Expanding medication options for pediatric ADHD

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9 for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.