1Molecular Psychiatry Laboratory - Department of Psychiatry, Hadassah - Hebrew University Medical center, Jerusalem, Israel.; 2The Herman-Danna Division of Pediatric Psychiatry, Department of Psychiatry, Hadassah - Hebrew University Medical Center; Jerusalem Israel.
Introduction: Molecular understanding of stimulant mechanism of action is mostly limited to rodent models. Aims: The current study investigated whether genome scale expression patterns may be informative of baseline ADHD symptom severity scores, and exposure to methylphenidate (MPH), and correlate with prospectively documented clinical response among previously drug naïve children with ADHD, and may point to molecular mechanisms underlying drug response.
Materials and Methods: Drug naive children with ADHD, were included, applying a standardized prospective assessment of medication treatment response. Blood was sampled before and after drug treatment. Genome scale expression patterns in mononuclear cells sampled from a subset of children who are responders to methylphenidate (MPH). Acute (2 hours) and sub acute (2 weeks) expression changes were calculated relative to baseline expression patterns at the drug naive phase, to determine if changes are informative of MPH exposure and may correlate with prospectively documented response. Affymetrix 1.0 ST arrays were used.
Results: 44 drug naive subjects with ADHD were ascertained. Microarray analyses on samples from the 10 subjects showing the best clinical response to standard MPH treatment, allowed classification of samples based on expression differences 2 hours as well as 2 weeks following MPH treatment. Baseline expression patterns correlated with ADHD psychopathology scores. Several known ADHD risk genes showed significant expression level correlations with baseline ADHD scores as well as changed significantly following MPH.
Conclusions: This is the first evidence in human subjects demonstrating surrogate mononuclear cell genome scale expression patterns are informative of MPH response and may be used to investigate response prediction and selective underlying molecular targets. These results may pave the way for additional pharmacogenetic research in peripheral mononuclear cells.