Ludger Tebartz van Elst, MD*; Simon Maier, PhD*; Stefan Klöppel, MD; Erika Graf, PhD; Carola Killius; Marthe Rump; Esther Sobanski, MD; Dieter Ebert, MD; Mathias Berger, MD; Andreas Warnke, MD; Swantje Matthies, MD; Evgeniy Perlov, MD*; Alexandra Philipsen, MD*
Background: Based on animal research several authors have warned that the application of methylphenidate, the first-line drug for the treatment of attention-deficit/hyperactivity disorder (ADHD), might have neurotoxic effects potentially harming the brain. We investigated whether methylphenidate application, over a 1-year period, results in cerebral volume decrease.
Methods: We acquired structural MRIs in a double-blind study comparing methylphenidate to placebo. Global and regional brain volumes were analyzed at baseline, after 3 months and after 12 months using diffeomorphic anatomic registration through exponentiated lie algebra.
Results: We included 131 adult patients with ADHD into the baseline sample, 98 into the 3-month sample (54 in the methylphenidate cohort and 44 in the placebo cohort) and 76 into the 1-year sample (37 in the methylphenidate cohort and 29 in the placebo cohort). Methylphenidate intake compared with placebo did not lead to any detectable cerebral volume loss; there was a trend toward bilateral cerebellar grey matter increase.
Limitations: Detecting possible neurotoxic effects of methylphenidate might require a longer observation period.
Conclusion: There is no evidence of grey matter volume loss after 1 year of methylphenidate treatment in adult patients with ADHD.
*These authors contributed equally to this work.
Submitted Oct. 8, 2015; Revised Feb. 19, 2016; Revised Mar. 29, 2016; Accepted Apr. 5, 2016; Early-released Aug. 30, 2016
Acknowledgements: The study was part of a multicentre research network on the psychotherapy of ADHD funded by the German Federal Ministry of Education and Research (BMBF; 01GV0605, 01GV0606, ADHD-NET). BMBF had no role in the trial other than funding. MEDICE Arzneimittel Puetter GmbH & Co. KG provided the trial medication (Medikinet retard licensed as Medikinet adult and matching placebo). The authors thank R. Fischer for advice in preparing the study protocol and assistance in managing SAEs, B. Feige for advice in data analysis, and C. Kaller for helpful support regarding methods and data analysis. The authors thank all participants and the 4 anonymous peer reviewers of an earlier version of the manuscript.
Affiliations: From the Section for Experimental Neuropsychiatry, Clinic for Psychiatry and Psychotherapy, University Freiburg Medical Center, Hauptstr, Freiburg, Germany (Tebartz van Elst, Maier, Klöppel, Killius, Rump, Perlov); Freiburg Brain Imaging, University Freiburg Medical Center, Freiburg, Germany (Tebartz van Elst, Maier, Klöppel, Killius, Rump, Ebert, Berger); the Department of Neurology, University Freiburg Medical Center, Freiburg, Germany (Klöppel); the Clinical Trials Unit, University Freiburg Medical Center, Freiburg, Germany (Graf); the Central Institute for Mental Health, Mannheim, Germany (Sobanski); the Clinic of Psychiatry and Psychotherapy, University Freiburg Medical Center, Freiburg, Germany (Ebert, Berger, Matthies, Philipsen); the Department for Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany (Warnke); and the Department of Psychiatry and Psychotherapy, Karl Jaspers Clinic, Faculty of Medicine and Health Sciences, European Medical School, Carl von Ossietzky University Oldenburg, Oldenburg, Germany (Philipsen).
Competing interests: L. Tebartz van Elst has been on the advisory boards of and has received speaker fees and travel assistance from Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GlaxoSmithKline, Servier, Janssen and Cyberonics. E Sobanski has been on the advisory boards of and has received speaker fees travel assistance and book royalties from Medice, Shire, Eli Lilly, Novartis, the German Ministry of Science & Education, Medizinisch Wissenschaftlicher Verlag (Medical Scientific Publishing, Berlin) and Dansk Psykologisk Forlag (Danish Psychological Publishers). A. Philipsen has been on the advisory boards of and has received lecture fees and travel assistance from Eli Lilly, Medice Arzneimittel Pütter GmbH, Novartis, and Shire. She is also the author of books and articles on psychotherapy published by Elsevier, Hogrefe, Schattauer, Kohlhammer, and Karger. No other competing interests declared.
Contributors: L. Tebarz van Elst, S. Maier, E. Graf, E. Sobanski, D. Ebert, M. Berger, S. Matthies, E. Perlov and A. Philipsen designed the study. S. Maier, C. Killius, E. Sobanski, A. Warnke, S. Matthies, E. Perlov and A. Philipsen acquired the data, which L. Tebartz van Elst, S. Maier, S. Klöppel, E. Graf, C. Killius, M. Rump and E. Perlov analyzed. L. Tebartz van Elst, S. Maier, S. Klöppel and M. Rump wrote the article, which all authors reviewed and approved for publication.
Trial protocol: The trial protocol is available from the corresponding author on request and is accessible on the leading centre’s institutional website (in German): www.uniklinik-freiburg.de/fileadmin/mediapool/07_kliniken/psy_psychiatrie/pdf/forschung/Pr%C3%BCfplan_Protokollversion_5_-Amendment-4_17.12.08.pdf.
Members of the COMPAS study group (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study; coordinating investigator: Prof. Dr. A. Philipsen, Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Director: Prof. Dr. M. Berger) are the following colleagues at the study sites in Würzburg (Würzburg University Hospital, Department of Psychiatry, Psychosomatics and Psychotherapy, Director: Prof. Dr. J. Deckert; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy,Director: Prof. Dr. A. Warnke), Berlin (Charité – University Medicine, Campus Benjamin Franklin, Department of Psychiatry and Psychotherapy, Director: Prof. Dr. I. Heuser), Mannheim (Central Institute for Mental Health, Clinic for Psychiatry and Psychotherapy, Director: Prof. Dr. A. Meyer-Lindenberg), Homburg (Saarland University Hospital and Saarland University Faculty of Medicine, Institute for Forensic Psychology and Psychiatry, Director: Prof. Dr. M. Roesler), Essen (LVR-Hospital Essen, Department for Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg- Essen, Director: Prof. Dr. J. Wiltfang), Mainz (University Medicine Mainz, Clinic for Child and Adolescent Psychiatry and Psychotherapy, Director: Prof. Dr. M. Huss), and Lörrach (St. Elisabethen Krankenhaus, Department of Child and Adolescent Psychiatry and Psychotherapy, Director: Dr. C. Keutler), and members of the Clinical Trials Unit at Medical Center – University of Freiburg (Director: R. Bredenkamp; G. Ihorst, E. Graf) as well as members of the Independent Data Monitoring Committee (Prof. Dr. H. Remschmidt, Prof. Dr. G. Wassmer, PD Dr. N. Wodarz). Independent supervision was carried out at the Institute for Psychology of Freiburg University (Dr. U. Frank) in cooperation with colleagues in private practice (Dr. F. Mayer-Bruns, K. Schehr). The health economic evaluation was planned and conducted by Prof. Dr. M. Schlander, Institute for Innovation and Valuation in Health Care, INNOVAL HC, Wiesbaden, Germany. Other projects in the network on psychotherapy research on ADHD (speaker: Prof. A. Philipsen, Medical Center – University of Freiburg, 2006–2012 Prof. Dr. A. Warnke, Würzburg University Hospital) are coordinated by Dr. T. Jans (Würzburg University Hospital, AIMAC [ADHD in mothers and children]), Prof. Dr. L. Tebartz van Elst (Medical Center – University of Freiburg, functional and morphometric brain mapping), and Prof. Dr. K.-P. Lesch (Würzburg University Hospital, molecular genetics).
Correspondence to: L. Tebartz van Elst, Section for Experimental Neuropsychiatry, Hauptstr. 5, 79104, Freiburg, Germany; email@example.com