The impact of individual and methodological factors in the variability of response to methylphenidate in ADHD pharmacogenetic studies from four different continents

Authors

  • Guilherme Polanczyk,

    1. ADHD Program, Child and Adolescent Psychiatric Division, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
    2. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK
    Search for more papers by this author
  • Stephen V. Faraone,

    1. Departments of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, New York
    Search for more papers by this author
  • Claiton H.D. Bau,

    1. Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
    2. Adult ADHD Outpatient Clinic, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
    Search for more papers by this author
  • Marcelo M. Victor,

    1. Adult ADHD Outpatient Clinic, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
    Search for more papers by this author
  • Katja Becker,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany
    2. Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty, Philipps-University of Marburg, Marburg, Germany
    Search for more papers by this author
  • Reta Pelz,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany
    Search for more papers by this author
  • Jan K. Buitelaar,

    1. Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Search for more papers by this author
  • Barbara Franke,

    1. Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    2. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Search for more papers by this author
  • Sandra Kooij,

    1. Adult ADHD Program/PsyQ, Center for Mental Health, The Hague, The Netherlands
    Search for more papers by this author
  • Emma van der Meulen,

    1. Bascule, Academic Center for Child and Adolescent Psychiatry, Amsterdam, The Netherlands
    Search for more papers by this author
  • Keun-Ah Cheon,

    1. Division of Child and Adolescent Psychiatry, Department of Psychiatry, Myong-Ji Hospital, Kwandong University College of Medicine, Koyang City, Kyunggi, South Korea
    Search for more papers by this author
  • Eric Mick,

    1. Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for more papers by this author
  • Diane Purper-Ouakil,

    1. AP/HP Hôpital Robert Debré, Child and Adolescent Psychopathology Unit, Paris, France
    2. INSERM U675, IFR02, Faculty X Bichat, University Paris VII, France
    Search for more papers by this author
  • Philip Gorwood,

    1. INSERM U675, IFR02, Faculty X Bichat, University Paris VII, France
    2. AP/HP Hôpital Louis Mourier, Colombes, France
    Search for more papers by this author
  • Mark A. Stein,

    1. HALP CLinic and ADHD Research Center, Institute for Juvenile Research, The University of Illinois at Chicago, Chicago, Illinois
    Search for more papers by this author
  • Edwin H. Cook Jr.,

    1. HALP CLinic and ADHD Research Center, Institute for Juvenile Research, The University of Illinois at Chicago, Chicago, Illinois
    Search for more papers by this author
  • Luis Augusto Rohde

    Corresponding author
    1. ADHD Program, Child and Adolescent Psychiatric Division, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
    • ADHD Program, Child and Adolescent Psychiatric Division, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2350 Porto Alegre, RS, Brazil.
    Search for more papers by this author

  • Please cite this article as follows: Polanczyk G, Faraone SV, Bau CHD, Victor MM, Becker K, Pelz R, Buitelaar JK, Franke B, Kooij S, van der Meulen E, Cheon K-A, Mick E, Purper-Ouakil D, Gorwood P, Stein MA, Cook EH, Rohde LA. 2008. The Impact of Individual and Methodological Factors in the Variability of Response to Methylphenidate in ADHD Pharmacogenetic Studies from Four Different Continents. Am J Med Genet Part B 147B:1419–1424.

  • Conflict of interests: Dr. Bau, Dr. Victor, Dr. Pelz, Dr. Franke, Dr. van der Meulen, and Dr. Cook Jr. do not have any potential conflict of interest. Dr. Polanczyk has been a speaker for Novartis. Dr. Faraone receives research support from, is on the speakers' bureaus of, and has had an advisory or consulting relationship with McNeil Pediatrics and Shire Laboratories; he also has had an advisory or consulting relationship with Novartis and Eli Lilly. Dr. Becker served in a consultancy role either personally or for ones employee from Eli Lilly, was on the speakers' bureaus of Eli Lilly and Astra Zeneca and received conference attendance support from Shire. Dr. Buitelaar is/has been a speaker for, or is/has been on the advisory board for Eli Lilly & Company, Shire US Inc, UCB, Medice, Janssen Cilag B.V, and Pfizer. Dr. Kooij is a speaker of and is on the advisory board for Janssen-Cilag B.V., and Eli Lilly & Company. Dr. Cheon received research support from Janssen Korea, and is on the speakers' bureaus of Janssen Korea and Eli Lilly; she also has had an advisory or consulting relationship with Eli Lilly Korea. Dr. Mick receives research support from Shire Laboratories, Janssen Pharmaceuticals Inc., McNeil Pediatrics, and Pfizer, and is on the consultant/advisory board for Shire Laboratories Inc., and Pfizer. Dr. Purper-Ouakil has been in the advisory board of Eli Lilly, is/has been involved in research/clinical trials with Eli Lilly, Pierre Fabre, Novartis, Servier, and received research support from Eli Lilly. Dr. Gorwood is in the advisory board of Janssen, Servier and Wyeth, has been involved in research/clinical trials with Eli Lilly, Lundbeck, Servier, and received research support from Eli Lilly and Wyeth. Dr. Stein is a consultant for Novartis and serves on their speaker's bureau. He also speaks for McNeil Pediatrics and receives research support from McNeil Pediatrics, Eli-Lilly, Novartis and Pfizer. Dr. Rohde was on the speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, and Novartis in the last 3 years. Currently, his only industry related activity is take part of the advisory board for Eli Lilly & Company. The ADHD Outpatient Program receives research support from the following pharmaceutical companies: Bristol-Myers Squibb, Eli-Lilly, Janssen-Cilag, and Novartis.

Abstract

Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: (a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta-regression analysis; (b) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies vs. randomized controlled trials) was significantly associated with heterogeneity of results (P = 0.001). At the individual level, age (P < 0.001), comorbid oppositional defiant disorder (P < 0.001), and pre-treatment scores (P < 0.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed. © 2008 Wiley-Liss, Inc.

Ancillary