ADHD Medication Essentials: Managing Symptoms, Avoiding Adverse Effects

ABSTRACT: Stimulants are first-line therapy for uncomplicated attention-deficit/hyperactivity disorder (ADHD), but there is no compelling evidence that one type of stimulant is more effective than another. Long-acting formulations generally are preferable, except in preschool-aged children, for whom short-acting stimulants are the only agents available in sufficiently low doses.

Nevertheless, medication should be considered only in those preschool-aged children with moderate to severe dysfunction, after implementation of a trial of behavioral interventions. Lisdexamfetamine is a stimulant option in patients with comorbid substance use. Atomoxetine may be first-line therapy in children with comorbid tics, substance abuse, or anxiety, and in those who have difficulties early in the morning.

Atomoxetine is also second-line therapy for children in whom trials of several stimulants have failed. Long-acting α-agonists are used to treat ADHD as standalone agents and as adjuncts to stimulants. Before starting ADHD pharmacotherapy, it is important to investigate the child’s personal and family cardiovascular history and to perform a complete physical examination. If adverse effects of stimulant treatment are bothersome and persistent, decreasing the dosage, switching to a different stimulant, or adding an additional agent may help.

Stimulant-induced insomnia may be addressed by switching to a nonstimulant therapy or be treated with low-dose clonidine, an antihistamine, trazodone, or melatonin.

A number of medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit/hyperactivity disorder (ADHD), and the evidence for the effectiveness of pharmacotherapy in ADHD is strong. While this strong evidence may facilitate decisions about whether to initiate pharmacotherapy for a child with ADHD, other questions remain. Which agent—and which formulation—will be best for a particular child? If a second agent must be tried, how is the transition from the first agent to the second best executed? What adverse effects are seen with the various ADHD medications? How should dosages be adjusted as children age? What alternative treatments are available, and are they effective? This article seeks to answer these and other questions that practitioners frequently confront about pharmacotherapy for children with ADHD.

CHOOSING AN INITIAL AGENT

For uncomplicated ADHD in children, psychostimulants are first-line therapy.¹ Research has demonstrated a 70% or greater response rate to a single stimulant and a greater than 90% cumulative response rate when both methylphenidate and dextroamphetamine are tried.² Moreover, in the multimodal treatment study by Klein et al,³ in which participants received up to 24 months of treatment, girls and boys responded equally well to stimulants, and improvements were maintained with continued medication treatment irrespective of the use of psychosocial interventions such as academic assistance, psychotherapy, social skills training, and parent training.^3-8 (In a follow-up study of these children after 36 months, the advantage found in the initial treatment phase did not persist; however, this may have been the result of poor medication adherence, poor follow-up, or age-related decline in ADHD symptoms.⁹)

Which stimulant? There is no compelling evidence that one type of stimulant is more effective than another, and the choice of whether to start with a methylphenidate-based agent or a dextroamphetamine-based agent depends on physician and patient preference.^10,11 However, if one type of stimulant fails, a stimulant in the other class should be tried before moving on to second-line agents.

Long-duration formulations are preferable to multiple doses of short- or intermediate-duration preparations because the former decrease stigmatization, eliminate the need for in-school dosing (thereby decreasing medication diversion in schools), probably have less abuse potential, are more easily titrated, and improve adherence.^1,11,12 Long-duration formulations may be used as initial treatment without the need to use short-duration formulations to titrate to the appropriate dosage.¹¹

Rapid-acting, long-duration stimulants generally are preferred over intermediate-and short-duration stimulants.¹² Rapid-acting, long-duration stimulants include methylphenidate (Concerta, Metadate CD, Ritalin LA) and mixed amphetamine salts (Adderall XR). Ritalin LA and Metadate CD work for up to 12 hours, simulating twice-daily methylphenidate. Concerta works for 12 hours or more, the equivalent of 3-times-daily methylphenidate. Adderall XR works 10 to 12 hours or longer, simulating twice-daily Adderall.¹² Metadate CD or Ritalin LA may be preferred when evening loss of appetite or initial insomnia is a concern. Concerta or Adderall XR may be preferred when after-school coverage is desired.¹²

In addition to long-duration stimulant formulations, the prodrug lisdexamfetamine (Vyvanse) and the methylphenidate transdermal system (Daytrana patch) have been found to be efficacious and tolerable in the treatment of ADHD.^13-16 Lisdexamfetamine is a long-duration formulation that in preliminary short-term studies has been shown to last up to 12 hours.¹⁵ However, lisdexamfetamine may not be considered rapid-acting, and initial evidence suggests that its absorption rate is midway between those of immediate-release and extended-release formulations of amphetamine.¹⁵ Because lisdexamfetamine is a prodrug, and the active drug is released gradually by a rate-limiting hydrolysis, it may be considered in patients with comorbid substance abuse.¹⁶ Lisdexamfetamine may have a lower risk for abuse and diversion than that of other stimulants.¹⁷

The methylphenidate transdermal system is an option for a child who cannot swallow a pill. Quillivant XR, a newly available, extended-release, liquid formulation of methylphenidate, also may be considered in this population.¹⁸

Whichever stimulant is chosen for initial treatment, increase the dosage as tolerated to maximal effectiveness.¹²

When to consider atomoxetine or an α-agonist. Atomoxetine (Strattera) also has been approved for the treatment of ADHD, and it may be considered a first-line treatment in patients with ADHD complicated by tics, substance abuse, or anxiety. Atomoxetine does not worsen tics and cannot be abused; moreover, preliminary evidence suggests that it may be effective for both ADHD and anxiety.^11,19 Although atomoxetine may take 4 to 6 weeks to achieve full effectiveness, some initial effects can be seen in 1 to 2 weeks,²⁰ and once it is effective, the benefits are seen 24 hours a day. Thus, atomoxetine also may be considered as first-line treatment for children who have particular difficulties in the mornings before a stimulant would take effect. In addition, if both classes of stimulants fail because of a lack of effectiveness or adverse effects, a trial of atomoxetine is recommended.

Extended-release guanfacine (Intuniv) and extended-release clonidine (Kapvay) also are FDA-approved for treatment of ADHD in children 6 years and older. Sufficient evidence supports the use of these agents as monotherapy in school-aged children, although it is not as strong as the evidence for stimulants or atomoxetine.²¹ Similarly to atomoxetine, these agents do not worsen tics and typically are not abused. The α-agonists have been used off-label to reduce tics in children and may be considered a first-line option when tics are comorbid with ADHD.²² The α-agonists also can be useful in treating ADHD with comorbid insomnia. The initial effects of α-agonists, like those of atomoxetine, are delayed in comparison to stimulants, with the benefits occurring in about 2 weeks.^20,23,24

Among the potential advantages of extended-release formulations of guanfacine and clonidine are once-a-day dosing and fewer adverse effects as a result of less fluctuation in plasma concentration.^23,24 The short-acting formulations of guanfacine and clonidine have long been used to treat ADHD. Of these agents, guanfacine is less sedating than clonidine and may be used for patients who cannot tolerate the sedating effects of clonidine.²⁵ Short-acting clonidine may be considered when sleep problems are more prominent.

The combination of an α-agonist and a stimulant often is used to ameliorate stimulant-associated insomnia, and this combination has been shown to reduce tics and conduct disorder symptoms that are comorbid with ADHD.²⁶ Both of the long-acting formulations of the α-agonists have been FDA-approved for adjunctive treatment with stimulants and can provide additional symptom reduction in patients with a partial response to stimulant treatment.^27,28 A small number of cases of sudden death were reported in the 1990s in children treated with a combination of short-acting clonidine and methylphenidate. However, there is controversy about whether a causal relationship exists, and no subsequent cases have been reported.^10,11 No cases of sudden death were reported in more-recent, large, multisite studies of the long-acting α-agonists in combination with stimulants.^27-31

FIRST-LINE AGENT DOSING GUIDELINES

Preschool-aged children. Medication for ADHD treatment in preschool-aged children should be considered only after a careful, comprehensive assessment. Inattention in preschool-aged children may not be secondary to ADHD and often is a variation of normal development. In addition, inattention may be secondary to a number of other conditions, such as language disorders, hearing loss, low intellectual functioning, or other forms of psychopathology.³² The American Academy of Pediatrics has published guidelines²¹ for ADHD treatment that recommend evidence-based parent- and/or teacher-administered behavioral therapy as first-line treatment in children 4 to 5 years of age. Medication treatment should be used in this age group only for patients with moderate to severe dysfunction. Regrettably, the results of a recent survey indicate that the majority of pediatric subspecialists do not follow these guidelines.³³

If the decision is made to use medication in addition to behavioral therapy, a short-acting formulation of methylphenidate often is required because of the lack of availability of sufficiently low doses of long-acting formulations.¹¹ Research data suggest efficacy and safety of this agent in children as young as 3 years old, but its use in the preschool age group remains off-label.^34,35 A conservative starting dosage is 0.15 to 0.3 mg/kg/day, dosed 2 or 3 times daily.^2,11 The dosage may be increased every 1 to 3 weeks until symptoms resolve or adverse effects limit further increases.¹¹ In studies of methylphenidate in preschoolers with ADHD, dosages have not typically gone above 1 mg/kg/day.^11,34 The clinician should monitor very carefully for adverse effects, and an off-medication trial period is recommended after 6 months of treatment to assess the need for ongoing medication intervention.³⁶

Increased susceptibility to adverse events is a concern in this age group.³⁷ Preschool-aged children with developmental delays may be particularly sensitive to adverse effects and may require a lower per-kilogram dosage.³⁸ Data are very limited on the use of agents other than methylphenidate and amphetamine in preschool-aged children. Although dextroamphetamine has been FDA-approved for this age group, the approval was based on less-stringent criteria. As a result, the American Academy of Pediatrics does not recommend its use in this age group.²¹

Elementary and middle school–aged children. Most of the studies on the treatment of ADHD have focused on this population. As with preschool-aged children, use a low starting dosage in elementary and middle school patients and titrate up every 1 to 3 weeks until symptoms remit or adverse effects prevent further titration.¹¹ Consider atomoxetine or an extended-release α-agonist when both classes of stimulants fail or a child has comorbid tics, anxiety, or substance use.^23,24,39

As children grow, they often require increases in their dosage to maintain therapeutic benefits. Continually assess treatment response and adjust the dosage as necessary to treat residual symptoms and minimize adverse effects.

High school–aged children. Patients of high school age are approached similarly to those in elementary and middle school, although the greater potential for medication diversion and abuse in this population needs to be monitored. Despite this potential, long-acting stimulants still are considered first-line agents in uncomplicated ADHD in this population. Adult-sized adolescents may require dosages higher than the FDA maximum for full effectiveness; however, patients taking such dosages should be monitored carefully for adverse effects.¹¹

Some data suggest that extended-release guanfacine may not be as effective in this population. However, this effect may have been the result of suboptimal dosages for larger children in this particular study.²⁴

ADVERSE EFFECTS

The adverse effects are similar for all stimulants (Table). Adverse effects from all classes of ADHD medication typically are manageable, and it is often not necessary to stop medication therapy.⁴⁰

Common adverse effects of stimulants. The most common adverse effects of stimulants are decreased appetite, weight loss, insomnia, and headache.¹¹ If these effects occur, monitor them carefully; they frequently will resolve with extended treatment.¹⁰ If adverse effects persist, they may be dealt with by decreasing the dosage or switching to a different stimulant; or they sometimes resolve when an additional agent is prescribed.¹¹ Treating adverse effects with an additional agent typically is reserved for cases in which there is a particularly robust response to the stimulant or a history of failing trials of numerous other agents.

Stimulant-induced insomnia may be managed by improving sleep hygiene.⁴⁰ Melatonin at a dosage of 2 to 6 mg/day also may be helpful.⁴¹ If these interventions are not effective, treatment with low doses of clonidine or an antihistamine may be considered.¹¹ Trazodone also may be used, although one must be cognizant of the risk for priapism in male patients.⁴² Evidence does not support the long-term use of these agents for insomnia.

Cyproheptadine may be helpful for ameliorating stimulant-induced loss of appetite,⁴³ but more typical strategies for this problem include medication holidays on non-school days and consumption of nutritious high-calorie foods. Giving medication after meals instead of before them and encouraging late-evening meals are other strategies for addressing stimulant-induced loss of appetite.⁴⁰

Less-common adverse effects of stimulants. These include tics, emotional lability/irritability, and adverse cardiovascular events.¹¹ If stimulant treatment induces or worsens tics to a problematic degree, an alternative medication may be considered or an α-agonist may be added.¹¹ The presence of emotional lability and/or irritability typically indicates that a change in medication is in order.

Although adverse cardiovascular events have been associated with stimulant use, a direct correlation has not been established, and the base rate of sudden death in children receiving ADHD medications does not appear to be greater than that in the general population.¹¹ The American Heart Association (AHA) initially recommended electrocardiography (ECG) screening in all children taking stimulants, but it later softened this statement. The corrected AHA statement indicates that it is reasonable to consider ECG in this population based on the history and physical examination.⁴⁴ It is recommended that all children who receive stimulants have a complete history and physical examination, with attention paid to cardiovascular history in the child and family members. Order further workup as appropriate. The AHA statement provides specific guidance for taking a cardiovascular history.⁴⁴

The methylphenidate transdermal system and dermatologic effects. In addition to the potential adverse effects mentioned above, the methylphenidate transdermal system is associated with cutaneous reactions. Mild to moderate redness commonly has been associated with its use, although this symptom generally is not severe enough to require discontinuation.⁴⁵ Alternation of patch sites, moisturization, and gentle skin care reduce the risk of irritation.⁴⁵ Topical corticosteroids also may be applied at previous patch sites if needed.⁴⁵ When the methylphenidate transdermal system is used as directed, allergic skin reactions are rare; however, it should be discontinued if an allergic reaction is suspected.⁴⁵

Effects of atomoxetine. Common adverse effects of atomoxetine include gastrointestinal complaints, decreased appetite, increased blood pressure and heart rate, sedation, and dizziness.^11,46 A review of clinical trials by the FDA resulted in a recent update of the safety labeling for atomoxetine.⁴⁷ In these trials, 5% to 10% of pediatric patients experienced clinically important changes in heart rate and blood pressure, prompting a warning that atomoxetine should not be used in patients with severe cardiovascular disorders whose conditions would deteriorate if they experienced an increase in blood pressure or heart rate.⁴⁷ Many of the other adverse effects of this agent diminish or resolve with time, although when headaches occur they tend to persist.⁴⁸

Most adverse effects can be managed effectively with dosage reductions; however, if the effects remain despite a reduced dosage, consider an alternative medication. Atomoxetine has a small risk of causing suicidal thinking in children and teenagers. Although an increase in suicide attempts has not been observed, it is important to discuss the potential for suicidal thoughts and to monitor for them over the course of treatment.⁴⁷ Hepatotoxicity is another rare but potentially serious adverse effect; discontinue atomoxetine in any child in whom jaundice, dark urine, or other signs of hepatotoxicity develop.¹¹ Routine monitoring of hepatic functioning is not recommended.¹¹

Effects of α-agonists. The most common adverse effects of extended-release guanfacine and clonidine are sedation, hypotension, bradycardia, and upper abdominal pain.^30,31 The sedative effects of these medications are most prominent when they are first started and subside over time.^23,49 Minor dose-related decreases in blood pressure and heart rate are common but not severe enough to warrant discontinuing medication.^23,24 With guanfacine, these effects decrease over time.²⁴ To decrease sedation, start at a low dose (1 mg for Intuniv and 0.1 mg for Kapvay) and increase at weekly intervals (by 1 mg for Intuniv and 0.1 mg for Kapvay). To prevent rebound hypertension, these agents should not be discontinued abruptly but should be decreased at 3- to 7-day intervals (by 1 mg for Intuniv and 0.1 mg for Kapvay).^30,31

The adverse effects of short-acting α-agonists are the same as those of the extended-release formulations but may be more pronounced because of their faster onset of action. To reduce the risk of sedation, start at a low dose and titrate up weekly. Initially prescribe 1 dose at night, and then add a morning dose after a week. Start guanfacine at 0.5 mg/day and titrate up until the desired effect is produced, usually at a dosage of 2 to 3 mg/day in divided doses. Start clonidine at 0.05 mg/day and increase similarly to an effective dose. Heart rate and blood pressure monitoring is required for all α-agonists. Before starting therapy with any α-agonist, obtain a full cardiovascular history and perform a cardiac examination, including ECG as indicated.²⁵

SWITCHing or Adding AGENTS

Consider an alternative agent for patients in whom the initial agent either is not effective or has intolerable adverse effects. Consider augmenting a stimulant medication with an extended-release α-agonist if initial benefit is evident with the stimulant but residual symptoms remain at the maximum or highest tolerated dose. Studies have shown this practice to be safe and to result in clinically meaningful symptom improvement.^28,29 Stimulants may be discontinued fairly quickly and an alternative agent started immediately. Atomoxetine requires a taper; however, a stimulant may be started before the taper is complete. Guanfacine and clonidine should be tapered, as well.

ALTERNATIVE AGENTS

If first- and second-line agents are ineffective, then one must reconsider the diagnosis and consider referral to a psychiatrist. The vast majority of children with uncomplicated ADHD will respond adequately to first-line agents, and alternative agents such as tricyclic antidepressants (TCAs), bupropion, and modafinil should be used with caution in this population.

Bupropion. Bupropion has demonstrated efficacy in the treatment of ADHD at doses of 100 to 300 mg/day.¹⁰ Common adverse effects include fatigue, headaches, dry mouth, sweating, constipation, and nausea.⁵⁰ The most serious adverse effect of bupropion is a decrease in the seizure threshold; this effect is most salient in patients with eating disorders and in those who receive more than 450 mg/day, and it may be less with the long-acting formulation.²⁵

TCAs. The adverse effect profiles of TCAs limit their usefulness; common adverse effects of these agents include sedation, weight gain, dry mouth, constipation, postural hypotension, and sexual dysfunction.⁴⁶ However, imipramine and nortriptyline have been shown to be effective in the treatment of ADHD.¹⁰ TCAs may be useful in patients with comorbid anxiety, depression, tics, or oppositionality.⁴⁶ Because of their potential for cardiac adverse effects, they require a baseline cardiac examination, including ECG, and periodic monitoring during treatment.¹¹ Desipramine has been associated with sudden death in children and should be used with extreme caution.⁹

Modafinil. This agent has been shown to be well-tolerated and efficacious in the treatment of ADHD. Concerns for Stevens-Johnson syndrome have prevented this medication from achieving FDA approval for ADHD treatment. Most studies have been in the adult ADHD population, with only one study in children.⁵¹ Modafinil may be useful as an alternative when decreased appetite is problematic, but its routine use is not recommended.⁵²

When nothing works. When a patient does not respond to stimulants, atomoxetine, α-agonists, or any of the above agents, or if unacceptable adverse effects develop, the ADHD diagnosis may be incorrect, or ADHD may be concomitant with another mental or physical disorder. In such a setting, consider consultation with a child and adolescent psychiatrist who specializes in ADHD and related conditions. No evidence supports the use of atypical antipsychotics in ADHD, and they should be used in this population only to treat comorbid disorders.

OTHER TREATMENTS

Psychological treatments are an important consideration. These are considered first-line interventions in preschool-aged children, but they also should be considered in older children with mild symptoms and to augment medication treatment. Behavioral therapy, parent training, and social skills training have demonstrated efficacy.⁵³

While further study is necessary to justify action recommendations, data from a meta-analysis examining restriction diets and food color additives suggest that approximately 33% of children with ADHD may respond to dietary restriction interventions.⁵⁴ Several studies also have been conducted on the efficacy of zinc supplementation, with both positive and negative results. The largest of these showed that zinc supplementation reduced hyperactive and impulsive symptoms without reducing inattention.⁵⁵ A small study showed iron supplementation to be helpful in a subset of ADHD patients with low serum ferritin levels.⁵⁵ The data for ω-3 fatty acids, acetyl-L-carnitine, and L-carnitine supplementation are less promising.⁵⁵ Millichap and Yee⁵⁶ offer a more in-depth discussion of diet in ADHD.

Ningdong granule, a traditional Chinese medication, showed equivocal results compared with methylphenidate in a controlled double-blinded study, with fewer reported adverse effects.⁵⁷ Other herbal treatments have been less effective. Ginkgo biloba was outperformed by methylphenidate in one double-blind placebo-controlled trial.⁵⁸ St John’s wort was no better than placebo for ADHD symptoms in a double-blinded study.⁵⁹

Single-vitamin megadose therapy has been proposed, but safety concerns are associated with this intervention. Non-Chinese herbals, homeopathic remedies, and antifungal therapy are unsupported by the literature.⁶⁰ Restricting simple sugars has not been shown to be helpful.⁶⁰

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Dr Horst is associate clinical professor of psychiatry and behavioral science at the University of California at Davis and the medical director of Sacramento County Child and Family Mental Health.