A randomized controlled multicenter trial on the multimodal treatment of adult attention-deficit hyperactivity disorder: enrollment and characteristics of the study sample
Adult ADHD is a frequent psychiatric disorder affecting relevant aspects of an individual’s life. The aim of our study group was to carry out the first randomized controlled multicenter study to evaluate the effects of psychotherapy compared to clinical management in combination with psychopharmacological treatment with methylphenidate (MPH) or placebo (Plac) in a factorial four-arm design. Here, we present the enrollment procedure and description of adult ADHD patients recruited for the trial. Four hundred and thirty-three adult patients with ADHD were randomized at seven study sites in Germany to four treatment conditions: manualized dialectical-behavioral-therapy-based group psychotherapy (GPT) plus MPH or Plac, or clinical management (CM) including supportive counseling plus MPH or Plac with weekly sessions in the first 12 weeks and monthly sessions thereafter. Assessment for eligibility included standardized scales and instruments. After prescreening of 1,480 patients, 518 were evaluated for trial participation and 433 were randomized. The main reasons for prescreening failure were lack of interest in participating (n = 205), difficulties in meeting the time and effort requirements for participation (n = 186), and contraindications for psychopharmacological treatment with MPH (n = 194). The full analysis set (FAS) comprised 419 adult ADHD patients (mean age 35.2 years, males/females 1:1). Fifty-seven percent of the patients suffered from the combined ADHD subtype. Prevalence of at least one current or lifetime axis-I comorbidity was 66 %. Axis-II comorbidity rates was 18 % (patients with comorbid borderline and antisocial personality disorders were excluded). Our network was able to recruit an adult ADHD sample essentially comparable to community samples. A selection bias was created by excluding patients unable or unwilling to participate, or who had somatic and psychiatric contraindications for stimulant treatment (Current Controlled Trials ISRCTN54096201, Funding: Federal Ministry of Education and Research 01GV0606).
KeywordsADHD Adults Psychotherapy Methylphenidate RCT COMPAS
Our network on psychotherapy of ADHD is supported by the German Federal Ministry of Education and Research (BMBF; 01GV0605, 01GV0606) within the framework research networks on psychotherapy. Furthermore, we want to thank all members of COMPAS teams at the study sites: Wuerzburg: PD C. Jacob, Dr. T. Jans, Dr. S. Groß-Lesch, M. Heine, A. Boreatti-Hümmer, J. Heupel, S. Reichert, S. Müller, S. Kreiker, A. Gessner, A. Conzelmann, and C. Bähne; Berlin: Dr. M. Colla, L. Gentschow, P. Kunze, and D. Langner; Mannheim: PD Dr. E. Sobanski, Dr. B. Alm, M. Schumacher-Stien, S. Bukow, and S. Argiriou-Martin; Homburg: Prof. Dr. M. Rösler, Prof. Dr. Wofgang Retz, PD Dr. P. Retz-Junginger, Dr. K. Römer, Dr. B. Leipnitz, Dr. S Doyran, and Dr. M. Schulte-Altedorneburg; Essen: Dr. Kis, Dr. M. Abdel-Hamid, V. Heinrich, PD Dr. M. Krämer, and PD Dr. J. Uekermann; Mainz: Prof. Dr. M. Huss, C. Kornmann, A. Bürger, G. Chervenkova, and P. Meinhardt; Freiburg: Prof. Dr. A. Philipsen, Dr. E. Graf, Dr. S. Matthies, Dr. M. Löwer, P. Borel, I. Jansen, S. Bonfico, M. Jooßens, C. Sadohara, M. Weber, M. Kamp, T. Dopatka, Dr. E. Perlov, and Dr. G. Ihorst; and Lörrach: Dr. C. Carl and Dr. C. Keutler. We thank Medice Arzneimittel Puetter GmbH & Co. KG for providing the trial medication (Medikinet retard licensed as Medikinet adult and matching placebo) and particularly Dr. R. Fischer for his advice in preparing the study protocol and his assistance in SAE management. We gratefully thank all participating patients for their cooperation.
Conflict of interest
A. Philipsen: advisory boards, lectures, phase III studies or travel grants within the last 3 years: Eli Lilly, Janssen-Cilag, Medice Arzneimittel Pütter GmbH, Novartis, and Shire, she is an author of books or articles on psychotherapy published by Elsevier, Hogrefe, Schattauer, Kohlhammer, and Karger publishers; E. Graf: none; T. Jans: none; S. Matthies: none; P. Borel: none; M. Colla: advisory boards, speaker’s honoraria or phase III studies within the last 3 years: Shire, Eli Lilly, and Novartis; L. Gentschow: none; D. Langner: none; C. Jacob received speaker’s honoraria by Medice and is member of the advisory boards of Medice; S. Groß-Lesch: none; E. Sobanski: advisory boards, IITs, lectures or Phase III studies within the last 3 years: Medice, Shire, Eli Lilly, and Novartis; B. Alm: advisory boards, lectures or phase III studies within the last 3 years: Medice, Eli Lilly; M. Schuhmacher-Stien: none; M. Rösler is member of the speakers bureau of Medice, Janssen, and Shire; he is a member of the advisory boards of Lilly, Shire, Medice, and Janssen. He performed clinical trials for Medice and Lilly; P. Retz-Junginger received salaries from Hogrefe Publishers; W. Retz received speaker’s honoraria by Medice, is member of the advisory boards of Novartis and Medice, has been involved in clinical trials conducted by BMBF, Vifor, Novartis, and Medice, and is an author of manuals, handbooks, and diagnostic tools published by Hogrefe, Springer, Kohlhammer, and Karger publishers; B. Kis received travel grants by Servier Deutschland GmbH and speaker’s honoraria by Medice and Servier Deutschland GmbH, is a member of the advisory boards of Medice and Novartis Pharma GmbH, and has been involved in clinical trials conducted by Eli Lilly/Lilly Deutschland GmbH; M. Abdel-Hamid: none; V. Heinrich has been involved in clinical trials conducted by Eli Lilly/Lilly Deutschland GmbH; M. Huss: within the past 3 years, he received speaker honoraria from Eli Lilly, Janssen-Cilag, Medice, Novartis, and Shire, he is principal investigator of phase II study sponsored by Lundbeck, principal investigator of several phase III studies sponsored by Shire and Novartis, and principal investigator/sponsor of three IIT studies (investigator initiated trials, phase III and IV) in unrestricted cooperation with Engelhardt Arzneimittel, Steiner Arzneimittel, and Medice; he worked as consultant for Engelhardt, Medice, Shire, and Steiner Arzneimittel and member in the Advisory boards of Eli Lilly, Medice, Novartis, and Shire; C. Kornmann: none; A. Bürger received travel grants by MSAGD in RLP (Ministerium für Soziales, Arbeit, Gesundheit und Demografie) and MBWWK in RLP (Ministerium für Bildung, Wissenschaft, Weiterbildung und Kultur); L. Tebartz van Elst received travel grants by Medtronic, Janssen, Otsuka, Lilly, and SCS and speaker’s honoraria by Otsuka, SCS, Lilly, Medtronic, and Janssen-Cilag; M. Berger: none.
- Carpenter JR, Roger JH, Kenward MG (2012) Analysis of longitudinal trials with protocol deviation: a framework for relevant, accessible assumptions, and inference via multiple imputation. (in press with Journal of Biopharmaceutical Statistics, due to appear in issue 6 (November/December) in volume 23 (2013))Google Scholar
- Fayyad J, De Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, De Girolamo G, Haro JM, Karam EG, Lara C, Lépine JP, Ormel J, Posada-Villa J, Zaslavsky AM, Jin R (2007) Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 190:402–409PubMedCrossRefGoogle Scholar
- Hesslinger B, Philipsen A, Richter H (2004) Psychotherapy in adult ADHD: a workbook. Hogrefe Verlag, GoettingenGoogle Scholar
- Hirvikoski T, Waaler E, Alfredsson J, Pihlgren C, Holmström A, Johnson A, Rück J, Wiwe C, Bothén P, Nordström AL (2011) Reduced ADHD symptoms in adults with ADHD after structured skills training group: results from a randomized controlled trial. Behav Res Ther 49(3):175–185PubMedCrossRefGoogle Scholar
- Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, Reif A, Walitza S, Romanos M, Strobel A, Brocke B, Schäfer H, Schmidtke A, Böning J, Lesch KP (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257(6):309–317PubMedCrossRefGoogle Scholar
- Jans T, Philipsen A, Graf E, Ihorst G, Gerlach M, Warnke A (2009) Does the treatment of maternal attention deficit and hyperactivity disorder (ADHD) enhance the efficacy of a behavioural parent training for the treatment of their children’s ADHD? Study protocol of a randomized controlled multicentre trail. Atten Defic Hyperact Disord 1(1):33–45PubMedCrossRefGoogle Scholar
- Jans T, Graf E, Jacob C, Zwanzger U, Groß-Lesch S, Matthies S, Perlov E, Hennighausen K, Jung M, Rösler M, Schulte-Altedorneburg M, von Gontard A, Hänig S, Sobanski E, Alm B, Poustka L, Bliznak L, Colla M, Gentschow L, Burghardt R, Salbach-Andrae H, Becker K, Holtmann M, Freitag C, Warnke A, Philipsen A (2013) A randomized controlled multicentre trial on the treatment for ADHD in mothers and children: enrolment and basic characteristics of the study sample. Atten Defic Hyperact Disord 5(1):29–40PubMedCrossRefGoogle Scholar
- Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Faraone SV, Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Walters EE, Zaslavsky AM (2006) The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 163(4):716–723PubMedCentralPubMedCrossRefGoogle Scholar
- Lindemann C, Langner I, Kraut AA, Banaschewski T, Schad-Hansjosten T, Petermann U, Petermann F, Schreyer-Mehlhop I, Garbe E, Mikolajczyk RT (2012) Age-specific prevalence, incidence of new diagnoses, and drug treatment of attention-deficit/hyperactivity disorder in Germany. J Child Adolesc Psychopharmacol 22(4):307–314PubMedCrossRefGoogle Scholar
- Manuzza S, Klein RG, Bessler A, Malloy P, LaPadula M (1998) Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry 155(4):493–498Google Scholar
- Pérez de Los Cobos J, Siñol N, Pérez V, Trujols J (2012) Pharmacological and clinical dilemmas of prescribing in co-morbid adult attention-deficit/hyperactivity disorder and addiction. Br J Clin Pharmacol [Epub ahead of print]Google Scholar
- Philipsen A, Richter H, Peters J, Alm B, Sobanski E, Colla M, Münzebrock M, Scheel C, Jacob C, Perlov E, Tebartz van Elst L, Hesslinger B (2007) Structured group psychotherapy in adults with attention deficit hyperactivity disorder: results of an open multicenter study. J Nerv Ment Dis 195(12):1013–1019PubMedCrossRefGoogle Scholar
- Philipsen A, Graf E, Tebartz van Elst L, Jans T, Warnke A, Hesslinger B, Ebert D, Gerlach M, Matthies S, Colla M, Jacob C, Sobanski E, Alm B, Rösler M, Ihorst G, Gross-Lesch S, Gentschow L, Kis B, Huss M, Lieb K, Schlander M, Berger M (2010) Evaluation of the efficacy and effectiveness of a structured disorder tailored psychotherapy in ADHD in adults: study protocol of a randomized controlled multicentre trial. Atten Defic Hyperact Disord 2(4):203–211PubMedCrossRefGoogle Scholar
- Safren SA, Sprich S, Mimiaga MJ, Surman C, Knouse L, Groves M, Otto MW (2010) Cognitive behavioral therapy vs relaxation with educational support for medication-treated adults with ADHD and persistent symptoms: a randomized controlled trial. JAMA 304(8):875–880PubMedCentralPubMedCrossRefGoogle Scholar
- Sobanski E, Brüggemann D, Alm B, Kern S, Philipsen A, Schmalzried H, Hesslinger B, Waschkowski H, Rietschel M (2008) Subtype differences in adults with attention-deficit/hyperactivity disorder (ADHD) with regard to ADHD-symptoms, psychiatric comorbidity and psychosocial adjustment. Eur Psychiatry 23(2):142–149PubMedCrossRefGoogle Scholar
- Statistisches Bundesamt (Federal Statistical Office) (2009) Statistisches Jahrbuch 2009 für die Bundesrepublik Deutschland (Statistical Yearbook 2009 for the Federal Republic of Germany). Statistisches Bundesamt, WiesbadenGoogle Scholar
- Surman CB, Monuteaux MC, Petty CR, Faraone SV, Spencer TJ, Chu NF, Biederman J (2010) Representativeness of participants in a clinical trial for attention-deficit/hyperactivity disorder? Comparison with adults from a large observational study. J Clin Psychiatry 71(12):1612–1616PubMedCentralPubMedCrossRefGoogle Scholar
- Wittchen HU, Zaudig M, Fydrich T (1997) SKID: Strukturiertes Klinisches Interview für DSM IV. Achse I und II, HogrefeGoogle Scholar