Attention-Deficit/Hyperactivity Disorder Subtypes Defined by Cognition Have a Distinct Neural and Clinical Profile and Differ in Response to Atomoxetine - 15/10/25
, Kristi R. Griffiths, PhD b, Simon D. Clarke, MBBS c, Michael R. Kohn, MD, PhD c, Leanne Williams, PhD aAbstract |
Objective |
Attention-deficit/hyperactivity disorder (ADHD) is clinically and etiologically heterogeneous across multiple levels of organization. This study sought to parse the heterogeneity of ADHD by identifying cognitive subtypes based on common features of ADHD, including inhibitory control, sustained attention, and working memory. To validate the subtypes, constructs at other meaningful levels of organization were used: quantitative electroencephalogram (qEEG), clinical symptoms, and response to treatment with atomoxetine and methylphenidate.
Method |
Hierarchical cluster analysis of cognitive measures defined clusters in 1 clinical sample (n = 112). Replication was tested in a second, held-out clinical sample (n = 336). Cluster subtypes were assessed for neural validation using resting-state qEEG and heart rate and for clinical applicability using ADHD and anxiety symptom ratings. Further, clusters were assessed for differential treatment response after 6 weeks of atomoxetine or methylphenidate.
Results |
Two clusters defined by specific cognitive profiles were identified and replicated. The inhibitory control subtype was distinguished by more activity in qEEG delta (β = −.47, p = 4.89 × 10−9), theta (β = −.39, p = 7.84 × 10−6), and beta (β = −.36, p = 4.21 × 10−7) bands and higher resting heart rate. Clinically, this subtype also had more severe anxiety (mean [SD] = 7.6 [6.0]) than the sustained attention subtype (mean [SD] = 4.7 [4.3], p = .02) and had a markedly better response to atomoxetine (β = 8.4, p = .008, Cohen’s d = 0.71).
Conclusion |
Cognitive performance appears to be effective for identifying ADHD subtypes that have a distinct neural basis and that may particularly benefit from nonstimulant medications such as atomoxetine.
Diversity & Inclusion Statement |
We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.
The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list.
Clinical Trial Registration Information |
International Study to Predict Optimised Treatment in Attention Deficit/Hyperactivity Disorder; NCT00863499.
Le texte complet de cet article est disponible en PDF.Key words : ADHD, atomoxetine, cognition, electroencephalography, methylphenidate hydrochloride
Plan
| John E. Leikauf received support for this study from the National Institute of Mental Health under grant 1K23MH121650-01A1. Michael R. Kohn, Simon D. Clarke, and Leanne Williams received funding for the ACTION project from the National Health and Medical Research Council Project 457424, and for the iSPOT-A trial from Brain Resource, Inc. |
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| Some preliminary analyses that later formed a portion of these results were reported at the AACAP 64th Annual Meeting; October 23-28, 2017; Washington, DC. |
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| Data Sharing: The datasets used in this analysis were collected as part of the ACTION and iSPOT-A studies. These datasets are available on request from Stanford BRAINnet at datasets. The BRAINnet repository meets the requirements for being public but also aligns with the procedures of other official public and scientific repositories such as HCP, ABCD, and NDA. This choice is in line with the FAIRness guidelines and it respects the original funding requirements, allowing for appropriate source contributions and citations. Our approach is specifically designed for scientific use, which includes limiting access to for-profit entities to comply with the original funding stipulations and participant consent. Therefore, total open access is not feasible. Our intention is to provide public access that is consistent with the consent agreements and the original funding intentions, similar to the data shared through NIH repositories. On Stanford BRAINnet, we established a data access request form that screens users, similar to other public repositories. |
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| Disclosure: John E. Leikauf, Kristi R. Griffiths, Simon D. Clarke, Michael R. Kohn, and Leanne Williams have reported no biomedical financial interests or potential conflicts of interest. |
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