Overview and Risk Factors

Attention deficit hyperactivity disorder (ADHD) is characterized by inattentiveness, hyperactivity, and poor impulse control. It is estimated to affect 5% to 10% of children, and up to 70% of cases persist into adolescence and adulthood. It can affect cognitive, academic, behavioral, emotional, and social functioning and may be associated with comorbid psychiatric conditions, such as oppositional-defiant and conduct disorders, learning disabilities, anxiety, depression, and, later in life, substance use disorders.

The disorder is probably of multifactorial origin. That is, it may be caused by a combination of genetic and environmental factors. Neurotransmitter abnormalities have been postulated, focusing on catecholamine metabolism in the cerebral cortex and basal ganglia. An imbalance between norepinephrine and dopamine in the prefrontal cortex is suspected. Methylphenidate, a stimulant that is effective in treating ADHD symptoms, is known to increase synaptic dopamine concentrations.

Inattention may present as disorganization, forgetfulness, frequent misplacing of things, inability to follow instructions, academic underachievement, distractibility, inability to finish tasks, poor concentration, careless mistakes, or poor attention to detail. Hyperactivity is identified by fidgeting, restlessness, difficulty remaining seated, and talking excessively or inability to remain quiet when appropriate.

Impulsivity is noted by difficulty waiting turns, disruptive classroom behavior, interrupting others, peer rejection, and attempting risky activities without considering consequences. Affected adults may show inattention and impulsivity, rather than hyperactivity, and may have difficulty keeping a schedule, managing money, staying with a job, or maintaining a marriage.

Risk Factors

Male gender. ADHD is identified 2 to 3 times more frequently in boys than in girls.

Age. About half of cases present earlier than age 4. Although some will remit by adolescence, others persist into adulthood. At present, no "adult-onset" variety is recognized; symptoms must have been present before 7 years old to meet diagnostic criteria.

Genetics. Some studies indicate that as much as 75% to 80% of risk may be genetic. Studies of twins reveal a 90% concordance in monozygotic twins. Several genes have been identified as possible candidates, most notably dopamine receptor and transporter genes.

Environmental factors. Early lead exposure or head injury may increase risk.

 Diagnosis

For a diagnosis of ADHD, the American Psychiatric Association requires at least 6 symptoms of inattention or at least 6 symptoms of hyperactivity and impulsivity, which are listed below.¹ Symptoms must have lasted for at least 6 months, must have begun prior to age 7, and must be present in at least 2 settings (eg, school and home). Also, there must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.

Symptoms of Inattention

• Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities.
• Often has difficulty sustaining attention in tasks or at play.
• Often does not seem to listen when spoken to directly.
• Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace.
• Often has difficulty organizing tasks and activities.
• Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort.
• Often loses things necessary for tasks or activities.
• Often easily distracted by extraneous stimuli.
• Often forgetful in daily activities.

Symptoms of Hyperactivity and Impulsivity

• Often fidgets with hands or feet or squirms in seat.
• Often leaves seat in classroom or in other situations in which remaining seated is expected.
• Often runs about or climbs excessively in situations in which these behaviors are inappropriate (in adolescents, or adults, may be limited to subjective feelings of restlessness).
• Often has difficulty playing or engaging in leisure activities quietly.
• Often "on the go" or acts as if "driven by a motor."
• Often talks excessively.
• Impulsivity.
• Often blurts out answers before questions have been completed.
• Often has difficulty awaiting turn.
• Often interrupts or intrudes on others (eg, butts into conversations or games).

A medical, neurologic, psychological, and cognitive evaluation should be performed to rule out underlying medical contributors, cognitive deficiencies, and mimicking disorders. Diagnosis of adult ADHD is similar to that in children, but may be complicated by a more subtle presentation, usually lacking the hyperactivity component.

 Treatment

Pharmacologic Treatments

Stimulants. Methylphenidate (Ritalin) and dextroamphetamine (Adderall), are effective in 60-70% of children with ADHD. They increase catecholamine release from presynaptic neurons. Sustained-release preparations and longer acting medications, such as dexmethylphenidate (Focalin), minimize rebound symptoms and irritability, as well as minimize disruptions in the school day caused by twice-daily or three-times-daily dosing schedules. Side effects may include decreased appetite, insomnia, anxiety, irritability, or headache. Moreover, sympathomimetic agents raise blood pressure and heart rate, potentially contributing to risk of sudden cardiac death.²

Modafinil (Provigil) is not yet approved for treatment of ADHD, due to several case reports of an association with Stevens-Johnson syndrome (a potentially fatal rash) in children.

Nonstimulants. Several classes of nonstimulant medications may be effective, although controlled studies are limited. They are generally used in patients who do not respond to or cannot tolerate stimulants.

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor and is the only FDA-approved nonstimulant for ADHD. The FDA has recently warned that this medication may cause hepatotoxicity. It should be avoided in patients with liver disease. If used, it should be discontinued in patients who develop jaundice or laboratory evidence of hepatotoxicity.

Among antidepressant medications, tricyclic antidepressants (eg, imipramine, nortriptyline) and dopamine reuptake inhibitors (eg, bupropion) have both been used with some anecdotal success, but are not approved for use in children. Bupropion is used frequently in adults as a first-line treatment because it is not a stimulant per se. Moreover, many adult patients have comorbid depression. Bupropion is not habit forming and is less likely to be abused than stimulants. Selective serotonin reuptake inhibitors do not appear to have as much effect as other antidepressants.

Clonidine is an alpha-2 adrenergic agonist, which may be useful in easily frustrated, highly aroused, and aggressive patients, as well as in children and adolescents with tic disorders. Side effects may include dizziness, syncope, palpitations, diaphoresis, pedal edema, or urinary changes. In addition, several drugs may interact with clonidine, including alcohol, barbiturates, beta-blockers, digoxin, cold medicines, and others. At this time, clonidine is not approved by the FDA for use in ADHD.

Gaunfacine is an alpha-2 adrenergic agonist, which may be useful in inattentive, impulsive, easily frustrated, highly aroused, and aggressive patients, as well as in children and adolescents with tic disorders.

Anticholinesterase inhibitors, such as tacrine and donepezil, and nicotinic analogues are currently being investigated.

Nonpharmacologic Treatments

Behavioral interventions are useful for many patients, particularly children. These might include seating near the teacher, daily report card with home reinforcement, and extended time to complete tasks.

Replacing television viewing with exercise may be a promising preventive approach. A growing body of evidence indicates that small children who watch relatively little television have a significantly lower risk for developing ADHD, compared to other children.³ In contrast to watching TV and other sedentary activities, physical activity in children plays a critical role in their growth and development.⁴ A meta-analytic review of studies found significant reductions in disruptive behavior in children who exercised regularly, particularly those with ADHD.⁵ The improvements may be partially explained by findings of a dopamine-agonistic effect of exercise.⁶ Also, sports and other social activities help children learn social skills appropriately.

Biofeedback. Electroencephalographic (EEG) biofeedback training may be a promising investigational treatment. Research studies have demonstrated that some individuals who have ADHD have excess slow-wave activity and reduced fast-wave activity, compared with matched peers. Using video and auditory feedback, individuals can learn to reduce their slow-wave activity and/or increase their fast-wave activity.⁷ Case series report that approximately 75% of patients have a positive clinical response.⁸

 Nutritional Considerations

The role of diet in ADHD has been controversial ever since it was first proposed in the book Why Your Child Is Hyperactive, by pediatrician Ben Feingold, M.D.⁹ Dr. Feingold demonstrated that the removal of synthetic colorings, flavorings, and preservatives from the diet led to a marked improvement in many children. (Feingold suspected a much wider array of dietary sensitivities, but those 3 were the easiest to study.) Later researchers failed to replicate these effects.

However, subsequent studies have reasserted the role of diet, suggesting that the list of offending agents may go beyond the food dyes, flavorings, and preservatives that were originally studied. Children with ADHD often have an allergic or other hypersensitive response to artificial colors, flavors, or preservatives,¹⁰ and recent studies suggest that a histamine response may underlie ADHD symptoms in some children (see below). In addition, some studies have suggested a contributory role of nutrient-poor meals and snacks.¹⁰ Such diets may contribute to the deficiency of nutrients (eg, iron and zinc) that have been documented in children with ADHD¹¹ and that are known to be required for neurotransmitter production.

The following nutritional factors are under study for their effect on ADHD:

Diets free of artificial flavorings, colors, and common allergens. At least 8 controlled studies have demonstrated significant behavioral improvement on oligoantigenic diets compared with regular diets, or behavioral deterioration on a placebo-controlled challenge with foods suspected of aggravating symptoms. In one of these, parental reports indicated that more than half the subjects exhibited a reliable improvement in behavior.¹² Typical oligoantigenic diets used previously included only lamb, chicken, potatoes, rice, banana, apple, cabbage, cauliflower, Brussels sprouts, broccoli, cucumber, celery, carrots, parsnip, salt, pepper, calcium, and vitamins.¹³ The therapeutic basis for such a regimen may lie in an allergic response (ie, histamine production) to artificial colors, flavors, and dyes. Histamine is a neurotransmitter; antagonism of its actions improves cognitive performance. Of note, the antihistamine diphenhydramine (Benadryl) was once a treatment for ADHD, although it was not as effective as stimulants. Other histamine receptor antagonists are currently being evaluated for potential application in ADHD.¹⁴

A meta-analysis of double-blind, placebo-controlled trials concluded that artificial food colors contribute one-third to one-half of the behavioral deterioration that would be observable when hyperactive children are taken off psychostimulants.¹⁵

Omega-3 fatty acids. Both omega-3 and omega-6 fatty acids have been reported to be lower in children with ADHD compared with other children, and limited data suggest that certain fatty acids (eg, eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA)) can affect behavior. However, clinical trials of polyunsaturated essential fatty acids in children with ADHD have produced inconsistent results.¹³ Of 6 published placebo-controlled trials of polyunsaturated essential fatty acids, 2 with gamma-linolenic acid were equivocal, 1 with DHA was negative, and 3 with a combination of GLA, EPA, and DHA were positive on some measures.¹³

Zinc. As a cofactor for neurotransmitters, zinc influences regulation of γ-aminobutyric acid (GABA), serotonin, and dopamine, all of which may play roles in ADHD.¹⁶ Poor zinc status, a common occurrence, can delay cognitive development and has been found with greater frequency in hyperactive children, compared with controls.¹⁶ Zinc status has been reported in a small sample to correlate with response to amphetamine treatment,¹⁶ and controlled clinical trials in the Middle East, an area of zinc deficiency, support the possibility that supplemental zinc (55-150 mg ZnSO4/day) may improve response to methylphenidate¹⁷ or improve symptoms of hyperactivity and impulsiveness when used as monotherapy.¹⁸ However, these reports leave questions about sample retention and data analysis, and further controlled clinical trials are required.

Aspartame or sucrose restriction and mineral supplements. Controlled trials of sugar-restricted diets found no effect on behavioral symptoms in ADHD, even in children thought to be sugar-sensitive.^13,19 Deficiency of several minerals (iron, copper, zinc, calcium) may influence neurotransmission in the central nervous system, and several studies have demonstrated mineral deficiencies in children with ADHD. However, controlled studies have not established a clear benefit of supplementation in individuals with ADHD.¹¹ Similarly, studies have not supported a causal role for aspartame in ADHD.²⁰

Orders

See Nutritional Requirements throughout the Life Cycle chapter.

What to Tell the Family

ADHD can impair learning, work performance, and social relationships. However, several treatments are available. Although many parents have understandable concerns about drug therapy, medications are highly effective and generally provide rapid and dramatic relief. Other options--behavioral treatment, special educational programming, and, for a subset, oligoantigenic diet--may be tried separately or in combination with medication.

 References

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2. Nissen, SE. ADHD drugs and cardiovascular risk. N Eng J Med. 2006; 354:1445-1448.

3. Christakis DA, Zimmerman FJ, DiGiuseppe DL, McCarty CA. Early television exposure and subsequent attentional problems in children. Pediatrics. 2004;113:708-713.

4. Cooper DM, Nemet D, Galassetti P. Exercise, stress, and inflammation in the growing child: from the bench to the playground. Curr Opin Pediatr. 2004;16:286-292.

5. Barkley RA. Adolescents with attention-deficit/hyperactivity disorder: an overview of empirically based treatments. J Psychiatr Pract. 2004;10:39-56.
 
6. Tantillo M, Kesick CM, Hynd GW, Dishman RK. The effects of exercise on children with attention-deficit hyperactivity disorder. Med Sci Sports Exerc. 2002;34:203-212.

7. Butnik SM. Neurofeedback in adolescents and adults with attention deficit hyperactivity disorder. J Clin Psychol. 2005;61:621-625.

8. Monastra VJ. Electroencephalographic biofeedback (neurotherapy) as a treatment for attention deficit hyperactivity disorder: rationale and empirical foundation. Child Adolesc Psychiatr Clin N Am. 2005;14:55-82.

9. Feingold B. Why Your Child Is Hyperactive. New York: Random House; 1974.

10. Boris M, Mandel FS. Foods and additives are common causes of the attention deficit hyperactive disorder in children. Ann Allergy. 1994;72:462-468.

11. Daley KC. Update on attention-deficit/hyperactivity disorder. Curr Opin Pediatr. 2004;16:217-226.

12. Kaplan BJ, McNicol J, Conte RA, Moghadam HK. Overall nutrient intake of preschool hyperactive and normal boys. J Abnorm Child Psychol. 1989;17:127-132.

13. Arnold LE. Alternative treatments for adults with attention-deficit hyperactivity disorder (ADHD). Ann N Y Acad Sci. 2001;931:310-341.

14. Leurs R, Bakker RA, Timmerman H, de Esch IJ. The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005;4:107-120.

15. Schab DW, Trinh NH. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr. 2004;25:423-434.

16. Arnold LE, DiSilvestro RA. Zinc in attention-deficit/hyperactivity disorder.
J Child Adolesc Psychopharmacol. 2005;15:619-627.

17. Akhondzadeh S, Mohammadi MR, Khademi M. Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial. BMC Psychiatry. 2004;4:9.

18. Bilici M, Yildirim F, Kandil S, et al. Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:181-190.

19. Wolraich ML, Lindgren SD, Stumbo PJ, Stegink LD, Appelbaum MI, Kiritsy MC. Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. N Engl J Med. 1994;330:301-307.

20. American Dietetic Association. Position of the American Dietetic Association: use of nutritive and nonnutritive sweeteners. J Am Diet Assoc. 2004;104:255-275.