Nonstimulant Agents for the Treatment of ADHD in Children

Release Date: May 1, 2014

Expiration Date: May 31, 2016


Chris Selby, PharmD Candidate
Southern Illinois University Edwardsville
School of Pharmacy
Edwardsville, Illinois

Laurie Schou, PharmD Candidate
Southern Illinois University Edwardsville
School of Pharmacy
Edwardsville, Illinois

Lisa Lubsch, PharmD, AE-C
Clinical Associate Professor
Department of Pharmacy Practice
Southern Illinois University Edwardsville
School of Pharmacy
Edwardsville, Illinois


Mr. Selby, Ms. Schou, and Dr. Lubsch have no actual or potential conflicts of interest in relation to this activity. The article reviews the off-label use of certain medications.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.


To inform pharmacists on the expanding treatment options for children with attention-deficit/hyperactivity disorder (ADHD) in order to ensure patient safety and optimize patient care.


After completing this activity, the participant should be able to:

  1. Identify which medications are classified as nonstimulant therapies for ADHD and are approved for pediatric use.
  2. Select and recommend an appropriate nonstimulant agent within the recommended treatment algorithm for children with ADHD.
  3. Evaluate potential drug interactions and adverse effects of nonstimulant therapies and their impact on patient safety.
  4. Counsel caregivers and children regarding nonstimulant therapies for ADHD.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders of childhood. Stimulant medication is considered first- and second-line therapy for the management of ADHD. Although stimulants are very effective in controlling the symptoms of ADHD, they may cause serious adverse effects. Nonstimulant medications including atomoxetine, clonidine, guanfacine, tricyclic antidepressants, and bupropion offer an alternative to recommended therapy for treatment of ADHD. Pharmacists are essential in identifying potential drug-drug interactions and counseling caregivers and children about ADHD medications, including the potential adverse effects of, precautions for, and other expectations of these therapies.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders of childhood. It is usually first diagnosed in childhood and often lasts into adulthood. The CDC found that approximately 5.4 million children were reportedly diagnosed with ADHD in 2007. Based on comprehensive telephone surveys of families in the United States, diagnoses rose by an average of 3% to 6% each year between 2000 and 2010.1 The latest epidemiologic information, which included responses collected between 2011 and 2012, shows a far higher prevalence. Approximately 6.4 million children (11%) aged 4 to 17 years were diagnosed with ADHD, a 16% increase since 2007.2 The rise was especially dramatic among boys, with an estimated one in five boys in high school diagnosed with the disorder. More than twice as many boys aged 4 to 17 years are diagnosed with ADHD—13.2% of boys compared to 5.6% of girls.1 It is unclear whether more children are developing ADHD or whether more are being diagnosed owing to improved identification methods.

ADHD is a condition characterized by impairment in the ability to self-regulate arousal and inhibit behavior according to socially acquired rules of conduct. Children with ADHD may have trouble paying attention or controlling impulsive behaviors, and/or may be overly active. There are three different types of ADHD, depending on which symptoms are strongest in the individual: predominantly inattentive, predominantly hyperactive-impulsive, and a combined type.

Research has demonstrated that ADHD has a very strong neurobiologic basis. Although precise causes have not yet been identified, there is little question that heredity makes the largest contribution to the expression of the disorder in the population. In instances where heredity does not seem to be a factor, foster care, low social class, prenatal exposure to alcohol and tobacco, lead poisoning, head trauma, and other external influences have all been found to contribute to the risk for ADHD to varying degrees.1

Typical ADHD management is multimodal. Behavior modification and, often, psychological therapy can teach children new skills to help manage their own behavior and interact well with others. Parents and caregivers should also learn about ADHD. Setting specific goals for the child to achieve in given time limits, rewarding the child when the goal is achieved, and being patient when it is not can positively impact the child's behavior. According to the American Academy of Pediatrics, the clinician should prescribe evidence-based parent- and/or teacher-administered behavior therapy as the first line of treatment for children <6 years of age. Methylphenidate may be initiated if the behavioral interventions do not provide significant improvement and there is moderate-to-severe continuing disturbance in the child's function. For children >6 years of age, the clinician should prescribe medications and/or behavior therapy as treatment for ADHD, preferably both.3 Medications considered first-line for treating ADHD are the stimulants, amphetamines, and methylphenidate. Most children with ADHD respond to stimulant medication, but stimulants do not work for all children with ADHD. The use and failure of either one of these agents does not preclude the use of the other agent, and both should be attempted in most children. Once both stimulants have been tried without achieving symptomatic control, the nonstimulant agents should be used next. These agents include one selective norepinephrine reuptake inhibitor, atomoxetine, and two alpha2 agonists. Both of the alpha2 agonists, clonidine and guanfacine, are only FDA-approved in extended-release forms.3 The three previously listed FDA-approved agents are approved for use in children at least 6 years of age. Other nonstimulant agents that are used off-label for ADHD include the immediate-release alpha2 agonists, tricyclic antidepressants (TCAs), and bupropion.


Strattera (atomoxetine) is a selective inhibitor of norepinephrine reuptake; however, the precise mechanism of action in treating ADHD is currently unknown, although it is believed to be due to presynaptic norepinephrine transporter inhibition. Atomoxetine is considered third-line therapy, after both stimulant agents, and is approved for monotherapy treatment, although more effects may be seen using atomoxetine in combination with a stimulant. There is little to no potential for abuse; this agent, therefore, is considered first-line in children where substance-abuse disorders may be a concern. Once administered, atomoxetine must be given continuously once or twice daily in order to reach a steady-state level. The twice-daily dosing has shown to improve symptom control at home without affecting symptom control during the school day.4 Peak therapeutic effect may take up to 6 weeks to achieve. Once this point is reached, effects last 24 hours per day and may carry over into the next day. Atomoxetine may be taken with or without food and is subject to metabolism primarily via the cytochrome P-450 (CYP2D6) enzyme. Owing to this metabolism, a number of clinically significant interactions can occur (TABLE 1). Typical adverse events and an increase in systolic or diastolic blood pressure, or both. More serious side effects are possible, though rare. Atomoxetine does have a black box warning for increased suicidal ideation in children and adolescents.5,6 Dosing of atomoxetine is determined by the child's weight (TABLE 2). Initial doses are titrated at no less than 3-day intervals, and if administered twice daily, the first dose should be given in the morning and the second dose in the late afternoon or early evening. Since atomoxetine is primarily metabolized via CYP2D6, dose adjustments may be needed for poor metabolizers and when taken with inhibitors. If taken with a strong CYP2D6 inhibitor or if the child is a poor CYP2D6 metabolizer and weighs <70 kg, the initial dose would be 0.5 mg/kg/day. The dose can be increased up to 1.2 mg/kg/day only if symptoms do not improve after 4 weeks and the initial dose is well tolerated. If the child weighs >70 kg, the initial dose would be 40 mg/day. The dose can be increased up to 80 mg/day only if symptoms do not improve after 4 weeks and the initial dose is well tolerated. Atomoxetine can be abruptly discontinued without a need for tapering.5,6



Clinical Trial Review: Of the three nonstimulant agents available, atomoxetine has the largest amount of trial evidence to support its use for treatment of ADHD.7-9 One trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled study where atomoxetine was studied in 170 children aged 6 to 16 years.9 These children received either placebo or once-daily atomoxetine that began titration at 0.5 mg/kg/day for 3 days followed by 0.75 mg/kg/ day for the remainder of the first week; the daily dose was then increased to 1.0 mg/kg/day. If a child reached the 1.0 mg/kg/day dose but still had more than minimal symptoms 4 weeks after randomization, the dose was escalated to 1.5 mg/kg/day. The primary outcome monitored was the change in ADHD-RS-IV (ADHD-RS-IV) from baseline. The ADHD Rating Scale-IV obtains parent ratings regarding the frequency of each ADHD symptom based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Parents are asked to determine symptomatic frequency that describes the child's home behavior over the previous 6 months. Children in the placebo group had a mean decrease of 5.0 points, while the children taking atomoxetine had a mean decrease of 12.5 points, P <.001. Main adverse effects of atomoxetine included vomiting and dyspepsia.


Kapvay (clonidine extended-release [ER]) is a nonspecific alpha2-receptor agonist that reduces sympathetic nerve impulses, resulting in reduced sympathetic outflow and a subsequent decrease in vasomotor tone and heart rate. The exact mechanism in ADHD is unknown at this time. Kapvay is currently considered fourth-line treatment and should be used adjunctively with a stimulant. Alpha agonists can be considered in children who do not respond adequately to stimulants or atomoxetine and/or have adverse effects associated with these agents, such as severe insomnia or loss of appetite, comorbid tics, aggression, eating disorders, or a potential for substance-abuse disorder. Clonidine is primarily metabolized hepatically and can be given without regard to meals. Common adverse effects include sedation, somnolence, hypotension, abdominal pain, dry mouth, and decreased appetite. Clonidine interacts with several medications (TABLE 1). Most of the interactions are additive adverse drug events rather than interactions due to CYP enzymes, as occurs with some of the other ADHD medications. It is recommended to monitor closely with concurrent use of these medications or to avoid the combination when possible.5,6

Clonidine immediate-release (IR) is usually initiated at a low dose at night to minimize adverse effects, especially sedation (TABLE 2). A morning dose may be added 3 to 7 days later followed by a midday dose in another 3 to 7 days. The dose should be titrated in increments of 0.05 to 0.1 mg two to four times a day to a maximum daily dose of 0.4 mg. Clonidine ER can be initiated at a dose of 0.1 mg at bedtime and increased as needed to obtain optimal response, by 0.1 mg/day at weekly intervals to a maximum total daily dose of 0.4 mg. Clonidine ER should be administered twice daily with an equal or higher dose at bedtime. Abrupt discontinuation of clonidine can lead to withdrawal hypertension and can result in a hypertensive crisis, making compliance with clonidine especially important. Clonidine IR should be tapered gradually by 0.05 mg and clonidine ER by 0.1 mg every 3 to 7 days.5,6

Clinical Trial Review: Clonidine has been well studied, but the ER form for treating ADHD is relatively new and, as such, has fewer data available, especially when compared to the stimulant medications.10-12 In one study, clonidine ER was evaluated in an 8-week, multicenter, randomized, double-blind, placebo controlled trial in which 238 children, aged 6 to 17 years, underwent randomization to one of three arms.13 These arms were placebo, 0.2 mg/day, and 0.4 mg/day. Children were titrated upward at 0.1 mg/wk to the final fixed-dose amounts. The primary outcome of this study was the children's response, which was assessed using the ADHD-RS-IV from baseline through Week 5, at which point all upward titrations had been completed. ADHD-RS-IV was completed at screening, baseline, and at each weekly visit through Week 8, at which point all medications had been titrated downward. ADHD-RS-IV total scores from baseline to the last treatment week were significantly decreased in the clonidine ER 0.2–mg/ wk group (mean reduction of 16.5 points, P <.0001) and clonidine ER 0.4 mg/wk group (mean reduction of 19.4 points, P <.0001) compared with placebo (mean reduction of 8.0 points).

The percentage of children experiencing adverse events requiring discontinuation were placebo 1%, clonidine ER 0.2 mg/day 7%, and clonidine ER 0.4 mg/day 19%. The most common adverse effects leading to discontinuation were somnolence and fatigue. The number of children who discontinued the medication may be higher than in practice owing to the fact that they were not allowed to reduce their dose if experiencing any adverse events and instead were treated as discontinuing the medication in terms of the safety analysis.


Intuniv (guanfacine ER) is a selective alpha2A-receptor agonist that reduces sympathetic outflow and leads to a corresponding decrease in heart rate and vasomotor tone. Additionally, guanfacine preferentially binds postsynaptic alpha2A receptors in the prefrontal cortex and has been theorized to improve delay-related firing of prefrontal cortex neurons. As a result of this binding, underlying working memory and behavioral inhibition are affected, thereby improving symptoms associated with ADHD. Guanfacine is primarily metabo lized via CYP3A4/5 enzymes, which can lead to a number of clinically significant interactions (TABLE 1).5,6

Guanfacine IR is also initiated at a low dose at night to minimize sedation (TABLE 2), and a morning dose may be added 3 to 7 days later followed by a midday dose in another 3 to 7 days. The dose can be titrated in this manner in increments of 0.5-1 mg two to four times a day to a maximum daily dose of 4 mg. Guanfacine ER is usually started at 1 mg once a day in the morning or evening at the same time each day. The dose can be titrated in increments of 1 mg/day at weekly intervals to a maximum daily dose of 4 mg. Since guanfacine is primarily metabolized via CYP3A4/5, dose adjustments may be needed when it is taken with inducers or inhibitors. When guanfacine is taken with a strong CYP3A4/5 inhibitor, the guanfacine dose should be halved. When guanfacine is taken with a strong CYP3A4/5 inducer, it should be gradually increased (in 1 to 2 weeks) by twofold. Abrupt discontinuation can lead to withdrawal hypertension and can result in a hypertensive crisis, making compliance with guanfacine guidelines especially important. Guanfacine IR should be tapered gradually by 0.5 mg and guanfacine ER by 1 mg every 3 to 7 days. Adverse events common to guanfacine are fatigue, headache, somnolence, sedation, dry mouth, irritability, and decreased appetite.5,6

Clinical Trial Review: There are several studies regarding the use of both the IR and ER formulations of guanfacine for ADHD.14-16 A study by Hunt et al looked at guanfacine IR in a small study of 13 patients, aged 4 to 20 years.17 Dosing was started at 0.5 mg/ day and was increased by 0.5 mg/day on every third day until optimal response was achieved without exceeding the 4-mg/day limit. The primary outcome was assessed using comparisons of Conners parent rating scales for hyperactivity, inattention, and immaturity. Patients experienced significant improvement in all three areas: hyperactivity (1.63 off, 0.94 on, 1 = 3.69, P <.01); inattention (1.92 off, 1.21 on, 1 = 3.32, P <.01); and immaturity (1.81 off, 0.92 on, 1 = 3.77, P <.01). Side effects as reported by study authors include transient increase in tiredness, decreased appetite, and headaches. While this study was small, it did help open the discussion on guanfacine for children with ADHD.

A study by Biederman et al evaluated the safety and efficacy of guanfacine ER in an 8-week, multicenter, randomized, double-blind, placebo-controlled trial in 345 children from 6 to 17 years of age.18 All children started taking 1 mg/day, and the dose was increased weekly by 1 mg/ day until the final assigned dose was reached. The dose was decreased weekly by 1 mg/day after 5 weeks until a dosage of 2 mg/day was reached in those who chose to enroll in the open-label extension study or 1 mg/day for 1 week and then discontinued in those children who did not enroll in the extension study. In the primary outcome, ADHD-RS-IV total scores from baseline to the last treatment week of the titration/maintenance period were significantly decreased in the guanfacine ER group (mean reduction, 16.7 points) compared with placebo (mean reduction, 8.9 points; P <.0001). Guanfacine ER was safe and generally well tolerated in daily doses of 2 mg, 3 mg, and 4 mg compared with placebo. The most commonly reported treatment-emergent adverse events were headache, somnolence, fatigue, upper abdominal pain, and sedation. Also, small-to-modest changes in blood pressure, pulse rate, and electrocardiogram parameters were observed but were not clinically meaningful.


Tricyclic Antidepressants

TCAs most frequently used in the treatment of ADHD include desipramine (Norpramin), imipramine (Tofranil), amitriptyline, and nortriptyline (Pamelor). The TCAs are typically prescribed when the child has not had a reduction in core symptoms with both classes of stimulants and a previously mentioned nonstimulant agent. They may also be prescribed if the child has depression or anxiety in addition to the ADHD. TCAs are thought to work by increasing the amount of norepinephrine in the central nervous system (CNS). Unlike with stimulants, it may take several days or even several weeks for the TCAs to produce therapeutic benefit, but once the optimal level is reached, benefits last throughout the day. TCAs need to be taken daily, and missing a dose or stopping the medicine abruptly may cause aches and flulike symptoms. If a patient is going to stop the TCA, it should be tapered off gradually over a period of 1 to 2 weeks.5,6

Common side effects of the TCAs may include, drowsiness, dry mouth, constipation, blurred vision, stomachaches, headaches, vivid dreams, and insomnia. More serious side effects may include problems in heartbeat or heart rhythm, as TCAs can slow down the transmission of the electrical signal to the heart. If there is a family history of heart problems there are or any heart problems in the child, these medications should be used with caution and close medical monitoring. TCAs may also increase the risk of seizures in children with a history of seizure disorder.5,6

TCAs should be initiated at a low dose and carefully titrated upward. Prior to starting any TCA, an ECG should be obtained. During treatment, heart rate should be monitored, and annual ECGs are also recommended. Medication interactions should be considered as well, especially those that inhibit CYP2D6 enzymes, which may elevate TCA levels to dangerous levels.19 Despite these limitations, TCAs are still used as fourth-line agents and are found to be effective in a subgroup of children who do not respond to stimulants. Also, they may be useful in children who have experienced exacerbations of tics while taking stimulants.

Clinical Trial Review: Of all the TCAs, imipramine and desipramine are the most studied.20 Imipramine was examined in more than 10 studies in pediatric ADHD, mostly in the 1970s. Ten studies reported moderate (30%-50% response rate) to robust (>50%) response, while only two studies reported a poor (<30%) response.21 Desipramine was shown to be superior to placebo in a double-blind, placebo-controlled trial, and the effect size was found to be similar to stimulants.22 In this randomized, parallel-design, 6-week clinical trial, desipramine was found to be effective in 62 children with ADHD, most of whom had failed to respond to a stimulant. Clinically and statistically significant results were found for desipramine (average daily dose 5 mg/kg) over placebo. In addition, desipramine-treated children showed a significant reduction in depressive symptoms compared with children who received placebo. Despite all the evidence, desipramine has fallen out of favor because of the concerns raised by the sudden and unexplained deaths of four children who were treated with desipramine.23 Although a causal link between these deaths and desipramine was never established, clinicians by and large use imipramine and nortriptyline as fourth-line agents.

Imipramine has been extensively studied in the treatment of ADHD.24 Imipramine is typically started at a divided dose of 1 mg/kg/day, with titration to doses of 2.0 to 2.5 mg/kg/day over a 1- to 2-week period (TABLE 2). If the response is inadequate or no response is noted, the dose is increased at a rate of 1 mg/kg/day for 1 week for up to a maximum of 4 mg/kg/day.

Nortriptyline was studied in a prospective, placebo-controlled discontinuation trial of 35 school-aged children.25 The dose of nortriptyline was titrated up to 1 mg/kg/day by the end of Week 1 and to 2 mg/ kg/day by Week 2, and was maintained at 2 mg/kg/ day unless adverse effects emerged or the child reported improved ADHD efficacy at a lower dose. The majority of children (80%) responded by Week 6 in the open phase. During the discontinuation phase, children randomized to placebo relapsed, while those receiving nortriptyline maintained the efficacy. Another TCA, protriptyline, was tried in a treatment-refractory ADHD, but the response was not significant.26


Bupropion is an atypical antidepressant with actions involving inhibition of norepinephrine and dopamine reuptake. Bupropion can be considered if stimulants and atomoxetine trials fail to provide adequate control of ADHD symptoms or lead to intolerable adverse effects, or be considered in children with a history of substance abuse or mood disorder. Owing to the shorter half-life of the sustained-release (SR) formulation of bupropion and its metabolites in children and adolescents, twice-daily dosing is recommended.27 Bupropion is usually initiated at a dose of 100 mg to 150 mg (3 mg/kg) and titrated to a maximum dose of 300 mg (6 mg/kg) daily in divided doses; any single dose should not exceed 150 mg (TABLE 2). Response to bupropion is usually seen within 2 weeks of starting a therapeutic dose. Bupropion is usually well tolerated, and possible side effects include dry mouth, nausea, vomiting, urticaria and rash, sedation, constipation, and irritability. Bupropion can lower the seizure threshold and can lead to seizures at higher doses and in children with a comorbid eating disorder. While not commonly used in treating ADHD, bupropion may have a small place in therapy in children who have not achieved control through the use of stimulants, atomoxetine, or other previously discussed medica tions, or who also present with comorbid mood disorder or pos sible substance-abuse disorder.

Clinical Trial Review: Study results have been inconsistent with bupropion treatment of ADHD in youth. A multisite, placebo-controlled trial using doses of 3 to 6 mg/kg/ day showed improvement in hyperactivity and conduct problems, and in parent and teacher ratings; however, the effect size was smaller than that typically found with stimulant medication.28 Bupropion has also been found to be effective in substance-abusing youth with comorbid ADHD and a mood disorder and in youth with ADHD and comorbid depression.29,30 In the latter study (Daviss et al) only parent ratings of ADHD symptoms showed improvement with bupropion, however, and improvement was not seen on teacher ratings.

Patient Education

Atomoxetine, as described above, carries a black box warning for increased suicidal ideation in children and adolescents.6 All healthcare providers need to be able to discuss this with their children and their parents. When children have a history of emotional problems, such as depression, these problems should be discussed with their doctor or pharmacist prior to beginning the medications as its use may lead to an exacerbation of existing mental or emotional problems, including the possibility of thoughts of suicide and violence. Children and their parents should be advised to speak with a healthcare professional immediately if any thoughts of suicide or violence occur or if they notice concerning behaviorial changes or an increase in aggression or hostility. Other rare but serious side effects that should be discussed with children and, when appropriate, with their parents include dark urine, jaundice, pruritus, or right upper quadrant tenderness, as these may be the signs of severe liver injury or hepatic failure. If a dose is missed, the child should take it as soon as he or she remembers, unless it is close to the time of the next dose. In that case, the child should then wait and take the next regularly scheduled dose. An extra capsule should not be taken to make up for a missed dose.

Being of the same medication class, the alpha2-adrenergic receptor agonists ER clonidine and guanfacine, share some counseling points. With both medications, caution is advised for children with a history of bradycardia, cardiovascular disease, heart block, hypotension, or syncope, since these could lead to more serious adverse effects. It is important to counsel on the importance of continuous therapy with either agent because abrupt discontinuation can lead to rebound hypertension. Children and their caregivers should be informed that CNS depressants, including alcohol, need to be avoided to prevent compounded effects. In age-appropriate patients, counseling points include not to drive or operate heavy machinery until they are aware of how the medication affects them.

TCAs and bupropion have a black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults. This risk must be balanced with the clinical need. Children should be monitored closely for suicidality or unusual changes in behavior. Parents and caregivers should be advised of the need for close observation and communication with healthcare professionals. Concomitant use of alcohol or medications that can increase the risk of seizures should be avoided. Children with a history of seizures, bulimia, or anorexia should avoid the use of bupropion. Children with a history of seizures, cardiovascular disorders, hyperthyroidism, or urinary retention should use great caution with or avoid the use of TCAs. TCAs should not be abruptly discontinued; a gradual taper is needed. Children should avoid activities requiring mental alertness or coordination until drug effects are realized. Children should be instructed to take bupropion early in the day/afternoon to prevent sleep problems.


Attention-deficit/hyperactivity disorder is a highly prevalent condition among children. ADHD is characterized by impairment in the ability to self-regulate arousal and inhibit behavior according to socially acquired rules of conduct. Successful treatment of ADHD depends on matching the child's needs and lifestyle with specific regimens. Behavioral modification and stimulant medications are typically first-line treatment options for ADHD. Nonstimulant medications including atomoxetine, clonidine, guanfacine, TCAs, and bupropion offer an alternative to first-line therapy. Pharmacists are essential in identifying potential drug-drug interactions and counseling caregivers and children about ADHD medications, including the potential adverse effects of, precautions for, and other expectations of these therapies.


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