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Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine

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ADHD Attention Deficit and Hyperactivity Disorders

Abstract

We identified relapse/maintenance-of-response (MOR) predictors following discontinuation of long-term atomoxetine treatment in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD) and assessed correlations between ADHD symptoms and quality of life (QoL). Post hoc analyses of data from two randomized, double-blind, placebo-controlled, phase 3 withdrawal studies in patients with ADHD meeting predefined response criteria before randomization. Study 1: patients (N = 163; 6–15 years) received atomoxetine (1.2–1.8 mg/kg/day) for 1 year, followed by randomization to atomoxetine (n = 81) or placebo (n = 82) for 6 months. Study 2: patients (N = 524; 18–50 years) received atomoxetine (80–100 mg/day) for ~6 months, followed by randomization to atomoxetine (n = 266) or placebo (n = 258) for ~6 months. Placebo patients were used for the analyses. Relapse: ≥50% worsening of prerandomization improvement in ADHD symptoms and ≥2 level severity increase on the Clinical Global Impression-Severity (CGI-S) scale at 2 consecutive visits; MOR: retaining ≥75% of prerandomization symptom improvement and CGI-S ≤ 2 at all visits (study 1); retaining ≥70% of prerandomization symptom improvement and CGI-S ≤ 3 at all visits (study 2). In adults, statistically significantly (P ≤ .05) increased likelihood of relapse was associated with prerandomization presence of Conners’ Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items “difficulty awaiting turn” and “careless mistakes.” In pediatric patients, less MOR was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item “does not listen”; in adults, less MOR was associated with prerandomization presence of CAARS-Inv:SV items “loses things” and “difficulty awaiting turn.” Changes in patients’ QoL after withdrawal from atomoxetine moderately correlated with changes in ADHD symptoms in pediatric patients and mildly in adults.

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Acknowledgements

Eli Lilly and Company contracted inVentiv Health Clinical, LLC, for statistical, writing, and editorial services. The authors thank Ms. Angela Lorio, full-time employee of inVentiv Health Clinical, LLC, for editorial support.

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Correspondence to Himanshu Upadhyaya.

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Conflict of interest

These analyses were sponsored by Eli Lilly and Company. Drs. Upadhyaya, Tanaka, Escobar, and Bushe are full-time employees and shareholders of Eli Lilly and Company. Ms. Lipsius and Dr. Heinloth are full-time employees of inVentiv Health Clinical, LLC. Dr. Dittmann has received compensation for serving as consultant or speaker, or he or the institution he works for have received research support or royalties from the following companies or organizations: EU (FP7 Programme), US National Institute of Mental Health (NIMH), German Federal Ministry of Health/Regulatory Agency (BMG/BfArM), German Federal Ministry of Education and Research (BMBF), German Research Foundation (DFG), Volkswagen Foundation, Boehringer Ingelheim, Ferring, Janssen-Cilag, Eli Lilly and Company, H. Lundbeck A/S, Otsuka/Takeda, Servier, Shire, and Theravance. Dr. Dittmann owns Eli Lilly and Company stock. Dr. Thome has obtained financial support (e.g. lecture honoraria, grants for research projects and scientific meetings, advisory-board membership) from AstraZeneca, Bristol-Meyers Squibb, Ever Neuro Pharma, Janssen-Cilag, Lilly, Lundbeck, Medice Arzneimittel Pütter, Merz Pharmaceuticals, Novartis Pharma, Pfizer Pharma, Roche, Servier, Shire, some of which are manufacturers of ADHD medication. Dr. Greenhill is a member of the Scientific Advisory Board for Quotient/Pearson, of the Foundation Grant Review Committee for Klingenstein Third Generation, of the Netronics Multisite Study Data and Safety Monitoring Board (DSMB), of the Board of the New York Council of Child and Adolescent Psychiatry, of the AHRQ Expert Panel on ADHD Review, and a laboratory consultant for Health Information Technologies (Columbia). The statistical analyses were performed by Dr. Tanaka and Ms. Lipsius. The manuscript was drafted by Dr. Heinloth and critically revised and approved by all authors before submission.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Protocols for both studies were reviewed and approved by the applicable organizational Ethical Review Boards.

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Informed consent was obtained from all individual participants or their guardians included in the study.

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Johannes Thome and Ralf W. Dittmann are co-first authors.

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Thome, J., Dittmann, R.W., Greenhill, L.L. et al. Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine. ADHD Atten Def Hyp Disord 9, 219–229 (2017). https://doi.org/10.1007/s12402-017-0227-8

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