Catechol‐O‐methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children

Abstract

Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drug-response is increasingly important. Here we present a case-control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case-control and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecol-O-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele was more frequent in the ADHD group (n = 173) compared to the healthy population (P = 0.016). The categorical analysis of 90 responders versus 32 non-responders showed an association between the Val-allele or Val/Val genotype and good methylphenidate response (P = 0.009 and P = 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity-Impulsivity scale (P = 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P = 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action.

Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder

“…Numerous studies have investigated the relationship between the Val158Met polymorphism and behavioral phenotypes and various psychiatric disorders. The COMT Val158Met genotype has been reported as a risk factor for schizophrenia, bipolar disorder, obsessive-compulsive disorder, aggressive behavior, and attention problems, although some studies conclude the opposite (Eisenberg et al, 1999;Kereszturi et al, 2008;Sengupta et al, 2008). The functional COMT Val158Met polymorphism has been thoroughly investigated in several psychiatric disorders (Craddock et al, 2006).…”

“…Past studies have revealed associations between the Val allele and forms of distractibility and "off-task" behavior (Sengupta et al, 2008;Holmboe et al, 2010). Others have reported an association between the Val allele and ADHD (Eisenberg et al, 1999;Kereszturi et al, 2008). Some groups, have found associations between the Met allele and increased ADHD symptom count or severity in young subjects (DeYoung et al, 2010;Palmason et al, 2010).…”

“…The COMT Val158Met genotype is thought to be a risk factor for schizophrenia, bipolar disorder, obsessive-compulsive disorder, aggressive behavior, and attention problems; however, there are some studies that advocate the opposite (Eisenberg et al, 1999;Sengupta et al, 2008;Kereszturi et al, 2008). Monuteaux et al (2009) replicated evidence that the COMT Val158Met is associated with phenotypic variation among children with ADHD.…”

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

“…The usually prescribed psychostimulant is methylphenidate (MPH) that presents an estimated 70% response rate in ADHD affected children (Elia et al, 1991;Spencer et al, 1996). According to pharmacogenetic studies, the inter-individual differences in stimulantresponse may be related to genetic influences (Kirley et al, 2003;Langley et al, 2005;Gilbert et al, 2006;Winsberg & Comings, 1999;Roman et al, 2002;Purper-Ouakil, 2008;Kereszturi et al, 2008;da Silva et al, 2008) and the search for candidate genes associated with ADHD focused on the catecholamine system. Genes associated with increased risk for ADHD are the dopamine transporter (DAT1) (Purper-Ouakil, 2008), the dopamine receptors (DRD4 and DRD5) (Van Tol et al, 1992), serotonin transporter (5-HTT), and synaptosomalassociated protein (SNAP-25) (Husain et al, 2007;Faraone et al, 2005;McGough et al, 2006).…”

“…Genes associated with increased risk for ADHD are the dopamine transporter (DAT1) (Purper-Ouakil, 2008), the dopamine receptors (DRD4 and DRD5) (Van Tol et al, 1992), serotonin transporter (5-HTT), and synaptosomalassociated protein (SNAP-25) (Husain et al, 2007;Faraone et al, 2005;McGough et al, 2006). Other genes of potential interest in pharmacogenetic studies include catehol-O-methyltransferase (COMT) (Kereszturi et al, 2008 ), the adrenergic 2-receptor (ADRA2A and ADRA1A) (da Silva et al, 2008;Polankzyk et al, 2007;Elia et al, 2009) (Fig. 2).…”