Results From 2 Proof-of-Concept, Placebo-Controlled Studies of Atomoxetine in Children With Attention-Deficit/Hyperactivity Disorder
Abstract
BACKGROUND: Atomoxetine is a nonstimulant drug being studied for the treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a highly specific inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. Results of 2 proof-of-concept studies are reported that tested the hypothesis that a selective inhibitor of presynaptic norepinephrine uptake would be effective for the treatment of ADHD in school-aged children. METHOD: Two identical 12-week, stratified, randomized, double-blind, placebo-controlled trials were conducted in children who met DSM-IV criteria for ADHD. The primary efficacy outcome measure was the mean change from baseline to endpoint in the Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD RS) total score. Secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S). RESULTS: A total of 291 patients were randomized in the 2 trials combined (Study 1, N = 147; Study 2, N = 144). Stimulant-naive patients were randomized to atomoxetine, placebo, or methylphenidate. Patients with prior stimulant exposure were randomized to atomoxetine or placebo. Atomoxetine significantly reduced ADHD RS total scores compared with placebo in each study (p <.001). Changes in the CGI-ADHD-S (Study 1: p =.003; Study 2: p =.001) and CPRS-ADHD Index (Study 1: p =.023; Study 2: p <.001) also showed atomoxetine to be statistically significantly superior to placebo in reducing ADHD symptoms. Atomoxetine was found to be well tolerated in this population of pediatric patients. CONCLUSION: Two studies of atomoxetine early in its development confirmed that atomoxetine, a specific and selective inhibitor of noradrenergic uptake, was effective for the treatment of children with ADHD. In addition, atomoxetine was found to be well tolerated.
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Nine randomized trials comparing methylphenidate and atomoxetine in ADHD children and adolescents were included, with a total of 2762 participants.
“Nine randomized trials comparing methylphenidate and atomoxetine, with a total of 2762 participants were included.”
Higher doses of atomoxetine administered twice daily may be more effective.
“The outcome in three of these trials favoured atomoxetine suggesting that higher doses of atomoxetine administered twice daily may be more effective.”
When data on standard deviations were missing, study authors were contacted or data were calculated using standard error of subgroups or confidence intervals.
“When data on standard deviations were missing, study authors were contacted to provide missing data [18] or it was calculated using the standard error of subgroups or confidence intervals [19-21].”
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“…affected neuroendocrine systems involved with growth mechanisms, also known to be under catecholaminergic control, although this possibility is unlikely, given that disturbances of hormonal levels have not been seen in previous studies with atomoxetine (Kratochvil et al. 2001; Spencer et al. 2002).”
Self-citationClemow, D. B., & Bushe, C. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115602489 · Cited by 74 · see citing works
“Based upon six RCTs of 6–9 weeks’ duration, approximately 60% of children or adolescents responded to atomoxetine, based on a ⩾ 25% reduction in the ADHD-RS total score (Block et al., 2009; Geller et al., 2007; Kelsey et al., 2004; Michelson et al., 2001, 2002; Spencer et al., 2002).”
BackgroundResultHazell, P., Zhang, S., Wolańczyk, T., Barton, J., Johnson, M., Zuddas, A., Danckaerts, M., Ladikos, A., Benn, D., Yoran‐Hegesh, R., et al. (2006) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-006-0506-y · Cited by 73 · see citing works
Svanborg, P., Thernlund, G., Gustafsson, P. A., Hägglöf, B., Poole, L., & Kadesjö, B. (2009) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-008-0725-5 · Cited by 71 · see citing works
Putukian, M., Kreher, J. B., Coppel, D., Glazer, J. L., Mckeag, D., & White, R. D. (2011) · Clinical Journal of Sports Medicine · doi:10.1097/jsm.0b013e3182262eb1
Upadhyaya, H. P., Desaiah, D., Schuh, K. J., Bymaster, F. P., Kallman, M. J., Clarke, D. O., Durell, T. M., Trzepacz, P. T., Calligaro, D. O., Nisenbaum, E. S., et al. (2013) · Psychopharmacology · doi:10.1007/s00213-013-2986-z · Cited by 68 · see citing works
“In 2002, it was approved by the US Food and Drug Administration (FDA) as an uncontrolled, nonstimulant treatment for pediatric, adolescent, and adult ADHD (Michelson et al. 2002, 2003; Spencer et al. 1998, 2002).”
BackgroundHepatic Events Associated with Atomoxetine Treatment for??Attention-Deficit??Hyperactivity Disorder
Bangs, M. E., Jin, L., Zhang, S., Desaiah, D., Allen, A. J., Read, H. A., Regev, A., & Wernicke, J. F. (2008) · Drug Safety · doi:10.2165/00002018-200831040-00008 · Cited by 68 · see citing works
Fu, D., Wu, D.-D., Guo, H.-L., Hu, Y.-H., Xia, Y., Ji, X., Fang, W.-R., Li, Y.-M., Xu, J., Chen, F., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.780921 · Cited by 66 · see citing works
Sumner, C. R., Schuh, K. J., Sutton, V. K., Lipetz, R. S., & Kelsey, D. K. (2006) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2006.16.699 · Cited by 66 · see citing works
“Several reports have provided evidence that (Michelson et al. 2001; Michelson et al. 2002; ENURESIS 701 Spencer et al. 2002; Michelson et al. 2003; Kelsey et al. 2004; Weiss et al. 2005).”
Kaplan, S. L., Heiligenstein, J. H., West, S. A., Busner, J., Harder, D. F., Dittmann, R., Casat, C. D., & Wernicke, J. F. (2004) · Journal of Attention Disorders · doi:10.1177/108705470400800202 · Cited by 66 · see citing works
“Early in the development of atomoxetine we conducted two identical, randomized, double-blind trials that assessed the safety and efficacy of atomoxetine compared with placebo in pediatric patients with ADHD (Spencer et al., 2002).”
MethodSelf-citationGordon, S. M., Tulak, F., & Troncale, J. A. (2004) · Journal of Addictive Diseases · doi:10.1300/j069v23n04_03 · Cited by 67 · see citing works
Atomoxetine hydrochloride for the treatment of attention-deficit/hyperactivity disorder
Caballero, J., & Nahata, M. C. (2003) · Clinical Therapeutics · doi:10.1016/s0149-2918(03)90092-0 · Cited by 68 · see citing works
Diagnosing and treating attention‐deficit/hyperactivity disorder in adults
Faraone, S. V., & Antshel, K. M. (2008) · World Psychiatry · doi:10.1002/j.2051-5545.2008.tb00179.x · Cited by 66 · see citing works
Core ADHD Symptom Improvement With Atomoxetine Versus Methylphenidate
Hazell, P., Kohn, M. R., Dickson, R. A., Walton, R., Granger, R. E., & van Wyk, G. W. (2010) · Journal of Attention Disorders · doi:10.1177/1087054710379737 · Cited by 65 · see citing works
“Although methylphenidate was included as a treatment arm in the Phase II studies conducted by Spencer et al. (2002), analyses directly comparing the efficacy of methylphenidate and atomoxetine were not reported.”
BackgroundMethodResultInfluentialPhRMA White Paper on ADME Pharmacogenomics
Williams, J. A., Andersson, T., Andersson, T. B., Blanchard, R. L., Behm, M. O., Cohen, N., Edeki, T. I., Franc, M. A., Hillgren, K. M., Johnson, K. J., et al. (2008) · The Journal of Clinical Pharmacology · doi:10.1177/0091270008319329 · Cited by 65 · see citing works
“In early trials, patients were given doses in accordance with genotype, with poor metabolizers receiving lower doses than extensive metabolizers.(5,6) After demonstrating safety and tolerability in poor metabolizers, atomoxetine was administered without regard for genotype in later clinical studies.”
BackgroundNonstimulant treatment of adult attention-deficit/hyperactivity disorder
Spencer, T. J., Biederman, J., & Wilens, T. E. (2004) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2003.12.001 · Cited by 65 · see citing works
Self-citationGau, S. S., Huang, Y., Soong, W., Chou, M., Chou, W., Shang, C., Tseng, W., Allen, A. J., & Lee, P. (2007) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2006.0091 · Cited by 65 · see citing works
“…discontinuation due to adverse events were less than 5% (Michelson et al. 2001; Spencer et al. 2001; Biederman et al. 2002; Michelson et al. 2002; Spencer et al. 2002; Buitelaar et al. 2004; Kelsey et al. 2004), indicating that atomoxetine is safe and well-tolerated in children and adolescents…”
BackgroundResultInfluentialKratochvil, C. J., Milton, D. R., Vaughan, B. S., & Greenhill, L. L. (2008) · Child and Adolescent Psychiatry and Mental Health · doi:10.1186/1753-2000-2-25 · Cited by 64 · see citing works
Self-citationThe impact of attention deficit hyperactivity disorder on recovery from mild traumatic brain injury
Bonfield, C. M., Lam, S. K., Lin, Y., & Greene, S. (2013) · Journal of Neurosurgery Pediatrics · doi:10.3171/2013.5.peds12424 · Cited by 64 · see citing works
Update on attention-deficit/hyperactivity disorder
Daley, K. C. (2004) · Current Opinion in Pediatrics · doi:10.1097/00008480-200404000-00020 · Cited by 63 · see citing works
Montoya, A. G., Amaia Hervas, G., Cardo, E., Artigas-Pallarés, J., Mardomingo, M. J., Alda, J. A., Gastaminza, X., García-Polavieja, M. J., Gilaberte, I., & Escobar, R. (2009) · Current Medical Research and Opinion · doi:10.1185/03007990903316152 · Cited by 64 · see citing works
Psychopharmacological Interventions
Biederman, J., & Spencer, T. J. (2008) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2007.12.001 · Cited by 62 · see citing works
Self-citationAttention-Deficit Hyperactivity Disorder
MAY, D. E., & Kratochvil, C. J. (2009) · Drugs · doi:10.2165/11530540-000000000-00000 · Cited by 62 · see citing works
“Data from the two initial studies were combined for a total of 291 children (aged 7–13 years) who were treated with atomoxetine or placebo twice daily at doses up to 2mg/kg/day for 10 weeks.([99]) Based on ADHDRS-IV total score reductions, atomoxetine was superior to placebo, with a resulting effect size of 0.”
BackgroundMethodSelf-citationDo Children and Adolescents With ADHD Respond Differently to Atomoxetine?
Wilens, T. E., Kratochvil, C., Newcorn, J. H., & Gao, H. (2006) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000190352.90946.0b · Cited by 59 · see citing works
Self-citationCharacterizing the ADHD phenotype for genetic studies.
Stevenson, J., Asherson, P., Hay, D., Levy, F., Swanson, J., Thapar, A., & Willcutt, E. (2005) · Developmental Science · doi:10.1111/j.1467-7687.2005.00398.x · Cited by 76 · see citing works
A critical appraisal of atomoxetine in the management of ADHD
Childress, A. C. (2015) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s59270 · Cited by 62 · see citing works
“A total of 291 (Study I, n=147 and Study II, n=144) children aged 7–12 years participated in two proof-ofconcept, 12-week, multicenter, double-blind, randomized, placebo-controlled trials.(26) A methylphenidate (MPH) group was included to validate study design.”
- Authors
- Spencer, T., Heiligenstein, J. H., Biederman, J., Faries, D. E., Kratochvil, C. J., Conners, C. K., & Potter, W. Z.
- Affiliations
- Massachusetts General Hospital (US)
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2002-12-15
- Volume
- 63
- Issue
- 12
- Pages
- 1140-1147
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2016483680
- Cited by
- 333
- References
- 0
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 10 · 2014: 17 · 2013: 12 · 2012: 13
- FWCI
- 16.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Social Sciences › Psychology › Neuropsychology and Physiological Psychology › Developmental and Educational Neuropsychology
- Keywords
- atomoxetine, attention deficit hyperactivity disorder, children, non-stimulant medication, norepinephrine transporter inhibitor, ADHD symptom reduction, methylphenidate, tolerability, ADHD Rating Scale
- MeSH terms
- Atomoxetine Hydrochloride, Antidepressive Agents, Attention Deficit Disorder with Hyperactivity, Child, Double-Blind Method, Female, Humans, Male, Propylamines, Treatment Outcome
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