This study aims to better understand the biological mechanisms involved in attention deficit hyperactivity disorder (ADHD) and to clarify why some children and adolescents respond well to methylphenidate (MPH)-the most commonly prescribed medication-while others do not. Although MPH is effective for many patients, a significant number experience limited benefits or problematic side effects such as appetite loss and sleep difficulties. Recent research suggests that inflammation and oxidative stress in the body may play an important role in ADHD. Some animal studies also indicate that MPH itself might trigger inflammatory processes, but this has never been examined directly in humans. The main goal of this research is to determine whether children with ADHD show differences in their nutritional, immune, and inflammatory profiles compared to children without ADHD, and whether these biological factors influence symptom severity, digestive problems, and response to treatment. The study also seeks to understand whether MPH has a measurable inflammatory effect in young patients and whether this could be linked to treatment tolerability. To answer these questions, the study combines several approaches. First, a case-control comparison will examine differences between children/adolescents with ADHD and age- and sex-matched controls. Second, a one-year follow-up of the ADHD group will evaluate changes over time and help identify biological predictors of treatment response and side effects. Finally, a cross-sectional analysis will investigate the role of polyphenols-natural antioxidant compounds found in food-in relation to inflammation, treatment outcomes, and gender differences. The primary focus is on comparing levels of the inflammatory marker IL-6 between children with ADHD and controls. Secondary objectives include assessing additional inflammatory and immune indicators, nutritional status, gastrointestinal symptoms, ADHD severity, irritability, and MPH tolerability. By identifying specific inflammatory and immune markers associated with ADHD and treatment response, this study hopes to improve understanding of the disorder and guide more personalized and effective treatment strategies for young patients. It will also provide the first human data on whether psychostimulant medications may have inflammatory effects.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
80
Children and adolescents with ADHD undergo diagnostic confirmation (K-SADS if not completed within 6 months), behavioral and functional questionnaires (ADHD-RS for cases only, P-ARI, R4PDQ, KIDMED), clinician-rated scales (CGI-S/I, PAERS), and venous blood sampling for plasma and PBMC analysis. They complete two assessments: one during stabilized medication and one after a minimum two-week medication interruption, consistent with clinical practice guidelines. Assessments occur during the school period to reduce confounding factors.
Children and adolescents without psychiatric disorders undergo behavioral and functional questionnaires (P-ARI, R4PDQ, KIDMED)and venous blood sampling for plasma and PBMC analysis.
Circulating IL-6 Levels in ADHD vs. Controls
Comparison of IL-6 levels between children and adolescents with ADHD and age- and sex-matched typically developing controls at baseline (V1).
Time frame: Baseline (V1)
CRP Levels in ADHD vs. Controls
Comparison of CRP levels between ADHD participants and matched controls at V1.
Time frame: Baseline (V1)
IL-1β Levels in ADHD vs. Controls
Comparison of IL-1β levels between ADHD participants and matched controls at V1.
Time frame: Baseline (V1)
IL-6 Levels in ADHD vs. Controls
Comparison of IL-6 levels between ADHD participants and matched controls at V1.
Time frame: Baseline (V1)
IL-10 Levels in ADHD vs. Controls
Comparison of IL-10 levels between ADHD participants and matched controls at V1.
Time frame: Baseline (V1)
TNF-α Levels in ADHD vs. Controls
Comparison of TNF-α levels between ADHD participants and matched controls at V1.
Time frame: Baseline (V1)
NfL Levels in ADHD vs. Controls
Comparison of NfL levels between ADHD participants and matched controls at V1.
Time frame: Baseline (V1)
CRP Levels in Medicated vs. Unmedicated ADHD Participants
Comparison of CRP levels in ADHD participants during medicated vs. unmedicated periods (V1 vs. V2).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
IL-1β Levels in Medicated vs. Unmedicated ADHD Participants
Comparison of IL-1β levels in ADHD participants during medicated vs. unmedicated periods (V1 vs. V2).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
IL-6 Levels in Medicated vs. Unmedicated ADHD Participants
Comparison of IL-6 levels in ADHD participants during medicated vs. unmedicated periods (V1 vs. V2).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
IL-10 Levels in Medicated vs. Unmedicated ADHD Participants
Comparison of IL-10 levels in ADHD participants during medicated vs. unmedicated periods (V1 vs. V2).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
TNF-α Levels in Medicated vs. Unmedicated ADHD Participants
Comparison of TNF-α levels in ADHD participants during medicated vs. unmedicated periods (V1 vs. V2).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
NfL Levels in Medicated vs. Unmedicated ADHD Participants
Comparison of NfL levels in ADHD participants during medicated vs. unmedicated periods (V1 vs. V2).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Pro- and Anti-Inflammatory Cytokine Plasma Levels for Immuno-Inflammatory Biotype Identification in ADHD patients
Exploration of the existence of distinct immuno-inflammatory profiles among children and adolescents with ADHD using unsupervised clustering methods to define High Inflammatory Profile vs Low Inflammatory Profile. Participants with ADHD will be categorized into distinct biotypes (High Inflammatory vs. Low Inflammatory) determined by the integrated analysis of pro- and anti-inflammatoru cytokines. Plasma levels of IL-6, IL-1β, IL-10, and TNF-α will be measured in pg/mL. These biomarkers will contribute to the identification of High vs Low inflammatory biotypes using unsupervised clustering methods.
Time frame: Baseline (V1)
C-Reactive Protein (CRP) Levels for Immuno-Inflammatory Biotype Identification in ADHD patients
Exploration of the existence of distinct immuno-inflammatory profiles among children and adolescents with ADHD using unsupervised clustering methods to define High Inflammatory Profile vs Low Inflammatory Profile. Participants with ADHD will be categorized into distinct biotypes (High Inflammatory vs. Low Inflammatory) determined by the integrated analysis of acute phase reactants. C-reactive protein (CRP) levels will be measured in mg/L. These biomarkers will contribute to the identification of High vs Low inflammatory biotypes using unsupervised clustering methods.
Time frame: Baseline (V1)
Neurofilament Light Chain (NfL) Levels for Immuno-Inflammatory Biotype Identification in ADHD patients
Exploration of the existence of distinct immuno-inflammatory profiles among children and adolescents with ADHD using unsupervised clustering methods to define High Inflammatory Profile vs Low Inflammatory Profile. Participants with ADHD will be categorized into distinct biotypes (High Inflammatory vs. Low Inflammatory) determined by the integrated analysis of a neuronal injury marker. Neurofilament Light chain (NfL) levels will be measured in pg/mL. These biomarkers will contribute to the identification of High vs Low inflammatory biotypes using unsupervised clustering methods.
Time frame: Baseline (V1)
Correlations between Immuno-Inflammatory Profiles & ADHD Symptoms
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and ADHD symptoms using the Attention Deficit Hyperactivity Disorder Rating Scale 'ADHD-RS'
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Immuno-Inflammatory Profiles & Gastrointestinal Symptoms
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and gastrointestinal symptoms using the Rome IV Pediatric Diagnostic Questionnaire 'R4DQ-child'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Immuno-Inflammatory Profiles & Treatment Tolerability/Effectiveness
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and treatment tolerability/effectiveness using the Pediatric Adverse Event Rating Scale 'PAERS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Immuno-Inflammatory Profiles & Treatment Tolerability/Effectiveness
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and treatment tolerability/effectiveness using the Visual Analog Scale 'VAS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Immuno-Inflammatory Profiles & Irritability
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and irritability using the Parental Affective Reactivity Index 'ARI-P'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Nutritional Profiles in ADHD vs. Controls
Comparison of nutritional profiles assessed using the Mediterranean Diet Quality Index in children and adolescents 'KIDMED' between children and adolescents with ADHD and age- and sex-matched typically developing peers.
Time frame: Baseline (V1)
Correlations between Nutritional and Immuno-Inflammatory profiles
Examination of correlations between nutritional profiles - using the Mediterranean Diet Quality Index in children and adolescents 'KIDMED' - and the immuno-inflammatory profiles (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Polyphenol Bioavailability & ADHD symptoms
Examination of correlations of polyphenol bioavailability - using a 3-day food-tracking diary and the Phenol-Explorer database - with ADHD symptoms using the Attention Deficit Hyperactivity Disorder Rating Scale 'ADHD-RS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Polyphenol Bioavailability & Irritability
Examination of correlations between polyphenol bioavailability - using a 3-day food-tracking diary and the Phenol-Explorer database - with irritability using the Parental Affective Reactivity Index 'ARI-P').
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Polyphenol Bioavailability & Immuno-Inflammatory Markers
Examination of correlations between polyphenol bioavailability - using a 3-day food-tracking diary and the Phenol-Explorer database - with immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL).
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Polyphenol Bioavailability & Treatment Tolerability/Effectiveness
Examination of correlations between polyphenol bioavailability - using a 3-day food-tracking diary and the Phenol-Explorer database - with psychostimulant treatment tolerability/effectiveness using the Pediatric Adverse Event Rating Scale 'PAERS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Polyphenol Bioavailability & Treatment Tolerability/Effectiveness
Examination of correlations between polyphenol bioavailability - using a 3-day food-tracking diary and the Phenol-Explorer database - with psychostimulant treatment tolerability/effectiveness using the Visual Analog Scale 'VAS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Immuno-Inflammatory Profiles & ADHD Symptoms
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and ADHD symptoms using the Attention Deficit Hyperactivity Disorder Rating Scale 'ADHD-RS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Immuno-Inflammatory Profiles & Irritabiliy
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and irritabiliy using the Parental Affective Reactivity Index 'ARI-P'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between immuno-inflammatory markers and ADHD symptoms
Examination of correlations between immuno-inflammatory markers (CRP, IL-6, IL-1β, IL-10, TNF-α, and NfL) and ADHD symptoms using Clinical Global Impression 'CGI'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between nutritional profiles and ADHD symptoms
Examination of correlations between nutritional profiles - using the Mediterranean Diet Quality Index in children and adolescents 'KIDMED' - and clinical symptoms using the Attention Deficit Hyperactivity Disorder Rating Scale 'ADHD-RS'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between nutritional profiles and overall clinical symptoms
Examination of correlations between nutritional profiles - using the Mediterranean Diet Quality Index in children and adolescents 'KIDMED' - and overall clinical symptoms using Clinical Global Impression 'CGI'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
Correlations between Polyphenol Bioavailability & overall clinical symptoms
Examination of correlations of polyphenol bioavailability using a 3-day food-tracking diary and the Phenol-Explorer database with overall clinical symptoms using Clinical Global Impression 'CGI'.
Time frame: Baseline (V1) and Follow-up (V2)(up to 6-months after V1)
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