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

Abstract

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.

Figure 1.

Flow diagram of participant progress through the study. Shading denotes procedures performed as part of the present study. ADHD indicates attention-deficit/hyperactivity disorder; fMRI, functional magnetic resonance imaging; and NIMH, National Institute of Mental Health.

Figure 2.

Treatment improved ratings of attention-deficit/hyperactivity disorder (ADHD) symptoms and response inhibition on the go/no-go task. A, Treatment significantly reduced ratings on the total score of the ADHD Rating Scale-IV-Parent Version (ADHD-RS-IV) (F_1,34=102.33, P<.001). The mean percentage improvement in the ADHD-RS-IV ratings was 55% for the methylphenidate group and 57% for the atomoxetine group. B, Treatment also increased the percentage of successful inhibitions on no-go trials of the go/no-go task (F_1,34=5.77, P=.02). There were no differences between the 2 medications in the improvement of symptom ratings and inhibitory function over treatment. Error bars indicate 1 SD. Asterisks indicate significant time effects (baseline vs posttreatment). Methylphenidate and atomoxetine both given in hydrochloride form.

Figure 3.

Common therapeutic action of methylphenidate hydrochloride and atomoxetine hydrochloride treatments for attention-deficit/hyperactivity disorder (ADHD). A, Symptomatic improvements with methylphenidate and atomoxetine use were associated with reductions in bilateral motor cortex activation in youth with ADHD (n=18 each). Results are displayed at P<.005 uncorrected, with a cluster threshold of greater than 100 contiguous voxels. B, Parameter estimates for left and right motor cortex signal change during treatment are plotted against percentage improvement in ratings on the ADHD Rating Scale-IV-Parent Version (ADHD-RS-IV change score). Parameter estimates were extracted from 8-mm-radius spheres centered at the peaks of maximal activation. Noncentered ADHD-RS-IV change scores are plotted for clarity. Regression lines in each scatterplot correspond to the lines of best fit.

Figure 4.

Unique therapeutic actions of methylphenidate and atomoxetine treatments for attention-deficit/hyperactivity disorder (ADHD). A, Symptom improvement was differentially related to gains in activation for the atomoxetine hydrochloride group and reductions in activation for the methylphenidate hydrochloride group in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex in youth with ADHD (n=18 each). Results are displayed at P<.005 uncorrected, with a cluster threshold at greater than 100 contiguous voxels. L indicates left; and R, right. B, Parameter estimates for signal change during treatment in the right inferior frontal gyrus, left anterior cingulate cortex/supplementary motor area, and bilateral posterior cingulate cortex are plotted against percentage improvement in ratings on the ADHD Rating Scale-IV-Parent Version (ADHD-RS-IV change score). Parameter estimates were extracted from 8-mm-radius spheres centered at the peaks of maximal activation. Noncentered ADHD-RS-IV change scores are plotted for clarity. Regression lines in each scatterplot correspond to the lines of best fit.