Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys

Abstract

The stimulant methylphenidate (MPX) and the nonstimulant atomoxetine (ATX) are the most commonly prescribed medications for attention deficit hyperactivity disorder (ADHD). However, no functional magnetic resonance imaging (fMRI) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX. A randomized, double-blind, placebo-controlled, crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX, ATX, and placebo during a stop task, combined with fMRI within 19 medication-naive ADHD boys, and their potential normalization effects relative to 29 age-matched healthy boys. Compared with controls, ADHD boys under placebo showed bilateral ventrolateral prefrontal, middle temporal, and cerebellar underactivation. Within patients, MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation, which correlated with enhanced inhibitory capacity. Relative to controls, both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo, while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX. The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX.

Keywords: atomoxetine; attention deficit hyperactivity disorder; functional magnetic resonance imaging; methylphenidate; motor response inhibition; stop task.

Figure 1.

Stop task. Subjects have to respond to go arrows (79.6% of trials, 294 trials) that point either right or left with a right/left button response. In 20.4% of trials (60 trials), the go-signals were followed (about 250 ms later) by stop-signals and subjects had to inhibit their motor responses. A tracking algorithm changed the time interval between go-signals and stop-signals according to each subject's performance on previous trials (average percentage of inhibition over previous stop trials, recalculated after each stop trial), resulting in 50% successful and 50% unsuccessful inhibition trials.

Figure 2.

Within-group activation for healthy control boys and boys with ADHD under either placebo, MPX, or ATX. Axial sections showing within-group brain activation for the healthy control boys and boys with ADHD under each condition (placebo, MPH, and ATX) for the contrast Successful inhibition—go trials. Talairach z-coordinates are indicated for slice distance (in mm) from the intercommissural line. The right side of the image corresponds to the right side of the brain.

Figure 3.

Between-group ANOVA comparisons between healthy control boys and boys with ADHD under placebo, MPX, or ATX. Axial sections showing the ANOVA between-group differences in brain activation between healthy control boys and boys with ADHD under each drug condition (placebo, MPX, and ATX) during successful inhibition in the stop task. Although both drugs normalized underactivation in the left and right VLPFC and cerebellum, rigorous effect size comparisons testing for normalization effects showed that the normalization was significant for both drugs in the left VLPFC, but only significant for MPX and not significant for ATX in the right VLPFC and cerebellum. Talairach z-coordinates are indicated for slice distance (in mm) from the intercommissural line. The right side of the image corresponds to the right side of the brain.

Figure 4.

Results of the repeated-measures ANOVA analysis on drug effect within ADHD boys. Axial sections showing the repeated-measures ANOVA results for the drug effect within ADHD patients (placebo, MPX, and ATX). Talairach z-coordinates are indicated for slice distance (in mm) from the intercommissural line. The right side of the image corresponds to the right side of the brain.

Figure 5.

Between-group ANOVA comparison between healthy control boys and boys with ADHD under MPX for the contrast of go–successful inhibition trials. Axial sections showing the ANOVA between-group difference effects in brain activation between healthy control boys and boys with ADHD under MPX. Talairach z-coordinates are indicated for slice distance (in mm) from the intercommissural line. The right side of the image corresponds to the right side of the brain.