HOLLYWOOD, FLA. – Activity in the regions of the brain associated with motivation and reward correlated with clinical improvements in attention-deficit/hyperactivity disorder symptoms in adults given lisdexamfetamine dimesylate, the results of an imaging study have shown.
"What we saw is that Vyvanse (lisdexamfetamine dimesylate) increases activity in the caudate and anterior cingulate, which then seems to show that the medication increases sensitivity to reward," Stephanie Duhoux, Ph.D., said in an interview about her poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.
Stephanie Duhoux, Ph.D.
"You could say that when they are taking this medication, these patients don’t need as much reward in order to get them to engage in an activity," said Dr. Duhoux of Icahn School of Medicine at Mount Sinai, New York, who was a new investigator award winner at this year’s ASCP meeting.
Building upon recent findings by Dr. Nora D. Volkow, director of the National Institute on Drug Abuse and her colleagues (Mol. Psychiatry 2011;16:1147-54) indicating that a dopaminergic dysfunction in the brain’s motivation-reward system might contribute to ADHD, Dr. Duhoux and her colleagues used imaging to study changes in the brains of 20 adults with ADHD after being treated with lisdexamfetamine dimesylate. Study participants, 11 of whom were men, ranged in age from 19 to 52 years. Lisdexamfetamine dimesylate, a class II stimulant, was approved in 2012 by the Food and Drug Administration for adult ADHD.
In the randomized, placebo-controlled, crossover study, each participant received the active drug for at least 4 weeks in an escalating stepped dose titration (30, 50, 70 mg). The participants were scanned twice; once after taking the placebo and also after at least 2 weeks of taking their best tolerated dose of the active drug.
The scans were done while the subject performed a passive-avoidance learning task where participants learned to associate whether their response to a specific image corresponded with a high chance of either winning or losing money. The participants were asked to respond when they thought they were going to win and avoid responding when they thought they were going to lose. The scans were intended to capture the effect of the drug on components of the motivation/reward circuitry and its impact on decision-making processes.
Each participant’s blood oxygen level–dependent (BOLD) signals were modeled according to the moment they chose or refused to respond to an image, and when they received the resulting feedback as to whether they’d won or lost money. Decision-related activity was modulated by the expected value that the participant had for the image, and the feedback processing was modulated by the difference between the result they had expected from their choice and the result that actually occurred (the prediction error).
For the scans, whole-brain analyses were used (P less than .005); the extent threshold was defined via Monte Carlo simulation. A small-volume correction was performed on the ventral striatum with a P value FWE (family-wise error) corrected of less than .05.
To examine the relationship between each participant’s regional BOLD signals during the imaging and their respective clinician ratings on the ADHD Rating Scale for adults, Dr. Duhoux and her colleagues used regression analyses and found that when compared to placebo, when the participant chose not to respond to an image, the stimulant increased the modulation of BOLD responses by the expected value of the image in the dorsolateral prefrontal cortex.
The drug also was associated with increased BOLD response in the ventral striatum when a reward was received. This response was modulated by the prediction error in the ventromedial prefrontal cortex. Increased activation in the ventral striatum and ventromedial prefrontal cortex with reward was positively correlated with greater improvement in ADHD Rating Scale scores.
These results suggest that "the medication helps increase the value of the stimulus and the person’s perception of the stimulus and also reinforces the ability to avoid responding to stimuli considered to be less rewarding," Dr. Duhoux said. "Practically speaking, this is associated with clinical improvements and makes patients more sensitive to an activity, so they engage more easily."
Dr. Duhoux said she had no relevant disclosures. This study was funded by Shire, maker of Vyvanse.
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