hyperactive–impulsive) subtypes. There is weak evidence preferentially linking the hyperactive–impulsive subtype to deficient inhibition, and the inattentive subtype to anxiety, social withdrawal, depression, and mental retardation. (5) The hyperactive–impulsive and combined subtypes are associated with oppositional and conduct disorder, and greater concurrent and lifetime impairment. (46)

Both ICD-10 and DSM-IV require evidence of pervasiveness, namely evidence of the disorder in more than a single setting. Yet the criteria for pervasiveness are rather unspecified, particularly in DSM-IV. The requirement for pervasiveness is meant to preclude the diagnosis of AD-HKD for children whose history is provided by a single, potentially unreliable informant or for those who have behavioural problems that arise in a single distressing environment. Reliable differences do exist among children whose symptoms are evident both at home and school, and those who, for the most part, exhibit symptoms at school, but not at home, or at home, but not at school. The pervasive subtype is the least prevalent—possibly 20 per cent of children with AD-HKD have it—but it tends to be the most seriously affecting. Its rate of comorbidity, psychosocial impairment, neurodevelopmental delay, and cognitive impairment is higher. (47) School-only AD-HKD, the most common subtype, (48) is typified by learning and cognitive deficits. The existence of a home-only subtype is the most contested. This subtype may be preferentially associated with psychosocial impairment.

Subtypes can also be based on the presence of comorbidity. The basis for this approach to subtyping is the possibility that some disorders (such as a reading disability, or an anxiety or conduct disorder that commonly coexists with AD-HKD) can generate a phenocopy of true AD-HKD. (49,50) According to the phenocopy hypothesis, the AD-HKD symptoms of a child with a reading disability, or an anxiety or conduct disorder may be a non-specific epiphenomenon of the underlying reading, anxiety, or conduct disorder, rather than true AD-HKD. Although these children seem to have AD-HKD, they actually have the comorbid condition. Consequently, AD-HKD arising in the context of these other disorders would not have the same correlates or cause, and may not respond to the same treatment as the AD-HKD that occurs in isolation. True comorbidity, on the other hand, implies that the comorbid condition represents a combination of each of the individual disorders.

True comorbidity arises from the association between the risk factors of each separate disorder, from a common cause for each disorder, or from the process that causes one disorder to increase the risk for the development of the second. (51)

Comorbid AD-HKD and conduct disorder, in particular, may represent a distinct disorder. Compared with children with conduct disorder or with AD-HKD, children with the combination of AD-HKD and conduct disorder have more severe cognitive and learning problems, a worse prognosis, a greater incidence of AD-HKD and conduct disorder among relatives, and greater psychosocial adversity. (52)

Neurochemical, treatment-response, and genetic and family-history data partially support the existence of the distinct subtypes of AD-HKD and bipolar disorder, and AD-HKD and anxiety disorder. (53)

Diagnosis and differential diagnosis

Assessment of children

AD-HKD is a diagnosis that is based primarily on a clinical evaluation that includes an interview with the parents about the child's development and behaviour, a direct examination of the child, and a review of the information provided by the child's classroom teacher. Semistructured interviews with parents and teachers have the advantage over questionnaires of eliciting descriptions of the child's behaviour in a wide range of home and school situations.

Rather than the informant's global impression about the presence of AD-HKD symptoms, the interviewer should elicit descriptions of the child's specific behaviours in a range of situations, such as those during structured and unstructured tasks, group and individual work, and academic and recreational activities. This approach minimizes the informant bias that arises from expectations of the child's behaviour or the presence of a comorbid psychopathology, such as oppositional or aggressive child behaviour. (26,27) Semistructured interviews also broadly cover the symptoms of potentially comorbid disorders and elicit descriptions of parenting practices and other contextual factors that are important for planning treatment. Similarly, a direct interview with the child's classroom teacher is preferable to a second-hand parental report of the child's behaviour at school or to a questionnaire completed by the teacher.

An interview with or direct observation of the child is important to the assessment. However, the clinician may be unable to observe the child's symptoms first-hand in all cases. Children with AD-HKD are able to suppress their inattentiveness, restlessness, and impulsiveness to a great extent in novel and highly structured situations, such as those afforded by the typical visit to the physician's office. However, parents and teachers can provide a picture of the child's typical behavioural, developmental, and social history, and response to variations in the environment (e.g. family upset or changing teachers). Direct examination of the younger child may be limited by the child's apparent lack of insight into his or her behaviour or an inability to communicate as a result of language or learning difficulties. Nevertheless, the individual child assessment may be useful for identifying comorbidities (e.g. anxiety or depression), monitoring treatment, and establishing the rapport required to sustain a prolonged intervention.

During the assessment, the physician must investigate the presence of a concurrent disorder and the relationship of the symptoms of a comorbid disorder and AD-HKD. For example, are the restlessness and inattentiveness of a child limited to a period of anxiety or depression? Are the AD-HKD symptoms part of a conduct disorder, substance use disorder, or Tourette's syndrome?

Since many children meet AD-HKD criteria almost exclusively on the basis of behavioural difficulties within the school context, it is essential to assess the presence of learning difficulties, the nature of the educational experience, and the relationship problems that are evident in this setting.

Many behaviour-rating scales measure the presence and intensity of AD-HKD symptoms (e.g. Conners' Parent and Teacher Rating Scales, 1997 Revised). (54) Since these scales distinguish children with the disorder from those without, these scales may be useful for screening community or clinical populations and for providing standardized measures of the severity of the symptoms so that they may be compared across samples or used to monitor treatment.

However, these scales have limitations. They are less useful for distinguishing children with AD-HKD from those with other disorders, and the wording of individual items on particular rating scales may make them inappropriate for use in some cultures.

Although there is robust evidence for cognitive, neuropsychological, neurophysiological, and biochemical deficits in children with AD-HKD, there are no known laboratory tests that have sufficient diagnostic sensitivity and specificity to distinguish children with AD-HKD from unaffected children, or from those with other disorders. Specific laboratory tests may be necessary to exclude suspected problems, such as poor hearing. Routine screening for thyroid abnormality is not indicated. Despite the increased prevalence of AD-HKD among persons with a generalized resistance to the thyroid hormone, thyroid abnormalities are rare among children with AD-HKD. (55)

Physicians should take the child's medical and developmental history or do a physical examination to identify primary medical disorders such as hearing and vision problems, seizure disorders, medical illnesses, and the effects of medication use.

Assessment of adolescents and adults

Diagnostic assessment for AD-HKD in adolescents requires an approach similar to that used for children. In contrast with children, however, the interview with adolescents may play a greater role in the assessment because they may have greater insight into their own social, scholastic, and behavioural problems.

The diagnostic process in adolescents is complicated in several ways. The manifestations of the disorder change with age. Gross motor activity decreases and an inner sense of restlessness, fidgetiness, and inattentiveness emerges as the primary problems in adolescence. It becomes more difficult to obtain an accurate description of the adolescent's behaviour, especially in the school and work contexts, because of the absence of a single teacher who is responsible for the adolescent throughout the day.

Establishing a diagnosis of AD-HKD among adults is also complicated in several ways. Adults with AD-HKD have high rates of anxiety, depression, and substance abuse, for which they may have received extensive treatment, often with medication. Consequently, AD-HKD uncomplicated by comorbid psychopathology is rare, in part, because of the consequences of lifetime AD-HKD. The effects of these disorders need to be carefully appraised.

Moreover, it is generally accepted that an adult diagnosis of AD-HKD requires continuity between the childhood AD-HKD and the adulthood disorder. (56) In many cases, there are no informants who knew the person as a child, and there may be no possibility of obtaining school records. Despite these obvious difficulties, the diagnosis of AD-HKD in adults seems to be reliable. (57,58) Practice variables for the assessment of AD-HKD in adults are detailed elsewhere. (59)

Epidemiology

AD-HKD is a relatively common disorder. Estimates of its prevalence vary, depending, to a great extent, on the diagnostic measures (e.g. questionnaires or interviews), age, and nature of the population studied (e.g. inner city or rural). Screening with behavioural questionnaires identifies between 10 and 20 per cent of the population as being affected. (60) Studies that use definitions based on DSM and that take into account some degree of pervasiveness and impairment, but allow comorbidity, report prevalence rates in the 5 to 10 per cent range. (61) When the more stringent ICD-based criteria are used and the diagnosis is restricted to the presence of the full syndrome without comorbid conditions, 1 per cent to 2 per cent prevalence rates are found (for a review see Swanson et al. (18)).

AD-HKD is more common in males. The ratio of males to females in community samples is approximately 3:1. (48) The prevalence of AD-HKD is highest among school-aged boys and lower among adolescents. In contrast, its prevalence among females seems lower, but is more stable across the range of ages (48)

In clinic samples, the combined subtype of AD-HKD is found in 60 per cent of cases; the predominantly inattentive subtype, in 30 per cent; and the hyperactive–impulsive subtype, in 10 per cent. (62) Higher lifetime rates of comorbid conduct, oppositional, bipolar, language, and tic disorders are found in those with the combined subtype.

Aetiology

Cognitive and neural basis of AD-HKD

AD-HKD is an aetiologically heterogeneous disorder caused by a range of biological, psychological, and social factors that most likely interact to increase the risk of having AD-HKD. Presumably, these factors have their effects on the neural substrate of cognition—for example, on executive functions, self-regulation, arousal, and motivation. These are the delaying, future-oriented, and intentional control processes of the cognitive system that guide action and behaviour. (63) They help maintain alertness, sustain attention and effort, inhibit inappropriate actions, and adjust behaviour when errors are made and circumstances change. Deficits in these processes result in the poorly regulated behaviour that is characteristic of AD-HKD in everyday life and during laboratory tasks. (64) These deficits produce a cascade of secondary impairments in behaviour, working memory, self-regulation of affect, internalization of speech, and development of conscience. (6)

Executive functions depend on a distributed neural system involving the prefrontal cortex and associated subcortical structures. (65,66) These neurones are rich in noradrenaline and dopamine—neurotransmitters that are known to play an important role in attention. (67,68) The involvement of these neural substrates in executive function is confirmed by primate lesion studies, (69,70) as well as by human imaging, electrophysiological, and neuropathological studies. (71,72)

In children with AD-HKD, neuroimaging studies confirm abnormalities in those regions of the brain that are implicated in executive function. (73) These studies report significantly smaller asymmetrical prefrontal and basal ganglia structures, particularly on the right side, in children with AD-HKD than in matched controls. (74,75) Correlations of magnetic resonance imaging-based anatomical measures and specific-task performance in children with a diagnosis of AD-HKD suggest that the right prefrontal cortex is involved in inhibiting attentional and behavioural responses, whereas the basal ganglia seem involved in the execution of these responses. (76)

Neurobiological and psychosocial risk factors

Neurobiological and psychosocial risk factors, especially those acting during the period of rapid brain growth during fetal development and early in life, may cause AD-HKD by disrupting the neural networks supporting executive function and related processes. These factors include fetal exposure to the mother's use of alcohol, drugs, or cigarettes, and the adverse effects of perinatal obstetrical complications or prematurity (for more information about these neurobiological and psychosocial risk factors see elsewhere (77,78 and 79)). AD-HKD occurs after traumatic brain injury in 25 per cent of cases. (80,81) or after exposure to environmental toxins such as zinc. (82) Maternal stress during pregnancy and poor quality of caregiving (83,84) are also implicated in the origin of AD-HKD.

Environmental risk factors probably interact, making the accurate assessment of the specific role of any single factor difficult. For example, genetic and environmental risks may interact in the case of a genetically predisposed infant and an affected parent. The results of twin studies (85) indicate that both shared and non-shared environmental effects contribute modestly to the incidence of the disorder.

Abnormal thyroid function may also be connected to AD-HKD. There is evidence of mutations in the thyroid receptor-b gene (86) in a subset of patients with generalized resistance to the thyroid hormone. This rare disorder is associated with an increased risk of AD-HKD. However, the prevalence of a thyroid hormone abnormality among children who have AD-HKD is exceedingly low. (87)

Genetic factors

Family, twin, adoption, and molecular studies offer strong evidence of a genetic component to AD-HKD. Studies of community (88) and clinic samples (89,90 and 91) show that relatives of AD-HKD probands have an increased risk for AD-HKD. Moreover, they are also at increased risk for antisocial personality disorder, conduct disorder, and other conditions such as anxiety, mood, and reading disabilities. (52) Twin studies find a markedly higher concordance of AD-HKD for monozygotic (79 per cent) than dizygotic (32 per cent) twins that is consistent with a genetic origin of AD-HKD. (85) Adoption studies (92) provide further evidence of a genetic component to AD-HKD; biological parents of AD-HKD probands are more likely to exhibit AD-HKD or related disorders than adoptive parents. Siblings of children with AD-HKD have two to three times the risk of having AD-HKD than siblings of normal controls. (93) Furthermore, the basic characteristics that comprise the syndrome of AD-HKD are highly heritable (e.g. hyperactivity (90)).

Inattentive, hyperactive–impulsive, and combined subtypes of AD-HKD have unique but associated genetic influences; there may be different genetic effects for AD-HKD subtypes based on their severity. (52,94)

The often dramatic effect of stimulant medication on children with AD-HKD, and the concentration of neurones rich in dopamine and norepinephrine in the neural areas involved in executive function, suggest a role for the genes involved in the noradrenergic and dopaminergic systems. (95,96) Molecular genetic research associates AD-HKD with specific candidate genes in the dopaminergic system. AD-HKD is associated with an allele of the dopamine transporter (97,98 and 99) and the D4 receptor gene (DRD4).(45) There is no evidence of genetic effects in the noradrenergic system such as in the monoamine oxidase system. (100)

The specific mechanism by which genetic and neurobiological factors influence the development of AD-HKD is unknown. Segregation analysis is consistent with a major locus gene effect that has low penetrance and polygenic transmission, and a genetic risk, which is reflected in a spectrum of psychiatric phenotypes. (93) However, it is likely that multiple genes confer susceptibility to the development of AD-HKD in particular persons. The effects of these susceptibility genes may be potentiated by the environmental neurobiological factors already described.

AD-HKD may be best viewed as the extreme of a behaviour that varies genetically throughout the entire population, rather than as a disorder with discrete determinants. (101) The high prevalence of AD-HKD in the general population suggests that it may have had an adaptive function in early human history. As a result, the genes for AD-HKD may have been selected for survival in environments typical of those of early humans. (102)

Course and prognosis

AD-HKD can be identified reliably in preschool-aged children, at which time it may be associated with marked impairment, aggression, and language delay. (103) Although preschool-aged children are referred for clinical assessment, most cases are referred after children start school.

Originally, AD-HKD was thought to be a largely transient phenomenon. In general, there is a tendency for symptoms, especially restlessness, to diminish when children reach adolescence, although inattentiveness and impulsiveness are more persistent. (104) It is now clear that the disorder persists into adolescence in half or more of the affected persons seen in clinics, and into adulthood in half or more of adolescent cases. (38,105,106 and 107)

In many cases, AD-HKD has effects on these children that persist throughout their adolescence and adulthood. Compared with their non-AD-HKD peers, previously affected persons are at approximately five times greater risk for substance use (tobacco, alcohol, illicit drugs), (108) antisocial behaviour (arrests, incarceration, aggression, trouble with the law, admission to juvenile facilities), and other psychiatric disorders such as depression and anxiety. (109) Academic and educational problems persist into adolescence; by the time they are adults, hyperactive children have completed significantly less schooling and hold lower-status jobs than their non-hyperactive peers. (39) Even those who no longer meet the criteria for AD-HKD in adolescence are at increased risk for substance abuse and antisocial disorders, suggesting the persistence of some residual or latent deficit. (110)

Poor outcome in adolescence and young adulthood is more likely when the affected child is living in adverse psychosocial circumstances (e.g. poverty, overcrowding, hostility in the parent–child relationship), (111) or has parents with AD-HKD or other psychiatric disorders. The outcome is also worse when the AD-HKD symptoms are severe and persistent, and when the child exhibits comorbid conduct, or a language or learning disorder in his or her early development. (112) Problematic social interactions are a major determinant of a poor outcome in adolescence. (105,111) Nevertheless, the AD-HKD itself increases the risk of a poor outcome, even when due allowance is made for the associated risk factors. (113)

Treatment

Pharmacological, behavioural, and combined pharmacological and behavioural interventions are the most commonly prescribed and best validated treatments for AD-HKD. Special diets, megavitamins, antimotion-sickness medication, and electroencephalographic biofeedback are unproven therapies that have also been used to treat AD-HKD.

Prevalence of medication use

Methylphenidate (Ritalin) and, to a much lesser extent, dextroamphetamine are the most frequently prescribed treatments for AD-HKD in North America. (114,115) Tricyclic antidepressants and a2-noradrenergic agonists, such as clonidine and guanfacine, are second-line drug treatments for children who have an inadequate response to stimulants. (116,117)

The number of prescriptions of medication for children with AD-HKD has more than doubled over the last two decades to 5 million in 1994 in the United States; about 3 per cent of persons aged 5 to 18 years (1.5 million children) are taking medication for AD-HKD. (114) The prevalence of the use of medication is lower in Canada, Europe, and Australasia than in the United States, but is beginning to rise. Community physicians rely heavily on medication for the treatment of AD-HKD; as many as 88 per cent of diagnosed children receive drug treatment. (118)

The steady increase in the use of medication is attributable to a number of factors. These include the more frequent identification of affected persons, in particular those with inattention only, the increased rate of identification and treatment of girls, adolescents, and adults, and the increased duration of the treatment of each patient. The increasing prevalence of the use of medication may also be linked to a lack of resources for non-drug treatment, physicians', educators', and parents' greater familiarity with and acceptance of medication, and an absence of convincing evidence that non-pharmacological interventions are as effective as those involving medication.

Neurobiology of the medications used to treat AD-HKD

All three catecholamine systems—dopaminergic, adrenergic, and noradrenergic—are implicated in the pathophysiology of AD-HKD and its response to pharmacological treatment. Dysregulation of the central noradrenergic system may result in the inefficient priming of the cortex (i.e. quietening of activation in preparation for action). Dopaminergic mechanisms have a critical role in executive function processes; peripheral adrenaline may have a significant function in the therapeutic response to stimulant medication. (119)

Stimulants are sympathomimetic amines that closely resemble neurotransmitters. Dextroamphetamine and methylphenidate are considered indirect catecholamine agonists. These stimulants facilitate the action of dopamine and noradrenaline agonists by inhibiting their reuptake, facilitating their release into the synaptic cleft, and inhibiting the catabolic activity of monoamine oxidase. (120) Weak antagonism of the a2-adrenergic receptors may also contribute to the central effects of the amphetamine. (121) Tricyclic antidepressants, which are also used in the treatment of AD-HKD, increase plasma noradrenaline by blocking its reuptake, but have virtually no effect on the dopaminergic system. This may explain why the primary impact of the tricyclic antidepressants is on the behavioural manifestations of AD-HKD and why these antidepressants are less beneficial for cognitive and academic functions. (122)

Pharmacology of stimulant medication

Methylphenidate is rapidly absorbed and easily crosses the blood–brain barrier. The effects of this stimulant are seen in 30 min. Its peak plasma level occurs in 1 to 2 h, and its half peak level in 3 h. Its absorption is unaffected by meals. (123) Of primary clinical importance is the duration of its effect; the effects of methylphenidate last only 1 to 4 h. Therefore, the medication must be taken repeatedly. The effect of sustained-release dexedrine (Dexedrine Spansules) lasts 9 h. (124) Sustained-release methylphenidate (Ritalin Sustained Release) is designed to have the same impact as 10 mg of regular methylphenidate taken twice daily. However, sustained-release methylphenidate may have a variable and slow onset of effect; it may take 3 h to take effect, and the effect may last only 5 h. (124)

Therapeutic effects of stimulants

Numerous placebo-controlled randomized control trials (for meta-analyses see elsewhere (125,126 and 127)) confirm the short-term beneficial effects of stimulants. The reduction of the overt behavioural manifestations of AD-HKD, such as restlessness, is robust and often immediate. Stimulant therapy results in clear and immediate improvement in the quality of social interactions, a decrease in aggressiveness, and an increase in compliance. More information about these effects of stimulant therapy can be found in the literature. (33,128,129)

Stimulants improve a child's performance on laboratory tasks. For example, stimulants increase accuracy, facilitate error detection and correction, improve the ability to focus on the most relevant aspects of the information, and decrease impulsive responses on laboratory measures of cognition without causing an overfocus of attention or perseverative thought, in most cases. (130) Moreover, stimulants prevent a decrement in performance after a failure, decrease the tendency to stop working on very difficult tasks, increase the effort that the child is willing to expend to obtain a reward, and increase the tolerance of frustration. (131,132) These apparent improvements are evident on a range of demanding divergent thinking tasks, not just on boring, simple, or repetitive tasks. Stimulants also improve academic productivity (the percentage of problems completed and the percentage completed correctly), (133) mathematical computational and word-discovery skills, (134,135) and verbal retrieval, (136) letter-search, and arithmetic skills. (137,138) There is scant evidence that the information learned while a child is receiving medication is recalled less easily later when he or she is off the medication (this is known as state-dependent learning). (139)

The majority of medicated children feel that the medication is helpful. (140) They notice that they have increased vigour and decreased fatigue when medicated. In a substantial proportion of children, their mood and self-esteem improve. (141,142) Medication does not seem to engender the belief that successes are attributable to external factors rather than to their own personal effort. (131) Even prolonged treatment with stimulants does not appear to increase the risk of drug use or abuse. (143) No reduction in height or weight over long periods of treatment has been reliably demonstrated. (144,145)

Children of preschool-age and those with low intelligence are somewhat less responsive to stimulants than school-aged children (146,147) and somewhat more prone to develop side-effects. (148,149) Stimulants are effective among adolescents, (150) adults, (125) and children with neurodevelopmental delay, (149) aggression, (151,152) comorbid tics, (153) or seizure disorders while they are seizure-free. (154) A greater severity of AD-HKD symptoms, younger age, and absence of symptoms of anxiety predict a better clinical response to stimulants. (44,155,156)

Variation among stimulants

Methylphenidate and dextroamphetamine tend to have rather similar effects, (157) although dextroamphetamine may cause more insomnia and emotional symptoms than methylphenidate. (158) Individual children may respond better to one preparation than to another. (159) If practitioners try both methylphenidate and dextroamphetamine at a wide range of doses for each child, the rate of positive behavioural response may be as high as 95 per cent. (160)

Long-acting preparations of stimulants are useful for non-compliant patients who think that taking medication at school is socially unacceptable and who find the cyclical nature of the stimulant's effects unpleasant. When given in equivalent doses, the immediate-release and sustained-release preparations of methylphenidate, dextroamphetamine, and pemoline (124) are equally effective.

Limitations of stimulant medication

There are important limitations of stimulant treatment. Many families and children feel that medication is an unacceptable treatment. Some families believe that the problems do not reside in the child, but rather in the child's key relationships, either at home or at school. Other families are concerned about the biological or ethical implications of treating young children with drugs or about the risk of drug dependence later in life. Non-compliance is another significant limitation of the treatment of AD-HKD with drugs, as it is with other drug treatments.

Non-compliance is more common in the treatment of adolescents because of their determination to make important decisions for themselves and their dislike of being different from their friends.

Medication also has a limited duration of action. Typically, children take immediate-release stimulant medication twice daily or a sustained-release preparation once daily. Under these circumstances, medication is no longer effective after school. As a result, dysfunctional social interactions may persist, resulting in adverse effects on both immediate and long-term social function. (111,161)

Another limitation is the marked variation in response to stimulant treatment that is evident, both across individual affected persons and outcomes. A beneficial impact on behaviour, as rated by their teachers, occurs in about 70 per cent of treated children, (125) but treatment normalizes the behaviour of only about half of these children. (133) Stimulants have only a limited impact on school grades. (133) Moreover, one-quarter of children with AD-HKD who are aggressive before treatment show no increase in prosocial behaviour or in processing social information. (140,162) Stimulant medication may increase socially inhibited behaviour, social withdrawal, and dysphoria. Consequently, the child may be perceived as socially unresponsive, which may decrease the extent to which peers or adults like the child. (31,163)

Stimulants may not be optimally effective for children with AD-HKD and comorbid anxiety. These children have a somewhat less robust behavioural response to stimulants and possibly a greater incidence of side-effects. (53,164,165) However, a differential treatment response has not been detected with long-term treatment. (166)

Although generally safe, stimulant medication does have side-effects in a significant proportion of recipients that, in some cases, result in the termination of treatment. Loss of appetite, weight loss, insomnia, headaches, and stomach-aches are the most frequent side-effects. (141,149,161,167) Disruption of sleep is not uncommon (e.g. delayed sleep onset). (168,169) Initial physiological side-effects tend to persist, whereas other side-effects such as irritability and moodiness may have a delayed onset. (161)

Pemoline has been withdrawn from some markets because of numerous reports of acute hepatic failure, although some authorities feel that the risk may have been overestimated. (170)

One of the most significant limitations of stimulant medication is the lack of evidence of its efficacy over prolonged periods of treatment. Few long-term studies (i.e. of a duration greater than 12 weeks) of medications have been done, even though the majority of treated children receive stimulants for 3 years or more. (105) Most published studies have had significant methodological flaws, such as uncertain medication status at the time of testing, inclusion of an atypical sample of AD-HKD subjects, a limited range of outcome measures, and a failure to consider side-effects. (171,172) Available evidence indicates that prolonged treatment with stimulants improves core behavioural symptoms, although few subjects progressed sufficiently that their behaviour could be considered normal. (173) On cessation of the medication, benefits dissipate rapidly, even after prolonged therapy. (174,175) Even with prolonged administration, stimulants do not reliably improve academic attainment, reduce the risk of developing antisocial behaviour, or facilitate peer relationships or self-esteem.

Health-care costs are an important measure of effectiveness. However, no evidence is available about how well stimulant medication reduces the overall health-care costs associated with AD-HKD.

Tolerance of the effect of methylphenidate may develop in some children over months or years of continuous therapy. (176,177) About one-third of these children may require an increased dose. However, few children seem to lose their initial favourable behavioural response as long as they remain on the medication, even after extended periods of therapy. (178)

Non-stimulant medications

Tricyclic antidepressants

Evidence from several double-blind placebo-controlled trials supports the use of tricyclic antidepressants for the treatment of AD-HKD. However, the effects of tricyclics on attention and cognition are not as persuasive as their effects on behaviour. (179) Tricyclic antidepressants increase plasma noradrenaline levels by blocking the reuptake of noradrenaline, but they have less effect on the dopamine system. Unlike the typical response to tricyclic antidepressants when they are used to treat depression, their effects on AD-HKD are apparent within 2 or 3 days.

Tricyclic antidepressants may cause such side-effects as dry mouth, dizziness, nausea, constipation, drowsiness, perspiration, and tremors. Although relatively infrequent, serious cardiovascular effects of these medications have raised concerns about their safety. Prolonged intraventricular conduction and elevated heart rate and diastolic blood pressure have been consistently reported in association with higher doses (i.e. > 3.5 mg/kg of desipramine or imipramine and > 1 mg/kg of nortriptyline) and relatively high serum concentrations of tricyclic antidepressants. (180) Adverse cardiac effects of these medications may be exaggerated when they are taken in combination with other medications such as thioridazine or terfenadine, which, by themselves, prolong cardiac conduction. Serious questions have been raised about the clinical use of tricyclic antidepressants, because of a small number of sudden deaths during routine treatment with desipramine of apparently healthy children who had no history of cardiovascular problems. No causal link has yet been established. (179)

Tricyclic antidepressants are considered a second-line intervention, after the efficacy of stimulants has been evaluated. Treatment with these antidepressants should be undertaken with caution and careful monitoring. (180) Recommendations for the safe use of tricyclic antidepressants include obtaining a baseline electrocardiogram, a family history of premature cardiac disease, and, possibly, a cardiological consultation. Another electrocardiogram and plasma levels should be obtained once a daily dose of 2.5 mg/kg per day has been reached, and should be repeated after subsequent increases. Because some people do not experience cardiovascular adverse effects when the treatment is initiated, but do so after more prolonged therapy, patients should be continuously monitored for cardiac effects. Tricyclic antidepressants should not be discontinued abruptly.

Clonidine and guanfacine

Clonidine and guanfacine are a 2-adrenergic agonists that are somewhat effective for the treatment of AD-HKD, although very few randomized controlled trials have been done. (181) Clonidine has a stronger effect on the behavioural symptoms of AD-HKD, but relatively weak or no effects on the cognitive deficits associated with the disorder. (181,182) Clonidine is generally well tolerated, but commonly causes sedation, especially at the outset of treatment. It may cause hypotension and bradycardia during the first hours after its administration; abrupt withdrawal of the drug may cause transient hypertension. Long-term use has been associated with depression. Clinicians should be aware that, in spite of its widespread use, the evidence supporting the use of clonidine for the treatment of AD-HKD is weak.

Guanfacine is longer acting, more receptor-specific, and less sedating than clonidine. The results of a small number of open studies suggest that guanfacine is a somewhat effective treatment of children and adolescents with AD-HKD. (183) Guanfacine may also be effective for children with AD-HKD and comorbid tic disorders.(184)

Other medications

Bupropion

Bupropion is an antidepressant with a pharmacological profile similar to that of stimulants. Conners et al. (185) reported that bupropion significantly improves the symptoms of AD-HKD without any concomitant deterioration in cognitive performance or serious side-effects. A direct comparison with methylphenidate found that bupropion is less effective in improving attention, but is otherwise comparable. (186) Bupropion, however, may induce or aggravate tics, making it a poor choice for children with AD-HKD and comorbid tic disorders. Persons taking bupropion should also be monitored for skin rashes and electroencephalographic abnormalities.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors, antidepressants with a well-established efficacy for core AD-HKD symptoms, are almost never used to treat children and adolescents because of dietary restrictions and potential adverse effects. 

Carbamazepine

Carbamazepine is an anticonvulsant that is structurally related to the tricyclic antidepressants. Although it has not been rigorously evaluated for the treatment of AD-HKD, a recent meta-analysis of the literature(187) suggests that treatment with carbamazepine improves the AD-HKD symptoms of a sizeable proportion of patients. But it has little effect on the aggressive symptoms of children with a primary diagnosis of conduct disorder. (188) The most common side-effects of carbamazepine are sedation, ataxia, tremors, headache, diplopia, incoordination, slurred speech, and dizziness. Because carbamazepine can cause haematological changes and liver abnormalities, these systems should be monitored in those taking this medication.

Neuroleptics

Neuroleptics used to treat AD-HKD-related symptoms improved behavioural symptoms in fewer than half of the affected children and adolescents, according to a review of earlier studies. (189) Improvement in cognition was even less apparent. Given the serious risks associated with both acute and long-term use of these drugs (e.g. sedation, dystonic reactions, tardive dyskinesia, and neuroleptic malignant syndrome), the use of antipsychotics for the management of AD-HKD is restricted to extreme cases of patients whose severe symptoms and impairment persist, even after exhaustive investigation of alternative treatments known to be both safer and more effective.

Combinations, augmentation, and subgroup-specific treatment

Treatment of AD-HKD with a single drug is the optimal goal. Occasionally, combinations are considered because of a suboptimal clinical response, side-effects, or the presence of some troubling comorbid condition such as tic and anxiety disorders. Combinations of medications can cause drug interactions. Few combinations have been adequately studied.

Behavioural treatment

Various non-pharmacological therapies have been used for AD-HKD as an alternative to medication, as a means to improve aspects of the disorder that are not optimally treated by medication, or as a method of augmenting the beneficial effects of medication. These interventions can be administered in various settings (the classroom, home, summer camp, and playground) by a range of personnel (teachers, parents, and mental health professionals) in individualized or group formats.

Few well-controlled studies of non-pharmacological interventions are available for evaluation. (171) The effects of specific treatments are not easily appraised, because most studies of non-pharmacological interventions involve simultaneous treatment with multiple therapies (e.g. combined social skills training and behavioural parent training) or treatments tailored to the needs of particular families. (190) Often studies are limited because of a small sample size, a lack of randomization and control, and recruitment from biased patient populations.

Behavioural parent training may be the most commonly prescribed non-pharmacological intervention for AD-HKD. Parent training is predicated on the observation that parents of children with AD-HKD use overly controlling and inefficient parenting strategies. (191) Parent-training programmes are based on social-learning theory principles; these programmes use direct instruction, modelling, and role playing to teach parents to reinforce positive behaviour, decrease the use of punitive strategies, and manage oppositional behaviour effectively. (192)

Parent-training programmes improve the parents' child-management skills, (193,194) enhance their self-confidence, and reduce the child's stress (195) and oppositional behaviour.(194) The important advantages of parent training are its relatively low cost; its ability to be delivered in the community rather than in clinics, thereby reducing barriers to participation; and its adaptability to the needs of specific ethnic or cultural groups. (192)

Parent training, however, does not reduce the core symptoms of AD-HKD as effectively as stimulant medication, nor is it able to enhance the effectiveness of stimulants.(196,197) The primary benefit of combined parent training and medication may be its reduction of secondary impairments such as the conflict between parents and children.

Behavioural therapy involves trained therapists (e.g. camp counsellors), parents, or teachers reinforcing positive behaviour, academic accomplishment, and response–cost procedures for disruptiveness (i.e. withholding rewards when inappropriate behaviour occurs) to alter behaviour. (198) Cognitive–behaviour therapy attempts to enhance self-control by teaching children self-instructional strategies. These therapies may yield short-term improvement. (199) Social skills training targets the child's problems with peers and adults, typically in a group setting. These therapies have been effective when administered on their own, (200,201) but there little evidence that social skills training is as potent as medication.

A variety of books and videos provide instruction on the management of children with AD-HKD. Videotaped programmes have proven effective for parents of young children with conduct disturbance. (202) Only programmes combining videotaped modelling with therapist-led group discussions result in stable improvement in their behaviour.(203) (See also: cognitive-behaviour therapies for children and adolescents)

Multimodal treatment

Recently, a large multisite treatment study in the United States compared drug treatment (mostly methylphenidate), drug treatment combined with an intensive psychosocial intervention (a combination of family therapy, social skills training, and classroom management), psychosocial intervention alone, and a typical community-based intervention in 576 school-aged children with AD-HKD. (160) All subjects received the same assessment, but those in the community-based intervention were referred to their family physicians for appropriate treatment. The results of this study demonstrated little evidence of an incremental effect of combined treatment over medication alone. The effects of psychosocial treatment, when administered without medication, were generally equivalent to those of a community-based treatment. Many children in the community-based intervention received medication, but they did not seem to progress as well as those who received medication managed by the study personnel. This finding suggests that medication management that is intensive and coupled with supportive counselling is superior to the medication treatment most children receive in the community.

In summary, non-drug interventions are an important treatment option, particularly for families who do not wish to use medication, but these interventions have only modest effects. Moreover, the psychosocial treatments that have been evaluated to date do not seem to potentiate the effects of medication on the core symptoms of AD-HKD, such as hyperactivity, but may reduce associated impairments, and improve social skills and self-esteem.

Management

General principles

Clinical management is guided by the knowledge that AD-HKD is a chronic condition that affects most aspects of a child's life and that is, in turn, shaped by a wide range of biological, psychological, and social factors. Consequently, a comprehensive assessment is the logical starting point for the management of a child with AD-HKD. This assessment must identify core AD-HKD symptoms, associated impairments in language and learning, and the concurrent emotional and behavioural conditions that frequently accompany the disorder. The treatment plan must consider the child's social context, including the quality of current schooling, the nature of parenting practices, and the extent of the parents' psychopathology. The longitudinal nature of the disorder dictates the need for a consistent case manager. Treatment must be flexible, both in kind and in intensity, to reflect the social, physiological, and cognitive developments and variations in the life situations of each child and his or her family.

Based on the available evidence, medication plays an important role in the treatment of AD-HKD. However, drug treatment must be instituted in the context of a comprehensive treatment plan. Rarely is medication prescribed as the sole treatment. For some children and families, medication will be an undesirable therapeutic option; for others, medication may be unnecessary or premature.

In clinical practice, however, physicians do encounter families who are not ready for or capable of undertaking treatments other than those involving medication. For many of these families, a period of behavioural improvement resulting from successful drug therapy may provide the impetus for entry into other essential non-pharmacological components of therapy. Some families may not consider non-drug interventions until they observe that an immediate increase in academic productivity does not necessarily translate into better grades at the end of the year, and that teachers' reports of improved behaviour at school do not ensure improved family relationships in the evenings. Other families may be too chaotic to use medications appropriately and may first need to try non-drug interventions under very close supervision or in an inpatient setting. Some families are more content with the decision to use medication if it follows a period of counselling or behavioural intervention. (204)

Initiating treatment with medication

Existing research supports what seems to be the typical approach to establishing drug therapy for children with AD-HKD. Initially, one of the two stimulants, methylphenidate or dextroamphetamine, is used. Initiating treatment with a regular-acting preparation rather than a long-acting preparation permits a more precise adjustment of the timing and dosing of the medication throughout the day. If one stimulant fails to produce the desired benefits or causes side-effects that are unacceptable, another is tried. Long-acting preparations of the psychostimulants are used when compliance is an issue or when the waxing and waning effect of shorter-acting preparations is undesirable.

Initiation of the treatment involves a slow increase of the dose to some target dose, often in the range of 0.5 to 0.7 mg/kg, given twice daily to begin with. However, a dose based on the milligram-per-kilogram calculation may result in doses that are too high for older or heavier children. Conversely, fixed doses (e.g. a target dose of 10 or 15 mg, twice daily) could result in doses that are too high for younger or lighter children. Some hybrid approach seems optimal; for example, targeting a dose of 0.7 mg/kg, but stopping at a maximum single dose set at 20 mg. The use of a third late-day dose of medication may be particularly useful for social and academic activities in the evening. To minimize insomnia and anorexia in the evening, typically, the third dose is half the dose administered during the day.

Various authorities (117) have recommended that a double-blind placebo-controlled trial is a necessary part of the process of initiating medication, even in a typical clinical practice. A systematic trial involves the double-blinded administration of various doses of medication and placebo in random order. Systematic trials are not particularly complicated and can be organized in a typical clinical practice.

On the other hand, the use of a systematic trial seems to have little advantage over the open trial described above. There is little evidence of a sustained placebo effect, and doses determined by a systematic trial tend to be similar to those determined by open titration. Consequently, the extra cost of a double-blind trial may not be justified. Many parents, however, are reassured by the rigour of a systematic trial, (205) which may, in itself, be ample justification for conducting the trial.

Education is an important part of treatment because it helps parents and the affected child develop an understanding of the nature of the disorder. This understanding may improve their decisions about treatment. Moreover, increased knowledge may result in more realistic expectations and better adherence to the treatment.

Monitoring side-effects

Regular contact with the child's teacher is useful for monitoring behavioural improvement and side-effects in the school setting. The physician can organize this contact by having the child's parents take a behaviour-rating and side-effects scale to the teacher before the child's follow-up visits. Obtaining information directly from the teacher is preferable to the usual procedure of asking the parents about the child's response in the school setting. In many cases, the parents actually do not see their child during peak-medication effects because he or she takes the medication twice daily during school hours.

The presence of physical complaints such as headaches and insomnia must be assessed before the child starts taking medication. Otherwise, these symptoms may be construed incorrectly as side-effects, once treatment starts. Side-effects must be monitored continuously because many have a late onset. (161)

Since some side-effects such as overfocusing, preservation, and dystonia are subtle and unreliably reported by teachers and parents, direct observation of the child is important. A useful strategy for monitoring the effects of medication is to have the child attend follow-up visits at a time of peak-medication effect, for example, 1 to 2 h after taking an oral dose of medication. The physician can then systematically observe the child for tics, stereotypical movements, perseveration, overfocusing, and other side-effects during the course of a routine office visit, in addition to obtaining the reports of parents and teachers.

Prevention

Primary prevention of AD-HKD, like that of other mental health disorders, requires that the population health-risk factors strongly associated with the disorder be identified before they can be altered to change outcomes. A range of psychosocial, biological, and developmental risks of AD-HKD has been identified, but each accounts for only a small portion of the variance in the incidence of the disorder. All these risk factors must be altered before a significant impact on the outcome is possible because we do not yet know which of these factors is primary.

We are now reasonably certain that preschoolers with the triad of AD-HKD, aggression, and impairment of language and learning are at particularly high risk for persistent AD-HKD, and for significant impairment in later life. (103) Nevertheless, many of these early cases of AD-HKD will dissipate without specific intervention, other severe cases will appear among older school-aged children, and most cases will not be identified by identifying preschoolers with AD-HKD, aggression, and impaired language and learning.

Early detection and intervention for targeted groups of children with AD-HKD may reduce impairment for the affected child and the burden of suffering for the families and communities. The modest results achieved in research to date indicate that these interventions will have to be very intensive, comprehensive (i.e. involve children, parents, and schools), and multidimensional (in other words, target behaviour, social interaction, and academic skills).

Given the high prevalence of AD-HKD, it is unreasonable to assume that traditional clinic-based services will be able to meet this considerable mental health need. Nevertheless, there is a clear need for a multidimensional, multidisciplinary, and comprehensive clinical assessment to establish the initial diagnosis, plan treatment, and support the long-term management of affected persons.

Conclusions

AD-HKD is a prevalent, persistent, impairing, and costly disorder. Although its origin is uncertain, biological, psychological, and social factors are clearly implicated. Medication is effective for many children, yet even this treatment appears limited, especially in its ability to alter the long-term outcome of the disorder. Nevertheless, medication can provide respite from the symptoms of AD-HKD during which time other essential aspects of therapy can be implemented. The development of acceptable, cost-effective, and widely available non-pharmacological therapies for AD-HKD remains a priority for the field, as does the development of further pharmacological options for those children who do not benefit from stimulants or other currently available medications. 

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