COMT Val108/158Met polymorphism and the modulation of task-oriented behavior in children with ADHD

Abstract

It has been suggested that the symptoms of attention-deficit/hyperactivity disorder (ADHD), including inattention and/or hyperactivity/impulsivity, translate into deficits in task-oriented behavior or problem-focused activity. The frontosubcortical dopamine pathway has been implicated in ADHD. One of the key modulators of extracellular dopamine levels in the prefrontal cortex is catechol-O-methyltransferase (COMT). The objective of this study was to examine the association of the COMT Val(108/158)Met polymorphism with (1) task-oriented behavior in children with ADHD, and (2) response of this behavior given methylphenidate (MPH) treatment. Children of Caucasian ethnicity, having ADHD (n=188), were assessed using the Restricted Academic Situation Scale (RASS). The RASS uses a simulated academic environment within the research clinic, to assess the child's ability for independent, sustained orientation to an assignment of math problems. Each child was administered placebo and MPH (0.5 mg/kg in a divided b.i.d. dose), each for a 1-week period, in a randomized, double-blind, crossover trial. On day 3 of the respective treatment week, the child was administered placebo/MPH in the clinic, and the acute change in behavior (before and 1 h after treatment) was evaluated on the RASS. Analysis was carried out using mixed model analysis of variance. Significant main effects of COMT genotype (F(2,184)=5.12, p=0.007) and treatment (F(1,184)=44.26, p<0.001) on task-oriented behavior were observed. However, no genotype by treatment interaction was observed. These results suggest that the COMT Val(108/158)Met polymorphism modulates task-oriented behavior, but it does not modulate the response of this behavior with MPH treatment.

Figure 1

Acute response of task orientation to placebo and methylphenidate as measured in the restricted academic situation. Restricted Academic Situation Scale (RASS) scores (mean ± SE), before and one hour after treatment with placebo (2 left bars) or methylphenidate (2 right bars). ***: p<0.000. The RASS score is the total number of behavioural events measured over a 15 minute time period. Behavioural events were recorded at 30-second intervals according to five categories: off-task, fidgets, out of seat, vocalizes and plays with objects.

Figure 2

Acute response of task orientation to placebo and methylphenidate as measured in the restricted academic situation in children with ADHD separated according to their genotype in the COMT(Val^105/158Met) polymorphism. Restricted Academic Situation Scale (RASS) scores (mean ± SE) before administration of either placebo (BP) or methylphenidate (BM) and one hour after administration of either placebo (AP) or methylphenidate (AM) in the three genotype groups. Dashed line indicates the mean of the RASS calculated over the four measurement times (before and after placebo and methylphenidate).