Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder

Roman, Tatiana; Szobot, Cláudia Maciel; Martins, Sílvia; Biederman, Joseph; Rohde, Luis Augusto; Hutz, Mara H.

doi:10.1097/00008571-200208000-00011

Cited by 154 publications

(130 citation statements)

References 12 publications

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“…The earliest studies reported an association between homozygosity of the 10-repeat allele and poor response to MPH. In addition to being naturalistic, these studies were based on small numbers of patients and grouped patients with 9/9 and 9/10 genotypes (Winsberg and Comings, 1999;Roman et al, 2002). A subsequent retrospective naturalistic study conducted on a sample of 119 patients reported an overtransmission of the 10-repeat allele from parents to children with good response to MPH (Kirley et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The pooled odds ratio derived from family-based association studies was reported to be 1:13 with 95% confidence interval ¼ [1.03-1.24] . Four published studies have investigated the relation between the 3 0 -UTR VNTR alleles/genotypes and therapeutic response to MPH (Winsberg and Comings, 1999;Roman et al, 2002;Kirley et al, 2003;Stein et al, 2005). Although each of these studies reported positive findings, there was no consistency with regard to the effect of each allele/genotype on therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

“…Although each of these studies reported positive findings, there was no consistency with regard to the effect of each allele/genotype on therapeutic response. Briefly, while Winsberg and Comings (1999) and Roman et al (2002) reported a better therapeutic response in children with the 9/10 genotype compared to children with the 10/10 genotype, Kirley et al (2003) reported that transmission of the 10-repeat allele was significantly greater in children retrospectively judged as very good responders to MPH. Stein et al (2005) was the only group that analyzed the 9/9 genotype group separately from the two other genotype groups and found that this group is less sensitive to the effects of MPH, suggesting a recessive mode of action of the 9-repeat allele.…”

Section: Introductionmentioning

confidence: 99%

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Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Joober

Grizenko

Sengupta

et al. 2006

Neuropsychopharmacol

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We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3 0 -untranslated region (3 0 -UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3 0 -UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p ¼ 0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3 0 -UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Joober

Grizenko

Sengupta

et al. 2006

Neuropsychopharmacol

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“…A number of studies have examined the role of naturally occurring DAT variants in the clinical response to methylphenidate, but results from these studies are not entirely consistent. While some studies show no difference in response to methylphenidate among groups of individuals with different DAT polymorphisms (Mick et al, 2006;van der Meulen et al, 2005;Zeni et al, 2007), other studies have shown an association between DAT polymorphism and the response to methylphenidate, but not always in the same direction (Cheon et al, 2005;Kirley et al, 2003;Roman et al, 2002;Winsberg and Comings, 1999). The DAT KO mouse has been examined for a number of behaviors.…”

Section: Cell Support and Signaling Proteins: Amphetamine And Methamphementioning

confidence: 99%

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Phillips

Kamens

Wheeler

2008

Neuroscience & Biobehavioral Reviews

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Amphetamines, including methamphetamine, pose a significant cost to society due to significant numbers of amphetamine-abusing individuals who suffer major health-related consequences. In addition, methamphetamine use is associated with heightened rates of violent and property-related crimes. The current paper reviews the existing literature addressing genetic differences in mice that impact behavioral responses thought to be relevant to the abuse of amphetamine and amphetaminelike drugs. Summarized are studies that used inbred strains, selected lines, single gene knockouts and transgenics, and quantitative trait locus (QTL) mapping populations. Acute sensitivity, neuroadaptive responses, rewarding and conditioned effects are among those reviewed. Some gene mapping work has been accomplished, and although no amphetamine-related complex trait genes have been definitively identified, translational work leading from results in the mouse to studies performed in humans is beginning to emerge. The majority of genetic investigations has utilized single-gene knockout mice and has concentrated on dopamine-and glutamate-related genes. Genes that code for cell support and signaling molecules are also well-represented. There is a large behavioral genetic literature on responsiveness to amphetamines, but a considerably smaller literature focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and behavioral toxicity. Also missing are genetic investigations into the effects of amphetamines on social behaviors. This information might help to identify at-risk individuals and in the future to develop treatments that take advantage of individualized genetic information.

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“…The 10-repeat allele of a variable number of tandem repeats (VNTR) situated in the 3 0 untranslated region of the DAT1 gene (mapping to 5p15.3) has been associated with the clinical ADHD phenotype in a number of studies (Cook et al, 1995;Gill et al, 1997;Daly et al, 1999). This variant may confer an enhanced therapeutic response to methylphenidate (MPH) (Kirley et al, 2003; but see Winsberg and Comings, 1999;Roman et al, 2002). Here, we ask whether an attentional phenotype is related to (a) genetic variation in the DAT1 VNTR and (b) the therapeutic efficacy of MPH in ADHD.…”

Section: Introductionmentioning

confidence: 99%

Association between Dopamine Transporter (DAT1) Genotype, Left-Sided Inattention, and an Enhanced Response to Methylphenidate in Attention-Deficit Hyperactivity Disorder

Bellgrove

Hawi

Kirley

et al. 2005

Neuropsychopharmacol

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A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3 0 variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.

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Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder

Cited by 154 publications

References 12 publications

Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Dopamine Transporter 3′-UTR VNTR Genotype and ADHD: a Pharmaco-Behavioural Genetic Study with Methylphenidate

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Association between Dopamine Transporter (DAT1) Genotype, Left-Sided Inattention, and an Enhanced Response to Methylphenidate in Attention-Deficit Hyperactivity Disorder

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