Long-term Effects of Multimodal Treatment on Adult Attention-Deficit/Hyperactivity Disorder Symptoms

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Key Points

Question

What are the long-term results of multimodal treatment for adult attention-deficit/hyperactivity disorder (ADHD) when comparing cognitive behavioral group psychotherapy (GPT) with individual clinical management (CM) in combination with either methylphenidate or placebo?

Findings

In this follow-up assessment of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a multicenter randomized clinical trial, 256 adults participated in follow-up 1.5 years after the intervention ended. The severity of ADHD symptoms improved in all 4 prior treatment groups, with no significant difference found between GPT and CM, but methylphenidate was associated with a larger improvement in symptoms compared with placebo.

Meaning

Results from the COMPAS trial demonstrate an improvement of ADHD symptoms over 1.5 years in adults with ADHD after 1 year of treatment with methylphenidate plus either GPT or CM.

Abstract

This follow-up assessment of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a multicenter randomized clinical trial, evaluates the long-term efficacy of multimodal treatment for attention-deficit/hyperactivity disorder (ADHD).

Abstract

Importance

Knowledge about the long-term effects of multimodal treatment in adult attention-deficit/hyperactivity disorder (ADHD) is much needed.

Objective

To evaluate the long-term efficacy of multimodal treatment for adult ADHD.

Design, Setting, and Participants

This observer-masked, 1.5-year follow-up of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a prospective, multicenter randomized clinical trial, compared cognitive behavioral group psychotherapy (GPT) with individual clinical management (CM) and methylphenidate (MPH) with placebo (2 × 2 factorial design). Recruitment started January 2007 and ended August 2010, and treatments were finalized in August 2011 with follow-up through March 2013. Overall, 433 adults with ADHD participated in the trial, and 256 (59.1%) participated in the follow-up assessment. Analysis began in November 2013 and was completed in February 2018.

Interventions

After 1-year treatment with GPT or CM and MPH or placebo, no further treatment restrictions were imposed.

Main Outcomes and Measures

The primary outcome was change in the observer-masked ADHD Index of Conners Adult ADHD Rating Scale score from baseline to follow-up. Secondary outcomes included further ADHD rating scale scores, observer-masked ratings of the Clinical Global Impression scale, and self-ratings of depression on the Beck Depression Inventory.

Results

At follow-up, 256 of 433 randomized patients (baseline measured in 419 individuals) participated. Of the 256 patients participating in follow-up, the observer-masked ADHD Index of Conners Adult ADHD Rating Scale score was assessed for 251; the mean (SD) baseline age was 36.3 (10.1) years; 125 patients (49.8%) were men; and the sample was well-balanced with respect to prior randomization (GPT and MPH: 64 of 107; GPT and placebo: 67 of 109; CM and MPH: 70 of 110; and CM and placebo: 55 of 107). At baseline, the all-group mean ADHD Index of Conners Adult ADHD Rating Scale score was 20.6, which improved to adjusted means of 14.2 for the GPT arm and 14.7 for the CM arm at follow-up with no significant difference between groups (difference, −0.5; 95% CI, −1.9 to 0.9; P = .48). The adjusted mean decreased to 13.8 for the MPH arm and 15.2 for the placebo arm (difference, −1.4; 95% CI, −2.8 to −0.1; P = .04). As in the core study, MPH was associated with a larger reduction in symptoms than placebo at follow-up. These results remained unchanged when accounting for MPH intake at follow-up. Compared with participants in the CM arm, patients who participated in group psychotherapy were associated with less severe symptoms as measured by the self-reported ADHD Symptoms Total Score according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) ( DSM- IV) of Conners Adult ADHD Rating Scale (AMD, −2.1; 95% CI, −4.2 to −0.1; P = .04) and in the subscale of reducing pure hyperactive symptoms, measured via the Diagnostic Checklist for the diagnosis of ADHD in adults (AMD, −1.3; 95% CI, −2.8 to 0.1; P = .08). Regarding the Clinical Global Impression scale assessment of effectiveness, the difference between GPT and CM remained significant at follow-up (odds ratio, 1.63; 95% CI, 1.03-2.59; P = .04). No differences were found for any comparison concerning depression as measured with the Beck Depression Inventory.

Conclusions and Relevance

Results from COMPAS demonstrate a maintained improvement in ADHD symptoms for adults 1.5 years after the end of a 52-week controlled multimodal treatment period. The results indicate that MPH treatment combined with GPT or CM provides a benefit lasting 1.5 years. Confirming the results of the core study, GPT was not associated with better results regarding the primary outcome compared with CM.

Trial Registration

isrctn.org Identifier: ISRCTN54096201

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Most cited references 44

Record: found
Abstract: found
Article: not found

Attention-deficit hyperactivity disorder.

Joseph Biederman, Stephen V Faraone (2005)

Attention-deficit hyperactivity disorder (ADHD) is a disorder of inattention, impulsivity, and hyperactivity that affects 8-12% of children worldwide. Although the rate of ADHD falls with age, at least half of children with the disorder will have impairing symptoms in adulthood. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and other findings have recorded obstetric complications and psychosocial adversity as predisposing risk factors. Converging evidence from animal and human studies implicates the dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits in the pathophysiology of ADHD, and molecular imaging studies suggest that abnormalities of the dopamine transporter lead to impaired neurotransmission. Studies during the past decade have shown the safety and effectiveness of new non-stimulant drugs and long-acting formulations of methylphenidate and amfetamine. Other investigations have also clarified the appropriate role of targeted psychosocial treatments in the context of ongoing pharmacotherapy.

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Record: found
Abstract: found
Article: not found

Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication.

Tomohiro Nakao, Joaquim Radua, Katya Rubia … (2011)

Structural neuroimaging studies in attention-deficit hyperactivity disorder (ADHD) have been relatively inconsistent and have mainly been conducted with pediatric samples. Furthermore, there is evidence that stimulant medication may have an effect on brain structure. The authors conducted a meta-analysis of voxel-based morphometry studies in children and adults with ADHD and examined the potential effects of age and stimulant medication on regional gray matter volumes. The PubMed, ScienceDirect, Web of Knowledge, and Scopus databases were searched for articles published between 2001 and 2011. Manual searches were also conducted, and authors of studies were contacted for additional data. Coordinates were extracted from clusters of significant gray matter difference between ADHD patients and healthy comparison subjects. Metaregression methods were used to explore potential age and stimulant medication effects. Fourteen data sets comprising 378 patients with ADHD and 344 healthy subjects met inclusion criteria. The ADHD group had global reductions in gray matter volumes, which were robustly localized in the right lentiform nucleus and extended to the caudate nucleus. Both increasing age and percentage of patients taking stimulant medication were found to be independently associated with more normal values in this region. Patients also had slightly greater gray matter volumes in the left posterior cingulate cortex. These findings confirm that the most prominent and replicable structural abnormalities in ADHD are in the basal ganglia. They furthermore suggest that ADHD patients may progressively catch up with their developmental delay with advancing age and that use of stimulant medication may be associated with normalization of structural abnormalities in ADHD, although longitudinal studies are needed to confirm both observations.

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Evaluating dopamine reward pathway in ADHD: clinical implications.

Nora D. Volkow, Gene-Jack Wang, Scott Kollins … (2009)

Attention-deficit/hyperactivity disorder (ADHD)--characterized by symptoms of inattention and hyperactivity-impulsivity--is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D(2)/D(3) receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [(11)C]cocaine and for D(2)/D(3) receptors using [(11)C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P < or = .001); for D(2)/D(3) receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D(2)/D(3) for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D(2)/D(3) in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P = .004). Ratings of attention correlated with D(2)/D(3) in the accumbens (r = 0.35; 95% CI, 0.15-0.52; P = .001), midbrain (r = 0.35; 95% CI, 0.14-0.52; P = .001), caudate (r = 0.32; 95% CI, 0.11-0.50; P = .003), and hypothalamic (r = 0.31; CI, 0.10-0.49; P = .003) regions and with DAT in the midbrain (r = 0.37; 95% CI, 0.16-0.53; P < or = .001). A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.

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Author and article information

Journal

Journal ID (nlm-ta): JAMA Netw Open

Journal ID (iso-abbrev): JAMA Netw Open

Journal ID (pmc): JAMA Netw Open

Title: JAMA Network Open

Publisher: American Medical Association

ISSN (Electronic): 2574-3805

Publication date (Electronic): 31 May 2019

Publication date Collection: May 2019

Publication date PMC-release: 31 May 2019

Volume: 2

Issue: 5

Electronic Location Identifier: e194980

Affiliations

[1 ]Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

[2 ]Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany

[3 ]Clinical Trials Unit, Institute of Medical Biometry and Statistics, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany

[4 ]Clinic and Polyclinic for Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany

[5 ]Clinic for Psychiatry and Psychotherapy, Medius Clinic, Kirchheim, Germany

[6 ]Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany

[7 ]Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Clinical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

[8 ]Department of Child and Adolescent Psychiatry and Psychotherapy, University Medicine Mainz, Mainz, Germany

[9 ]Institute for Forensic Psychology and Psychiatry, Saarland University Faculty of Medicine, Homburg/Saar, Germany

[10 ]Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany

[11 ]Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

[12 ]Center of Mental Health, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany

Author notes

Article Information

Accepted for Publication: April 3, 2019.

Published: May 31, 2019. doi:10.1001/jamanetworkopen.2019.4980

Corresponding Author: Alexandra Philipsen, MD, Department of Psychiatry and Psychotherapy, University of Bonn, Siegmund-Freud-Straße 25, Bonn D-53127, Germany ( alexandra.philipsen@ 123456ukbonn.de ).

Author Contributions: Drs Graf and Philipsen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lam and Matthies contributed equally to this work.

Concept and design: Lam, Matthies, Graf, Retz, Jans, Berger, Tebartz van Elst, Philipsen.

Acquisition, analysis, or interpretation of data: Lam, Matthies, Graf, Colla, Jacob, Sobanski, Alm, Rösler, Retz-Junginger, Kis, Abdel-Hamid, Müller, Lücke, Huss, Jans, Tebartz van Elst, Philipsen.

Drafting of the manuscript: Lam, Matthies, Graf, Rösler, Müller, Philipsen.

Critical revision of the manuscript for important intellectual content: Lam, Matthies, Graf, Colla, Jacob, Sobanski, Alm, Retz, Retz-Junginger, Kis, Abdel-Hamid, Müller, Lücke, Huss, Jans, Berger, Tebartz van Elst, Philipsen.

Statistical analysis: Lam, Graf, Philipsen.

Obtained funding: Retz, Jans, Tebartz van Elst, Philipsen.

Administrative, technical, or material support: Matthies, Colla, Rösler, Retz, Retz-Junginger, Abdel-Hamid, Muller, Huss, Jans, Berger, Tebartz van Elst, Philipsen.

Supervision: Matthies, Colla, Sobanski, Retz, Kis, Müller, Huss, Berger, Tebartz van Elst, Philipsen.

Conflict of Interest Disclosures: Dr Lam reported receiving speaker’s honoraria and travel grants from Medice Arzneimittel Pütter GmbH and having authored books and articles on ADHD published by Elsevier, Thieme Medical Publishers, Springer, and Oxford University Press. Dr Matthies reported receiving speakers’ fee from Janssen-Cilag and being involved in clinical trials conducted by Janssen and Lundbeck outside the submitted work. Dr Colla reported serving on the advisory boards of Eli Lilly and Co, Janssen, and Novartis; receiving speaker honoraria from Eli Lilly and Co and Novartis; and participating in phase 3 studies with Eli Lilly and Co and Novartis outside the submitted work. Dr Jacob reported serving on the advisory board of Medice, Janssen, and Shire and receiving honoraria from Shire and Janssen. Dr Sobanski reported receiving honoraria from Medice, Eli Lilly and Co, and Novartis; serving as a member of the advisory boards of Medice, Shire, Eli Lilly and Co; and participating in trials with Medice, Novartis, Janssen-Cilag, and Eli Lilly and Co. Dr Alm reported receiving honoraria from Medice; serving on the advisory board of Eli Lilly and Co; participating in phase 3 studies with Medice, Novartis, Janssen-Cilag, and Eli Lilly and Co; and participating in investigator-initiated trials with Eli Lilly and Co. Dr Rösler reported serving as a member of the advisory boards of Medice, Eli Lilly and Co, and Janssen; serving as a member of the speakers’ bureaus of Medice, Eli Lilly and Co, Shire, and Novartis; and performing clinical studies for Medice. Dr Retz reported receiving honoraria from Medice; serving as a member of the advisory board of Medice; and participating in clinical trials sponsored by the Federal Ministry of Education and Research, Novartis, and Medice. Dr Kis reported receiving honoraria from Medice, Servier Laboratories, and Eli Lilly and Co; serving as a member of the advisory boards of Medice, Servier Laboratories, and Shire; receiving personal fees and nonfinancial support from Medice, Eli Lilly and Co, and Han-Huber publishers; and being the author and editor of book chapters on ADHD psychopathology and diagnostic instruments published by the Hogrefe publishing group. Dr Abdel-Hamid reported being the author and editor of diagnostic instruments published by the Hogrefe publishing group. Dr Müller reported receiving honoraria and travel grants from Servier Laboratories and LivaNova. Dr Huss reported serving as a member of the advisory boards of Eli Lilly and Co, Engelhardt Arzneimittel, Janssen-Cilag, Medice, Novartis, Shire, and Steiner Arzneimittel within the past 5 years; serving as a consultant to Engelhardt Arzneimittel, Medice, and Steiner Arzneimittel; receiving honoraria from Eli Lilly and Co, Engelhardt Arzneimittel, Janssen-Cilag, Medice, Novartis, and Shire; and receiving unrestricted grants for investigator-initiated trials from Eli Lilly and Co, Medice, Engelhardt Arzneimittel, and Steiner Arzneimittel. Dr Jans reported authoring books and articles on psychotherapy. Dr Tebartz van Elst reported serving on advisory boards, delivering lectures, and receiving travel grants within the last 3 years from Eli Lilly and Co, Janssen-Cilag, Novartis, Shire, UCB, GlaxoSmithKline, Servier Laboratories, Janssen, and Cyberonics. Dr Philipsen reported serving on the advisory board for Shire; receiving honoraria from Takeda; receiving travel support from Janssen-Cilag; and delivering lectures, participating in phase 3 studies, and receiving travel grants from Eli Lilly and Co, Janssen-Cilag, Medice, Novartis, and Shire; and being the author of books and articles on psychotherapy published by Elsevier, Hogrefe, Schattauer, Kohlhammer, and Karger publishers. No other disclosures were reported.

Funding/Support: The study was part of a multicenter research network on the psychotherapy of ADHD funded by the German Federal Ministry of Education and Research (BMBF; 01GV0605, 01GV0606, ADHD-NET).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium includes the following members: Isabella Heuser, MD (director), Michael Colla, MD, Laura Gentschow, DiplPsych, Paula Kunze, DiplPsych, and Daina Langner, PhD, Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charité–University Medicine Berlin, Berlin, Germany; Alexandra Lam, MD, Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Jens Wiltfang, MD (director), Bernhard Kis, MD, Mona Abdel-Hamid, PhD, Viola Heinrich, Dr rer medic, Markus Krämer, MD, and Jennifer Uekermann, PhD, Department of Psychiatry and Psychotherapy, LVR-Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Duisburg and Essen, Germany; Alexandra Philipsen, MD (coordinating investigator), Erika Graf, PhD, Swantje Matthies, MD, Marc Loewer, MD, Patricia Borel, DiplPsych, Imke Jansen, MD, Steffi Bonfico, DiplPsych, Manuel Jooßens, DiplPsych, Chiharu Sadohara, DiplPsych, Manfred Weber, Melanie Kamp, Tatja Dopatka, DiplBiol, Evgeniy Perlov, MD, and Harald Richter, PhD, Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Michael Rösler, MD, Wolfgang Retz, MD, Petra Retz-Junginger, PhD, Konstanze Roemer, MD,Birgit Leipnitz, MD, Sabine Doyran, MD, and Monika Schulte-Altedorneburg, MD, Institute for Forensic Psychology and Psychiatry, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg/Saar, Germany; Christine Carl, PhD, and Clemens Keutler, MD (director), Department of Child and Adolescent Psychiatry and Psychotherapy, St Elisabethen Krankenhaus, Lörrach, Germany; Michael Huss, MD, Catherine Kornmann, DiplPsych, Arne Bürger, PhD, Galina Chervenkova, MD, and Patricia Meinhardt, Department of Child and Adolescent Psychiatry and Psychotherapy, University Medicine Mainz, Mainz, Germany; Andreas Meyer-Lindenberg, MD (director), Esther Sobanski, MD, Barbara Alm, MD, Martina Schumacher-Stien, DiplPsych, Simon Bukow, MD, and Sotiria Argiriou-Martin, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Clinical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Jürgen Deckert, MD (director), Andreas Warnke, MD (director), Christian Jacob, MD, Thomas Jans, PhD, Silke Groß-Lesch, MD, Monika Heine, MD, Andrea Boreatti-Hümmer, MD, Julia Heupel, Susanne Reichert, MD, Sabine Müller, Susanne Kreiker, MD, Alexandra Gessner, Annette Conzelmann, DiplPsych, and Christina Bähne, DiplPsych, Department of Psychiatry, Psychosomatics and Psychotherapy and Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany; and Rainer Bredenkamp, MD (director), Gabriele Ihorst, PhD, and Erika Graf, PhD, Clinical Trials Unit, University Medical Center, University of Freiburg, Freiburg, Germany. The independent data monitoring committee included Helmut Remschmidt, MD, Department of Child and Adolescent Psychiatry, Philipps University, Marburg, Germany; Gernot Wassmer, PhD, Institute for Medical Statistics, Informatics, and Epidemiology, University of Cologne, Cologne, Germany; and Norbert Wodarz, MD, Department of Psychiatry, University of Regensburg, Regensburg, Germany. Independent supervision was carried out by Ulrike Frank, PhD, Institute for Psychology of Freiburg University, with Friederike Mayer-Bruns, MD, and Kirsten Schehr, PhD, private practice, Freiburg, Germany; health economic evaluation was planned and conducted by Michael Schlander, MD, Institute for Innovation and Valuation in Health Care, Wiesbaden, Germany.

Additional Information: Other projects in our network on psychotherapy research in ADHD (speaker: Alexandra Philipsen, MD; 2006-2012, Andreas Warnke, MD, University Hospital of Würzburg, Würzburg, Germany) are coordinated by Thomas Jans, PhD (ADHD in mothers and children), Ludger Tebartz van Elst, MD (functional and morphometric brain mapping), and Klaus-Peter Lesch, MD, University Hospital of Würzburg (molecular genetics).

Additional Contributions: MEDICE Arzneimittel Puetter GmbH and Co KG provided the trial medication (Medikinet retard licensed as Medikinet adult and matching placebo). Roland Fischer, MD (MEDICE Arzneimittel Pütter GmbH and Co KG), gave his advice in preparing the study protocol, and he assisted in the serious adverse events management. He was not compensated for his work.

Data Sharing Statement: See Supplement 3.

Article

Publisher ID: zoi190209

DOI: 10.1001/jamanetworkopen.2019.4980

PMC ID: 6547099

PubMed ID: 31150084

SO-VID: 8e7c2db9-7590-42ed-9a4b-dd466b70adb2

License:

This is an open access article distributed under the terms of the CC-BY License.

History

Date received : 1 February 2019

Date accepted : 3 April 2019

Funding

Funded by: Federal Ministry of Education and Research

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Long-term Effects of Multimodal Treatment on Adult Attention-Deficit/Hyperactivity Disorder Symptoms : Follow-up Analysis of the COMPAS Trial

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Key Points

Question

Findings

Meaning

Abstract

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Related collections

Multimodal Learning Material

Most cited references 44

Attention-deficit hyperactivity disorder.

Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication.

Evaluating dopamine reward pathway in ADHD: clinical implications.

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Cited by 15

Most referenced authors 743