An update in attention deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurobehavioral disorder in children.¹ ADHD is a chronic, debilitating condition that affects approximately 5.4 million children aged 4 to 17 in the United States. Prevalence estimates have varied from 3% to 7% in school-aged children, and recent parent surveys reveal that 9.4% of children aged 4 to 17 in the United States have been diagnosed with ADHD. Boys are diagnosed with ADHD 4 times as often as girls. This difference could be due to both a selection bias, since boys are more active, as well as to a true gender difference.² The annual cost of ADHD for each child is estimated to be between $12,005 and $17,458 in the United States.³ The 2005 annual societal costs are estimated to be between $36 billion and $52 billion.⁴ ADHD was previously thought to be a childhood disorder with adults outgrowing symptoms, but ADHD has been shown to continue into adulthood in up to 60% of patients.⁵

The most common symptoms of ADHD are impulsivity, hyperactivity, and inattention. ADHD can affect all aspects of a child’s life, including schoolwork and relationships with family and friends.⁵ Parents can be stressed due to difficulties with children at home or on outings. Siblings of children with ADHD report feelings of victimization, responsibility for caretaking, and sorrow in relation to the child with ADHD.⁵ Inability to succeed in the classroom can lead to low self-esteem in children with ADHD and place them at risk for substance abuse and injury from high-risk behavior.⁵

The criteria for diagnosis of ADHD are defined within the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV–TR), listed in Table 1 (page 99), although there are proposed changes for DSM V.⁶ DSM V will continue to have the exact wording of each of the 18 symptoms as in DSM-IV, but examples such as “overlooks or misses details, work is inaccurate” and “starts tasks but quickly loses focus and is easily side-tracked; fails to finish schoolwork, household chores, or tasks in the workplace” have been proposed for some symptoms to make ADHD more easily diagnosed across the lifespan.⁷ Another significant proposed change for DSM V is to change the requirement for symptoms to be present by 7 years of age to symptoms are present by 12 years of age. Both of these changes would be expected to increase the prevalence of ADHD.⁷ ADHD diagnosis relies heavily on reports from parents and teachers to determine if patients meet the criteria. It is anticipated DSM V will place a greater emphasis on providers receiving information from 2 different informants. 

Many times ADHD may be diagnosed by primary care providers rather than psychologists and psychiatrists. It has been reported that DSM criteria were used by only 38% of primary care providers to diagnose a child with ADHD, and psychiatrists have reported using intuition to reach clinical decisions.^2,3 Reasons why providers do not use the guidelines are presumed to be lack of awareness of the key recommendations of the guidelines, lack of agreement with the guidelines, and patient-related factors.³ The etiology of ADHD suggests that there are neurochemical, neurophysiological, genetic, and psychosocial components for the disorder. There is a heredity link for ADHD that has been determined through family history and twin studies.²

The most recent clinical practice guideline from the American Academy of Pediatrics (AAP) expanded the age range for evaluation and diagnosis of ADHD from 6 to 12 years to 4 to 18 years.⁸ The guideline places emphasis on the use of DSM-IV–TR recommendations criteria and on gathering information from multiple sources. The guideline states that ADHD is a chronic disease and children with ADHD should be followed in the manner recommended by the chronic care model and the medical home. 

The guideline includes recommendations for treatment of ADHD; these vary by the patient’s age and the literature.⁸ The goal of treatment in ADHD is to minimize hyperactivity and improve attention. Treatment of ADHD is often approached through multiple modalities including medications and behavioral therapy.¹ Review of the literature by the Agency for Healthcare Research and Quality concluded that medication management is effective for school-age children and should be recommended first line.⁹ In preschoolers who do not respond to behavioral therapy, methylphenidate (MPH) is recommended first line. This is in accordance with the AAP guideline.

For preschool-age children (4 to 5 years), AAP recommends behavioral therapy be tried first.⁸ If behavioral therapy does not provide significant improvement, treatment with medication can be considered. Dextroamphetamine has an indication for pediatric use, but this indication was given when FDA requirements were less stringent.⁸ The strongest study to support use of MPH in small children is the Preschool ADHD Treatment Study (PATS).¹⁰ It is important to note that PATS was limited to preschool-aged children who had moderate to severe dysfunction. Based on these data, AAP recommends that only preschool-aged children with moderate to severe dysfunction who meet PATS inclusion criteria be considered for drug treatment.⁸ PATS included preschoolers aged 3 to 5.5 years with moderate to severe dysfunction who had symptoms that had persisted at least 9 months, with dysfunction present at home and other places (preschool or daycare), and whose dysfunction did not improve with behavioral therapy.¹⁰ PATS demonstrated that preschoolers’  ADHD symptoms significantly decreased with MPH treatment. PATS concluded that MPH was tolerated well by preschoolers; however, adverse reactions of emotional lability and dysphoria presented more commonly than in school-age children.¹⁰ Preschoolers did respond at lower doses than used in the school-age studies, which correlates with pharmacokinetic data for slower clearance in children 4 to 5 years of age.¹¹ For treatment of preschoolers, it is recommended to start with a low dosage and  titrate slowly. It is important to note that treatment with MPH for preschool-aged children is an off-label use.

For school-age children, stimulants continue to be recommended as the first-line agent, followed by nonstimulants atomoxetine, extended-release guanfacine, and then extended-release clonidine.⁸ FDA-approved medications for the treatment of ADHD are listed in Table 2 (page 100). These medications have all been shown to reduce the core symptoms of ADHD, but substantially more literature exists for stimulants.⁸ Stimulants were first reported more than 70 years ago for treatment of behavioral disorders in children.¹² Stimulants have the most evidence of efficacy and safety for ADHD in the school-age population and have been shown to improve attention and to decrease hyperactivity and impulsivity. Children may respond to one stimulant but not another; therefore, failure of one class does not mean that stimulants will not be useful.¹ Stimulants are available as either MPH or amphetamines. 

The landmark study by the MTA Cooperative Group demonstrated that in school-age children with ADHD (7 to 9.9 years), medication management with stimulants (alone or with behavioral therapy) is superior to behavioral treatment and treatment in the community.¹³ The study, which was conducted for 14 months, concluded that stimulants were tolerated well, even with a third dose in the afternoon. It was postulated that the patients receiving medication management had better symptom control than community treatment patients who were also on MPH medications due to better dose optimization.¹³ The medication management group had closer follow-up and had higher doses of MPH.  Based on these data, the AAP recommends that primary care clinicians should titrate doses of ADHD medications to achieve maximum benefit with minimum side effects.⁸ Stimulant medications can be titrated every 3 to 7 days.⁸ Expected effects from stimulants are seen immediately, so multiple trials can be done in a short timeframe. Stimulants are generally well-tolerated, but common adverse effects include insomnia, anorexia, headaches, nausea, abdominal pain, sadness, and irritability.

Most of the recent developments for stimulant treatments for ADHD have been formulation changes to extend duration of action. The longer-acting formulations allow for simplification of dosing, increased adherence, and the potential for once-daily dosing.¹¹

Dexmethylphenidate XR has a quick onset, within 30 minutes, and lasts up to 10 hours at the recommended dose. If patients are transitioning to dexmethylphenidate XR from MPH, then half the daily dose is the recommended starting dose; however, if patients are switching from dexmethylphenidate to the extended-release product, an equivalent starting dose is recommended.¹⁴ Even though it is an extended-release product, the capsules can be opened and the beads can be sprinkled on food for patients who are unable to swallow capsules.¹⁴

The MPH transdermal patch is worn up to 9 hours per day, but has an onset of up to 2 hours, so parents should be advised to apply the patch or have the child apply the patch upon awakening.¹⁴ It has been approved for wear at durations of 4 and 6 hours for children who may sleep longer. The patch should be applied to the hip area and was shown to have a 31% decrease in bioavailability if applied to the scapular area.¹⁴

Lisdexamfetamine is the first prodrug approved for the treatment of ADHD. It is activated when lysine is cleaved from the drug during metabolism. It is hypothesized that this medication will have limited abuse potential compared to other stimulants. It lasts up to 12 hours after administration but has a longer onset due to requiring metabolism for activation.¹⁴ One advantage of this medication may be its ease of administration for younger children who have difficulty swallowing capsules. The capsule can be dissolved in water for administration due to its unique metabolism unlike the beaded extended-release formulations that can only be sprinkled on food.¹⁵ Multiple formulations of stimulants for ADHD allow patient-centered medication regimens to be developed.

It has been approximated that up to 30% of children do not respond to stimulants.¹⁶ Currently, there are 3 FDA approved nonstimulants for treatment of ADHD. Atomoxetine was the first nonstimulant to be approved and works by selective inhibition of the presypnaptic norepinephrine reuptake transporter.¹⁶  It inhibits the reuptake of norepinephrine; however, it has no effect on dopamine in the striatum or nucleus accumbens.  This decreased effect on dopamine makes it less likely to be abused than stimulants.¹⁶ Atomoxetine has weight-based dosing in school-age children (aged 6 to 12) up to 1.4 mg/kg/day, and the benefit is typically seen in 2 to 8 weeks after initiation.  Studies have found no greater efficacy at a higher dosage.¹⁶ Long-term studies have shown that treatment with atomoxetine remains effective at 12 and 18 months of therapy.⁹ The most common side effects of atomoxetine are gastrointestinal upset and somnolence.⁸ These side effects can be minimized with a slow dose titration. Atomoxetine has warnings for hepatotoxicity and suicidality risk.  Patients initiated on atomoxetine should be monitored closely for mood and behavioral changes.¹⁴

Two of the nonstimulant medications for ADHD are α₂-adrenergic agonists, extended-release guanfacine and extended-release clonidine.  These medications have indications for treatment alone or as adjunctive treatment with stimulant medications for ADHD. Other medications utilized for adjunctive therapy have only anecdotal evidence and are used off-label.⁸ The α₂-adrenergic agonists require dose tapering prior to discontinuation to avoid rebound hypertension and cannot be abruptly stopped like the stimulants and atomoxetine. The most common adverse effects of the α2-adrenergic agonists are somnolence and dry mouth.

The AAP guideline has special considerations for treatment of adolescent patients (12 to 18 years) that include screening the patient for substance abuse and diversion of medications.⁸ AAP recommends that clinicians monitor symptoms and refill history to be alert for signs of misuse or diversions. The guideline further recommends considering use of a medication without abuse potential such as atomoxetine, extended-release guanfacine, or extended-release clonidine, or with less abuse potential such as lisdexamfetamine, transdermal MPH, or MPH OROS.⁸ Both transdermal MPH and MPH OROS make extraction of the MPH more difficult, reducing medication abuse potential, and lisdexamfetamine has lessened medication abuse potential since it must be ingested before activation. Finally, AAP recommends longer-acting formulations or late afternoon short-acting medications to ensure symptom coverage for periods when teenagers may be driving.⁸

There are 2 adverse effects of medications for ADHD that may cause practitioners and families concern. Guidelines from the European ADHD Guidelines Group were recently released to assist practitioners with managing adverse effects.¹⁷ The stimulant medications and atomoxetine have been shown to decrease appetite and cause growth delay. It is thought that reduced caloric intake and lack of proper nutrition due to the decreased appetite may enhance the growth delay seen in children treated with medications for ADHD.¹⁷ Loss of appetite with both MPH and atomoxetine can be long term and may not attenuate over time. Providers should monitor the patient’s height and weight and body mass index at least every 6 months.¹⁷ In order to decrease appetite suppression, the medication can be given after meals, and the use of high-caloric snacks should be encouraged. Height reduction is dose-dependent and reversible after treatment is discontinued. If patients fall below 2 percentile lines, consider dose reduction, drug holiday, medication change, or a referral to a pediatric endocrinologist or growth specialist.^11,17

In recent years, reports of serious and fatal cardiovascular events in children taking stimulants have been well-publicized and have brought up the concern of the cardiovascular risk associated with stimulants.¹⁸ It has been known that stimulants raise blood pressure and heart rate in children, and recent studies have shown that tolerance to these effects does not develop with time. FDA has reviewed reports and issued warnings about the use of stimulants in patients with cardiovascular disease.¹⁸ Most of the data regarding cardiovascular risk in children taking stimulants are from trials conducted to test efficacy and may not be powered to assess cardiovascular risk. Cooper et al conducted a retrospective cohort study to determine if children and young adults given ADHD medications were at an increased relative risk for cardiac events compared with nonusers.¹⁹ In the study, medical records of 1.2 million children and young adults (ages 2 to 24) were reviewed, and it was determined that ADHD medication users were not at increased risk for cardiovascular events (adjusted HR, 0.75; 95% CI, 0.29–1.72). The AAP guideline recommends expanding the history of patients with ADHD to include cardiac symptoms, Wolf-Parkinson White syndrome, sudden death in the family, long QT syndrome, and hypertrophic cardiomyopathy.⁸ The European ADHD Guidelines Group also recommends measuring baseline heart rate and blood pressure, repeating every 3 to 6 months, and performing auscultation to identify any murmurs.¹⁷ While ADHD was once thought of as a childhood disorder, it is now known to have a longitudinal course in some patients. AAP guideline have extended the age range for ADHD evaluation and diagnosis to 4 to 18 years, and proposed DSM V criteria require an onset of symptoms by age 12.  The American Academy of Child and Adolescent Psychiatry recommends that treatment be individualized for patients.¹¹ ADHD treatment offers symptomatic reduction of inattention and hyperactivity, which allows patients to better perform in home, school, and work environments. Stimulants remain first-line therapy for ADHD; multiple formulations allow a patient’s medication regimen to be optimized to their individual needs.  Nonstimulants such as atomoxetine, extended-release guanfacine, and extended-release clonidine offer new treatment options for patients who may not respond to stimulants. Duration of the treatment should last as long as impairing symptoms persist, but the need for therapy should be reevaluated periodically since some children with ADHD may have reduced symptoms over time.¹¹

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