Association of dopamine, serotonin, and nicotinic gene polymorphisms with methylphenidate response in ADHD

Tharoor, Hema; Lobos, Elizabeth A.; Todd, Richard D.; Reiersen, Angela M.

doi:10.1002/ajmg.b.30637

Cited by 26 publications

(22 citation statements)

References 24 publications

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“…A total of 16 studies published between 1999 and 2010 matched the search criteria (see Table 1), resulting in a final sample of 1572 subjects [44][45][46][47][48][49][50]52,[54][55][56][57][58][59][60] including N ¼ 799 10R homozygotes and N ¼ 773 carriers of genotypes other than 10R/10R (one study did not report genotype frequencies 53 ). The random-effects model revealed a nonsignificant summary effect size of d ¼ À 0.05 (95% confidence interval (CI): À 0.2 to 0.1, z ¼ À 0.698, P ¼ 0.52, I 2 ¼ 38.2%, 95% CI for I 2 : 11.72-91.02%, see Figure 1a), suggesting that genotype was not a significant predictor of treatment response.…”

Section: Resultsmentioning

confidence: 99%

“…40 Although some studies have shown that the 9R allele is associated with better clinical response to methylphenidate, 27,[44][45][46][47] other studies have shown the opposite pattern [48][49][50] or have failed to observe a significant effect. [51][52][53][54][55][56][57][58][59] A recent review has summarised the literature on this topic and an early meta-analysis of six studies in childhood ADHD reported that 10R homozygotes showed poor methylphenidate response. 60 However, further studies on children and adults have appeared since then.…”

Section: Introductionmentioning

confidence: 99%

“…60 However, further studies on children and adults have appeared since then. 47,48,50,[53][54][55][56][57][58][59] In order to update the literature review and clarify inconsistencies in the literature on this important topic we, therefore carried out a comprehensive meta-analysis of the association between the SLC6A3 VNTR and clinical response to methylphenidate in childhood as well as in adult patients with ADHD. We compared the quantitative response as reflected by changes in ADHD symptom scores to methylphenidate treatment between non-10/10 carriers and 10R homozygotes, a grouping of genotypes commonly undertaken in SLC6A3 association studies.…”

Section: Introductionmentioning

confidence: 99%

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Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

2013

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Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder. Treatment with methylphenidate, which blocks dopamine and noradrenaline transporters, is clinically efficacious in reducing the symptoms of ADHD. However, a considerable proportion of patients show no or only insufficient response to methylphenidate. Following a pharmacogenetic approach, a number of studies have suggested that heterogeneity in treatment response across subjects might to some extent be due to genetic factors. In particular, a variable number tandem repeat (VNTR) polymorphism in the 3' untranslated region of the SLC6A3 gene, which codes for the dopamine transporter, has been considered as a predictor of treatment success. However, the literature has so far been inconsistent. Here we present results of a meta-analysis of studies investigating the moderating effect of the SLC6A3 VNTR on response to methylphenidate treatment in subjects with ADHD. Outcome measures from 16 studies including data from 1572 subjects were entered into a random-effects model. There was no significant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment (P>0.5) and no effect on specific symptom dimensions of hyperactivity/impulsivity and inattention (all P>0.2). However, in a subanalysis of naturalistic trials, we observed a significant effect of d=-0.36 (P=0.03), indicating that 10R homozygotes show less improvement in symptoms following treatment than the non-10/10 carriers. This meta-analysis indicates that SLC6A3 VNTR is not a reliable predictor of methylphenidate treatment success in ADHD. Our study leaves unanswered the question of whether other genetic polymorphisms or nongenetic factors may contribute to the observed heterogeneity in treatment response across ADHD subjects.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

2013

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“…In this study, we focussed on a genetic variant that to our knowledge is the only one in SLC6A2 whose capacity to influence gene expression directly has been shown in biochemical assays, confirming the formation of a new transcription factor binding site. Genetic variants of candidate genes recently have been reported to influence the efficacy of pharmacological therapy in ADHD (Kooij et al 2008;Tharoor et al 2008). Recent studies investigating the association of SLC6A2 polymorphisms with response to stimulant medication reported differing results Song et al 2011;Lee et al 2011).…”

Section: Discussionmentioning

confidence: 96%

No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample

Renner

Nguyen

Romanos

et al. 2011

ADHD Atten Def Hyp Disord

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Noradrenergic neurotransmission influences executive functions, attentional performance, and general alertness, involving neuronal networks affected in attention deficit/hyperactivity disorder (ADHD). The norepinephrine transporter facilitates the reuptake of norepinephrine and dopamine in the prefrontal cortex and represents the main target of atomoxetine, an effective drug in the treatment of ADHD. Due to its influence on catecholaminergic signaling, variants of the coding gene (SLC6A2) have been widely investigated in ADHD. Several previous studies report an association between single nucleotide polymorphisms located in SLC6A2 and ADHD; however, the findings are inconsistent. The variant A-3081T (rs28386840) has been shown to have major influence on the expression levels of SLC6A2 due to sequence alteration at a repressor binding site, with the T-allele being associated with ADHD. We tested this potential association of A-3081T in a German family-based ADHD sample of 235 children from 162 families, which has a power >99% based on the previously reported odds ratios. There was no evidence for an overtransmission of the risk allele T (transmission rate: 48.5%, P = 0.55). We conclude that A-3081T is not a major risk variant in our ADHD sample, though SLC6A2 remains an interesting candidate gene in ADHD, especially for the inattentive subtype.

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“…Different polymorphisms concerning the dopaminergic, serotonergic and noradrenergic systems were studied extensively and some of them seem to be related to ADHD [38][39][40][41][42] or correlated with the response to stimulant treatment [43,44]. However, polymorphisms of genes responsible for neuronal differentiation in early stages of development like Nurr1 (NR4A2) failed to be associated with ADHD [45].…”

Section: Adhd Pathophysiologymentioning

confidence: 97%

Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention-Deficit/Hyperactivity Disorder

Bock

Gerlach²,

Rothenberger³

2010

CPD

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In recent years an increased use of psychotropic medication in children has been observed, but little is known about the influence of this medication on brain maturation. Probably, because of methodological problems and/or ethical aspects. It means that only naturalistic observational studies might allow to get some insight in humans. But even animal studies touching this issue are scarce and heterogeneous. Nevertheless, postnatal brain development is highly sensitive to the effects of psychotropic drugs, either in the short- and/or long-term. Therefore, more and better information is needed. The main targets of psychotropic drugs are the monoaminergic transmitter systems that are related to brain networks for motor behavior, motivation, emotion, and cognition. In order to elucidate the mechanisms of drug development interactions and their long-term consequences on brain and behavior, animal studies might provide a good basis for a better understanding and guidance of research in humans. Hence, this article reviews the possible influence of those psychotropic drugs on postnatal brain development in animals (mostly rats and rodents) which are widely used to treat common psychiatric disorders in children and adolescents like depression and attention-deficit/ hyperactivity disorder (ADHD). Moreover this review refers to the obvious problems of the available animal studies (including experimental animal models of child psychiatric disorders) which seem to be of limited value in translating experimental knowledge to the complexity of clinical understanding and practice.

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Association of dopamine, serotonin, and nicotinic gene polymorphisms with methylphenidate response in ADHD

Cited by 26 publications

References 24 publications

Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample

Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention-Deficit/Hyperactivity Disorder

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