INTRODUCTION — Attention deficit hyperactivity disorder (ADHD) is a disorder that manifests in childhood with symptoms of hyperactivity, impulsivity and/or inattention . The symptoms affect cognitive, academic, behavioral, emotional, and social functioning.
Several types of medications are available to treat ADHD in children and adolescents: stimulants, selective norepinephrine reuptake inhibitors, alpha-2-adrenergic agonists, and antidepressants (table 1). This topic will provide an overview of the pharmacology of medications used to treat ADHD in children and adolescents. Choosing a particular medication for an individual patient is discussed separately. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Choice of agent'.)
Other topics related to ADHD are presented separately:
STIMULANTS — Stimulant drugs include methylphenidates (methylphenidate and dexmethylphenidate) and amphetamines (dextroamphetamine and mixed dextroamphetamine-amphetamine salts). Stimulant drugs, with or without behavioral interventions, generally are the first-line treatment for school-aged children (≥6 years) and adolescents with uncomplicated ADHD . Stimulants are controlled substances and require a schedule II prescription. Stimulants are available in short-, intermediate-, and long-acting formulations (table 2A-B).
The exact mechanism of action of stimulants in ADHD is unknown. However, stimulants affect the dopaminergic and noradrenergic systems, causing the release of catecholamines from storage sites at the central nervous system synapses .
Methylphenidate — Short-acting methylphenidate (eg, Ritalin, Methylin) is available as a tablet, chewable tablet, or liquid (table 2A) . Behavioral effects may be seen within 30 minutes . The duration of action is three to five hours and the half-life is two to three hours.
Long-acting methylphenidate is available in tablets, chewable tablets, oral disintegrating tablets, capsules, oral suspension, and a patch [6-8]. The onset and duration of action vary depending upon the formulation (table 2B) :
●Single pulse wax matrix sustained release tablets (eg, Metadate-ER) have onset of action within 20 to 60 minutes and last up to 8 hours.
●Osmotic release methylphenidate tablets (Concerta) are coated with immediate release methylphenidate (for initial dosing) and use an osmotic pump to gradually release methylphenidate to approximate a three-times-per-day dosing schedule. Osmotic release methylphenidate usually has onset of action within 20 to 60 minutes and lasts up to 12 hours. Osmotic release methylphenidate tablets must be swallowed whole.
●Extended release orally disintegrating tablets (Cotempla XR-ODT) contain a mixture of immediate release and extended release methylphenidate. They have onset of action within one hour and last up to 12 hours . Although the prescribing information indicates that extended release orally disintegrating tablets should be taken consistently with or without food, we suggest that they be taken consistently with food – given the general stimulant effect of appetite suppression. (See 'General adverse effects' below.)
●Sustained release capsules (eg, Aptensio XR, Focalin XR, Metadate CD, Ritalin LA) contain a mixture (usually one-to-one) of immediate release and enteric-coated delayed release beads (or pearls) and generally approximate a twice-per-day dosing schedule . They typically have onset of action within 20 to 60 minutes and may last up to 12 hours. Delayed release/extended release methylphenidate capsules (Jornay PM) contain beads within two film coatings: an outer coating that delays release for approximately 10 hours and an inner coating that controls release throughout the day . Sustained release stimulant capsules can be opened and sprinkled on soft foods.
●Serdexmethylphenidate-dexmethylphenidate (Azstarys) capsules contain 70 percent serdexmethylphenidate (a prodrug of dexmethylphenidate) and 30 percent dexmethylphenidate (the d-enantiomer of methylphenidate) . Dexmethylphenidate is immediately released and serdexmethylphenidate is converted to dexmethylphenidate slowly over several hours. Serdexmethylphenidate-dexmethylphenidate has an onset of action within 1 hour and may last up to 13 hours.
●The oral suspension (Quillivant XR) and chewable tablet (Quillichew ER) are a racemic mixture of the d- and l-isomers of methylphenidate; the d-isomer is more active. It has onset of action within one hour and lasts as long as 8 hours (Quillichew ER) or 12 hours (Quillivant XR) .
●The methylphenidate patch (Daytrana) delivers methylphenidate transdermally. The methylphenidate patch has onset of action of 60 minutes. The duration of action may be as long as 12 hours but can be controlled by early removal of the patch (the effects last approximately two to three hours after the patch is removed). The methylphenidate patch should not be cut ; if a lower dose is needed a lower dose (ie, smaller) patch should be prescribed.
The dose-response rate of methylphenidate is highly variable, and careful dose titration is necessary within the limitations of available formulations [13,14]. Guidelines for the initial dose and dose titration for methylphenidate preparations are provided in the tables (table 2A-B). We do not suggest weight-based dosing, but as a general guide, significant reduction in core symptoms (ie, hyperactivity, impulsivity, and inattention) typically occurs at doses between 0.3 and 0.6 mg/kg. Dexmethylphenidate (the d-enantiomer of methylphenidate) is generally efficacious at doses approximately one-half of those needed for methylphenidate [4,15]. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Dose titration'.)
Amphetamines — Amphetamines can be prescribed as a single salt (dextroamphetamine, amphetamine sulfate) or as mixed dextroamphetamine-amphetamine salts. Lisdexamfetamine is a prodrug of dextroamphetamine that is pharmacologically activated after oral ingestion and was designed to discourage drug misuse [4,16].
Amphetamine medications for ADHD are available in immediate and sustained release preparations (table 2A-B). The immediate release preparations of amphetamine and dextroamphetamine-amphetamine are available as tablets or oral solution, and have an onset of action of 20 to 60 minutes and a reported duration of up to 6 hours (table 2A) [4,17].
Longer-acting preparations (6 to 13 hours) of amphetamine and dextroamphetamine-amphetamine are available as capsules, a liquid suspension, tablets, orally disintegrating tablets, chewable tablets, or a patch [18-22]. The onset and duration of action vary depending upon the formulation (table 2B), typically ranging from 20 to 60 minutes for onset of action and at least 10 hours' duration .
●Sustained release capsules (eg, Adderall XR, Mydayis) contain a mixture of immediate release and enteric-coated delayed release beads (or pearls) and approximate a twice-per-day or three-times per day dosing schedule . They typically have onset of action within 20 to 60 minutes and last up to 10 hours (Adderall XR and generic) or 16 hours (Mydayis). Sustained release amphetamine capsules can be opened and sprinkled on soft foods.
●Lisdexamfetamine (Vyvanse) capsules or chewable tablets have onset of action within 60 minutes and lasts up to 10 hours. Capsules can be opened and dissolved in water.
●Dyanavel extended release amphetamine tablets have an onset of action within 60 minutes and last up to 13 hours.
●The liquid suspension of Dyanavel extended release amphetamine has an onset of action within 60 minutes and lasts up to 13 hours. It should not be mixed with food or other liquids before administration.
●The pharmacokinetics of extended release orally disintegrating amphetamine (Adzenys XR-ODT) suggest an onset of action within 60 minutes and duration of approximately 10 hours.
●The dextroamphetamine patch (Xelstrym) delivers dextroamphetamine transdermally . It has onset of action within two hours. The duration of action may be as long as 12 hours but can be controlled by early removal of the patch (the effects last for several hours after the patch is removed). The dextroamphetamine patch should not be cut; if a lower dose is needed, a lower dose (ie, smaller) patch should be prescribed.
Stimulant adverse effects — Stimulants have been used to treat ADHD since the 1930s  and generally are considered to be safe [25,26]. Rare, serious adverse events have been reported in children being treated with stimulants, but a causal association has not been established . The potential risks of stimulants should be discussed with patients and caregivers when choosing a treatment strategy. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Pretreatment education'.)
Although ADHD is common among children with epilepsy, methylphenidate does not appear to increase the frequency or severity of seizures in children who are receiving appropriate anticonvulsant medications. (See "Epilepsy in children: Comorbidities, complications, and outcomes", section on 'Attention deficit hyperactivity disorder'.)
General adverse effects — Many of the side effects of stimulants are mild, of short duration, and reversible with adjustments to the dose or dosing interval [2,26-29]. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Managing stimulant adverse effects'.)
The frequency of most side effects is similar with methylphenidate and amphetamines. However, treatment with mixed dextroamphetamine-amphetamine salts may be associated with greater decrease in weight over time and increased risk of irritability than treatment with methylphenidate [30,31]. Side effects may occur more frequently in preschool children than in older children .
Relatively common side effects include appetite suppression, poor growth or weight loss during childhood, sleep disturbance, jitteriness, emotional lability, and social withdrawal [27,33-37]. Deceleration of linear growth may occur but appears to attenuate over time; cessation of treatment may result in normalization of growth [38-43]. Although clinical studies have suggested that adult height is not affected, average adult height was lower among participants in a randomized trial who used stimulants consistently over 16 years than in participants whose stimulant use was negligible (-4 cm [1.6 inches]) or inconsistent (-2.7 cm [1 inch]) or in a local comparison group (-3.3 cm [1.3 inches]) . At a mean age of 24.7 years, average adult weight was greater in participants with consistent stimulant use than in the local comparison group (+7.5 kg [16.5 pounds]).
Growth should be regularly monitored during treatment with stimulants . Less common side effects include increased heart rate and blood pressure, headache, dizziness, gastrointestinal symptoms, priapism in males, and peripheral vasculopathy, including Raynaud phenomenon [28,44-46].
Patients treated with the methylphenidate patch may develop contact sensitization if the patch is worn in the same location every day [12,47]. The methylphenidate patch has also been associated with permanent loss of skin color (chemical leukoderma) [48,49]. Among the 51 cases reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System database between April 2006 and December 2014, the time to onset of leukoderma after starting the patch ranged from two months to four years. The area of depigmentation ranged up to 8 inches (20.3 cm) in diameter. In 43 cases, the loss of pigmentation was limited to the application site, but seven patients also had depigmentation in other areas. The depigmentation may be disfiguring but is not harmful. Patients who notice hypopigmentation or depigmentation should seek medical attention. The methylphenidate patch should be discontinued and the patient transitioned to another long-acting treatment (table 2B and table 3).
Cardiovascular effects — Adverse cardiovascular effects of stimulants and the cardiac evaluation for children receiving pharmacotherapy for ADHD are discussed separately. Blood pressure and heart rate should be monitored before and during treatment with stimulants . (See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder".)
Priapism — Priapism is a rare complication of methylphenidate stimulants [50-52]. Review of data submitted to the FDA Adverse Event Reporting System identified 15 cases of priapism in male methylphenidate recipients between 1997 and 2012 . Most of the cases occurred in males <18 years (median age 12.5 years, range 8 to 33 years); two cases required surgical treatment. Priapism occurred in a variety of settings including increased dose, longer than typical dosing interval, and temporary or permanent discontinuation of methylphenidate stimulants.
Priapism has also been reported among four male patients taking amphetamine stimulants for ADHD . However, the correlation between amphetamine stimulants and priapism is uncertain because these patients were also taking other medications associated with priapism.
The diagnosis and treatment of priapism are discussed separately. (See "Priapism".)
●Psychosis – Children and adolescents treated with stimulant medications rarely may develop psychotic symptoms (eg, hallucinations, delusional thinking, or mania), but causality has not been established [53-56].
In pooled analysis of data from 49 randomized trials of medications used to treat ADHD (35 of which evaluated stimulants), psychotic symptoms developed in 11 children during 743 person-years of follow-up (incidence rate of 1.48 episodes per 100 person-years) . In subsequent analysis of two commercial insurance claims databases that evaluated psychosis requiring treatment with antipsychotic medication after initiation of stimulant therapy in 221,846 adolescents and young adults (age 13 to 25 years), 343 episodes occurred in 143,286 person-years of follow-up (incidence rate of 2.4 episodes per 1000 person-years) . The median time between initiation of stimulant and the psychotic episode was 128 days. The absolute risk was higher with amphetamines than with methylphenidate (2.83 versus 1.78 episodes per 1000 person-years, hazard ratio 1.7, 95% CI 1.3-2.1).
Although it is not possible to predict which patients will develop psychotic symptoms after initiation of stimulants , the risk may be increased in children with a family history of mental illness (eg, major depressive disorder, bipolar disorder) .
●Suicidal thinking – Rare cases of suicidal thinking have been reported among individuals taking stimulants for ADHD, but causality has not been established [58-60].
Tics — Stimulant medications have been reported to be associated with new onset of tics or worsening of tics in children with tic disorders . Tics or a family history of tics are included as a contraindication to some forms of methylphenidate and may be considered a potential adverse effect of both methylphenidate and amphetamines. Nonetheless, stimulant medications often improve attention and behavior without worsening tics in children who have chronic tics or Tourette syndrome [62-67]. (See "Tourette syndrome: Management", section on 'Attention deficit hyperactivity disorder'.)
ADHD and tic disorders frequently coexist: Approximately 20 percent of children with ADHD develop chronic tic disorders and approximately 50 percent of children with chronic tics or Tourette syndrome have comorbid ADHD [65,68]. Given the frequency of comorbid tic disorders and ADHD and the typical waxing and waning pattern of tics, new or worsening tics in children who receive stimulant medications may be coincidentally rather than causally associated [66,69]. In a 2015 meta-analysis of 22 randomized trials (2385 participants) comparing stimulant medications and placebo in children with ADHD, the proportion of children with new or worsening tics was similar in the stimulant and placebo groups (5.7 versus 6.5 percent, respectively; relative risk 0.99, 95% CI 0.78-1.27) . The risk of new or worsening tics was not associated with stimulant formulation, dose, duration of treatment, or patient age. Other meta-analyses evaluating the treatment of ADHD in children with comorbid tic disorders found that dextroamphetamine prescribed at higher than the usual recommended doses was associated with exacerbation of tics, but methylphenidate was not [65,67].
Taken together, these findings suggest that children with tics and ADHD can benefit from stimulant medications without worsening of tics, but higher-than-usual doses of dextroamphetamine should be avoided. For children in whom stimulant medications were discontinued because of new or worsening tics, resuming treatment with stimulants may be warranted, particularly if the behavioral response to nonstimulant medications was inferior to that with stimulants.
Diversion and misuse — Stimulant diversion consists of the transfer of medication from the patient for whom it was prescribed to another individual . Stimulant misuse consists of taking higher doses of medication than prescribed to achieve euphoria or combining stimulant medications with illicit drugs or alcohol .
A systematic review of studies related to diversion and misuse of ADHD medications indicated that 5 to 9 percent of grade- and high-school-age students and 5 to 35 percent of college-age individuals reported nonprescribed stimulant use in the year before the study . The proportion of students with stimulant prescriptions who were ever asked to give, sell, or trade their medications ranged from 16 to 29 percent. Diversion and misuse were more common among White students, members of fraternities and sororities, students with lower grade point averages, and those who report ADHD symptoms. Diversion and misuse also was more common with immediate than extended release preparations. The most commonly reported reasons for stimulant diversion and misuse included studying, staying awake, improved alertness, experimenting, and "getting high."
In a survey that compared diversion and misuse of psychotropic medications (eg, stimulants, selective serotonin reuptake inhibitors, tricyclic antidepressants, alpha-adrenergic agonists, etc) among 55 adolescents and young adults with ADHD and 42 adolescents and young adults with other conditions, stimulant diversion and misuse were more frequent among subjects with ADHD than with other conditions (11 versus 0 percent for diversion and 22 versus 5 percent for misuse) . All of the ADHD subjects who diverted or misused their medication had either comorbid conduct disorder or substance use disorder.
Contraindications to stimulants — Contraindications to stimulant medications may include :
●Symptomatic cardiovascular disease
●Moderate to severe hypertension
●Known hypersensitivity or idiosyncrasy to sympathomimetic amines
●Motor tics or Tourette syndrome
●History of drug abuse
●Concurrent use or use within 14 days of the administration of monoamine oxidase inhibitors
SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS
Indications and use — Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor that can be used to treat ADHD in children, adolescents, and adults [2,72]. It is not a controlled substance . Atomoxetine is an alternative to stimulants for children (≥6 years) and adolescents who have a substance abuse problem, household member with a substance abuse problem, tics, or severe side effects with stimulants.
Atomoxetine is an oral capsule and can be taken once or twice per day; the capsule should be swallowed intact . When administered once daily, efficacy is better with morning than evening dosing . However, evening dosing is associated with fewer overall adverse effects than morning dosing and may be better tolerated when initiating therapy (though no specific type of adverse event is more common with morning dosing). Some side effects (eg, headache) may improve if the total daily dose is divided twice per day.
The duration of action of atomoxetine is at least 10 to 12 hours [5,75]. In a 2013 systematic review of five randomized trials, the initial onset of action ranged from one to four weeks ; full response typically was not achieved until 6 to 12 weeks. Atomoxetine must be given every day without "drug holidays" . Atomoxetine may be discontinued abruptly if a decision is made to discontinue it. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Termination of therapy'.)
The dose of atomoxetine depends upon the child's weight:
●Children and adolescents weighing ≤70 kg should be started at a dose of 0.5 mg/kg for a minimum of three days and then titrated up to a daily dose of approximately 1.2 mg/kg in either one or two daily doses; the maximum daily dose should not exceed 1.4 mg/kg or 100 mg, whichever is less.
●Patients who weigh more than 70 kg should be started at a dose of 40 mg for a minimum of three days, followed by an increase to approximately 80 mg; after two to four weeks, the dose may be increased to a maximum of 100 mg if additional benefit is needed.
Atomoxetine is metabolized through the cytochrome P450 (CYP2D6) enzyme pathway. Dose adjustments may be necessary for patients receiving drugs that are strong inhibitors of CYP2D6 (eg, paroxetine, fluoxetine) [4,78,79].
Atomoxetine adverse effects
●General adverse effects – Common adverse effects of atomoxetine include weight loss, abdominal pain, decreased appetite, vomiting, nausea, dyspepsia, headache, dizziness, somnolence/fatigue, and irritability [2,26,29,80,81]. The risk of adverse effects may be affected by genetic variations in the cytochrome P450 (CYP2D6) enzyme pathway .
●Cardiovascular effects – Atomoxetine has stimulatory effect on the sympathetic nervous system, and rare, but serious, cardiovascular events, including sudden death, may occur during treatment with atomoxetine [73,82]. Children should be evaluated for cardiac disease before initiation of pharmacotherapy for ADHD. This evaluation is discussed separately. (See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder", section on 'Pretreatment clinical evaluation'.)
●Suicidal thinking – Atomoxetine has a boxed warning and additional warning statements regarding the increased risk of suicidal thinking in children and adolescents treated with atomoxetine.
In a small number of patients, atomoxetine has been associated with an increased risk of suicidal thinking [83,84]. Combined analysis of 12 short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine in 2208 patients (1357 of whom received atomoxetine) showed an increased risk of suicidal thinking among patients in the atomoxetine group (0.4 percent versus none of the controls; one patient in the atomoxetine group and none of the control patients attempted suicide) . In subsequent pooled analysis of data from 714 patients who were treated with atomoxetine for ≥3 years, 1.5 percent reported suicidal ideation and 0.3 percent reported suicide attempt . However, in a longitudinal register-based study that included >6000 patients treated with atomoxetine and used within-patient comparisons, the risk of suicidal behavior was the same during periods of ADHD treatment with nonstimulant medication as it was during periods of no treatment (hazard ratio 0.96, 95% CI 0.72-1.30) . In a retrospective cohort of 279,315 patients (age 5 to 18 years) treated with atomoxetine or stimulants for ADHD and followed for 12 months, suicide events (suicide or suicide attempt) were rare (0.08 percent); atomoxetine was not associated with an increased risk of suicide or suicide attempt .
Children and adolescents taking atomoxetine should be closely observed for clinical worsening, agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior, particularly during the first four to five months of therapy and when the dose is increased or decreased. The observation should include daily observation by families and caregivers and frequent contact with the prescribing clinician. Additional information for patients and health care professionals is available from the US Food and Drug Administration (FDA).
●Psychiatric effects – In addition to suicidal thinking, other rare psychiatric adverse effects may occur during treatment with atomoxetine. These include emergence of psychotic or manic symptoms (eg, hallucinations, delusional thinking, mania) in patients with no previous history of psychosis or mania and emergence of aggressive behavior or hostility . Patients should be screened for risk factors for bipolar disorder (eg, family or personal history of mania and depression) before initiation of atomoxetine. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Prerequisites'.)
●Tics – Atomoxetine use has been associated with the onset of motor tics [87,88]. However, in a randomized controlled trial in 148 children and adolescents with ADHD and comorbid tic disorders, treatment with atomoxetine did not exacerbate tic symptoms compared with placebo . Two meta-analyses of studies evaluating treatment of ADHD in children with comorbid tic disorders found that atomoxetine improved ADHD behaviors without exacerbating tics [65,67].
●Liver injury – Idiosyncratic severe liver injury has been reported in children and adults treated with atomoxetine [90-93]. Among six patients reported to the FDA, the duration of treatment before liver injury varied from 3 weeks to 730 days (median 63 days) . In one patient the evaluation was suggestive of type 1 autoimmune hepatitis, but the others had no alternative explanation for liver injury . None of the patients required liver transplantation, and most recovered after discontinuation of atomoxetine; there was one death, but it was not clear if atomoxetine caused or contributed to the death .
Patients taking atomoxetine should contact their health care provider if they develop signs or symptoms of severe liver disease (eg, fatigue, anorexia, nausea, vomiting, pruritus, dark urine, jaundice, right upper quadrant tenderness, unexplained "flu-like" symptoms); liver enzymes should be measured . Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and cases of severe liver injury reported to the FDA MedWatch program .
●Hypersensitivity to atomoxetine or any component
●Concurrent use or use within 14 days of the administration of monoamine oxidase inhibitors
●Current or past history of pheochromocytoma
●Severe cardiovascular disorders in which an increase in diastolic blood pressure >15 mmHg, an increase in systolic blood pressure >20 mmHg, or an increase in heart rate >20 beats/minute would be expected to cause clinical deterioration
Viloxazine is an extended release capsule that is taken once per day. The capsule may be swallowed whole or opened to sprinkle the entire contents onto one teaspoon of applesauce. It should not be crushed, cut, or chewed. Contraindications include concomitant use or use within 14 days after discontinuing a monoamine oxidase inhibitor and concomitant use of certain CYP1A2 substrates. For additional information, refer to the Lexicomp drug interactions program.
The recommended initial dose and titration vary with age:
●6 to 11 years – Initial dose 100 mg orally once daily; may increase by 100 mg weekly to the maximum dose of 400 mg
●12 to 17 years – Initial dose 200 mg orally once daily; may increase by 200 mg weekly to the maximum dose of 400 mg
Clinical experience with viloxazine is limited. In randomized prelicensure trials, viloxazine resulted in greater improvement from baseline on the ADHD Rating Scale, fifth edition than placebo (difference of approximately 5 to 7 points after six to eight weeks of treatment) . In one trial, symptom improvement was evident as early as week 1 of treatment .
Viloxazine has a boxed warning and additional warning statements regarding the increased risk of suicidal thinking in children and adolescents treated with viloxazine . In clinical trials, adverse effects included an increased risk of suicidal thoughts and behaviors compared with patients receiving placebo (0.9 versus 0.4 percent). Patients treated with viloxazine should be monitored for suicidal behavior.
Other adverse effects include increased heart rate and blood pressure, somnolence, fatigue, insomnia, decreased appetite, nausea, vomiting, and irritability.
ALPHA-2-ADRENERGIC AGONISTS — Alpha-2-adrenergic agonists (eg, extended release clonidine or guanfacine) usually are reserved for children and adolescents who respond poorly to a trial of stimulants or selective norepinephrine reuptake inhibitors (eg, atomoxetine), have unacceptable side effects with stimulants or selective norepinephrine reuptake inhibitors, or have significant comorbid conditions. Alpha-2-adrenergic agonists may take up to two weeks for initial response (compared with 20 minutes to a few hours for stimulants) and there are fewer data regarding their efficacy than for stimulants and atomoxetine . Extended-release alpha-2-adrenergic agonists are US Food and Drug Administration approved as monotherapy for ADHD or as adjuncts to stimulant medications.
Extended release clonidine — Extended release clonidine (KAPVAY) can be used for the treatment of ADHD or as an adjunct to stimulant therapy for the treatment of ADHD in children and adolescents aged 6 to 17 years . Clonidine is not a controlled substance and has no known potential for abuse.
Extended release and immediate release clonidine are not interchangeable on an mg-per-mg basis because they have different pharmacokinetic profiles.
The initial dose of extended release clonidine is 0.1 mg at bedtime; the dose should be titrated to response in increments of 0.1 mg at weekly intervals (maximum 0.4 mg/day). Extended release clonidine should be administered twice per day, divided equally or with the higher dose administered at bedtime . The duration of action is at least 10 to 12 hours . Discontinuation of clonidine requires tapering to prevent a rebound increase in blood pressure.
In the few controlled studies that have been reported, clonidine was effective in reducing symptoms in patients with ADHD but not as effective as stimulants [98,99]. The combination of extended release clonidine and stimulant medication is also effective in reducing symptoms in children with a partial response to stimulants . Clonidine may be useful in over-aroused, easily frustrated, highly active, or aggressive individuals . Although there are few randomized controlled trials with multiple drugs, the addition of clonidine to stimulant therapy may help offset some of the common stimulant side effects.
In two meta-analyses, alpha-2-adrenergic agonists were associated with improvements in ADHD symptoms and comorbid tics [65,67]. Clonidine has been used without increased morbidity in children with ADHD and comorbid tics or Tourette syndrome [63,65,67].
Side effects of clonidine include sedation, depression, bradycardia, headache, and possible hypotension [102-104]. Oral clonidine may cause generalized rash, urticaria, or angioedema in patients with a history of hypersensitivity reactions to transdermal clonidine .
Extended release guanfacine — Extended release guanfacine (Intuniv) can be used for once-daily treatment of ADHD or as an adjunct to stimulant therapy in children and adolescents aged 6 to 17 years [105-110]. Guanfacine has a longer half-life and fewer side effects than does clonidine.
Extended release and immediate release guanfacine are not interchangeable on an mg-per-mg basis because of differences in bioavailability.
Extended release guanfacine is administered once per day . It can be administered in the morning or the evening, whichever is best for the patient and caregiver . The initial dose is 1 mg per day; the dose should be titrated to response in increments of 1 mg at weekly intervals (typical maximum 4 mg/day; a maximum dose of 7 mg/day may be used for adolescents >12 years who weigh >58.5 kg [129 pounds], but this dose may be associated with somnolence) [112,113]. The duration of action is at least 10 to 12 hours. Extended release guanfacine requires one to two weeks for initial response. Discontinuation of guanfacine requires tapering by ≤1 mg every three to seven days to prevent a rebound increase in blood pressure . During the taper, blood pressure and heart rate should be monitored .
In a randomized trial in 345 patients (6 to 17 years), extended release guanfacine was efficacious in improving ADHD symptoms compared with placebo (reduction in ADHD-Rating Scale-IV [ADHD-RS-IV] score of 16.7 versus 9.7 points); adverse effects included headache, fatigue, abdominal pain, and sedation . Additional randomized trials support the efficacy of guanfacine compared with placebo in improving symptoms in children and adolescents with ADHD and with ADHD and comorbid oppositional defiant disorder [108,109,116].
In randomized trials comparing extended release guanfacine combined with methylphenidate, extended release guanfacine alone, and methylphenidate alone, the combination of guanfacine and methylphenidate was well-tolerated but provided only small but significant improvements in ADHD symptoms compared with monotherapy ; the combination of guanfacine and methylphenidate improved working memory compared with guanfacine alone but was not superior to methylphenidate alone and did improve other cognitive domains .
In two meta-analyses, alpha-2-adrenergic agonists were associated with improvements in ADHD symptoms and comorbid tics [65,67]. Guanfacine has been used in open or small trials to treat children with ADHD and Tourette syndrome whose tics worsened with stimulants or in whom clonidine was poorly tolerated (either because of its sedative side effects or short duration) [65,67,119,120].
ANTIDEPRESSANTS — Antidepressants that have been used in the treatment of ADHD include tricyclic antidepressants (imipramine, desipramine, nortriptyline), and dopamine reuptake inhibitors (eg, bupropion). These medications usually are reserved for children and adolescents who respond poorly to a trial of stimulants or selective norepinephrine reuptake inhibitors (eg, atomoxetine) or have unacceptable side effects. Antidepressants are not US Food and Drug Administration approved for treatment of ADHD but can be used to treat comorbid anxiety or depression .
Tricyclic antidepressants — Tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin. With the availability additional nonstimulant medications, tricyclic antidepressants usually are reserved for children and adolescents who respond poorly to a trial of stimulants, selective norepinephrine reuptake inhibitors (eg, atomoxetine), or alpha-2-adrenergic agonists; have unacceptable side effects with these medications; or have significant comorbid conditions.
A 2014 systematic review identified six randomized trials comparing tricyclic antidepressants with placebo for the treatment of ADHD in 216 children and adolescents (five trials used desipramine; one used nortriptyline) . In a meta-analysis of three trials (125 participants), treatment with tricyclic antidepressants improved core ADHD symptoms (odds ratio 18.5, 95% CI 6.3-54.4). In one trial (68 participants), desipramine was more efficacious than clonidine in reducing ADHD symptoms. An earlier systematic review of four trials comparing tricyclic antidepressants with methylphenidate found either no difference in response or slightly better results with methylphenidate .
Tricyclic antidepressants have been associated with adverse cardiovascular events. The 2014 systematic review found mild increases in diastolic blood pressure and pulse rates, appetite suppression (with desipramine), and increased weight gain (with nortriptyline) . Additional side effects that may limit the usefulness of tricyclic antidepressants include anticholinergic effects (eg, dry mouth, constipation, urinary retention), fatigue, and lowering of the seizure threshold [25,122].
Before tricyclic antidepressants are used to treat ADHD in children, a review of the patient's history (for heart disease and symptoms including palpitations, dizziness, syncope, or near syncope) and family history (for sudden unexpected death at less than 40 years, long QT syndrome or other arrhythmias, and hypertrophic cardiomyopathy) should be obtained . In addition, an electrocardiogram should be obtained at baseline and when the dose has been optimized because tricyclic antidepressants can cause arrhythmia [124,125]. In children with resting heart rate ≥130 beats/min, PR interval >200 millisec, QRS >120 millisec, QTc >460 millisec, or symptoms such as palpitations, syncope, or near syncope [124,125], treatment with drugs other than tricyclic antidepressants and/or pediatric cardiology consultation may be indicated.
Bupropion — Bupropion, an antidepressant that blocks the reuptake of norepinephrine and dopamine, has more stimulant properties than the tricyclic antidepressants . It is of modest efficacy in decreasing hyperactivity and aggressive behavior . Adverse effects include irritability, anorexia, insomnia, motor tics, and a decreased seizure threshold (at doses greater than 450 mg/day) .
In controlled trials, modafinil (Sparlon, marketed as Provigil), another stimulant, appeared to improve the core symptoms of ADHD compared with placebo [128-130]. However, it was associated with serious dermatologic and psychiatric reactions (eg, Stevens Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, anxiety, mania, hallucinations, suicidal ideation) [128-131]. It is not approved for use in children for any indication ; the US Food and Drug Administration's Pediatrics Advisory Committee has unanimously recommended that the label include language that specifically warns against its use in children .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Attention deficit hyperactivity disorder".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Beyond the Basics topics (see "Patient education: Symptoms and diagnosis of attention deficit hyperactivity disorder in children (Beyond the Basics)" and "Patient education: Treatment of attention deficit hyperactivity disorder in children (Beyond the Basics)")
●Stimulants – Stimulant drugs include methylphenidate and amphetamines. Stimulants are controlled substances and require a schedule II prescription. Stimulants are available in short-, intermediate-, and long-acting formulations (table 2A-B). (See 'Stimulants' above.)
Stimulants generally are considered safe, with mild, reversible, and manageable side effects. However, there have been rare reports of serious adverse events, including sudden unexpected death, priapism, psychosis, and suicidal thinking. The potential risks of stimulants should be discussed with patients and caregivers when choosing a management strategy. (See 'Stimulant adverse effects' above and "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Pretreatment education'.)
●Selective norepinephrine reuptake inhibitors – Atomoxetine and viloxazine are selective norepinephrine reuptake inhibitors. They are not controlled substances. Atomoxetine generally is considered safe, but there have been rare reports of serious adverse effects, including liver injury and an increased risk of suicidal thinking. Clinical experience with viloxazine is limited. (See 'Selective norepinephrine reuptake inhibitors' above.)
●Alpha-2 adrenergic agonists and antidepressants – Alpha-2-adrenergic agonists (eg, clonidine, guanfacine) and antidepressants (eg, tricyclic antidepressants, bupropion) usually are reserved for children or adolescents who respond poorly to a trial of stimulants or selective norepinephrine reuptake inhibitors (eg, atomoxetine), have unacceptable side effects with stimulants or atomoxetine, or have significant comorbid conditions that can be treated directly with these medications. (See 'Alpha-2-adrenergic agonists' above and 'Antidepressants' above.)
●Choosing a medication – Choosing a particular medication for an individual patient is discussed separately (table 1). (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Choice of agent'.)
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