Pharmacogenetics of methylphenidate response in attention deficit/hyperactivity disorder: Association with the dopamine transporter gene (SLC6A3)

Abstract

Pharmacogenetic studies investigating the 40-bp VNTR polymorphism at SLC6A3 and methylphenidate response have shown conflicting results and large differences in study design and efficacy endpoints. Our objective was to investigate the relation between the 3'-VNTR at SLC6A3 and variability in methylphenidate response in a sample of 141 ADHD children and adolescents, assessed before and after methylphenidate treatment with both clinical and neuropsychological outcome measures. 10-R homozygotes were significantly overrepresented in the low response group, but no genotype effect was shown in cognitive variables improvement. A meta-analysis of pharmacogenetic studies with comparable data (responders vs. non-responders) on a total of 475 subjects showed a significant association between the 10-10 genotype and low rates of methylphenidate response (mean Odds Ratio = 0.46; 95% CI [0.28-0.76]). Heterogeneity between these studies did not reach a significant level but, as publications with different endpoints were excluded from this meta-analysis, our results do not rule out a possible influence of study design.

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).…”

“…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). 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.…”

Pediatric pharmacogenetic and pharmacogenomic studies: the current state and future perspectives

“…It was estimated approximately 70% of response rate to methylphenidate (MPH), the most commonly prescribed psycho-stimulant, in ADHD affected children [20,21]. Pharmacogenetic studies suggest that inter-individual differences in stimulantresponse may be related to genetic influences [22][23][24][25][26][27][28][29]. The search for candidate genes associated with ADHD has been largely driven by the understanding that medications for the disorder have drug targets in the catecholamine system.…”

Neurobiologie du trouble déficit de l’attention/ hyperactivité

“…Les études ultérieures n'ont pas toutes répliqué ces résultats, probablement du fait de la grande diversité des métho-des employées. Les données issues de notre cohorte clinique d'enfants et d'adolescents ont cependant confirmé l'association du génotype 10-R/10-R (R pour répétitions) du VNTR 3'UTR du DAT1 avec une réponse thérapeutique de moins bonne qualité, selon deux critères de réponse thérapeutique [26]. Une méta-analyse des études pharmacogénéti-ques ayant étudié ce polymorphisme retrouve également l'association du génotype 10-R/10-R et d'une moindre réponse au traitement avec un OR (odds ratio) de 0,46 (IC95 % 0,28-0,76) [26].…”

“…Les données issues de notre cohorte clinique d'enfants et d'adolescents ont cependant confirmé l'association du génotype 10-R/10-R (R pour répétitions) du VNTR 3'UTR du DAT1 avec une réponse thérapeutique de moins bonne qualité, selon deux critères de réponse thérapeutique [26]. Une méta-analyse des études pharmacogénéti-ques ayant étudié ce polymorphisme retrouve également l'association du génotype 10-R/10-R et d'une moindre réponse au traitement avec un OR (odds ratio) de 0,46 (IC95 % 0,28-0,76) [26]. Bien que moins étudiés, d'autres polymorphismes tels que le VNTR DRD4*7 (dopamine D4 receptor), seul [27] ou en interaction avec le variant L de la région promotrice du transporteur de la sérotonine (5-HTTLPR) [28], ont été associés à la réponse au méthylphénidate.…”