Attention deficit hyperactivity disorder (ADHD) is characterized by persistent inattentiveness, impulsivity, and/or hyperactivity that interfere with functioning and are present in 2 or more settings.[1] The disorder affects an estimated 11% of US children aged 4-17, with increased prevalence in teen years, and more than 4% of American adults.[2],[3] It can affect cognitive, academic, behavioral, emotional, and social functioning, and may be associated with comorbid psychiatric conditions. These include oppositional-defiant and conduct disorders, learning disabilities, anxiety, depression, and, later in life, substance-use disorders.

This neurobehavioral disorder is probably 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, 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, maintaining steady employment, or maintaining relationships

Risk Factors

Male gender. ADHD is identified 2-3 times more frequently in boys than in girls. Boys are more likely to experience hyperactivity symptoms, which makes the illness easier to recognize, and are also more likely to engage in disruptive behavior, calling attention to themselves and making a diagnosis more likely.[4]

Age. The average age of diagnosis is 7 years.[2] Although some cases remit by adolescence, others persist into adulthood. ADHD has been historically considered a disorder that develops in childhood; however, new evidence is beginning to suggest that some cases may be late-onset or adult-onset.[5] Relative age, compared to other children within a classroom, also has an effect. The age at which a child starts school is based on the month of his or her birthday, and ages within a classroom can vary by up to 12 months. In a large study in Iceland, investigators found that between the ages of 7 and 14, children in the youngest third of the class were 50% more likely to be prescribed stimulant medication for ADHD.[6]

Genetics. Siblings of an individual with ADHD are at increased risk of the disorder, and there is a 90% concordance in monozygotic twins.[7] Several genes have been identified as possible candidates, notably dopamine receptor and transporter genes.

Environmental factors. Early lead exposure or head injury may increase risk.[8],[9],[10]

Other factors. Lower socioeconomic status and exposure to childhood abuse may also be risk factors.[11],[12]

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, as outlined in the DSM-5. Symptoms must have lasted for at least 6 months and must have onset before age 12. Prior to 2013, when the latest diagnostic manual was released, the age of onset was 7. A growing body of evidence suggests that the age of onset does not appear to affect a patient’s neuropsychological profile or response to treatment, suggesting that ADHD can be appropriately diagnosed in those with a later onset.[13] Symptoms must be present in at least 2 settings (e.g., school and home). There must also be clear evidence of clinically significant impairment in social, academic, or occupational functioning. Symptoms must be considered excessive for the developmental level of the child, and other possible causative mental disorders must be ruled out.[1] A medical, neurological, 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. Adults may develop compensatory mechanisms that mask the symptoms. For example, rather than displaying forgetfulness in daily activities, an adult with ADHD may rely on extensive smart phone calendar alarms to manage his or her schedule. Investigation into possible compensatory mechanisms should be included in a diagnostic evaluation.[14]

Treatment

A thorough history and physical exam, focusing particularly on cardiovascular stability as well as potential for substance abuse, should be performed prior to initiation of pharmacologic therapy for ADHD.[15] The presence of a substance use disorder will complicate the treatment; however, it should not be viewed as an absolute contraindication to the use of medications with abuse potential, such as psychostimulants. Effective treatment of ADHD can actually reduce the risk for a substance use disorder by as much as 85%.[16],[17]

Stimulants

Methylphenidate and dextroamphetamine 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 lisdexamfetamine, minimize rebound symptoms and irritability, as well as minimize disruptions in the school day caused by twice-daily or three-times-daily dosing schedules. Sustained-release preparations also produce less euphoria, reducing the risk of abuse and diversion.[19] Side effects may include decreased appetite, insomnia, anxiety, irritability, or headache. These often resolve on their own as the patient adjusts to the medication. More long-term effects include elevated blood pressure and heart rate, potentially contributing to risk of sudden cardiac death in individuals with preexisting risk factors.[20] Stimulants may inhibit childhood growth patterns, reducing height potential up to 2 cm.[21]

Nonstimulants. Several classes of nonstimulant medications may be effective, although controlled studies are limited.

Atomoxetine is a selective norepinephrine reuptake inhibitor. It may be most appropriate for patients with a history of medication abuse or family members who may abuse medication.[13] The Food and Drug Administration has warned that this medication may cause hepatotoxicity, suicidal thinking, and serotonin syndrome (when used along with fluoxetine). It should be discontinued in patients who develop jaundice or laboratory evidence of hepatotoxicity. Most patients find it less effective than stimulants however, it is a first line treatment for adults, followed by antidepressants.[22]

Among the antidepressant medications, small studies have demonstrated that bupropion and desipramine have potential benefit for ADHD.[23]

Clonidine and guanfacine are alpha-2 adrenergic agonists that may be useful in children but have not been well studied in adults. Side effects may include hypotension, sedation, fatigue, headache, and urinary changes. In addition, several drugs may interact with clonidine, including alcohol, barbiturates, beta-blockers, digoxin, and cold medicines. Combined use with methylphenidate requires monitoring of blood pressure and heart rate. When an alpha-2 agonist is discontinued, it must be tapered slowly to avoid potentially dangerous rebound hypertension.

Allergic rhinitis treatments. ADHD prevalence may be higher in children with allergic rhinitis.[24] One study found a decrease in ADHD scores solely with treatment of allergic rhinitis.[25]

Nonpharmacologic Treatments

Behavioral interventions are recommended as initial treatment for preschool-aged children with ADHD and may help to augment pharmacotherapy for school-aged children.[26] Behavioral interventions include parent-child therapy as well as school-based interventions, such as seating near the teacher, daily report card with home reinforcement, and extended time to complete tasks.

Physical activity in children plays a critical role in their growth and development.[27] Research suggests physical activity may help to reduce the symptoms of ADHD in children.[28] Sports and other social activities help children learn appropriate social skills.

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.[29] Case series report that approximately 75% of patients have a positive clinical response.[30]

Nutritional Considerations

The role of diet in ADHD has been controversial ever since it was first proposed by pediatrician Ben Feingold in the book Why Your Child Is Hyperactive.[31] 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 three were the most accessible for study. Later research suggested that these sensitivities were relevant in only relatively few ADHD cases. However, subsequent studies have supported a causal role of diet. They suggest that unhealthy Western dietary patterns, including dairy products, sugar, salt, and fat, and minimal consumption of whole grains, fruits, vegetables, and fish are associated with increased risk of ADHD.[32],[33] This association may be stronger in boys than girls.[34]

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

Diets free of artificial food colorings and common allergens.
Artificial food colorings do not appear to cause ADHD but may exacerbate symptoms in some ADHD patients.[35] An elimination diet is a valuable tool to identify problematic foods.[36] At least 8 controlled studies have demonstrated either significant behavioral improvement on oligoantigenic (elimination) diets compared with regular diets, or behavioral deterioration on a placebo-controlled challenge with foods suspected of aggravating symptoms. In one of these studies, parental reports indicated that more than half the subjects exhibited a reliable improvement in behavior on an oligoantigenic diet.[37] A 2017 review of double-blind, placebo-controlled trials concluded that elimination diets, referenced as “few-foods diets,” may be a beneficial short-term diagnostic treatment for ADHD, although likely dependent upon families who are highly motivated and supportive, given the time and effort required to find the offending foods.[38] A study looking at 35 years of elimination diets found that > 70% of children responded positively.[39]

Some children with ADHD may also be sensitive to foods other than artificial colorings, such as milk, chocolate, soy, eggs, wheat, corn, and legumes, as well as salicylate-containing foods (e.g., grapes, tomatoes, and oranges).[39]

Aspartame or sucrose restriction. Controlled trials of sugar-restricted diets found no effect on behavioral symptoms in ADHD, even in children thought to be sugar-sensitive.[40] Similarly, studies have not supported a causal role for aspartame in ADHD.[41]

Adequate vitamin and mineral intake or supplementation. Deficiency of several minerals (iron, copper, zinc, magnesium, calcium) is common in ADHD patients, and theoretically may influence neurotransmission in the central nervous system.[42],[43] Some studies have suggested a contributory role of nutrient-poor meals and snacks.[33] Controlled studies have not established a clear benefit of supplementation, though research on multinutrient supplementation looks promising.[44],[45],[46],[47]

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. Poor zinc status is common and can delay cognitive development; it has been found with greater frequency in hyperactive children compared with controls. A small study in Canada found ADHD children were 8 times more likely to have zinc deficiency compared with age-matched population data.[48] Zinc status has been reported in a small sample to correlate with response to amphetamine treatment, 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 methylphenidate or improve symptoms of hyperactivity and impulsiveness when used as monotherapy.[48],[49],[50] However, these reports leave questions about sample retention and data analysis, and further controlled clinical trials are required.[51]

Iron. A 2017 meta-analysis found low serum ferritin levels to be more prevalent in patients with ADHD than in healthy controls. Iron deficiency is associated with decreased dopamine transporter density and activity, causing increased extracellular dopamine. Deficiency may also result in dysfunction in the basal ganglia.[52] Iron supplementation may therefore improve symptoms in ADHD patients with low serum ferritin.[53],[54]

Polyunsaturated fatty acids. ADHD patients may have lower levels of omega-3 fatty acids, higher levels of omega-6 and a higher n6:n3 ratio.[55],[56] A 2016 meta-analysis supports these findings and suggests this leads to an overproduction of pro-inflammatory cytokines that alters neurotransmitter systems.[57] The efficacy of supplementation continues to be evaluated.[58],[59]

Oxidative stress. Markers of inflammation may be higher in ADHD patients, suggesting insufficient responses to oxidative stress.[60],[61] This could be exacerbated by nutrient-poor diets. Some have hypothesized that antioxidant-rich plant compounds such as Ginkgo biloba, ginseng, and pycnogenol (pine bark extract) may help reduce oxidative stress.[62]

A diet based on whole grains, beans, fruits, and vegetables could supply these nutrients as well as antioxidants to reduce inflammation, although the direct benefit of this on ADHD symptoms has not been evaluated through clinical trials.

Orders

See Basic Diet Orders chapter and Nutritional Requirements Throughout the Life Cycle chapter.

What to Tell the Family

ADHD can impair learning, work performance, and social relationships; however, several effective treatments are available. Although many parents have understandable concerns about drug therapy, medications are highly effective, generally provide significant relief, and, in some cases, reduce the risk of developing a substance use disorder. Other options—behavioral treatment, special educational programming, and for some, an oligoantigenic diet—may be tried separately or in combination with medication.

References