Neurological and biological correlations of ODD with ADHD in children and adolescents: a systematic review

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) often coexists with Oppositional Defiant Disorder (ODD), exacerbating impairment. The distinct neurological and biological patterns that differentiate this comorbidity from ADHD alone remain unclear. METHOD: We conducted systematic review of multi model correlates differentiating ODD+ADHD from ADHD alone following PRISMA 2020 with databases like MEDLINE, EMBASE, CINAHL, PsycINFO and Web of Sciences until August 2025. 144 full texts were reviewed and 26 studies were selected for final inclusion after 1457 records with 37 other sources. Designs included cross-sectional case-control studies, longitudinal studies, and imaging based on the ABCD framework, while measures covered structural and functional MRI, diffusion MRI, resting and task fNIRS, EEG and ERP, HPA-axis and immune-metabolic biomarkers, and executive and cognitive indices. The evaluation of bias employed RoB 2, ROBINS-I, and JBI, while synthesis utilised Braun-Clarke thematic analysis. RESULTS: Oppositionality involved limbic-striatal and cerebello-cortical differences, with ODD+ADHD showing greater executive and emotion-processing deficits than ADHD alone. ODD was linked to lower cortisol and reduced sympathetic reactivity, while ADHD showed higher cortisol and tryptophan-kynurenine shifts, with cytokines decreasing after methylphenidate. CONCLUSION: ODD along with ADHD showed a distinct neurobiological and physiological pattern from ADHD alone. Such pattern is marked by greater executive and emotional regulation deficits with unique stress-response patterns, highlighting the need for tailored assessments and intervention approaches.