Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole

Kwon, Jun Soo; Kim, Euitae; Kang, Do‐Hyung; Choi, Jung Seok; Yu, Kyung‐Sang; Jang, In‐Jin; Shin, Sang-Goo; group, APLUS study

doi:10.1016/j.euroneuro.2008.07.010

Cited by 53 publications

(30 citation statements)

References 32 publications

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“…This indicates a possible, partial role for the Taq1A polymorphism in response to aripiprazole (70). Two other previous studies in 2008 both also had positive findings in relation to Taq1A and clinical response to aripiprazole using the PANSS scale (71 [rs3803300] and AKT1-SNP5 [rs2494732]) were significantly associated with response to risperidone, using the PANSS scale (72).…”

Section: Pharmacodynamicssupporting

confidence: 48%

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Changasi

Shams

Pouget

et al. 2014

Translational Developmental Psychiatry

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Background and purpose: Antipsychotics (APs) are the primary method of treatment for schizophrenia and other psychotic disorders. Unfortunately, lengthy trial-and-error approaches are typically required to find the optimal medication and dosage due to a large interindividual variability with outcome to AP treatment. The literature has shown abundant evidence for a genetic component in individuals' responses to APs. Pharmacogenetic studies analyze specific genetic markers and their association with symptom improvement and occurrence of side effects with APs. This research aims to optimize AP drug treatment by usage of predictive testing and to personalize medicine. Recent findings: This review will highlight the most consistent findings in pharmacogenetics of APs and will update the reader on the clinical implications. This will include how genetic variants modulate AP drug levels, side effects, and therapeutic symptom improvement (i.e. response) to AP treatment. Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect sizes appear to be particularly high in the genetics of side effects compared to response. One example is antipsychotic-induced weight gain where the leptin, HTR2C and in particular the melanocortin-4-receptor (MC4R) genes have been implicated in weight gain in children and adolescents. Consistent findings were also obtained for genes implicated in tardive dyskinesia and agranulocytosis. However, the most clinically relevant findings pertain to genes involved in drug metabolism such as the CYP2D6 and CYP2C19 genes which have been included in the first genetic test kits such as the Amplichip †

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Section: Pharmacodynamicssupporting

confidence: 48%

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Changasi

Shams

Pouget

et al. 2014

Translational Developmental Psychiatry

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“…Drawing on previous reports, we also established two genotype groups for the DRD2 -141C locus: -141C deletion carriers (Ins/Del) and non-carriers (Ins/Ins), and designated -141C Del carriers as the 'high' and non-carriers as 'low' DA genotypes. Since previous studies of DRD2 Taq1A have used either T (A1) or C (A2) allele homozygotes as a reference group (Bakker et al, 2008;Jonsson et al, 1999;Kwon et al, 2008;Pohjalainen et al, 1998), and other research suggests additive effects for the number of DRD2 Taq1A alleles on relative change in DRD2 expression levels (Noble et al, 1991), we modeled allele load effects of the DRD2 Taq1A on overall DA transmission with C allele homozygotes designated as the 'high' DA genotype, T allele homozygotes as the 'low' DA genotype and heterozygotes as 'intermediate' DA genotype. The DRD4 7-repeat allele carriers were considered 'high', while other allele combinations were considered 'low' DA genotypes.…”

Section: Genetic Profile Scoresmentioning

confidence: 99%

Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity

Nikolova

Ferrell

Manuck

et al. 2011

Neuropsychopharmacol

251

240

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Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT 158 Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene-environment interactions research establishing trajectories of risk for psychopathology.

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“…The DA D2 receptor gene is a risk gene for schizophrenia (Shi et al, 2008) and the polymorphism, TAQ-1A (rs1800497), which is associated with schizophrenia (Parsons et al, 2007), predicts response to treatment with risperidone (Ikeda et al, 2008) and aripiprazole (Kwon et al, 2008). An fMRI study of healthy individuals (Klein et al, 2007b) found that A1 allele carriers, with putatively reduced striatal DA receptor density (Pohjalainen et al, 1998;Jonsson et al, 1999;Ritchie and Noble, 2003), showed decreased dACC activation in response to errors and decreased avoidance learning, suggesting that they were less efficient in learning from errors.…”

Section: Drd2 Taq-iamentioning

confidence: 99%

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

Manoach¹,

Agam²

2016

Innovations in Cognitive Neuroscience

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Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromallyunaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach.

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Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole

Cited by 53 publications

References 32 publications

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

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