Pathophysiology

AD/HD is a heterogeneous disorder of unknown cause. Structural and functional neuroimaging studies have not identified a unique origin. Although a positive family history is typical, no specific genetic marker has been identified, and studies that have found a familial association fail to distinguish between the actions of genes and family-specific environmental causes. The neurobiologic processes involved in attention and inhibition necessitate coordination of cortical and subcortical functioning; the most critical structure for maintaining alertness and attention is the reticular activating system, whereas the ability to inhibit distractions is cortically mediated at the prefrontal cortex. Circuits that connect these areas help to control how the brain both sustains and filters attention in response to stimuli. Executive functions are major tasks of the frontal lobes. MRI of the right mesial prefrontal cortex in persons with AD/HD strongly supports decreased activation (low arousal) during tasks that require inhibition of a planned motor response and timing of a motor response to a sensory cue. There is also evidence of weakened activity in the right inferior prefrontal cortex and left caudate during a task that involves timing of a motor response to a sensory cue. The catecholamines are the main neurotransmitters with frontal-lobe function. Catecholamine-controlled dopamine and norepinephrine appear to be important in linking subcortical areas to the frontal lobe. Stimulant drugs probably work by increasing “background” dopamine levels in the synapses. However, diagnostic trials of stimulant medications have failed to distinguish between children with and those without AD/HD.

The key features of AD/HD are inattention and hyperactivity/impulsivity. Although the disorder occurs in individuals of all races and socioeconomic strata, a 6:1 male:female ratio has been noted in childhood, and a positive family history is common. Environmental factors associated with AD/HD include poverty, maternal psychopathology, and family conflict, although none of these has been determined to be causally linked with AD/HD. Substance abuse, school failure, and, later, difficulty in maintaining a job may be associated with AD/HD; however, evidence suggests that patients who are treated properly with medication and who are given support do very well. It is estimated that up to 65% of children with AD/HD have at least one other comorbid condition such as depression, conduct disorder, oppositional defiant disorder, Tourette’s syndrome, or a learning disability.

Disease Process

The diagnosis of AD/HD in children is made after observation and history taking. It requires a documented history of inattention and impulsivity, with or without hyperactivity, causing impairment in at least two settings (usually home and school) before the age of 7. Symptoms must have been prominent for at least 6 months. AD/HD is common, affecting 4% to 12% of school-age children and 3% to 4% of adults. Childhood AD/HD is a prerequisite for the diagnosis of AD/HD in adults, but it is increasingly recognized that adults may have the disorder, along with symptoms that were present in childhood, without ever having received a formal diagnosis as a child.

The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV-TR), defines three subtypes of AD/HD: attentional, hyperactive/impulsive, and combined, which is usually a combination of attentional and hyperactive forms. In children with AD/HD, Predominantly Inattentive Type, inattention is the major problem. The child cannot focus on instructions or tasks, fails to finish schoolwork, often loses things, cannot organize, and is forgetful and easily distracted. Inattentive children may not be noticed in the school setting because they are not disruptive. Thus, their condition often is not diagnosed until they are attending middle or high school.

The second subtype of AD/HD defined by the DSM-IV-TR is AD/HD, Predominantly Hyperactive-Impulsive Type. These children receive more attention in the classroom—often negative attention—because they fidget, cannot wait their turn, interrupt others, act as if “driven by a motor,” talk incessantly, have difficulty enjoying quiet leisure activities, and act impulsively. These children often come to the attention of the health care provider because of concerns expressed by parents and teachers as early as preschool or kindergarten.

Finally, children with AD/HD, Combined Type, exhibit both behavior sets.

AD/HD is a dimensional, not a categorical, disorder with varying degrees of severity, some so mild that they may almost appear normal. In children, hyperactivity usually predominates. Although the hyperactive behavior may abate, or may be better controlled, with age, the attentional cluster of symptoms—inattention, lack of concentration, forgetfulness, shift in activities, executive operation dysfunction, and disorganization—tend to persist. Adolescents often display oppositional and restless behavior. Adults have increased problems with attention- and executive-level functioning and may underperform in their jobs.

The major neurologic functions that are disturbed by neurotransmitter imbalance of AD/HD are the executive function tasks. The six major execution function tasks that are most commonly distorted with this disorder are (1) shifting from one mindset or strategy to another (e.g., flexibility), (2) organization (e.g., anticipating both needs and problems), (3) planning (e.g., goal setting), (4) working memory (e.g., receiving, storing, and then retrieving information with short-term memory), (5) separating affect from cognition (i.e., detaching one’s emotions from one’s reason), and (6) inhibiting and regulating verbal and motoric action (e.g., jumping to conclusions too quickly, difficulty waiting in line in an appropriate fashion).

Before AD/HD is diagnosed, other causes of impaired concentration and memory should be ruled out through a comprehensive neurologic and behavioral examination. Laboratory studies typically are not necessary but may include comprehensive metabolic panel, thyroid studies, and heavy metal screening, with particular attention to lead and toxicology screens. Absence and simple partial seizures can present with staring spells; an electroencephalogram may be indicated to rule out seizures. Children with sleep disorders that interfere with REM sleep may present with inattention and poor school performance; a comprehensive sleep study may be needed to evaluate this possibility. Other psychiatric diagnoses that should be considered and ruled out include anxiety disorders, affective disorders, adjustment disorders, behavioral disorders, and developmental disorders, including speech and language delays, which may cause a child to appear inattentive as a result of an inability to understand classroom directions.

Even though AD/HD has been recognized in children, awareness is only now increasing about the fact that adolescents and adults may have AD/HD and may not have had treatment. In many of these individuals, the condition is diagnosed when they have problems with employment or when they seek treatment for depression or another type of medical problem. Much of the information generated by research about children with AD/HD appears to apply to adults also. Adults benefit from behavioral therapy and from the use of medication to keep them focused and functional.

Amphetamine-like Drugs

Methylphenidate is a mild cortical stimulant with CNS actions similar to those of the amphetamines. It inhibits the reuptake of both norepinephrine and dopamine in the cerebral cortex. This results in an increase in neurotransmitter in the synaptic cleft and enhanced stimulation of the cerebral cortex and subcortical structures. In normal children, as well as in children with AD/HD, this effect enhances the child’s ability to selectively filter stimuli, leading to a decrease in motor activity and an increase in attention and cognition. Dexmethylphenidate contains the more pharmacologically active of the dextro and levo isomers.

Amphetamines

Amphetamines are sympathomimetic amines with CNS stimulant activity. Norepinephrine is released from central noradrenergic neurons. At high doses, dopamine may be released. The site of action for appetite suppression is thought to be the lateral hypothalamic feeding center. Peripheral α and β activity includes elevation of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant actions. Lisdexamfetamine is a prodrug of dextroamphetamine and a relatively new product.

Norepinephrine Reuptake Inhibitors

The mechanism of action of atomoxetine is selective reuptake of presynaptic norepinephrine. It does not bind to monoamine receptors in the brain, thereby decreasing the risk of adverse reactions compared with older norepinephrine reuptake inhibitors.

α_2- Adrenergic Receptor Agonists, Analeptics, Antidepressants, and Stimulants

A variety of other drugs have been approved for use in AD/HD, including guanfacine, an oral, centrally acting, α_2- adrenergic receptor agonist usually used in the treatment of hypertension. It is similar to clonidine, the extended form Kapvay, which has been approved for use in AD/HD. Some antidepressants may also be helpful in AD/HD, but they are not discussed in detail in this chapter (see Chapter 47). Antidepressants and α-agonists may cause adverse cardiac effects.

Psychostimulants

Caffeine, a methylxanthine, competitively blocks adenosine receptors and is a potent stimulant of the CNS. It also produces cardiac stimulation, dilation of coronary and peripheral blood vessels, constriction of cerebral blood vessels, skeletal muscle stimulation, augmentation of gastric acid secretion, and diuretic activity. It may produce tachycardia or premature ventricular contractions as well. The CNS-stimulating effects and associated constriction of cerebral blood vessels are effective as analgesic adjuncts. It also increases absorption of ergot alkaloids. Tolerance to these effects may develop.

Modafinil is a pharmacologically distinct psychostimulant approved for use in shift work sleep disorders, sleep apnea, narcolepsy, and excessive daytime sleepiness in adults. Although the exact mechanism of action is unknown, studies have demonstrated that it inhibits the reuptake of dopamine and activates glutamatergic circuits while inhibiting GABA. It is thought to have less abuse potential because of the absence of euphoric effects. It is used off-label but recommended for AD/HD.

Standardized Guidelines

Evidence-Based Recommendations

Cardinal Points of Treatment

Treatment options are listed in order of preference:

Nonpharmacologic Treatment

Drug therapy is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms related to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential, and psychosocial intervention generally is needed.

Classes or counseling for parents in behavior modification (such as point systems that allow children to earn rewards) is often considered an integral part of the treatment plan for AD/HD. Additionally, social skills training, cognitive-behavioral therapy, support groups, biofeedback, and meditation all have been integrated into comprehensive, multidisciplinary management programs, although empirical evidence for the efficacy of these interventions is lacking. The new American Association of Pediatric guidelines provide an appendix with specific information on working with parents and teachers to obtain the best treatment results.