Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is commonly diagnosed in children and adolescents, but it can persist into adulthood. The condition is characterized by inattention, impulsivity, and hyperactivity, which can interfere with a person’s ability to function in school, work, and social situations.1 Current statistics in the US show that ADHD prevalence is higher in children than adults: 9.8% of children between the ages of 3 and 17 (approximately 6 million children) are diagnosed with ADHD, compared with 4.4% of adults (Figure 1).2,3
Although ADHD diagnoses among adults in the US increased at a much higher rate than diagnoses in children between 2007 and 2016 (123.3% among adults vs 26.4% among children),4 the prevailing consensus is that adult ADHD is underdiagnosed,5 suggesting that the true number of adults with ADHD may be even higher than current estimates.
In children and adolescents, ADHD negatively impacts quality of life (QOL); it is associated with poor sleep patterns, low mood and happiness, antisocial behaviors, and an increased risk of developing oppositional defiant disorder and conduct disorder.6 Poor social outcomes can be a lifetime impact of ADHD, which is associated with increased risk of substance abuse, criminality, academic and occupational underperformance, and premature death.7 Among adults, ADHD may cause poor work performance due to difficulties in focusing, prioritizing tasks, and time management, leading to missed meetings and deadlines. ADHD in adults may manifest as restlessness, inattention, disorganization, and impulsivity.8 At the societal level, ADHD can significantly impact economic growth in a negative way, increase health care utilization costs, increase stress, and reduce QOL.8,9
ADHD is considered a lifelong disorder; therefore, its treatment must span the spectrum of development from childhood through adulthood.7 Nonpharmacologic intervention can be effective for some patients, and it includes counseling as well as behavioral and environmental modifications.10 However, according to the organization Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD), pharmacological intervention is needed if there is functional impairment in 2 or more functions, including a combination of hyperactivity, impulsivity, and inattentiveness.11 Indeed, pharmacological treatments have been reported to be effective for symptoms of ADHD, improving sustained attention, reducing impulsive behaviors, and improving activity levels.10
Given the negative consequences of ADHD, its treatment is essential in both children and adults. Several treatment options are available; this article focuses on agents approved by the US Food and Drug Association (FDA), specifically stimulant and nonstimulant treatment options.
What to Consider Before You Treat
The decision to prescribe medication should be made after a thorough diagnostic evaluation, ensuring that the diagnostic criteria are met in children, adolescents, and adults.12,13 Several factors must be considered when deciding to initiate and select treatment, including the individual’s age, medication abuse or misuse risk, and cardiovascular safety.14 The presence of comorbid conditions is also a key consideration, as other neuropsychiatric disorders — including depression, mood or anxiety problems, and, specifically in children, autism spectrum disorder and Tourette syndrome — commonly complicate ADHD and must also be treated.15
There are 2 main pharmacological agents used to treat ADHD: stimulants (methylphenidate and amphetamine) and nonstimulant medications (atomoxetine, viloxazine, guanfacine, and clonidine). While both types of agents are effective, they are also associated with various side effects and different durability of symptom control that can result in a nonadherence rate ranging from 15% to 87%.7 These limitations must be taken into consideration when selecting treatment.
Selecting the initial agent may be challenging due to the number of medications available. However, when choosing an initial ADHD treatment, stimulant medications are generally the first-line option, although there are exceptions.8 Other factors to consider include the time of day when a patient is most symptomatic, the ability to swallow a tablet or capsule, concern about abuse or diversion with the patient or a household member, and patient or caregiver treatment preference.
Daytime functioning or evening commitments may also influence treatment choice.16 When developing a treatment plan, particularly for adults, it is essential to recognize that the demands of work and home life may necessitate the use of agents with symptom control that is effective throughout the day and into the evening. The potential for drug dependency, withdrawal symptoms from discontinuation, and serious cardiovascular events are also important considerations, especially for stimulant medications.1,8
ADHD Treatment Options
Stimulants
Stimulant medications increase norepinephrine and dopamine neurotransmission in the brain’s prefrontal cortex; the 2 classes of stimulants used for treatment of ADHD are amphetamines and methylphenidate. Amphetamines primarily increase dopamine concentration by acting as a competitive inhibitor of dopamine, directly binding on dopamine and norepinephrine transporter binding sites. Similarly, methylphenidate increases the synaptic concentration of dopamine to amplify dopaminergic neurotransmission by inhibiting presynaptic dopamine transporters of central adrenergic neurons and, to a lesser degree, inhibiting norepinephrine transporters.10
Approximately 30 stimulants are FDA-approved for the treatment of ADHD.16 There are 2 forms of stimulants: immediate-release stimulants (short-acting, with effects lasting up to 6 hours) and extended-release stimulants (long-acting, with effects generally lasting up to 12 hours).10 The FDA-approved stimulant options for treating ADHD are summarized in Table 1.10,16-41
While stimulant medications are effective in the first-line setting, they are plagued by side effects, poor tolerability, and suboptimal ADHD symptom control in up to 30% of patients, which limits their optimal use.15 Furthermore, stimulant medications are generally short-acting, and most extended-duration formulations have a maximum of 12 hours duration and are therefore not suitable for individuals who need a full day of symptom control.16 Their potential for misuse, abuse, and dependency requires a label as a Schedule II (CII) drug.It has also been reported that long-term use of stimulant medication in children may attenuate growth, causing a modest reduction in adult height and increased weight and body mass index.15 The formulation of lisdexamfetamine dimesylate (Vyvanse®) as a prodrug, converted to the active drug dextroamphetamine after gastrointestinal absorption, is believed to have a lower abuse potential than other stimulants, although abuse potential can still occur at high dosages.42
Serdexmethylphenidate/dexmethylphenidate (Azstarys™), FDA-approved in 2021, is a dual short-acting (dexmethylphenidate) and long-acting (serdexmethylphenidate) stimulant approved for the treatment of ADHD in patients 6 years of age and older. A dual formulation of short-acting and long-acting stimulants might lower the number of pills required by individuals who need both long- and short-acting stimulants to control their ADHD symptoms. However, a high potential for abuse and dependence is noted as a warning on the label.43
Selecting a particular stimulant medication over another remains a collaborative decision between a health care professional and a patient or caregiver based on careful assessment and preference for short-acting vs long-acting formulations. Currently, there is no empirical evidence for a clear advantage of amphetamine over methylphenidate or vice versa for treatment of children and adolescents, and there are no guidelines to help decide which stimulant to use first.44
ADHD symptoms in 25% to 40% of children and 20% to 50% of adults are suboptimally managed with stimulants despite their efficacy, in part due to a combination of inadequate symptom reduction or undesirable adverse effects or contraindications.1 Nonstimulant medications may therefore be the superior choice for these patients.
Nonstimulants
Nonstimulant treatments for ADHD target norepinephrine, a potent agonist of the dopamine D4 receptor, which is strongly associated with ADHD and risk-taking behaviors.45 Nonstimulant treatment options are considered if the first-line stimulant fails to treat the symptoms adequately, if patients cannot tolerate stimulants, or if there are contraindications present.9 However, under certain circumstances, nonstimulant medications can be used as first-line treatment for children and adolescents — for example, in patients with comorbid tic, substance abuse, anxiety, or depressive disorders, or due to a caregiver’s preference.44
The 4 nonstimulants currently FDA-approved for ADHD are classified into norepinephrine reuptake inhibitors (atomoxetine hydrochloride [Strattera®]46 and viloxazine extended release [Qelbree®])47 and alpha-2 (α-2) adrenergic agonists (guanfacine extended release [Intuniv®]48 and clonidine hydrochloride extended release [Kapvay®]).49 FDA-approved nonstimulant ADHD medications are summarized in Table 2.46-50
Norepinephrine Reuptake Inhibitors
Atomoxetine Hydrochloride
Atomoxetine hydrochloride, a relatively selective norepinephrine reuptake inhibitor with a weak effect on the serotonin transporter, was approved by the FDA in 2002 and is indicated for use in children and adults.46 Atomoxetine hydrochloride is metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Consequently, individuals who are poor metabolizers due to genetic polymorphism have a prolonged drug half-life of 19 to 21 hours, compared with approximately 4.5 hours in individuals who are extensive metabolizers.50 There is a need for caution with concomitant use of atomoxetine hydrochloride with specific medications that alter CYP2D6 enzymes, such as fluoxetine and paroxetine, which may induce poor metabolizer status, even in patients who are usually extensive metabolizers. Atomoxetine hydrochloride’s time to response has not been clearly defined; however, the available data suggests wide variations in initial symptom improvement between 2 and 10 weeks. Treatment for up to 3 months is needed to determine whether an individual responds to atomoxetine hydrochloride.50
Viloxazine Extended Release
Viloxazine extended release, approved by the FDA in 2021, is a selective norepinephrine reuptake inhibitor that also exhibits selective serotonergic activity and is indicated for the treatment of ADHD in adults and children 6 years and older.1,47 Viloxazine has a well-established safety and pharmacokinetic profile through its long-standing use as an antidepressant.1 Its efficacy, and its subsequent approval for the treatment of ADHD in children and adults, was demonstrated in phase 3 randomized clinical trials involving 477 children aged 6 to 11 years (ClinicalTrials.gov identifier: NCT0324730) and 374 adults (ClinicalTrials.gov identifier: NCT04016779). In both studies, viloxazine was well-tolerated, and it demonstrated statistically significant improvements in ADHD symptoms.51,52
While atomoxetine hydrochloride and viloxazine are norepinephrine reuptake inhibitors, there are key differentiators between them; unlike atomoxetine hydrochloride, which is primarily metabolized by the CYP2D6 enzyme, viloxazine is partially metabolized by CYP2D6 and also by the UDP-glucuronosyltransferase 1-9 (UGT1A9) and UDP-glucuronosyltransferase 2B15 (UGT2B15) enzymes.1 Viloxazine has a longer half-life than atomoxetine hydrochloride and consequently requires less frequent dosing. Furthermore, viloxazine offers an alternative delivery route to swallowing a pill because it is offered in a beaded formulation that can be sprinkled on applesauce or pudding without altering its pharmacokinetic profile. Due to its documented antidepressant activity, viloxazine may have benefits in treating depression and anxiety in patients with ADHD, although these added benefits have not been studied. There is a need for caution when coadministering viloxazine with other medications; for example, viloxazine inhibits cytochrome P450 1A2 (CYP1A2), the enzyme that metabolizes duloxetine and clozapine and therefore can result in higher levels of the latter drugs. In addition, viloxazine is a weak inhibitor of cytochrome P450 3A4 (CYP3A4) and therefore can increase drug levels metabolized by this enzyme, including dextromethorphan and guanfacine.50
α-2 Adrenergic Agonists
Clonidine and Guanfacine Extended-Release Formulations
For over 3 decades, the α-2 adrenergic agonists clonidine and guanfacine have been used to treat ADHD. However, the immediate-release formulations had a short duration of action and required multiple daily dosings.50 The development of extended-release formulations of clonidine (approved by the FDA in 1974)49 and guanfacine (approved by the FDA in 1986)48allowed for less frequent dosing, and both agents are FDA-approved for use as monotherapy or in combination with stimulants.50 Both extended-release formulations are approved for use in children 6 to 17 years.48,49
Although guanfacine and clonidine have the same mechanism of action, they have some important differences; for example, compared with clonidine, guanfacine has been reported to be more selective for the α-2 receptor, has a longer half-life and duration of action, and is potentially less sedating.50
Guanfacine is primarily metabolized by CYP3A4, requiring a dose increase if coadministered with CYP3A4 inducers such as phenobarbital, phenytoin, and glucocorticoids, and a dose reduction if taken with CYP3A4 inhibitors such as erythromycin, clarithromycin, verapamil, and grapefruit.50
CYP2D6 primarily metabolizes clonidine in the liver. Due to genetic polymorphism, variants of CYP2D6 may impact prototypic plasma concentration and metabolite concentration after taking clonidine; these variants have been studied in the Chinese population.53
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Reviewed February 2023
