A preliminary study on methylphenidate-regulated gene expression in lymphoblastoid cells of ADHD patients

Abstract

Objectives. Methylphenidate (MPH) is a commonly used stimulant medication for treating attention-deficit/hyperactivity disorder (ADHD). Besides inhibiting monoamine reuptake there is evidence that MPH also influences gene expression directly. Methods. We investigated the impact of MPH treatment on gene expression levels of lymphoblastoid cells derived from adult ADHD patients and healthy controls by hypothesis-free, genome-wide microarray analysis. Significant findings were subsequently confirmed by quantitative Real-Time PCR (qRT PCR) analysis. Results. The microarray analysis from pooled samples after correction for multiple testing revealed 138 genes to be marginally significantly regulated due to MPH treatment, and one gene due to diagnosis. By qRT PCR we could confirm that GUCY1B3 expression was differential due to diagnosis. We verified chronic MPH treatment effects on the expression of ATXN1, HEY1, MAP3K8 and GLUT3 in controls as well as acute treatment effects on the expression of NAV2 and ATXN1 specifically in ADHD patients. Conclusions. Our preliminary results demonstrate MPH treatment differences in ADHD patients and healthy controls in a peripheral primary cell model. Our results need to be replicated in larger samples and also using patient-derived neuronal cell models to validate the contribution of those genes to the pathophysiology of ADHD and mode of action of MPH.

Key words::

• attention-deficit-/hyperactivity disorder
• methylphenidate
• gene expression
• disease models
• microarray analysis

Acknowledgements

We gratefully acknowledge the excellent technical assistance of Theresia Töpner, Joyce Auer and Margarete Göbel. We would like to thank Rainer Burger and Florian Proft for their technical advice.

Statement of Interest

This study was supported by the Interdisciplinary Center for Clinical Research (IZKF) grant Z-3/24 to SKS; HW and CJS were supported by the IZKF grant Z-6. AR and KPL are supported by the Deutsche Forschungsgemeinschaft (KFO125 to AR and KPL, TRR58/A1 and A5 to KPL, and TRR58/B6 and Z2 to AR, RE1632/5-1 to AR, RTG1256 to KPL and AR). This work was supported by the BMBF (DZHI, project 01EO1004) and the European Commission (EC FP7 project Aggressotype (FP7-Health-2013-Innovation-1 602805). The funding sources had no other role than financial support. AR participated in two non-interventional trials sponsored by Astra Zeneca. CJ has received speaker's honoraria by Medice and Novartis and is a member of the advisory boards of Medice.

Supplementary material available online

Supplementary Table I.