Research reportEffects of methylphenidate, desipramine, and l-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder
Introduction
The two main problems in children with Attention Deficit Hyperactivity Disorder (ADHD) (DSM-IV) are attentional deficiency and impulsivity/hyperactivity. Methylphenidate (MPH) is assumed to ameliorate both and is the most frequently prescribed drug for children with ADHD. MPH affects two neurotransmitter systems: it increases the amount of both dopamine (DA) and noradrenaline (NA) in the synaptic cleft [16]. However, it is unclear which of the two influences ameliorate the ADHD behavior. To get more insight into the working of MPH, in the current study two drugs working more selectively on either of the two neurotransmitter systems were used. Furthermore, we opted for drugs, which also mimic as closely as possible the working mechanism of MPH. As far as NA is concerned, MPH has been shown to block its re-uptake [43], therefore, to mimic this effect we used desipramine (DMI) as a selective NA re-uptake inhibitor. It is highly specific for the noradrenergic system and has no direct effect on dopaminergic activity. Although many studies have been conducted with DMI and ADHD children, these studies mainly focused on the clinical effects of DMI [4], [5]. In one of the few laboratory studies on ADHD and DMI [10], attention was measured with the AX version of the Continuous Performance Task (CPT). DMI did not improve the commission or omission error rates. Gualtieri et al. [13] reported the results of a study in which ADHD children received a low, medium, and high dose of DMI and placebo. Again, no improvement after DMI administration was found on CPT scores. Rapport et al. [34] conducted a study with DMI, MPH, combined medication of DMI and MPH, and placebo. No effect of DMI was noted on the rates of omission and commission errors in either the CPT-AX task or CPT double-letter version.
The second comparison drug is l-dopa, which increases synaptic DA and has no direct effect on NA [16],1 although its mechanism of action (DA agonism) is admittedly different from that of MPH, which inhibits re-uptake of DA and NA [42]. The only two studies that investigated the effects of l-dopa in children with ADHD found no clinical or cognitive improvements [19], [45].
One of the main problems of children with ADHD is impulsivity (DSM-IV), which is operationalized in the current study as the inability to stop unwanted ongoing behavior in the stop-task [20], [21]. In the stop-task a choice-reaction time task is performed and sometimes a tone is presented which instructs the children to inhibit their response to the choice task stimuli. Several studies showed that ADHD children have a deficient inhibitory control compared to normal control children in the stop-task [15], [27], [37] (see for an overview Oosterlaan et al. [28] and Tannock [41]), a finding also confirmed by us [30]. An additional advantage of the stop-task is that the choice-reaction time part of the test supplies us with a valid attentional test, thus enabling us to measure attention and inhibition in the same task.
In only one study the influence of MPH on behavioral inhibition of ADHD children has been studied using a stop-task. Tannock et al. [40] addressed the effect of MPH on ADHD and inhibitory control in a placebo-controlled study. They used 0.3 and 1.0 mg/kg MPH and found that MPH improved stopping performance but only with the higher dose. In the current study, we also use an intermediate dose (15 mg tablets, a mean dose of 0.46 mg/kg).
No studies have been carried out investigating DMI or l-dopa effects on inhibitory control in humans. However, some human and animal studies [6], [18], [36] suggest that dopaminergic mechanisms predominantly affect response-related processes (e.g. response preparation), whereas noradrenergic mechanisms are more involved in controlled processing, perhaps including inhibitory function. This would lead to the hypothesis that it is the noradrenergic effect of MPH that is related to improvement in inhibitory function [35].
In sum, the main hypothesis in this study is whether by contrasting the effects of MPH with those of DMI and l-dopa, respectively, as working more on NA and DA systems, we can determine whether the MPH effects on attention and/or inhibition are more noradrenergic rather than dopaminergic in nature.
Section snippets
Subjects
Participants were 16 ADHD children (all boys, mean±S.D., age 10.4±1.4 years (range: 7–12 years), weight 35.4±11.2 kg (range: 22–61 kg), full scale IQ on WISC-R 95.4±14.6) with a diagnosis of ADHD according to DSM-III-R criteria. They were referred to the outpatient clinic of the Utrecht Department of Child and Adolescent Psychiatry. All referred children and their parents participated in a series of extensive diagnostic evaluations, which followed a structured protocol. In the interview with the
Reaction time
A main effect of drug was found for the reaction time (F(3,13)=9.87, P<0.01). Pair-wise tests showed that reaction time under MPH was shorter than placebo (F(1,15)=18.79, P<0.005). DMI and l-dopa did not differ from placebo, respectively (F(1,15)=0.16, P=0.692) and (F(1,15)=4.54, P<0.05).
Omission rate
A drug main effect was detected (F(3,13)=3.54, P<0.05). Further testing indicated that the omission rate under MPH was the lowest (4.5%) and differed from placebo (F(1,15)=9.06, P<0.01). Although DMI yielded
Performance
The main question in the current study was whether by contrasting the effects of MPH with those of DMI and l-dopa, we could determine whether the MPH effects on attention and/or inhibition are mediated more by the noradrenergic or dopaminergic system.
MPH improved attentional performance to the go-stimuli (decrease of percentage of omission, choice-errors, and reaction time to the visual stimuli). As to the question whether the positive effect of MPH on attention might be more noradrenergic or
Acknowledgements
This research was supported by NWO Grant 575-63-082.
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2016, Epilepsy and BehaviorCitation Excerpt :Specifically, performance in the stop-signal task in both animals and humans has been found to improve from medication that increases extracellular levels of NE, like atomoxetine [14–17] and methylphenidate [18]. Moreover, patients with ADHD, who are generally impaired in inhibition capabilities and are simultaneously assumed to suffer from insufficient NE levels, show improved response inhibition when medicated with drugs that boost NE, like desipramine and methylphenidate [19,20]. Similarly, certain doses of guanfacine impair stopping probably via a decrease in NE release [16,21]; but see [22].