Julie A. Dopheide and Stephen R. Pliszka
KEY CONCEPTS
Untreated or ineffectively treated childhood attention deficit/hyperactivity disorder (ADHD) can lead to poor school performance, poor socialization, and increased risk for traffic accidents, psychiatric comorbidities, unemployment, and incarceration during adolescence and adulthood.
ADHD is 80% genetic in origin, and it is associated with decreased brain volume, a delay in cortical thickening, and dysregulation of the “default mode network,” a brain system that regulates attention, prioritization of information, memory, and impulse control.
Symptoms of inattention or hyperactivity and impulsivity or all three must be present during childhood and cause functional impairment in two different settings for 6 months to meet diagnostic criteria for ADHD.
Pretreatment assessment of overall physical and mental health, psychiatric comorbidities, and goals of treatment must be set prior to initiating pharmacotherapy.
Preschoolers, school-age children, adolescents, and adults with ADHD all can benefit from nonpharmacologic interventions that include a healthy diet, education on ADHD, and potentially effective cognitive and behavioral treatments.
The psychostimulants, methylphenidate or amphetamine salts, are the most effective pharmacologic treatment options for all ages with a rapid therapeutic effect, typically within 1 or 2 hours of an effective dose.
α2-Adrenergic agonists such as extended-release preparations of guanfacine and clonidine are less effective than stimulants in monotherapy and are used as adjuncts to improve symptom control, particularly oppositional behaviors and insomnia.
When ADHD coexists with bipolar disorder, it is necessary to first stabilize the mood with lithium, an anticonvulsant, or an atypical antipsychotic before adding an ADHD-specific medication such as a psychostimulant.
When ADHD coexists with other psychiatric conditions, such as anxiety disorders, major depression, or Tourette’s disorder, it is optimal to treat the most functionally impairing disorder first (whether it is ADHD or the co-occurring condition) and then treat the second disorder.
Atomoxetine is a good option to manage ADHD symptoms in adolescents and adults with substance abuse disorders. It has a delayed onset of effect (2 to 4 weeks), but it has no abuse potential.
INTRODUCTION
Once considered primarily a childhood disorder, attention deficit/hyperactivity disorder (ADHD) is now known to persist into adolescence for 75% and into adulthood for approximately 50% of individuals.1,2The American Academy of Pediatrics (AAP) considers ADHD a chronic condition that requires ongoing management.1 Functionally impairing inattention, impulsivity, and hyperactivity in the ADHD brain have been correlated with neuroanatomical and functional brain changes.3,4 It is unusual for an individual to display signs of the disorder in all settings or even in the same setting at all times; however, there is a persistent pattern of symptoms that persists for 6 months or more.3,5 Co-occurring anxiety, mood disorders, learning disabilities, medical conditions, and substance abuse must be considered in assessment and treatment. Behavioral interventions and medications are effective for all ages, but there are special considerations for treatment plan development and monitoring in each age group.1–3
The psychiatric assessment of a child requires obtaining information from the child, parents, caregivers, and teachers.1 Treating children with psychotropic drugs requires a very different approach than treating adults. Children undergo neurologic, physiologic, and psychosocial changes throughout development. Age-related pharmacodynamic and pharmacokinetic differences can alter drug disposition and response. Psychotropic drug treatment of children is intended to control symptoms or behaviors that impair learning and development.1,3 Children may not be able to articulate symptom response or adverse effects of a medication. 
Adolescents and adults with ADHD may not have been diagnosed and treated during childhood, putting them at greater risk for the psychosocial consequences of ADHD including unemployment, unstable relationships, substance abuse, and incarceration.1–3,6,7
EPIDEMIOLOGY
In 2010, 5 million children in the United States aged 3 to 17 years had ADHD (8%). Boys (11%) were about twice as likely as girls (6%) to have ADHD. Non-Hispanic white and black children were more likely to have ADHD compared with children of Hispanic or Asian descent.8 Worldwide rates of ADHD in children range from 4% to 12%.3 Several epidemiologic studies, including surveys conducted by the National Institutes of Health (NIH), have documented rates of adult ADHD between 3% and 5% with comparable rates in men and women.2,3
Prescriptions for ADHD medication increased in all age groups from 1998 to 2005, particularly in adolescents and young adults.3,9 A National Poison Control Center study estimated that between 1998 and 2005, prescriptions for teenagers and preteenagers increased 133% for amphetamine products, 52% for methylphenidate products, and 80% for both.9 The FDA used prescription records from 59,000 retail pharmacies to analyze prescribing rates in 2010 compared with those in 2002 in children aged 0 to 17 years for several therapeutic areas including antibiotics, proton-pump inhibitors, antidepressants, and ADHD medications. Overall pediatric prescribing decreased 7% over the 8 years studied, but prescriptions for ADHD medications increased by 46%. Methylphenidate was the most commonly prescribed drug in the ADHD category, but usage remained constant from 2002 to 2010, whereas usage of amphetamine products dropped by 15%.10 Usage of dexmethylphenidate, lisdexamfet-amine, and guanfacine increased from 2004 to 2010, while usage of atomoxetine in youth decreased.10
ETIOLOGY AND PATHOPHYSIOLOGY
Both genetic and nongenetic factors are implicated in the pathogenesis. First-degree relatives of an individual with ADHD have a fourfold to eightfold increased chance of developing ADHD compared with the general population; mean heritability (the proportion of variance due to genetics) is around 80%.11 Candidate gene studies have implicated the dopamine transporter and receptor genes as well as the SNAP25 and COMT genes, but they have been found to account for only a small portion of the variance in ADHD symptoms. Genome-wide association studies (GWAS) have suggested that 40 to 80 different genes might be involved in ADHD, each conveying a small degree of risk.12
GWAS studies have previously focused on common variants, assuming a small number of genetic alterations, common in the population, accounted for most of the genetic risk in ADHD; this is clearly not the case.13 Recently genetic studies have focused on multiple rare variants, that is, hundreds or even thousands of genetic variants might be involved in ADHD, such that each patient has a unique genetic pattern. Patients might have copies or deletions in the genome that cover multiple genes called copy number variants (CNV). These CNV studies have implicated a number of systems in ADHD: cholinergic receptors, cholesterol metabolism, and genes for CNS development,14 an area of chromosome 15q13,15 as well as glutamate metabotropic receptors.16 Thus, the pathophysiology of ADHD may go well beyond the catecholamine systems that have been the focus of most studies to date.
Environmental factors may be involved in the etiology of ADHD, as well. Children with fetal alcohol syndrome, lead poisoning, and meningitis have a higher incidence of ADHD symptomatology.3,17 ADHD is associated with a variety of environmental risks, including obstetric adversity, maternal smoking, and adverse parent–child relationships.3,17
Although there are no definitive pathophysiologic markers for ADHD, imaging studies show subjects with ADHD have decreased total brain volume relative to controls in multiple brain regions (right prefrontal cortex, caudate nucleus, anterior cingulate gyrus, and cerebellum). Global thinning of the cortex has been observed in children with ADHD, and comparative studies show there is a delay in cortical thickening in ADHD brains relative to age-matched controls.3 There is evidence showing that adults with ADHD whose symptoms remitted over time have increased cortical thickening and greater brain volume in key regions controlling attention and behavior than those with residual ADHD symptoms across adulthood.18
Functional magnetic resonance imaging (MRI) studies during inhibitory control tasks in patients with ADHD show reduced activity in prefrontal and anterior cingulate cortex, deficits which may be reversed with stimulant treatment.19,20 Adults and children with ADHD show decreased activation of the ventral striatum when anticipating reward.21,22 
Alterations in the “default mode” attention network have been found in adults with ADHD.3 The default mode network consists of the medial prefrontal cortex, medial parietal lobe or precuneus, as well as the posterior cingulate. These areas are active during the “resting state” when attention is not engaged; this system is actively suppressed during active attention. A lack of connectivity between the prefrontal cortex and precuneus (located in the midline of the parietal lobe) is associated with failure of suppression of the default mode network, causing lapses in attention and inhibitory control.23 Recently, methylphenidate has been shown to decrease aberrant default mode network activation in children with ADHD.24
CLINICAL PRESENTATION
The AAP guideline for the diagnosis, evaluation, and treatment of ADHD in children and adolescents recommends an evaluation for any child 4 to 18 years of age who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity.1 
At least six symptoms of inattention or hyperactivity and impulsivity causing impairment in more than one major setting for 6 months and an onset of symptoms before age 7 are currently required by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) for a diagnosis of ADHD.5Validated rating scales, such as the Connors Rating Scales—revised (CRS-revised), are recommended for objective symptom ratings from parents and teachers in different age groups.1,3,7 The age criteria will likely be raised to 12 years old in the fifth edition of the DSM (DSM-5), given that cases of ADHD without prominent hyperactivity may be missed in childhood.25 The DSM-5 may lower the number of symptoms required to make a diagnosis in adolescents and adults, given that epidemiologic studies have shown that adolescents and adults have fewer numbers of symptoms than children, but the symptoms are just as impairing.2,7,26 These proposed changes in the DSM-5 are controversial, as some are concerned that they may result in a dramatic increase in diagnosis of ADHD and an increase in the prescribing of ADHD medications.27 To make a diagnosis of ADHD, the clinician should rule out alternative causes of symptoms (learning disability, situational stressor) and assess for other conditions that may coexist with ADHD including oppositional defiant and conduct disorders, tics, and sleep and mood disorders.
Clinical Controversy…
The DSM-5 will likely lower the number of symptoms required to make a diagnosis in adolescents and adults, given that epidemiologic studies have shown that adolescents and adults have fewer numbers of symptoms than children, but the symptoms are just as impairing. These proposed changes in the DSM-5 are controversial to some who are concerned that they may result in a dramatic increase in the diagnosis of ADHD and an increase in the prescribing of ADHD medications.7,26,27
CLINICAL PRESENTATION ADHD
General
• Onset of symptoms must be before 7 years of age.
Symptoms
• Six or more of the symptoms must be present for 6 months; significant impairment must be seen in two or more settings (e.g., home and school); symptoms must be documented by parent, teacher, and clinician.
• Inattention:
• Often fails to give close attention to details or makes careless mistakes in schoolwork or other activities
• Often has difficulty sustaining attention
• Often has difficulty organizing tasks and activities
• Avoids tasks that require sustained mental effort
• Often does not seem to listen when spoken to directly
• Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace
• Is easily distracted by extraneous stimuli
• Is often forgetful in daily activities
• Loses things necessary for activities
• Hyperactivity and impulsivity:
• Often fidgets with hands or feet or squirms in seat
• Often leaves seat when remaining seated is expected
• Often runs about or climbs excessively at inappropriate times
• Often has difficulty playing quietly
• Often interrupts or intrudes on others
Data from American Psychiatric Association. Disorders usually first evident in infancy, childhood or adolescence. In: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association, 2000:39–134.
Preschoolers (3 to 5 Years)
The DSM-IV-TR diagnostic criteria for ADHD can be applied to preschool-age children, although it may be difficult to document symptoms in multiple settings with different caregivers if the child does not attend preschool.28,29Enrollment in a qualified preschool and a parent training program is often recommended. Both can help parents develop reasonable expectations for their child’s development and foster the development of management skills for problem behaviors. Although methylphenidate has been found safe and effective for ADHD in 4- and 5-year-olds, behavioral interventions are recommended first. Medications can be considered when the child has moderate to severe symptoms unresponsive to behavioral interventions. The clinician needs to weigh the risks of starting medication at an early age against the harm of delaying diagnosis and treatment.1
School Age (6 to 11 Years)
Most cases of ADHD are first realized during ages 6 to 9 years, with the child having difficulty academically and/or socially in school and at home. Most children have combined inattentive and hyperactive or impulsive symptoms that cause functional impairment. This period is crucial to the child’s success in school, socialization, and the development of his or her sense of self; therefore, accurate diagnosis and treatment is critical. Comorbid oppositional defiant disorder (ODD), conduct disorder, and aggression are indicators that the child is at greater risk for delinquency and substance abuse in adolescence.30,31 This is the most well-studied age group, with strong data showing benefits of recognition and treatment with behavioral interventions and medications.1
Adolescents (12 to 18 Years)
Hyperactivity decreases in adolescents, and inattention and impulsivity are the more prominent functionally impairing symptoms. There may be fewer numbers of symptoms of ADHD in adolescence, but the symptoms present cause significant functional impairment.26 Higher rates of delinquency, drug and alcohol use, and psychiatric comorbidity have been documented in adolescents with ADHD compared with in those without ADHD.1,6,7,26 Assessment for substance abuse and risk of diversion must be considered before starting stimulant medications. Speeding and increased motor vehicle accidents occur at higher rates in teens with ADHD compared within those without the disorder.1,6
Adults
The presence of multiple comorbid conditions, particularly conduct or mood disorder, can increase the likelihood of ADHD chronicity into adulthood. DSM-IV-TR criteria for ADHD in childhood also apply to adults. Inattentive symptoms are the most common and functionally impairing in adults, but hyperactive and impulsive symptoms are experienced by many and are associated with higher rates of bipolar disorder and psychosis.2 Cognitive deficits (e.g., executive functioning, working memory, task prioritization, lower IQ) have been documented in adults with ADHD in addition to a greater risk for unstable relationships, unemployment, psychiatric hospitalization, and incarceration compared with those without ADHD.2,7,32 An ADHD screening tool is available to facilitate assessment in adults not diagnosed during childhood (http://www.addcoach4u.com/documents/adultadhdscreenertest1.pdf).33
TREATMENT
ADHD-specific cognitive and behavioral interventions are increasingly recognized as necessary components of an overall treatment plan aimed at symptom relief and optimal functioning. Several studies show combining medications with behavioral interventions produces the greatest symptom relief and the best outcomes.
Desired Outcomes
Specific goals of treatment or desired outcomes must be identified (e.g., able to sit in chair for 20 minutes; completes homework assignments, or no longer blurts out comments in class without being called upon). For adults, the desired outcome may be to read an entire newspaper before starting another project, improving safety while driving, or successfully completing tasks on time at work.2,17,32
Nonpharmacologic Therapy
Educational, Cognitive, and Behavioral Interventions
Education on ADHD as a biologic disorder with brain-derived causes is essential for destigmatizing ADHD and improving treatment acceptance. Parent training and behavioral interventions such as positive rewards for good behavior and structured limit setting are recommended as first-line interventions before medication trials in preschoolers (3- to 5-year-olds) with ADHD. Behavioral interventions for ADHD are described in Table 46-1. It is crucial to get parents, teachers, and clinicians involved to coordinate care and provide consistent behavioral management for the child at home and at school. School-age children (6 to 11) also benefit from these behavioral interventions in addition to strategies, such as breaking up homework assignments into shorter, manageable segments. Although it varies by state, children and adolescents with ADHD may qualify for an individualized educational program (IEP) that allows for more time to take an exam, preferred seating, and modified work assignments.1,28 It is noteworthy that most studies comparing behavioral intervention with stimulant therapy in youth found a much stronger effect on ADHD core symptoms from stimulants.1,3,4 Combined behavioral and stimulant therapy resulted in greater improvements on academic and conduct measures in some studies with greater parent and teacher satisfaction ratings. Combining behavioral interventions with stimulants may allow for lower doses of stimulant that can reduce the risk of adverse effects.1
TABLE 46-1 Behavioral Interventions for ADHD
Recommended behavioral interventions for adolescents and adults include keeping an external organizer (e.g., smart phone, notebook with “to-do” lists) and breaking up activities into short, manageable tasks. Recognizing triggers for distraction and making a point of thinking before acting are useful interventions and are recommended during cognitive behavioral therapy (CBT) sessions designed to manage adult ADHD.34,35 Establishing a regular schedule that includes exercise and relaxation can be beneficial as well. Controlled studies have shown that ADHD-specific CBT was more effective than psychoeducation and relaxation in adults with ADHD whose symptoms were only partially responsive to medication.34 Similarly, adults with ADHD that partially responded to medications benefited more from a group-administered metacognition program (2 h/wk over 12 weeks) compared with supportive therapy sessions administered for the same amount of time.35 The metacognitive therapy was designed to develop organizational skills and executive function self-management skills. Yoga, meditation, and some dietary supplements have been recommended for ADHD as well, but they should not take the place of more established effective treatments, such as medications and cognitive interventions.
Dietary Interventions
Extensive research has evaluated dietary interventions for ADHD, primarily in children with some adolescent data. When iron and zinc are supplemented in youth with known deficiencies, the therapeutic benefit of stimulant therapy can be enhanced, frequently allowing lower effective doses.36,37 Omega-3 supplements can benefit some individuals with few side effects, but results are not consistently better than placebo. Additive-free and oligoantigenic elimination diets (e.g., omitting red/orange food dye in lunch meat and hot dogs; avoiding allergenic foods such as dairy and wheat) have been found useful only in small numbers of children who do not respond to other interventions. Although scientific evidence is lacking, there is a universal belief among families that the avoidance of sugar and artificial sweeteners improves ADHD symptoms. The attention paid to sugar avoidance and healthy diet is the more likely reason for improved behavior. An overall healthy diet with the proper balance of protein, fresh produce, and fiber is recommended.37
Pharmacologic Therapy
Figure 46-1 provides an algorithm for drug selection in the treatment of ADHD.
FIGURE 46-1 Algorithm for drug selection in the management of attention deficit/hyperactivity disorder (ADHD). Treat predominant disorder first, reassess, and consider alternative or adjunct medications for optimal symptom control. (DEX, dextroamphetamine; DMPH, dexmethylphenidate; MPH, methylphenidate; MXA, mixed amphetamine salts; TCA, tricyclic antidepressant.) (Data from references 3, 17, 45, 61, 63, 64, and 68.)
Stimulants
Stimulants are considered first-line therapy in most cases of ADHD; however, comorbid conditions impact the drug selection process. Pharmacotherapy should be considered whenever a thorough diagnostic assessment results in a diagnosis of ADHD. Several studies demonstrate the superiority of stimulants over behavioral interventions in alleviating core symptoms of ADHD.3,38,39 Several studies show improvement in academic performance in medicated children with ADHD versus those unmedicated. A NIH study of 594 fifth graders with ADHD showed those medicated (greater than 90% took stimulants) had 2.9 points higher math scores and 5.4 points higher reading scores compared with unmedicated children.39 Another study involving 363 ten- to 18-year-olds with ADHD showed medication improved but did not normalize cognition.40
Stimulants (e.g., methylphenidate, dexmethylphenidate, mixed amphetamine salts, and dextroamphetamine) are the most effective drug treatment options, with an effect size of 0.9 compared with nonstimulant drug treatment options whose effect sizes range from 0.5 to 0.7 signifying lower efficacy.1,3,41 Methylphenidate and amphetamines block dopamine and norepinephrine reuptake; amphetamines also increase catecholamine release.42 Both drugs inhibit monoamine oxidase (MAO), amphetamines more potently than methylphenidate.42 Because different stimulants work through slightly different mechanisms, the lack of response to one chemical class of stimulant (e.g., methylphenidate or dexmethylphenidate) does not preclude response to another class (e.g., dextroamphetamine including lisdexamfetamine or mixed amphetamine salts).3,4
Stimulant dosing should be titrated for maximum individual efficacy and minimum side effects (see Table 46-2).3,4,43–45
TABLE 46-2 Dosing of Stimulant Drugs Used in the Treatment of ADHD
With immediate-release stimulants, most patients require a two or three times daily dosing schedule because of the short half-lives of these drugs (2 to 4 hours for methylphenidate and dexmethylphenidate and ∼4 to 6 hours for dextroamphetamine or mixed amphetamine salts).3,4,17,45 Drug response is maximal during the absorption phase, is evident in 15 to 30 minutes, and lasts 2 to 6 hours.3,4,17,45
Drug delivery systems of once-daily products (amphetamine aspartate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate [Adderall XR]; methylphenidate [Concerta]; methylphenidate [Daytrana]; dexmethylphenidate [Focalin XR]; methylphenidate [Metadate CD]; and methylphenidate long-acting [Ritalin LA]) provide 8 to 12 hours of symptom control.3,4,17,41,45,46Concerta uses an oral osmotic (OROS) controlled-release delivery system, whereas other oral preparations use combinations of immediate-release and extended-release beads.3,4,45 Concerta is a nondeformable tablet, and it should not be given to children with GI narrowing because of the risk of obstruction. Methylphenidate transdermal system provides 12 hours of symptom control when worn for 9 hours.41,45,46 Older wax-matrix sustained-release (SR) products (e.g., Ritalin SR) are less effective and infrequently used.3,4,17 Once-daily stimulant formulations are the preferred treatment for ADHD in most individuals due to convenience and better medication adherence.3,4,17,47 Immediate-release formulations have the advantage of lower cost, less insomnia, and potentially fewer growth effects versus extended-release products.3,48 Adolescents and adults with ADHD are also responsive to stimulants.2,3,45,49 Methylphenidate is effective in adolescents and adults in doses up to 1.5 mg/kg daily.2,3,17 Lisdexamfetamine is a prodrug conjugated to an amino acid that requires cleavage during metabolism to the active dextroamphetamine. It has a longer time to onset of effect but may provide a smoother blood level compared with extended-release formulations. It is intended to pose less abuse potential.41
Administration of stimulant medications with food can delay the absorption and subsequently delay the onset of therapeutic effect by 30 minutes to 1 hour for immediate-release preparations, and 1 to 2 hours for extended-release preparations.43 Total bioavailability of stimulant can be decreased by 10% to 30% with coadministration of food, more so for beaded formulations of extended-release stimulant compared with OROS methylphenidate or lisdexamfetamine.43
Adverse Effects The most common adverse effects of stimulants and their management strategies are listed in Table 46-3. Uncommon to rare but potentially serious adverse effects are discussed in the following sections.
TABLE 46-3 Stimulant Adverse Effects and Their Management
Psychiatric The FDA has added warnings to the labeling of all stimulants and atomoxetine. Hundreds of postmarketing reports of three broad categories of psychiatric adverse events have been associated with stimulants: psychosis or mania, aggression or violent behavior, and severe anxiety or panic attacks. All of these reactions require dose reduction or cessation of stimulant therapy and supportive treatment.3,50An analysis of placebo-controlled trials in children showed a rate of stimulant-induced psychosis of 1.49 per 100 person years with no psychosis occurring in the placebo group. Hallucinations involving visual or tactile sensations of insects, snakes, or worms were typical in children. Stimulants should not be given to manage attention in individuals with primary psychotic illnesses such as schizophrenia or schizoaffective disorder due to the high risk of worsening psychosis.50,51
Cardiac A boxed warning for cardiovascular risks including sudden unexplained death has been added to ADHD stimulant drug labeling.52,53 Clinical trial data show that children who take stimulants for ADHD can have an increased heart rate by ∼5 beats/min and/or increased blood pressure by 2 to 7 mm Hg.54 A 10-year review showed a 20% increased risk for emergency department visits for cardiac symptoms in those taking either methylphenidate or amphetamine.54 Of note, these individuals were more likely to have a coexisting anxiety disorder.
In order to assess the risk of adverse cardiac outcomes, two studies of large healthcare databases compared rates of sudden cardiac death, heart attack, and stroke in those taking stimulants compared with in those not taking stimulants. The first study of 1.2 million 2- to 24-year-olds (mean age at baseline 11.1 years) taking stimulants for an average of 2.1 years showed that 3.1 per 100,000 experienced a serious cardiac event. This was no greater than rates in the general population. The second study included 150,000 users of stimulants aged 25 to 64 years old matched to 2 nonusers of stimulants (443,000). Duration of stimulant use was tracked by electronic prescription records and calculated in “person years” with an average of 107,000 person years in the stimulant user group. This study in adults found no greater risk of sudden death, heart attack, or stroke in stimulant users versus nonstimulant users. The relatively short duration of use and overall good health of those studied may have biased the results. These studies add to earlier findings showing no increased risk of serious cardiac events with stimulant use, and, therefore, no restriction in stimulant use has been recommended.52,53
Stimulant products generally should be used with caution in pediatrics or adults with known structural cardiac abnormalities. The American Heart Association recommends careful screening of all children and adolescents prior to initiating pharmacologic therapy for ADHD, including a medical and family history and physical examination.55 The physician should consider a baseline electrocardiogram (ECG) if history suggests cardiovascular disease, but a routine ECG is not necessary.4 The FDA did not find the risk of sudden unexplained death to be greater in those taking stimulants than in the general population; therefore, no restriction in stimulant use has been recommended.4,45,49
Growth Two reviews that analyzed approximately 32 studies indicated that stimulant treatment of ADHD can affect growth, but the effects are minimal or insignificant for most children. A study of 579 children showed a decrease of ∼1 cm/y (∼0.5 in) in height over 1 to 3 years of continuous treatment with methylphenidate and a weight deficit of 3 kg (6.6 lb) in the first year of treatment and 1.2 kg (2.6 lb) in the second year of treatment.3 Amphetamine products may be associated with more growth effects than methylphenidate according to separate studies.3 Proposed mechanisms of stimulant effects on growth include alterations in growth hormone or growth factor, decreased thyroxine secretion, and suppression of appetite leading to reduced caloric intake.3,48 Two case–control studies, with approximately 140 boys and 110 girls, assessed growth effects after taking stimulant medication over a 10-year period and found no significant effect on growth in boys or girls taking stimulants compared with matched controls not taking stimulant. The average duration of stimulant use was 7.5 years.56
In most cases, children should be given a drug-free trial every year.3,17,45 Time off stimulant appears to lessen stimulant growth suppressant effects, but evidence is lacking to firmly determine the impact of drug holidays on growth.3,49 Consideration must be given to the risks of negative effects on learning, socialization, and self-image while off stimulant therapy when determining the frequency and duration of the drug-free trial. Annual drug holidays provide time to reassess the need for continued treatment.3,49 Drug dosage often varies from year to year, largely because of age-related pharmacokinetic changes. As a child develops, hepatic metabolism slows, and volume of distribution increases.43
Nonstimulants
Extended-release guanfacine, extended-release clonidine, and atomoxetine are less effective alternatives to the stimulants for treatment of ADHD in children and adolescents. Atomoxetine is also approved in adults. Their potential benefits relative to stimulants include no abuse potential, less potential for growth effects, and less sleep disturbance.3 See Table 46-4 for dosing.
TABLE 46-4 Dosing and Adverse Effect Monitoring of Nonstimulant Drugs for ADHD
Atomoxetine Atomoxetine is a selective norepinephrine reuptake inhibitor that should be taken in divided doses in the morning or late afternoon by children for improved tolerability. Adults can take it once daily, usually in the morning.2,3 Placebo-controlled, short-term trials (6 to 12 weeks) have shown that atomoxetine is effective in reducing ADHD symptoms in children, teens, and adults, and long-term studies show ongoing benefit and safety for children and adolescent responders out to 4 years.57 A controlled trial comparing atomoxetine, OROS methylphenidate, and placebo over 6 weeks in 6- to 16-year-old patients showed that both drugs were significantly better than placebo at improving ADHD symptoms, but OROS methylphenidate was superior to atomoxetine.3,49 There was evidence for a preferential response to atomoxetine in some individuals.49
Atomoxetine has a significantly slower onset of therapeutic effect than stimulants (2 to 4 weeks vs. 1 to 2 hours with an effective stimulant dose), and full benefit may not be seen for 6 to 8 weeks.3,49Atomoxetine is sometimes combined with a stimulant in partially responsive patients based on limited data from open trials and case series describing fewer late-day rebound effects and better sleep when atomoxetine is given in the evening; however, adverse effects are additive.3,49
Atomoxetine Adverse Effects Possible adverse effects of atomoxetine, and their management, are similar to those of stimulants, including upset stomach, and psychiatric and cardiac adverse effects (see Table 46-4). Atomoxetine has less growth suppression risk compared with stimulants, but it has a greater risk of fatigue, sedation, and dizziness compared with stimulants or bupropion. Unlike stimulants, atomoxetine labeling includes a bolded warning of potential for severe liver injury following reports in two patients. Continuation studies have not shown evidence for liver toxicity with long-term use; however, a case of idiosyncratic liver toxicity requiring liver transplantation in a 10-year-old boy was reported.57,58 Also, it is the only FDA-approved ADHD medication with a labeled warning for new-onset suicidality, 0.4% in atomoxetine-treated patients versus 0% in patients receiving placebo.3 Sexual side effects, primarily decreased libido, have been reported in adults taking atomoxetine.49
α2-Adrenergic Agonists Guanfacine and clonidine are central α2-adrenergic agonists, acting both presynaptically to inhibit norepinephrine release and postsynaptically to increase blood flow in the prefrontal cortex. Increased blood flow in the prefrontal cortex has been shown to enhance working memory and executive functioning. Both interact with a multitude of neurotransmitter systems, including catecholamine, indolamine, and α2-receptors on parasympathetic neurons, opioids, imidazole, and amino acid systems.42
Guanfacine has a longer elimination half-life and duration of action (18 hours) compared with clonidine (12 hours), and its greater selectivity for the α2a-receptor, compared with clonidine, imparts less sedation and dizziness.59 Clonidine and guanfacine are not as effective as stimulants for monotherapy treatment. In addition to being approved as monotherapy, extended-release clonidine and guanfacine are FDA approved as adjuncts to stimulants and have been shown to further decrease ADHD symptoms in children and adolescents only partially responsive to stimulants. Both are prescribed frequently as adjuncts to reduce disruptive behavior, control aggression, or improve sleep in youth.3,49,59 Neither have been studied sufficiently for ADHD in adults.
Guanfacine XR can be given once daily during monotherapy while clonidine XR should be given twice daily for optimal symptom coverage. Both are considered acceptable second-line agents for children and adolescents unresponsive to or unable to tolerate stomach upset or insomnia with stimulant medications. Extended-release guanfacine and clonidine are more sedating than stimulants or atomoxetine; therefore, sleepiness during the school day requires careful monitoring.59
α2-Adrenergic Agonist Adverse Effects The most common side effects of clonidine and guanfacine are dose-dependent sedation, hypotension, and constipation.3,45,59 Sedation usually subsides after 2 to 3 weeks of therapy.3,17,59 Of concern are reports of bradycardia, syncope, rebound hypertension, heart block, and sudden death with immediate-release clonidine.3,49,59 Four children have died on the combination of methylphenidate and immediate-release clonidine; however, complicating factors make it impossible to link the drug combination directly with the cause of death.59 Extended-release guanfacine and clonidine appear to pose a lower risk of cardiac adverse effects according to available safety data.59,60
Bupropion and Tricyclic Antidepressants Bupropion, a monocyclic antidepressant, is a weak dopamine and norepinephrine reuptake inhibitor with no significant direct effect on serotonin or MAO. Its active metabolites augment noradrenergic and dopaminergic function. Investigations with bupropion in children demonstrated efficacy greater than placebo in two controlled trials and efficacy comparable with methylphenidate (n = 15 children) in another controlled trial.3,17 Bupropion has been found beneficial for adolescents with depression and ADHD. For adults with ADHD, the number needed to treat (NNT) is between 4 and 5 compared with “2” with stimulant therapy.46Bupropion causes less appetite suppression and weight loss compared with stimulants but has a greater risk of seizures.3,46,49
Bupropion and Tricyclic Antidepressant Adverse Effects Bupropion’s adverse effects include nausea, which can resolve over time or with slower dosage titration, and rash, which can require discontinuation of therapy if severe (see Table 46-4). Bupropion should not be used in children with a seizure or eating disorder because of unacceptable risk of seizures in these patients. It can cause or exacerbate tics.3,49
Possible CNS adverse effects of tricyclic antidepressants (TCAs) include dizziness, aggressiveness, excitement, nightmares, insomnia, forgetfulness, and irritability. Similar to other antidepressants, TCAs carry a warning of the risk of new-onset suicidality in pediatric patients and young adults up to the age of 24 years.61 TCAs should be taken throughout the week and not just on school days. TCA-withdrawal effects are severe in children and include nausea, vomiting, and diarrhea.61 Signs of CNS toxicity are confusion, impaired concentration, hallucinations, and delusions.
TCAs are last-line agents because they are the most dangerous in overdose and pose the greatest risk for cardiovascular side effects.17,49 Imipramine and desipramine are the most systematically studied TCAs in the treatment of ADHD, although nortriptyline is also effective.17 The onset of TCA clinical response occurs within the first 2 to 4 weeks.17
Lithium and Anticonvulsants Lithium and anticonvulsants are used increasingly to control aggression and explosive behavior in patients with a diagnosis of ADHD. Some patients actually can have childhood-onset bipolar disorder or combined ADHD–bipolar disorder.3,62 
Lithium, valproate, and carbamazepine are effective for explosive behavior, aggression, and impulsivity, but they are not beneficial treatments for a child with the inattentive subtype of ADHD. Dosing starts in low divided doses with titration over 1 to 2 weeks to therapeutic response.62,63
Antipsychotics Conventional antipsychotics such as chlorpromazine and haloperidol can improve symptoms of hyperactivity and impulsivity but can have negative effects on learning and cognitive functioning and can cause extrapyramidal side effects (e.g., dystonia and tardive dyskinesia) that limit their usefulness.3,64 Second-generation antipsychotics such as risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have been used to control severe aggression in refractory cases of ADHD, particularly if conduct disorder or bipolar disorder coexists. They pose a lower risk of extrapyramidal side effects compared with conventional agents, but they can cause metabolic side effects such as hyperlipidemia, hyperglycemia, and weight gain.63,64 Ziprasidone has the lowest risk of metabolic side effects among these second-generation antipsychotics.
Comorbidity
Individuals with ADHD often present with comorbidities (Fig. 46-1). If multiple drugs are started simultaneously, it is impossible to determine the impact of each drug. The predominance and urgency of symptoms guide the drug selection process. For example, if a child presents as severely anxious or depressed with associated attentional problems, then an antidepressant should be initiated first with monitoring to determine if attentional symptoms improve.3,45 When a child presents with severe ADHD and associated anxiety or depression, a stimulant should be initiated to treat the more severe ADHD. If ADHD symptoms improve significantly, but anxiety or depression persists, then an antidepressant can be added.3,45 Studies show that stimulants do not routinely make anxiety disorders worse, but they might not improve symptoms either.3,4,49 In a child with epilepsy, methylphenidate is safe and effective; however, the child should be stabilized and seizure-free on an anticonvulsant prior to initiation of the stimulant.65
ADHD and Substance Abuse
Genetics, age (16 to 25 years old), psychosocial factors, and comorbidities all influence one’s risk for drug and alcohol abuse.66 ADHD itself is a known risk factor for the development of a substance use disorder, and the most commonly abused substances are alcohol and marijuana. A 3-year outcome study of children diagnosed with ADHD showed that they were at least twice as likely to engage in substance abuse (alcohol, cigarettes, marijuana) compared with youth from their same school system without ADHD. The rate of abusing alcohol, cigarettes, and/or marijuana was 17.4% in those diagnosed with ADHD compared with 7.4% in those without ADHD. Children receiving stimulant medication did not have higher rates of abuse compared with those not receiving a stimulant.67
Parents frequently express concern that treating their child with a stimulant, particularly early treatment, may increase the risk of substance abuse. Followup studies show that stimulant therapy for ADHD neither increases nor decreases the risk of subsequent drug or alcohol abuse. One study showed that later onset of stimulant initiation (age 8 to 12) was associated with more substance use compared with those starting treatment earlier. In this study, the subgroup with early treatment (before the age of 8) did not differ from comparison subjects in lifetime rates of nonalcohol substance use (27% vs. 29%, respectively). It is possible that early stimulant treatment of ADHD has a protective effect toward the emergence of conduct disorder, which usually precedes antisocial personality disorder and increases the risk for delinquency and drug abuse.
Having conduct disorder along with ADHD further increases an individual’s risk of substance abuse. In a prospective study of 11-year-old twins with ADHD and conduct disorder (760 female and 752 male twins) from the Minnesota Twin Family study, having conduct disorder and the hyperactive/impulsive subtype of ADHD predicted substance abuse (nicotine, cannabis, alcohol) at age 14, whereas the inattentive subtype of ADHD had a much lower risk of substance abuse. Youth with aggression combined with hyperactive and inattentive symptoms had greater rates of substance abuse compared with healthy youth or those with only inattentive symptoms. Alcohol and drug use was significantly greater in those with both aggression and inattentive symptoms. Treatment plans targeting aggression and conduct disorder are needed to lower the risk of substance abuse.
Atomoxetine, α2-agonist, or bupropion is a preferred agent for individuals with ADHD and active substance abuse disorders. If an individual is in recovery, a stimulant can be utilized with close supervision.
Clinical Controversy…
The use of stimulants to treat ADHD in individuals with a substance use disorder or history of drug or alcohol abuse is controversial. A diagnosis of ADHD confers at least a twofold greater risk of adolescent and adult substance abuse. The risk is greater if conduct disorder, antisocial personality, or bipolar disorder coexists. There is the risk that the individual with ADHD may abuse the stimulant, particularly if he or she is prone to substance abuse. Vigilance among prescribers and careful risk versus benefit assessment is necessary.3,67
ADHD and ODD/Conduct Disorder
ODD associated with ADHD in children is responsive to stimulant medication treatment, and once treated, ODD may be less likely to develop into the more severe conduct disorder. A study in aggressive 6- to 13-year-olds with ADHD found that systematic weekly methylphenidate titration to an average dose of 52 mg/day along with behavioral therapy resulted in optimal symptom control without the need for antiaggressive medications such as risperidone or quetiapine. This prevents exposure to the risk of atypical antipsychotic side effects such as weight gain, diabetes, hyperprolactinemia, and extrapyramidal side effects. Studies in adolescents taking OROS methylphenidate found most of them needed between 54 and 72 mg/day for optimal therapeutic benefit.44 Studies in adolescents and adults with ADHD show that doses of stimulant above the recommended daily maximum are frequently needed for optimal symptom control prompting the American Academy of Child and Adolescent Psychiatry to publish an “off-label maximum dosage of 100 mg/day for methylphenidate and 60 mg/day for dextroamphetamine and mixed amphetamine salts.” These dosage ranges appear in the academy’s practice parameter on the treatment of ADHD.2,17
Tourette’s and ADHD
Pharmacotherapy with stimulants increases dopaminergic and noradrenergic activity, which has the potential to aggravate or precipitate tics, although short- and long-term studies in 71 children showed no worsening of tics with methylphenidate dosed up to 0.5 mg/kg/day.3 Studies examining the comparative effects of methylphenidate and dextroamphetamine on tics in children found the majority experienced improvement in ADHD symptoms with acceptable effects on tics. Methylphenidate was better tolerated than dextroamphetamine.3,4
A double-blind, placebo-controlled trial compared methylphenidate or clonidine monotherapy with combination methylphenidate and clonidine in patients with ADHD and Tourette’s disorder. Combination therapy demonstrated the greatest benefit in reducing symptoms of ADHD and tics (P <0.0001).3 Clonidine appeared most helpful for impulsivity and hyperactivity, whereas methylphenidate was most helpful for inattention. All treatments were well tolerated, but sedation was common (28%) in those receiving clonidine.3 Patients and caregivers should be aware of the risks of using stimulants in children with Tourette’s disorder (see ADHD and Substance Abuse above); careful monitoring is essential.3
A controlled trial of atomoxetine versus placebo in 117 children with ADHD and Tourette’s disorder over 18 weeks showed treatment with atomoxetine 0.5 to 1.5 mg/kg/day improved symptoms of both, with overall good tolerability. Treatment-emergent nausea, decreased appetite, decreased body weight, and increased heart rate occurred significantly more often in those receiving atomoxetine compared with in those receiving placebo.3
Clonidine or guanfacine alone is a less effective alternative to stimulants in the treatment of children with Tourette’s disorder and ADHD. Guanfacine was administered to 34 children (mean age 10.4 years), with ADHD and tic disorder during an 8-week placebo-controlled trial at a dose of 1.5 to 3 mg/day. Tic severity decreased by 31% in the guanfacine group compared with 0% in the placebo group.3 There was a mean improvement of 37% on the teacher-rated ADHD scale compared with 8% improvement with placebo. Clonidine and guanfacine’s cardiovascular effects warrant careful clinical monitoring.3,68
Methylphenidate, clonidine, guanfacine, and atomoxetine appear to reduce ADHD symptoms in children with tics. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may nonetheless exacerbate tics in individual cases. In these instances, treatment with α-agonists or atomoxetine may be an alternative.68
Personalized Pharmacotherapy
Factors that should be taken into account to personalize pharmacotherapy for ADHD include age, co-occurring conditions including substance abuse, effectiveness of treatment, side effect sensitivities, and patient or family preference. An individual’s ability to metabolize a drug and the drug’s pharmacokinetic profile and drug interaction potential should also be considered. To date, genomic studies have not provided information to guide therapy.
Pharmacokinetic and Drug Interactions
Methylphenidate is de-esterified prior to elimination and is less likely to have metabolic drug interactions compared with mixed amphetamine salts. Gender has been shown to influence the absorption of methylphenidate, with males having increased bioavailability compared with females.43 Variability in dosage requirements for amphetamine salts, atomoxetine, bupropion, and TCAs can be due to interpatient variability in plasma concentration achieved at a given dose. All are metabolized via cytochrome P450 (CYP) 2D6, and bioavailability and half-life can be four to eight times greater in those taking a CYP2D6 inhibitor (e.g., bupropion, fluoxetine, or paroxetine) or in poor metabolizers. For example, atomoxetine’s half-life is 5 hours in extensive metabolizers and 19 hours in poor metabolizers.3 Bupropion is metabolized faster in prepubertal children, making twice-daily dosing optimal for efficacy (even for bupropion SR).3 Twice-daily dosing of atomoxetine is optimal in children and adolescents to improve tolerability.3 Once-daily dosing of bupropion or atomoxetine is possible for most adults. If tolerance develops after months of therapy, a dosage adjustment can be necessary to compensate for age-related changes in distribution and metabolism.
EVALUATION OF THERAPEUTIC OUTCOMES
Careful documentation of baseline symptoms and complaints over a 1-month predrug period is essential to the evaluation of therapeutic and adverse outcomes. Investigation regarding family history of psychiatric disorders and cardiac disease is essential to determine risk for related adverse drug reactions and to implement appropriate monitoring.3,45,49 Baseline symptoms can be measured using videotapes, clinician rating scales (e.g., ADHD Rating Scale IV, Vanderbilt ADHD Diagnostic Scale), or both. In addition, height, weight, and eating, and sleeping patterns should be recorded at baseline and every 3 months.3,45,49
After the initiation and titration of any drug treatment, it is necessary that parents, teachers, and clinicians assess the overall functioning of the child or adult using standardized rating scales to determine if significant therapeutic benefit justifies continuing medication.3,45,49 There is a lack of standardized assessment tools for adults; however, the adult ADHD screening tool can be useful.33 Therapeutic effects of the stimulants include decreased motor activity and impulsivity and increased attention span.3,45,49 This suggests that stimulants are indicated for ADHD symptoms and not for primary learning disorders. The benefits of drug therapy must outweigh the potential for adverse effects to justify continued treatment.3,45,49
Atomoxetine and bupropion also require monitoring to detect changes in appetite, weight, and sleep patterns, as well as pulse and blood pressure. An adequate trial of atomoxetine or bupropion consists of 6 weeks at maximum tolerated doses unless response occurs at a lower dose.3,45,49
When guanfacine or clonidine is given, careful clinical monitoring for fatigue, dizziness, and autonomic changes (e.g., blood pressure and pulse) is recommended.3,45,59 The American Heart Association has stated that electrocardiographic monitoring is not required for clonidine treatment in children, although many clinicians continue to assess for ECG changes.55 When discontinuing treatment, clonidine and guanfacine should be withdrawn slowly (0.05 mg clonidine/0.5 mg guanfacine reductions every 3 to 7 days) to prevent rebound hypertension or behavioral dyscontrol.59,60 A therapeutic trial requires 1 to 2 months to assess therapeutic response, although increased sleep usually occurs immediately.
The effects of TCAs on the ECG should be monitored carefully. Of more concern are reports of sudden death in children taking desipramine or imipramine.3,49,61 Children and adolescents given TCAs should have pretreatment and followup ECGs to assess the effects of TCA therapy on cardiac rate and rhythm.61
ABBREVIATIONS
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