Attention-Deficit/Hyperactivity Disorder Subtypes Defined by Cognition Have a Distinct Neural and Clinical Profile and Differ in Response to Atomoxetine.

OBJECTIVE ADHD is clinically and etiologically heterogeneous across multiple levels of organization. We 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. We sought to validate the subtypes using constructs at other meaningful levels of organization: quantitative electroencephalogram (qEEG), clinical symptoms, and response to treatment with atomoxetine and methylphenidate. METHOD Hierarchical cluster analysis of cognitive measures defined clusters in one 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 six 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 = -0.47, p = 4.89*10ˆ-9), Theta (β = -0.39, p = 7.84*10ˆ-6), and Beta (β = -0.36, p = 4.21*10ˆ-7) bands, and higher resting heart rate. Clinically, this subtype also had more severe anxiety (M = 7.6, SD = 6.0) than the sustained attention subtype (M = 4.7, SD = 4.3, p = 0.02), and had a markedly better response to atomoxetine (β = 8.4, p = 0.008, Cohen's d = 0.71). CONCLUSION Cognitive performance appears effective for identifying ADHD subtypes that have a distinct neural basis and that may particularly benefit from non-stimulants such as atomoxetine.