Background <p>Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition with high societal impact. While psychostimulants like methylphenidate (MPH) are first-line treatments, 10–20% of patients show insufficient efficacy, and many experience side effects such as sleep and appetite disturbances. Emerging evidence suggests that neuroinflammation and oxidative stress contribute to ADHD pathophysiology. Animal studies indicate that MPH may induce pro-inflammatory processes, but this has yet to be characterized in humans.</p> Methods <p>The ANIME study (ADHD Nutritional, Inflammatory, and Metabolic Endophenotypes) employs a combined case-control and prospective cohort design. A case-control study will compare the immune, inflammatory, and nutritional profiles of 40 children/adolescents with ADHD against 40 age- (± 2 years) and sex-matched typically developing controls. The ADHD group will have a follow-up visit to assess the impact of psychostimulant treatment). The primary outcome is the comparison of the immune and inflammatory markers’ levels, particularly IL-6 levels, at baseline. Secondary outcomes include deep immunophenotyping via spectral flow cytometry (Cytek Aurora) and high-sensitivity multiplex proteomics (NULISA), alongside assessments of polyphenol bioavailability, diet quality (KIDMED), and clinical symptoms.</p> Discussion <p>ANIME will provide an in-depth characterization of the “inflammatory biotype” in ADHD, specifically examining how psychostimulants interact with pre-existing immune states. By integrating metabolic, nutritional, and clinical data, the study aims to identify biomarkers for treatment response and tolerability, ultimately informing personalized care and future trials of antioxidant-rich adjunct therapies like polyphenols.</p> Trial registration <p>Clinicaltrials.gov. Number: NCT07417878 (<a href="https://clinicaltrials.gov/study/NCT07417878">https://clinicaltrials.gov/study/NCT07417878</a>). Registered on the 13th of Febraury, 2026.</p>