Psychological Medicine

Original Articles

Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory

A. Cubilloa1 , A. B. Smitha1 , N. Barretta1, V. Giampietroa2, M. Brammera2, A. Simmonsa2a3a4 and K. Rubiaa1 c1

a1 Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, London, UK

a2 Department of Neuroimaging, Institute of Psychiatry, King's College London, London, UK

a3 Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK

a4 NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Trust and Institute of Psychiatry, King's College London, London, UK


Background The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM).

Method A total of 20 medication-naive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, double-blind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys.

Results Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced fronto-temporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects.

Conclusions The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM.

(Received February 16 2012)

(Revised January 16 2013)

(Accepted March 05 2013)

(Online publication April 19 2013)

Key words

  • Atomoxetine;
  • attention deficit hyperactivity disorder;
  • functional magnetic resonance imaging;
  • methylphenidate;
  • n-back;
  • working memory


c1 Address for correspondence: K. Rubia, Ph.D., Department of Child and Adolescent Psychiatry/SGDP, P046, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF, UK. (Email:


  These authors contributed equally as joint first authors.