Attention-deficit/hyperactivity disorder subtypes defined by cognition have a distinct neural and clinical profile and differ in response to atomoxetine

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; https://www.clinicaltrials.gov/study/NCT00863499.