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Mental health
Protocol
Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis
  1. Samuele Cortese1,2,
  2. Nicoletta Adamo3,
  3. Christina Mohr-Jensen4,
  4. Adrian J Hayes5,6,
  5. Sahar Bhatti5,6,
  6. Sara Carucci7,
  7. Cinzia Del Giovane8,
  8. Lauren Z Atkinson5,6,
  9. Tobias Banaschewski9,
  10. Emily Simonoff10,
  11. Alessandro Zuddas7,11,
  12. Corrado Barbui12,
  13. Marianna Purgato12,13,
  14. Hans-Christoph Steinhausen14,15,16,
  15. Farhad Shokraneh17,
  16. Jun Xia17,
  17. Andrea Cipriani5,6,
  18. David Coghill18,19,20
  19. on behalf of the European ADHD Guidelines Group (EAGG)
    1. 1Department of Psychology, Developmental Brain-Behaviour Laboratory, Academic Unit of Psychology, Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, and Solent NHS Trust, Southampton, UK
    2. 2New York University Child Study Center, New York City, New York, USA
    3. 3MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
    4. 4Research Unit of Child and Adolescent Psychiatry, Aalborg Psychiatric Hospital, Aalborg University Hospital, Aalborg, Denmark
    5. 5Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
    6. 6Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
    7. 7Child and Adolescent Neuropsychiatric Unit, ‘A. Cao’ Paediatric Hospital, ‘G. Brotzu’ Hospital Trust, Cagliari, Italy
    8. 8Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
    9. 9Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty, Central Institute of Mental Health, Mannheim/Heidelberg University, Mannheim, Germany
    10. 10Institute of Psychiatry, Psychology and Neurosciences, King's College London, and the Maudsley Hospital, London, UK
    11. 11Child and Adolescent Neuropsychiatry Unit, University of Cagliari, Cagliari, Italy
    12. 12Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy
    13. 13Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA
    14. 14Department of Child and Adolescent Psychiatry, Psychiatric University Clinic Zurich, Switzerland
    15. 15Department of Clinical Psychology and Epidemiology, Psychology, University of Basel, Basel, Switzerland
    16. 16Department of Capital Region Psychiatry, Child and Adolescent Mental Health Centre, Copenhagen, Denmark
    17. 17Cochrane Schizophrenia Group, Institute of Mental Health, a Partnership between the University of Nottingham and Nottinghamshire Healthcare NHS Trust, UK
    18. 18Division of Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
    19. 19Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
    20. 20Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
    1. Correspondence to Dr David Coghill; d.r.coghill{at}dundee.ac.uk

    Abstract

    Introduction Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles.

    Methods and analysis We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings.

    Ethics and dissemination No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences.

    Trial registration number CRD42014008976.

    • Attention-Deficit/Hyperactivity Disorder
    • pharmacological treatment
    • acute treatment
    • systematic review
    • network meta-analysis

    This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

    https://doi.org/10.1136/bmjopen-2016-013967

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      Footnotes

      • Twitter Follow Andrea Cipriani @And_Cipriani

      • Collaborators Members of the European ADHD Guidelines Group (EAGG): Asherson Phil, Banaschewski Tobias, Brandeis Daniel, Buitelaar Jan, Coghill David, Cortese Samuele, Daley David, Danckaerts Marina, Dittmann Ralf W, Dopfner Manfred, Ferrin Maite, Hollis Chris, Holtmann Martin, Konofal Eric, Lecendreux Michel, Rothenberger Aribert, Santosh Paramala, Sergeant Joseph A, Simonoff Emily, Sonuga-Barke Edmund J, Soutullo Cesar, Steinhausen Hans-Christoph, Stevenson Jim, Stringaris Argyris, Taylor Eric, van der Oord Saskia, Wong Ian and Zuddas Alessandro.

      • Contributors SC drafted the protocol (except the literature search and statistical analysis sections). FS and JX drafted the literature search section. CDG drafted the statistical analysis section. All other coauthors critically reviewed the protocol and amended it.

      • Funding This project is supported by Stichting Eunethydis (European Network for Hyperkinetic Disorder) Foundation. The European ADHD Guidelines Group (EAGG) is working group of Eunethydis. No input from external funders was provided.

      • Competing interests SC has received reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH), a non-profit organisation, in relation to lectures that he delivered for ACAMH. CM-J has been a speaker for HB Pharma/Medice. SC collaborated within projects from the European Union (7FP) and has received travel support from Shire Pharmaceutical Company; she collaborated as subinvestigator in sponsored clinical trial by Shire Pharmaceutical Company. TB served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Medice, Novartis, Oxford outcomes, Otsuka, PCM scientific, Shire and Viforpharma. He received conference support or speaker's fee by Medice, Novartis and Shire. He is/has been involved in clinical trials conducted by Shire and Viforpharma. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. AZ has received honoraria for participating to Advisory board or Data Safety Monitory Boards from Eli Lilly, Otsuka, Lundbeck, Takeda and EduPharma. He has also received royalties from Oxford University Press and Giunti OS, and research grants from Lundbeck, Roche, Shire and Vifor. H-CS has worked as an advisor and speaker for the following pharmaceutical companies: Janssen-Cilag, Eli Lilly, Novartis, Medice, Shire and UCB and has also received unrestricted grants for postgraduate training courses or conferences and research by Janssen-Cilag, Eli Lilly, Novartis, Medice and Swedish Orphan International. He receives book royalties from Cambridge University Press, Elsevier, Hogrefe, Huber, Klett and Kohlhammer publishers. AC has served as an expert witness for a patent litigation case about quetiapine extended-release and is supported by the NIHR Oxford Cognitive Health Clinical Research Facility. DC reports grants and personal fees from Shire, personal fees from Eli Lilly, grants from Vifor, personal fees from Novartis, personal fees from Oxford University Press.

      • Ethics approval No ethical issues are foreseen.

      • Provenance and peer review Not commissioned; externally peer reviewed.