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

Joober, Ridha; Grizenko, Natalie; Sengupta, Sarojini M.; Amor, Leïla Ben; Schmitz, N.; Schwartz, George J.; Karama, Sherif; Lageix, Philippe; Fathalli, Ferid; Torkamanzehi, Adam; Stepanian, Marina Ter

doi:10.1038/sj.npp.1301240

Cited by 58 publications

(60 citation statements)

References 27 publications

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“…58) for the homozygous 9 repeat genotype. Of note, the difference between parent and teacher ratings iand pharmacogenetic effects of DAT1 is similar to that reported by Joober et al [28].Recently, the first pharmacogenetic study of adults with ADHD reported no relationship between DAT1 genotype and response in 66 subjects titrated to a maximum methylphenidate dose of 1.3mg/kg/day [34]. However, the sample included only 3 individuals with the 9/9 genotype, and llmited statistical power to detect an effect for this genotype group.…”

supporting

confidence: 74%

“…and 54mg of OROS methylphenidate [27]. Individuals homozygous for the less common 9-repeat allele demonstrated a non-linear dose-response curve, had more stimulant related side effects, and remained more impaired during treatment Similar findings were reported for the 9/9 genotype group in a double-blind, placebo controlled trial of 159 children with ADHD conducted in Montreal [28]. Although children with either the 9/10 and 10/10 genotypes displayed a significant positive response to 10 mg. of MPH, the 9/9 genotype group displayed a negative response on parent symptom ratings only ( effect size = −.…”

supporting

confidence: 68%

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The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

Stein

McGough²

2008

Child and Adolescent Psychiatric Clinics of North America

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SynopsisCurrently, ADHD treatment is often determined empirically through trial and error until an adequate response is obtained or side effects occur. ADHD is highly heritable and there is wide individual variability in response to ADHD medications, suggesting that the mechanism of action of stimulant medications may provide clues for genetic predictors of response. The promise of ADHD pharmacogenetics is far reaching, and includes the potential to develop individualized medication regimens that improve symptom response, decrease risk for side effects, improve long-term tolerability, and thus contribute to long-term treatment compliance and improved general effectiveness. Early ADHD pharmacogenetic studies have focused predominantly on catecholamine pathway genes and response to methylphenidate. Future efforts will also examine a wider range of stimulant and non-stimulant medications on a range of outcome measures and time periods. Based upon these studies, the potential for personalizing ADHD treatment in clinical practice will be determined. IntroductionAttention-Deficit/Hyperactivity Disorder (ADHD) is a common and treatable behavioral syndrome that typically emerges during childhood or adolescence and often persists into adulthood. There are an increasing number of stimulant and non-stimulant medication options for ADHD, with numerous new compounds in development [1]. In acute treatment studies, stimulant medications generally demonstrate large effect sizes on ADHD symptom reduction relative to placebo, with slightly smaller effect sizes in adult studies [2]. Surprisingly, only a minority of children and adolescents with ADHD remain on medication consistently Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. despite persistence of symptoms and impairments. Even among responders, there is marked variability in optimal dosage, duration of effect, and tolerability. Moreover, in spite of acute symptom reduction from ADHD medications, as yet there is little evidence of long-term response and improvement in functioning among those children who received treatment [4,5]. Furthermore, there are few reliable predictors of medication response. In the absence of these data, treatment is often determined "empirically" in clinical practice through a gradual titration of different dosages and trial and error approach to different medications. NIH Public AccessADHD is a highly heritable disorder [6]. 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 [7]. Conve...

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supporting

confidence: 74%

supporting

confidence: 68%

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

Stein

McGough²

2008

Child and Adolescent Psychiatric Clinics of North America

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“…Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25)(26)(27)(28)(29)(30) that DA signaling perturbations contribute to risk for ADHD. Noncoding variation in the SLC6A3 gene that encodes DAT has also been associated with ADHD medication response (26)(27)(28).…”

supporting

confidence: 64%

“…The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30) that DA signaling perturbations contribute to risk for ADHD. Noncoding variation in the SLC6A3 gene that encodes DAT has also been associated with ADHD medication response (26)(27)(28).Attention to the impact of DAT genetic variation on behavioral changes underlying mental illness was raised with the studies of Giros et al in their pioneering analysis of the DAT knockout (DAT KO) mouse (29). These investigators found that elimination of DAT expression leads to reduced presynaptic DA levels, increased extracellular DA, and profound locomotor hyperactivity in a novel environment (29), suggesting the utility of these mice as an ADHD model.…”

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confidence: 99%

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The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Mergy¹,

Gowrishankar²,

Gresch

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPHevoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.T he neurotransmitter dopamine (DA) plays a key role in regulating brain circuits that control reward, attention, and locomotor activity (1-3), Accordingly, dopaminergic dysfunction is believed to contribute to several neuropsychiatric disorders including Parkinson's disease (4), bipolar disorder (BPD) (5), drug abuse and addiction (6), and attention-deficit hyperactivity disorder (ADHD) (7,8). The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11). AMPH is structurally similar to DA and, as a result, is transported by DAT, competing with DA during the reuptake process. AMPH also induces DAT-mediated nonvesicular release, also termed "DA efflux," a process that involves the actions of intracellular signaling proteins such as CamKIIα (12-16) and , alterations in interactions with DAT-associated proteins and phospholipids (12,14,20), and changes in DAT phosphorylation (12,16,(21)(22)(23)) that biases the transporter toward an efflux-competent mechanism. Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30)...

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2010

The Science of ADHD

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

Cited by 58 publications

References 27 publications

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

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