Role of the retinoid X receptor–peroxisome proliferator-activated receptor-γ axis in adolescent attention-deficit hyperactivity disorder

Studies have reported the retinoid X receptor (RXR)–peroxisome proliferator-activated receptor-γ (PPAR-γ) axis, a heterodimeric nuclear receptor complex regulating synaptic plasticity and neuroinflammation, in neurodevelopment, with emerging evidence suggesting its disruption contributes to cognitive impairments akin to those in attention deficit hyperactivity disorder (ADHD). This study included 104 adolescents with ADHD and 87 age-matched neurotypical adolescents. All participants completed working memory and go/no-go tasks. Clinical symptoms were assessed using the Swanson, Nolan, and Pelham IV scale and the Child Behavior Checklist Dysregulation Profile. Fasting serum levels of RXR-α, PPAR-γ, and PPAR-γ coactivator 1α were quantified via enzyme-linked immunosorbent assay. Generalized linear models adjusted for demographic characteristics, ADHD medications, and clinical symptoms revealed that adolescents with ADHD had reduced RXR-α levels ( p = 0.001; Cohen’s d = 0.47) compared with neurotypical adolescents. No significant between-group difference was noted in the level of PPAR-γ or PPAR-γ coactivator A. Furthermore, RXR-α levels negatively associated with the mean reaction time in the go/no-go task (β = -0.001; Wald χ2 = 0.475; p = 0.029). To the best of our knowledge, this study is the first to demonstrate reduced peripheral RXR-α levels in human adolescents with ADHD, independent of medication status and symptom severity, extending preclinical retinoid signaling evidence. Further investigation is required to elucidate the neuromechanisms linking ADHD to the RXR–PPAR-γ axis.