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The Efficacy of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Clinical Research

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Abstract

Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6–1.3, vs. placebo, at 6–18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n = 72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n = 618) indicated that responses at 4 weeks may predict response at 6–9 weeks, although another pooled analysis of open-label data (n = 338) suggests that the probability of a robust response to atomoxetine [≥40 % decrease in ADHD–Rating Scale (ADHD-RS) scores] may continue to increase beyond 6–9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3–12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.

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Notes

  1. Response was defined as “at least a 25 % decrease from baseline on the ADHD-RS-IV [ADHD–Rating Scale–IV] total score”.

  2. Remission was defined as “each ADHD-RS-IV item score ≤1 at the end of the treatment”.

  3. However, these results should be viewed with caution, particularly as the congress abstract does not state a definition for “treatment failure”, and we are not aware of these results having been published in a full-length peer-reviewed study paper or of being replicated.

  4. The primary outcome measure was comparison of mean time to relapse, defined as an increase in ADHD-RS total score to 90 % of the score at study entry and an increase in CGI–Severity [CGI-S] score of ≥2 points above the CGI-S score at the end of the initial 10 weeks of treatment. A secondary definition of relapse (≥50 % worsening in ADHD-RS severity score above the last pre-randomization visit) resulted in similar relapse rates [atomoxetine, 6/81 (7.4 %); placebo, 16/82 (19.5 %); p = 0.037; relative risk ratio, 3.0 (95 % CI 1.2–7.6)]. A greater number of patients who received atomoxetine completed the 6-month randomized phase [65/79 (82.3 %)] than did those who received placebo [54/81 (66.7 %); p = 0.030].

  5. The definition of non-inferiority was “if the lower limit of the 2-sided 95 % CI for the difference in proportion of responders (ATX [atomoxetine] minus MPH [methylphenidate]) is greater than −15%, ATX will be considered non-inferior to MPH”.

  6. In the meta-analysis paper [143], and the source study in this paper, it is unclear whether ‘deprenyl’ referred to L-deprenyl (also known as selegiline), D-deprenyl, or a racemic mixture.

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Acknowledgments and conflicts of interest

N.C. Savill, K. A. Day, E. Anand, T. Treuer, and H. P. Upadhyaya are full-time employees and stock holders of Eli Lilly and Co.

J. K. Buitelaar has been a consultant, a member of an advisory board, and/or a speaker for Janssen-Cilag BV, Eli Lilly, Bristol-Myers Squibb, Organon/Schering Plough, UCB, Shire, Medice, and Servier.

D. Coghill has served in an advisory/consultancy role for Flynn Pharma, Otsuka, Lilly, Janssen, Medice, Pfizer, Schering-Plough, Shire, and Vifor. He received conference attendance support, conference support, or speaker’s fees from Flynn Pharma, Eli Lilly, Janssen, Medice, Novartis, and Shire. He has been involved in clinical trials conducted by Eli Lilly and Shire and has received research funding from Eli Lilly, Janssen, Shire, and Vifor.

This review was funded by Eli Lilly and Company. K. A. Day performed the predefined literature database searches, and J. K. Buitelaar and N. C. Savill selected relevant literature from the search results. All authors contributed to the conception/design of the manuscript, and critically reviewed and thus participated in writing the manuscript. All authors approved the final version of the manuscript, and agree to be accountable for this work. Michael Riley, PhD, from Trilogy Writing and Consulting GmbH, Frankfurt, Germany, provided medical writing support on behalf of Eli Lilly and Company.

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Authors and Affiliations

  1. Eli Lilly and Co., Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL, UK

    Nicola C. Savill

  2. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands

    Jan K. Buitelaar

  3. Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, The Netherlands

    Jan K. Buitelaar

  4. Eli Lilly and Co., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK

    Ernie Anand

  5. Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN, USA

    Kathleen Ann Day & Himanshu P. Upadhyaya

  6. Eli Lilly and Co., Neuroscience Research, Budapest, Hungary

    Tamás Treuer

  7. Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK

    David Coghill

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Correspondence to Nicola C. Savill.

Appendix

Appendix

1.1 Strategy used in ‘Search 1’

Database: EMBASE <1974 to 2013 July 25>, Ovid MEDLINE® <1946 to July Week 3 2013>, Ovid MEDLINE® In-Process and Other Non-Indexed Citations <July 25, 2013>

1 exp atomoxetine/(3060)

2 exp attention deficit disorder/(54376)

3 1 and 2 (2079)

4 limit 3 to [human and (child <unspecified age> or preschool child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to 17 years>)] [Limit not valid in Ovid MEDLINE®, Ovid MEDLINE® In-Process; records were retained] (725)

5 limit 4 to year = “2001–Current” (722)

6 5 use oemezd (722)

7 atomoxetine.mp. (4248)

8 tomoxetine.mp. (146)

9 LY139603.mp. (17)

10 7 or 8 or 9 (4289)

11 exp Attention Deficit Disorder with Hyperactivity/(54376)

12 10 and 11 (2818)

13 limit 12 to [humans and year = “2001–Current” and “all child (0 to 18 years)”] [Limit not valid in EMBASE; records were retained] (2468)

14 13 use mesz, prem (476)

15 6 or 14 (1198)

16 remove duplicates from 15 (879)

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Savill, N.C., Buitelaar, J.K., Anand, E. et al. The Efficacy of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Clinical Research. CNS Drugs 29, 131–151 (2015). https://doi.org/10.1007/s40263-014-0224-9

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