Association of the Dopamine Transporter Gene (DAT1) With Poor Methylphenidate Response

Winsberg, Bertrand G.; Comings, David E.

doi:10.1097/00004583-199912000-00006

Cited by 234 publications

(187 citation statements)

References 24 publications

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“…This suggests a recessive effect of the 9-repeat allele on the phenotype of stimulant nonresponse. The association of genotypes containing the 10-repeat allele with a positive response to MPH is in agreement with the findings of Kirley et al (2003), but differs from the Winsberg and Cummings and Roman et al studies (Winsberg and Cummings, 1999;Roman et al, 2001). Kirley et al (2003) reported that transmission of the 10-repeat allele was significantly greater in children who displayed a 'very good' retrospectively rated response to MPH as compared to those with 'mediocre' or 'no response' in a sample of 117 Irish school children.…”

Section: Discussionsupporting

confidence: 81%

“…Kirley et al (2003) reported that transmission of the 10-repeat allele was significantly greater in children who displayed a 'very good' retrospectively rated response to MPH as compared to those with 'mediocre' or 'no response' in a sample of 117 Irish school children. In contrast, Winsberg and Cummings (1999) reported that 86% of 14 'poor' responders (defined as less than a 50% reduction in ADHD symptoms on parent ratings) were homozygous for the 10-repeat allele, as compared to 31% of 16 'positive' responders in a sample of 30 stimulant naive African-American children with ADHD. Using a similar methodology but with a Brazilian sample, Roman et al (2001) reported that 47% of those with the 10/10 genotype demonstrated a 50% reduction in ADHD ratings, as compared to 75% of ADHD youth with the 9/10 and 9/9 genotypes included in the same group (Roman et al, 2001).…”

Section: Discussionmentioning

confidence: 95%

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Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Stein

Waldman

Sarampote

et al. 2005

Neuropsychopharmacol

130

117

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Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3 0 -untranslated region (3 0 -UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n ¼ 47), ages 5-16 years (mean ¼ 9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS s MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3 0 -UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 95%

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Stein

Waldman

Sarampote

et al. 2005

Neuropsychopharmacol

130

117

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“…The authors concluded that the DAT1 40bp VNTR 10 repeat, when homozygous, may be associated with greater problems with inhibition and attention and that variation at this allele mediates stimulant related changes in cortical activity. Such a finding seems to conflict with those of Winsberg and Comings (1999) who had previously found a higher incidence of the 10/10 repeat pairing in African-American children who were not responsive to methylphenidate treatment. Jacobsen et al (2000) also found that the normal adults who were homozygous had significantly reduced dopamine transporter binding in striatum on SPECT scan relative to those having at least one 9 repeat allele.…”

Section: Nih-pa Author Manuscriptcontrasting

confidence: 63%

“…Why this should be the case is unclear. The 9/10 genotype is associated with greater dopamine transporter binding and better methylphenidate response in children with ADHD (Winsberg & Comings, 1999). Since most children with ADHD are positive responders to this drug, it is the 9/10 genotype that may have a greater association with clinical cases of ADHD and its severity, as we found, than does the 10/10 genotype.…”

Section: Discussionsupporting

confidence: 45%

An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood

Barkley

Smith

Fischer

et al. 2006

American J of Med Genetics Pt B

104

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Several candidate gene polymorphisms have been implicated in attention deficit hyperactivity disorder (ADHD), including DAT1 40bp VNTR, DRD4 7+, and DBH TaqI A2 alleles. We used the Milwaukee longitudinal study of hyperactive (N=122) and normal (N=67) children to compare participants with and without these respective polymorphisms on ADHD-related behavioral ratings at childhood, 8 years later in adolescence, and 13+ years later into young adulthood. Neuropsychological tests were given at the adolescent and young adulthood follow-up. No differences were found between the DRD4-7+ and 7-repeat polymorphism. The DBH TaqI A2 allele, when homozygous, was associated with being more hyperactive in childhood, having more pervasive behavior problems at adolescence, and earning less money on a Card Playing Task in adulthood. At adolescence, poorer test scores were also found only in the hyperactive group with homozygous for this allele. The DAT1 40bp VNTR heterozygous 9/10 repeat, however, differed from the 10/10 repeat pair in many respects, having greater ADHD and externalizing symptoms at all three follow-ups, more cross-situational behavioral problems at both childhood and adolescence, poorer mother-teen relations at adolescence, and lower class rankings in high school. Participants with the 9/10 pair in the control group also had lower work performance, a lower grade point average in high school, greater teacher rated externalizing symptoms at adolescence, and greater omission errors on a continuous performance test in adulthood. The DAT1 40bp VNTR 9/10 polymorphism pairing appears to be reliably associated with greater symptoms of ADHD and externalizing behavior from childhood to adulthood, and with family, educational, and occupational impairments. We also present a contrary view on the appropriate endophenotypes for use in behavioral genetic research on ADHD.Children with Attention Deficit Hyperactivity Disorder (ADHD), or what was previously diagnosed as Hyperactive Child Syndrome, are characterized by developmentally inappropriate levels of inattentive, impulsive, and hyperactive behavior that arise early in childhood and occur across multiple settings (American Psychiatric Association, 1968, 1980, 2001. Follow-up studies of hyperactive children suggest that from 35-80 percent of NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cases diagnosed in childhood will persist into adolescence Gittelman et al., 1985). By adulthood, 49-66% will have significant symptoms of the disorder or meet diagnostic criteria for it (Barkley et al., 2002;Mannuzza et al., 1993Mannuzza et al., ,1998 Rasmussen & Gillberg, 2002;Weiss and Hechtman, 1993).Biological relatives of children with the disorder are more likely to have ADHD (Biederman et al. 1990, Biederman et al. 1992, Biederman et al. 1995, Maher et al. 1999, Samuel et al. 1999. Numerous twin studies found that genetic factors account for the majority of variance in this trait with an average heritability of .75-.80, with more recent studies u...

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“…28 In addition, the DAT1 10R has been associated with poor response to methylphenidate (MPH) in ADHD. 29,30 MPH has been shown to block the dopamine transporter in vivo, 31,32 and may therefore be more effective in those individuals who have more in vivo availability of the transporter.…”

mentioning

confidence: 99%

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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Association of the Dopamine Transporter Gene (DAT1) With Poor Methylphenidate Response

Cited by 234 publications

References 24 publications

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

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