Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder

Arch Gen Psychiatry. 2012 Sep;69(9):952-61. doi: 10.1001/archgenpsychiatry.2011.2053.


CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / therapeutic use*
  • Atomoxetine Hydrochloride
  • Attention Deficit Disorder with Hyperactivity / diagnosis
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / psychology
  • Brain / drug effects*
  • Brain Mapping
  • Central Nervous System Stimulants / therapeutic use*
  • Child
  • Female
  • Frontal Lobe / drug effects
  • Gyrus Cinguli / drug effects
  • Humans
  • Image Interpretation, Computer-Assisted*
  • Image Processing, Computer-Assisted
  • Imaging, Three-Dimensional
  • Inhibition, Psychological
  • Magnetic Resonance Imaging*
  • Male
  • Methylphenidate / therapeutic use*
  • Motor Cortex / drug effects
  • Neural Pathways / drug effects
  • Neuropsychological Tests
  • Parietal Lobe / drug effects
  • Propylamines / therapeutic use*
  • Psychomotor Performance / drug effects
  • Treatment Outcome


  • Adrenergic Uptake Inhibitors
  • Central Nervous System Stimulants
  • Propylamines
  • Methylphenidate
  • Atomoxetine Hydrochloride