Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder

Cheon, Keun‐Ah; Jun, Jin-Yong; Cho, Daeyeon

doi:10.1097/yic.0b013e328306a977

Cited by 34 publications

(33 citation statements)

References 43 publications

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“…Relevant to dopaminergic and noradrenergic transmission, we found support for earlier observations 19, 38, 39 that variants in COMT moderated clinical benefit from MPH. However, contrary to studies in healthy subjects 37 and typical ADHD, in our data set met -carriers showed a greater reduction in hyperactivity with MPH treatment than val/val homozygotes.…”

Section: Discussionsupporting

confidence: 88%

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders

et al. 2013

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Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1–DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

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Section: Discussionsupporting

confidence: 88%

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders

et al. 2013

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“…In Caucasians, the Met allele was reported to be associated with better cognitive function (Bruder et al 2005;Aguilera et al 2008). Conversely, studies of East Asian samples indicated that the Val allele is associated with better cognitive function (Cheon et al 2008;Yeh et al 2009;Wang et al 2013). Considering the converse association findings of cognitive function mentioned above with COMT Val158Met in Caucasians and East Asians (Palmatier et al 1999) and the difference in the lifetime prevalence rate of MDD in Western vs. East Asian countries (Kessler et al 1994;Hwu et al 1996;Parker et al 2007), it is plausible to assume that the variant potentially involves MDD pathogenesis with ethnic differences, which may contribute to the inconsistency of previous findings.…”

Section: Introductionmentioning

confidence: 93%

Meta-Analysis of the COMT Val158Met Polymorphism in Major Depressive Disorder: Effect of Ethnicity

Wang

Yuan

et al. 2016

J Neuroimmune Pharmacol

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The COMT (catechol-O-methyltransferase) Val158Met polymorphism (rs4680) is a potential susceptibility variant for major depressive disorder (MDD). Although many genetic studies have examined the association between MDD and this polymorphism, the results were inconclusive. In the present study, we conducted a series of meta-analyses of samples consisting of 2905 MDD cases and 2403 controls with the goal of determining whether this variant indeed has any effect on MDD. We revealed a significant association in the comparison of Val/Val + Val/Met vs. Met/Met (OR =1.180; 95 % CI = 1.019, 1.367; P = 0.027), Val/Met vs. Val/Val (OR =1.18; 95 % CI = 1.038, 1.361; P = 0.013), and Val/Met vs. Met/Met (OR =1.229; 95 % CI = 1.053, 1.435; P = 0.009). Further meta-analyses of samples with European ancestry demonstrated a significant association of this SNP with MDD susceptibility in Val/Val + Val/Met vs. Met/Met (OR =1.231, 95 % CI = 1.046, 1.449; P = 0.013) and Val/Met vs. Met/Met (OR =1.284, 95 % CI = 1.050, 1.484; P = 0.012). For the samples with East Asian ancestry, we found a significant association in both allelic (Val vs. Met: OR =0.835; 95 % CI = 0.714, 0.975; P = 0.023) and genotypic (Met/Met + Val/Met vs. Val/Val: OR =1.431, 95 % CI = 1.143, 1.791; P = 0.002; Val/Met vs. Val/Val: OR =1.482, 95 % CI = 1.171, 1.871; P = 0.001) analyses. No evidence of heterogeneity among studies or publication bias was observed. Together, our results indicate that the COMT Val158Met polymorphism is a vulnerability factor for MDD with distinct effects in different ethnic populations.

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“…A functional polymorphism at COMT’s codon 158 results in a single amino acid change (met for val) which changes enzyme activity levels. 39 Two of three studies have suggested a significant association between MPH effects on ADHD symptoms and this COMT polymorphism 20,25,40 (Cohen’s d effect sizes not available).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

Froehlich¹,

Epstein²,

Nick³

et al. 2011

Journal of the American Academy of Child & Adolescent Psych

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Objective Due to significant individual variability in Attention Deficit/Hyperactivity Disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examines the role of 4 catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method 89 stimulant-naïve children with ADHD aged 7–11 participated in a randomized, double-blind, crossover trial of long-acting MPH. Parents and teachers assessed each child’s response on placebo and three MPH dosage levels using the Vanderbilt ADHD rating scales. Children were genotyped for polymorphisms in the dopamine transporter’s (DAT) 3’ untranslated region, dopamine receptor D4‘s (DRD4) exon 3, catechol-O-methyltransferase’s (COMT) codon 158, and adrenergic α2A-receptor’s (ADRA2A) promoter. Linear mixed models evaluated gene, dose (mg/kg/day), and gene*dose effects on inattentive and hyperactive-impulsive domain outcomes. Results The most statistically significant gene*dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms, with participants lacking the DAT 10-repeat allele experiencing greater improvements in symptoms with increasing dose compared to 10-repeat carriers (p=0.008), and those lacking the DRD4 4-repeat allele showing less improvement across MPH doses compared to 4-repeat carriers (p=0.02). Conclusions This study suggests that DAT and DRD4 polymorphisms may be associated with individual variability in methylphenidate dose-response, although further research in larger samples is required to confirm these findings and their clinical utility.

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Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder

Cited by 34 publications

References 43 publications

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders

Meta-Analysis of the COMT Val158Met Polymorphism in Major Depressive Disorder: Effect of Ethnicity

Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

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