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A New Nonstimulant Treatment for ADHD

Authors: Alisa R. Gutman   John J. Spollen III, MDFaculty and Disclosures



A novel approach to the pharmacologic treatment of attention deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults has generated a great deal of interest and was the subject of an entire symposium at the American Academy of Child and Adolescent Psychiatry 49th Annual Meeting. Chaired by Laurence Greenhill, MD,[1] of the Department of Psychiatry, Columbia University, New York City, NY, this symposium offered a comprehensive look at this new intervention.

A Norepinephrine Transporter (NET) Inhibitor for ADHD

Metabolism and Efficacy

Atomoxetine (ATM), a potent NET inhibitor, has been recently developed as a novel treatment for ADHD in both adults and children. It binds the NET with 4.5 nM affinity and shows specificity for the NET as compared with other monoamine transporters (serotonin transporter, 152 nM; dopamine transporter, 658 nM). In addition, ATM shows low affinity (Ki > 1 mcM) at several other receptor classes that are often associated with side effects, including muscarinic acetylcholine receptors (M1/M2), alpha and beta noradrenergic receptors, histaminergic receptors (H1/H2), dopaminergic receptors (D1/D2), and serotonin receptors (5-HT1-7). The drug is rapidly and completely absorbed with a Tmax of 1 hour and is metabolized via hepatic CYP2D6 and excreted in the urine. Most individuals metabolize ATM with a half-life of 5 hours.

Any treatment for ADHD must be safe for children; the algorithm required for development and safety data must control the amount of risk to this sensitive population. Because ATM is intended as a chronic treatment for a nonlife-threatening disorder for which effective treatments already exist, risk tolerance, safety assessments, and long-term data are essential. Clinical pharmacology in adults should be performed first, and these safety data later bridged to children. Long-term safety data are also essential in any pharmacologic therapy for children. To make this type of data available, acute studies feed into an open-label extension assessing up to 5-year treatment with ATM.

Additionally, since ATM is metabolized via CYP2D6, a genetically polymorphic pathway, drug exposure varies considerably for a given dose from one patient to another. For this reason, safety must be demonstrated for all patients throughout the proposed dose range. This was accomplished by doing CYP2D6 genotyping for each patient under double-blind conditions for analysis purposes; clinicians titrate dose and assess safety, tolerability, and efficacy without knowing metabolic status. Metabolic status was divided into extensive metabolizers (EM), who metabolize the drug with a 5-hour half-life, and poor metabolizers (PM), who metabolize the drug with a 19-20 hour half-life. Without knowledge of the metabolic status, physicians came to the same doses for EM and PM patients.

Results indicate that EM and PM patients were similar in all adverse events except decreased appetite and insomnia, both of which were higher in the PM patients. Patient discontinuation due to adverse events was similar for both populations. Of note, patient dropout due to lack of efficacy was lower in the PM patients, suggesting that ATM had higher efficacy in the PM patients. Thus, as the PM and EM patients show only small differences in adverse events and efficacy, it is possible to treat both populations with a single dosing schedule. The dosing recommendation, based on dose response studies, is 1.2 mg/kg/day administered once or twice a day.[2]

Trials for ADHD in Children, Adolescents, and Adults

A multitude of trials have been performed to establish safety and efficacy of ATM for ADHD. Six placebo-controlled studies in children and 2 identical placebo-controlled studies in adults have been performed amounting to approximately 4000 exposures in children and more than 500 exposures in adults. The first proof-of-concept studies in children and adolescents indicated a decrease in the ADHD Rating Scale (ADHD-RS) total score with ATM administration. Dose-response studies showed comparable decreases in both the inattentive and hyperactive/impulsive symptom domains.[2] No interaction was found between a comorbid diagnosis of oppositional behavior and drug efficacy. Of particular interest is the functional improvement observed in this trial, with dose-dependent improvements on psychosocial measures, self-esteem, and parent impact on both emotional state and time spent dealing with the disorder. An open-label study performed by Kratochvil and colleagues[3,4] also showed comparable decreases in ADHD-RS.

In a trial observing efficacy with once-daily dosing, ADHD-RS decreased by 12.8 for the ATM group and only 5 for the placebo group.[5] Conners parent and teacher ratings also showed significant decreases. Looking at the time course of response, the ATM group separated from placebo at 1 week. This is particularly significant because a full dose of ATM was not given until several weeks into the trial, reflecting a dose response of the drug on ADHD symptomatology. In a school study of once-daily dosing in which teachers were interviewed by phone before clinic visits as a primary measure of treatment outcome, ADHD-RS teacher scores decreased with ATM treatment. Persistence of effect and onset of action were measured via daily parent diary records and showed significant differences in the morning and evening with the ATM group. Adult studies of ATM have shown similar results to the child studies. Long-term data out to 36 weeks shows a decrease in the Conners adult rating with ATM treatment and positive impact on functional domains.

Long-term Safety

The pediatric tolerability profile in acute placebo-controlled trials is quite good, with the most prevalent side effects being abdominal pain, decreased appetite, vomiting, irritability, and somnolence. No preclinical or clinical events suggest serious safety concerns, and no patients have been discontinued from drug treatment due to abnormal lab values. ATM is associated with increased cardiovascular tone and shows increases in heart rate, systolic blood pressure, and diastolic blood pressure. Minimal effects were found in the QTc interval.

Adults with ADHD do not show an identical tolerability profile to children. Adverse events reported in adults include dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, and erectile dysfunction. Cardiovascular side effects were also found with mild increases in diastolic and systolic blood pressure as well as pulse. In the 2 adult studies, discontinuation was similar between the ATM and placebo groups, suggesting that ATM was well tolerated and adverse events were not significant enough to deter patients from continuing therapy. Results from interaction studies indicated no significant problems with ATM coadministration with methylphenidate, fluoxetine, desipramine, or food. ATM is contraindicated with monoamine oxidase inhibitor coadministration, and some problems were seen with albuterol coadministration.

The Place of ATM in the Therapeutic Armamentarium

The effect size with ATM treatment is approximately 0.7, and efficacy has been repeatedly demonstrated in multiple large, well-controlled, multisite studies. Similar effect sizes are seen between ATM and stimulants in separate studies, and a small open-label study showed similar effect size between ATM and methylphenidate (MPH). An adequately powered, controlled, head-to-head study comparing ATM with MPH is currently in progress. Studies have shown that ATM works as well for the inattentive symptoms as the hyperactive/impulsive symptom domain, suggesting that it has broad anti-ADHD efficacy. It shows similar efficacy for patients in the inattentive subtype and those with a diagnosis of combined ADHD. It also works well across home, school, and individual functioning measures. ATM has the potential to help patients with ADHD in areas of impairment outside of school, as indicated by dramatic improvement in a dose-dependent fashion on measures of psychosocial well being, self-esteem, and parent impact. Additionally, good efficacy has been found in patients with comorbid disorders on both ADHD symptoms and symptoms of the comorbid disorder including depression, oppositionality, and tics/Tourette syndrome.

An advantage to ATM as a treatment strategy for ADHD is that it is not abusable. ATM does not bind to any receptors that have been associated with abuse. ATM administration does not cause increases in dopamine in the striatum or the nucleus accumbens, 2 areas involved in the circuitry of drug abuse. In addition, ATM has not been found to be reinforcing in self-administration studies and is therefore not a drug associated with abuse liability in humans. This removes significant barriers to treatment for both patients and physicians. For the ADHD patient, this is an important safety factor for a high-risk population. For the clinician, this amounts to less professional concern and risk for the prescribing doctor.

It is also possible that ATM would be a useful treatment for patients who fail stimulant therapy. As 60.4% of study participants in the ATM trials had stimulant exposure, there is a large body of data on patients with both stimulant and ATM treatment. ATM has shown robust effects in children and adolescents who were previously exposed to stimulants. While there are no data to indicate whether these patients failed stimulant therapy, it should be noted that their participation in the study indicates that they were not completely satisfied with stimulants.


ATM shows promise as a new nonstimulant treatment for ADHD in children 6 years of age and older, adolescents, and adults. Numerous clinical trials have been performed in different populations to assess both clinical efficacy and long-term safety. Six large placebo-controlled trials have established acute efficacy, and open-label safety trials suggest that clinical benefit is maintained in the long term with minimal side effects. Further investigations are under way to expand data on long-term safety and assess efficacy in subpopulations.


  1. Greenhill LL, Michelson D, Newcorn JH, Spencer TJ, Kratochvil J. Update on atomoxetine: a new non-stimulant treatment for ADHD. Program and abstracts of the American Academy of Child and Adolescent Psychiatry 49th Annual Meeting; October 22-27, 2002; San Francisco, California. Symposium 40.
  2. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108:E83.
  3. Kratochvil CJ, Bohac D, Harrington M, Baker N, May D, Burke WJ. An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2001;11:167-170.
  4. Kratochvil CJ, Heiligenstein JH, Dittmann R, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry. 2002;41:776-784.
  5. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159:1896-1901.