Expanding medication options for pediatric ADHD

INTRODUCTION

Molly is a nine-year-old girl who was diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD) by her pediatrician and prescribed a long-acting methylphenidate formulation at a typical dose (1 mg/kg). She has tolerated long-acting methylphenidate without side effects and has had significant improvement in her academic performance and school on-task behavior. She takes methylphenidate before school at 7:00 AM and it usually wears off around 3:30 PM. Molly and her parents are pleased with her response to methylphenidate, but report that she has a lot of difficulty getting ready for school each morning due to distractibility. In the evenings she has trouble staying seated to do homework and frequently interrupts and argues with family members, but has not been able to tolerate afternoon dosing of immediate release methylphenidate due to insomnia.

Attention-deficit/hyperactivity disorder (ADHD), the most common childhood neurobehavioral condition, is characterized by difficulties with sustaining attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems, which is consistent with the mechanisms of action for ADHD medications.¹ Management of ADHD includes both pharmacologic and nonpharmacologic (behavioral and psychoeducational) interventions.^{2, 3} In the past ten years, there has been a remarkable expansion in knowledge about ADHD pharmacotherapy. This article provides an overview of the efficacy, side effects, and dosing for the three ADHD medication classes currently approved by the U.S. Food and Drug Administration (FDA) - the psychostimulants, atomoxetine, and the alpha adrenergic agonists, including guidance on choosing between as well as combining these medication classes. Special considerations, such as medication effects on tics, cardiovascular considerations, and substance abuse liability are also discussed.

Psychostimulants

Two classes of psychostimulants, the methylphenidates and amphetamines, are first-line agents for ADHD. Their main mechanism of action involves blockade of dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening of monoamine oxidase’s actions (which slows dopamine and norepinephrine degradation) and enhanced release of dopamine into the synaptic space.¹ The efficacy and response rates are similar for the methylphenidate and amphetamine classes, although up to 25% of patients may respond to only one and not to both.¹ Recent reports state that more than 90% of patients will have a beneficial response to one of the psychostimulants.¹ Abundant evidence exists for the beneficial effects of stimulant medications on the core ADHD symptom domains of inattention, hyperactivity, and impulsivity.² Improvements in additional domains--noncompliance, aggression, social interactions, and academic productivity—have also been observed.^{4, 5}

Over the past 20 years, there has been increased recognition of the pervasive impairments associated with ADHD, impacting functioning in social, family, and extracurricular settings in addition to school. Therefore, practitioners have shifted in their prescribing practices to use more long-acting, rather than immediate-release, stimulant preparations to reduce the need for in-school dosing, improve compliance, and obtain more after school treatment effects. With long-acting formulations, there is a slower rise and fall of stimulant levels in the brain, which may contribute to decreased side effects and drug abuse potential.⁶ See Tables 1 and 2 for further information regarding titration, dosing, and duration of action for the different psychostimulant preparations.

Table 1.

General Titration and Discontinuation Principles for the Three FDA-approved ADHD Medication Classes^{2, 24, 26, 31}

Medication Classes	Stimulants		Non-stimulants
	Methylphenidates	Amphetamines	Norepinephrine Reuptake Inhibitor	α2 Adrenergic Agonists
Generic Medication Names	Methylphenidate, Dexmethylphenidate	Mixed Amphetamine Salts, Dextroamphetamine, Lisdexamfetamine	Atomoxetine	Clonidine ER (Extended Release) Guanfacine ER (Extended Release)
Dosing / Titration Strategy	-No factors have been identified that reliably predict medication efficacy or optimal dose; effective dosage not based on age or weight. -Start at a low dose, may titrate upward every 3–7 days until effective symptom remission, unacceptable side effects develop, or maximum dose is reached. -Because preparations in one psychostimulant class may not produce identical clinical responses in individual patients, when a patient has inadequate response to one stimulant, clinicians may elect EITHER to try additional preparations in that same class (i.e., try dexmethylphenidate in a patient who had partial response to methylphenidate), or to try a preparation from the alternative class. -Sometimes several different stimulant medications or dosages must be tried before finding one that works for a particular child.		-Weight based for children <70 kg. -For patients >70 kg, there is a standard starting and maximum dose. -Initial effects may be seen in 1–2 weeks, but maximal response may not be achieved for 4–6 weeks.	-Effective dosage not based on age or weight. -Start at lowest dose, may titrate up to next dose after at least 1 week on each dose until symptoms remit, unacceptable side effects develop, or maximum dose is reached. -Initial effects may be seen in 1–2 weeks, but maximal response may not be achieved for 4–6 weeks.
Medication “Holidays” (Breaks from Medication) and Discontinuation	-Medication “holidays” are an option since stimulants are effective on the day given whether or not they are given on the preceding days. -Can discontinue without weaning.		-Must be administered consistently to be effective (not amenable to drug “holidays”). -Can discontinue without weaning.	-Must be administered consistently to be effective (not amenable to drug “holidays”). -Wean dose gradually (by 0.1mg for clonidine ER and 1mg for guanfacine ER every 3–7 days) to prevent rebound hypertension on discontinuation.

Table 2.

Dosing and Duration of Action for Specific U.S. Food and Drug Administration (FDA)-Approved ADHD Medications^{2, 24, 31}

Medication Class	Medication (Brand Names)	Starting Dose	Typical Total Daily Maximum Dose†	Dosing Interval	Duration of Action	Comments
Stimulant	Short-acting methylphenidate (Ritalin§, Methylin, Methylin Chewable, Methylin Solution)	5mg	60mg	BID-TID (q4 hours)	3–5 hours	-For those who do not swallow pills, Methylin has liquid and chewable preparations. -Methylin solution is available in 5mg/5ml and 10mg/5ml concentrations.
Stimulant	Intermediate-acting methylphenidate (Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR§)	10 mg (for all but Ritalin SR [20mg])	60mg	Once daily	3–8 hours	-For those who do not swallow pills, Metadate CD and Ritalin LA capsules can be opened and microbeads sprinkled on and ingested with food.
Stimulant	Extended release methylphenidate, osmotic-release oral system [OROS] (Concerta§)	18 mg	54 mg (<13 years old) or 72 mg (≥13 years old)	Once daily	12 hours	-Must be swallowed whole. Opening or crushing capsule damages the osmotic pump delivery system. -Has less abuse liability because osmotic pump delivery system makes it difficult to extract the methylphenidate for snorting or intravenous injection.
Stimulant	Extended release methylphenidate, oral suspension (Quillivant XR)	20mg	60mg	Once daily	12 hours	-Available in 25mg/5ml concentration.
Stimulant	Extended release methylphenidate, dermal (Daytrana)	10mg	30mg	Once daily, Apply for up to 9 hours	3 hours after patch removal (up to maximum of 15 hours)	-Greater absorption occurs when applied to the buttocks rather than the subscapular area. -Dosages for patch are not equivalent to dosages of oral methylphenidate preparations. -Has less abuse liability because intradermal delivery system makes it difficult to extract the methylphenidate for snorting or intravenous injection.
Stimulant	Short-acting dexmethylphenidate (Focalin§)	2.5mg	20mg	BID	4–6 hours	-1 mg dexmethylphenidate is equivalent to 2 mg oral methylphenidate
Stimulant	Extended-release dexmethylphenidate (Focalin XR)	5mg	30mg	Once daily	8–12 hours	-For those who do not swallow pills, capsules can be opened and microbeads sprinkled on and ingested with food. -1 mg dexmethylphenidate is equivalent to 2 mg oral methylphenidate
Stimulant	Short-acting mixed amphetamine salts (Adderall§)	2.5–5mg	40mg	Once daily-BID	6 hours	-1 mg amphetamine is equivalent to 2 mg oral methylphenidate
Stimulant	Extended release mixed amphetamine salts (Adderall XR)	5mg	40mg	Once daily	10 hours	-For those who do not swallow pills, capsules can be opened and microbeads sprinkled on and ingested with food. -1 mg amphetamine is equivalent to 2 mg oral methylphenidate
Stimulant	Short-acting dextroamphetamine (Dexedrine§, DextroStat, ProCentra)	2.5mg	40mg	BID-TID	4–6 hours	-For those who do not swallow pills, ProCentra oral suspension (5mg/5ml) can be used. -1 mg dextroamphetamine is equivalent to 2 mg oral methylphenidate
Stimulant	Intermediate-acting dextroamphetamine (Dexedrine SR§)	5mg	40mg	Once daily-BID	≥ 6hrs	-For those who do not swallow pills, capsules can be opened and microbeads sprinkled on and ingested with food. -1 mg dextroamphetamine is equivalent to 2 mg oral methylphenidate
Stimulant prodrug	Lisdexamfetamine (Vyvanse)	20mg	70mg	Once daily	10–12 hours	-For those who do not swallow pills, capsules can be opened and contents mixed with water, then ingested (efficacy when mixed with other liquids has not been ascertained). -Has less abuse liability because prodrug form makes it difficult to extract the stimulant for snorting (cleavage of lysine is necessary to convert lisdexamfetamine to the active dextroamphetamine form). -Dosages not equivalent to dextroamphetamine dosages, data on methylphenidate dosage equivalents not available.
Norepinephrine Reuptake Inhibitor	Atomoxetine (Strattera)	Patients <70 kg: 0.5 mg/kg/day for 1 week, then increase to 1.2mg/kg/day. Patients ≥70 kg: 40mg, then increase to 100mg/day	Patients <70 kg: 1.4 mg/kg/day. Patients ≥70 kg: 100mg/day	Once daily-BID	18–24 hours	-BID dosing (early AM and evening) may improve efficacy and decrease side effects -Does not have abuse liability.
α2 Adrenergic Agonist	Guanfacine ER (Intuniv)	1 mg	4 mg	Once daily	~24 hours	-Does not have abuse liability.
α2 Adrenergic Agonist	Clonidine ER (Kapvay)	0.1 mg	0.4 mg	Once daily -BID	12–24 hours	-Does not have abuse liability.

^§Available in generic form

^†Certain patients may require higher than the average recommended dosing of stimulant medication due to limited response to lower doses or the combination of medication classes. There is extant literature on this matter,³² as well as ample empirical evidence of child psychiatrists having patients on total daily doses of stimulants above the typical maximum. Careful attention to cardiovascular considerations and other adverse effects is recommended in these situations. Flexibility and alliance with primary care physician and family is also crucial, as it permits the child psychiatrist to gather data about the tolerability and effectiveness of the chosen medication in order to make an informed clinical decision.

The most common stimulant side effects are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms (irritability and nervousness) can be seen with stimulants, but these behaviors are also sometimes improved, rather than worsened, by stimulant treatment.⁵ All the same side effects are possible with the methylphenidates and amphetamines,² with many studies indicating no differences between methylphenidate and amphetamine in their side effect profiles.¹ Other studies have suggested that sleep and emotional side effects may be more prominent with amphetamines compared to the methylphenidates,⁷ although response varies by individual.

Tics were once considered a contraindication to stimulant treatment, but there is little evidence that methylphenidate leads to a worsening of tics in the majority of children.⁸ Similarly, there is little evidence that low dose amphetamine and dextroamphetamine lead to worsening of tics, although significant tic exacerbation has been observed with higher dose dextroamphetamine treatment.^{8, 9} In patients with ADHD and tic disorders, a trial of stimulant medications is appropriate with monitoring for worsening of tics.

Although concerns about stimulant effects on cardiovascular parameters have increased in recent years, in the majority of patients, heart rate (HR) and blood pressure (BP) changes are not clinically significant (average increases: 1–2 beats/minute for HR and 1–4 mmHg for systolic and diastolic BP).⁹ However, stimulants may be associated with more substantial increases in HR and BP in a subset of individuals (5–15%).⁹ Several large studies of children and adults in the general population have failed to find an association between stimulant treatment and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^9–11 However, due to reports of sudden cardiac death in children with underlying heart disease while taking stimulants,¹² clinicians are advised to screen patients and to evaluate further (considering an electrocardiogram and/or cardiologist evaluation) before starting stimulant medications if a personal or family history of specific cardiovascular risk factors are present (see Perrin et al and Cortese et al for review of screening questions and conditions).^{9, 13}

Studies on the effect of stimulants on growth have demonstrated modest reductions in height (in the range of 1–2 cm after 3 years of treatment) that appear dose-dependent and are similar across the methyphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment cessation and no adverse effects on final adult height.^{9, 14} However, more study is needed to clarify the growth effects of continuous stimulant treatment from childhood to adulthood.

Families have expressed concern about stimulant treatment as a “gateway” to substance abuse. However, studies have failed to show an increased risk of later substance abuse in individuals with ADHD who were treated with stimulants during childhood. Some studies document lower rates of later substance abuse in youths who received ADHD medications, although other studies show no effect of stimulant treatment on subsequent substance use disorder risk.⁹ However, clinicians should be aware that stimulant medications do have potential for misuse (e.g. to get ‘high,’ for performance enhancement, to suppress appetite, etc.). Misuse of stimulants is most common with short-acting preparations, and generally more difficult with long-acting stimulant preparations, as the extraction of the active ingredients for snorting is more difficult.^{2, 9} Therefore, clinicians should monitor refill requests and patient behavior for signs of stimulant misuse, and be alert for signs of illegal drug use in patient family members.

Psychotic symptoms (including hallucinations, delusions, mania, and extreme agitation) can be seen with stimulant treatment but are rare, occurring at a rate of approximately 1.5%.⁹

Atomoxetine

Atomoxetine, FDA-approved in 2002 for the treatment of ADHD, is effective and generally well tolerated, although it lags behind psychostimulants in efficacy.² Atomoxetine is a potent norepinephrine reuptake inhibitor.¹⁵ Atomoxetine does not produce euphoria, does not have drug abuse liability, and has not been linked to increased tic onset or severity.¹⁶ In addition, atomoxetine treatment has been associated with lower rates of sleep initiation difficulties compared to stimulants.¹⁵ Some studies also suggest that atomoxetine may have mild beneficial effects on anxiety disorders.¹⁵ Thus, for patients who have significant issues with anxiety or insomnia during stimulant treatment, atomoxetine is a reasonable alternative.

Tables 1 and 2 provide further information regarding dosing and duration of action for atomoxetine. Common atomoxetine side effects include sedation/fatigue, upset stomach, nausea/vomiting, reduced appetite, headache, and irritability.¹⁵ It is important to inform patients that atomoxetine carries an FDA “black box warning” for suicide risk, as a review of 14 studies showed that suicidal ideation was more common on atomoxetine than placebo, although no suicides occurred in any trials.¹⁷ Hepatotoxicity is an very rare atomoxetine-related adverse event,¹⁸ so although routine liver enzyme testing is not required, atomoxetine should be discontinued if jaundice or liver enzyme elevations occur. Other rarely reported but potentially serious side effects include clinically important changes in heart rate (≥20 beats/min) or blood pressure which occur in a subset (~5–10%) of patients on atomoxetine.¹⁹ Similar to stimulants, the risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low. However, clinicians are advised to screen for a personal and family history of cardiovascular risk factors and, if present, evaluate further before starting atomoxetine, with routine HR and BP monitoring recommended for all patients.^{9–11, 13} Atomoxetine has also been linked to growth delays compared to expected trajectories in the first 1–2 years of treatment, with a return to expected measurements after 2–3 years of treatment on average, although persist decreases were observed in those who were taller or heavier than average prior to treatment.²⁰

α₂ Adrenergic Agonists

Guanfacine ER and Clonidine ER, the extended release (ER) formulations of the α₂ adrenergic agonists, were FDA-approved for the treatment of ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine are also often employed in ADHD treatment.²¹ Their mechanism of action involves stimulation of the pre- and post-synapic α₂ adrenergic receptors, which control norepinephrine release and cell firing rate.²² The α₂ agonists are considered a second-line treatment for ADHD as their efficacy and response rate for core ADHD symptoms lags behind psychostimulants.²² In addition to treating core ADHD symptoms, guanfacine and clonidine are also used to treat tics and oppositional/aggressive behavior when comorbid with ADHD.^{21, 23} Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²¹ The α₂ agonists do not produce euphoria or have drug abuse liability.²

Tables 1 and 2 provide guidelines for prescribing guanfacine ER and clonidine ER. Their most common adverse effect is drowsiness, while other common side effects include dizziness, irritability, headache, abdominal pain.²¹ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure. However, α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^{21, 24, 25} as well as rebound hypertension on abrupt discontinuation.²¹ Thus, it is advisable to screen patients for a personal and family history of cardiovascular risk factors and, if risk factors are present, evaluate further before initiating α₂ agonists.

Combining ADHD Medication Classes

Combination therapy with more than one ADHD medication class is sometimes employed when use of one class does not provide adequate symptom coverage or is limited by problematic side effects.^{21, 26} For example, stimulants are sometimes combined with low dose atomoxetine (0.5–1.0 mg/kg/day) when atomoxetine does not cover ADHD symptoms in the school setting as well as stimulants, but stimulants do not adequately cover evening symptoms or patients experience problems with evening stimulant rebound.²⁶ To date, prospective study of the safety and efficacy of combining atomoxetine and stimulants is limited, but the available evidence suggests improved symptom control for some, but not all patients, and a lack of serious adverse events (see Treuer et al for review).²⁷

Stimulants have also been combined with α₂ agonists when children have inadequate response to psychostimulants alone, or in cases of comorbid ADHD and aggression or tics.²¹ Although early case reports raised concern regarding the safety of combining stimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine are generally well-tolerated when co-administered with stimulants.^{21, 25, 28}

Case Continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment when methylphenidate is not active in her system (e.g., mornings and evenings). Afternoon stimulant dosing was attempted to address evening difficulties, but was precluded by adverse effects on sleep. At this point, it would be a 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 extended release, or clonidine extended release—could be added to her current day-time stimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional Considerations

• -While most studies comparing behavior therapy to stimulant medication have found a stronger effect on core ADHD symptoms from stimulants than from behavior therapy, combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than medication alone.² It is also reasonable and consistent with clinical practice guidelines to forgo medication treatment and employ behavior therapy alone, particularly if parents feel uncomfortable with or children have not tolerated medication treatment.^{2, 3} Among ADHD nonpharmacologic interventions, evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects.²
• -Certain patients have limited response to the FDA-approved ADHD medications or their combination. In these cases, an additional option can be bupropion, an antidepressant with indirect dopamine and noradrenergic effects, which has been shown to be effective for the treatment of ADHD in controlled trials of both children and adults.²⁹
• -Clinicians frequently encounter children who meet criteria for ADHD as well as additional anxiety or mood disorders. Box 1 provides a summary of treatment recommendations in these comorbid cases (see Pliszka, SR et al²⁶ and Singh MK et al³⁰ for further information).

Box 1: ADHD and Comorbidity with Anxiety or Mood Disorders.

Comorbid Conditions	Treatment Recommendation
ADHD and Anxiety	It is not recommended to start treatment with multiple separate ADHD and anxiety agents simultaneously, since primary treatment of one disorder may improve symptoms of the other. Clinicians are advised to either use atomoxetine to treat both ADHD and anxiety OR first treat ADHD with a stimulant, then add a selective serotonin reuptake inhibitor (SSRI) if anxiety does remit with stimulant treatment.26
ADHD and Depression	It is not recommended to start treatment with multiple separate ADHD and depression agents simultaneously, since primary treatment of one disorder may improve symptoms of the other. Rather, expert consensus advises to treat whichever disorder is most severe first, then add an agent for the second disorder if monotherapy does not improve both disorders.26
ADHD and Bipolar Disorder	Pharmacotherapy for bipolar disorder (involving mood stabilizers or atypical antipsychotics) should be initiated and manic symptoms stabilized before beginning treatment with psychostimulants.30

Bottom Line

In general, the evidence base supports stimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and alpha-2 agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Clinical Points

• -Treatment with stimulant medications should be initiated at a low dose with gradual titration upward until either adequate symptom control is achieved or side effects develop. Effective stimulant dosage is not closely correlated with age, weight or symptom severity.
• -Clinicians should monitor refill requests and patient behavior for signs of stimulant misuse, and be alert for signs of illegal drug use in patient family members.
• -The psychostimulants that are least likely to be misused to produce a “high”/euphoria include lisdexamfetamine, dermal methylphenidate, and osmotic release oral system (OROS) methylphenidate because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• -Stimulants have not been shown to exacerbate tics in most children with comorbid ADHD and tic disorders. However, in cases where stimulants are associated with tic exacerbation, treatment with atomoxetine or the alpha-2 agonists is reasonable.
• -For patients whose use of stimulants is limited by their adverse effects on sleep, atomoxetine and the adrenergic agonists should be considered as alternative or adjunctive treatment.
• -All three classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children with underlying cardiovascular conditions. Therefore, before initiating treatment, clinicians should screen patients for a personal or family history of cardiovascular risk factors and obtain further evaluation if indicated.