Expanding medication options for pediatric ADHD

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.