Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: Replication and exploration

Hwang, Rudi; Tiwari, Arun K.; Zai, Clement C.; Felsky, Daniel; Remington, Eli; Wallace, Tessa; Tong, Ryan P.; Souza, Renan P.; Oh, Gabriel; Potkin, Steven G.; Lieberman, Jeffrey A.; Meltzer, Herbert Y.; Kennedy, James L.

doi:10.1016/j.pnpbp.2011.11.018

Cited by 36 publications

(23 citation statements)

References 91 publications

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“…In recent years, a growing number of studies have investigated the relationship between DRD5 and schizophrenia (Muir et al, 2001;Pal et al, 2009;Hwang et al, 2012). Some studies have reported an association between genetic variations in the DRD5 gene and schizophrenia (William et al, 1997;Muir et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…To date, no evidence has been found for a role of DRD5 in schizophrenia, despite several studies in this area (Muir et al, 2001;Ikeda et al, 2008;Pal et al, 2009;Hwang et al, 2012). It is noteworthy that a number of these studies focused mainly on the rs2076907 (-226G/C), a common polymorphic SNP in the 5'UTR (Kim et al, 2007), and rs6283(978T/C), a common polymorphic SNP in the coding region (Sullivan et al, 2001) , but there is little evidence that these two SNPs have an association with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese

Zhao¹,

Ding²,

Pang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Dopamine (DA) has been implicated in the pathophysiology of several psychiatric disorders, including schizophrenia. Thus, genes related to the dopaminergic (DAergic) system are good candidate genes for schizophrenia. One of receptors of the DA receptor system is dopamine receptor 5 (DRD5). Single nucleotide polymorphisms (SNPs) in the regulatory regions of DRD5 gene may affect gene expression, influence biosynthesis of DA and underlie various neuropsychiatric disorders related to DA dysfunction. The present study explored the association of SNPs within the DRD5 gene with paranoid schizophrenia in Han Chinese. A total of 176 patients with schizophrenia and 206 healthy controls were genotyped for four DRD5 SNPs (rs77434921, rs2076907, rs6283, and rs1800762). Significant group differences were observed in the allele and genotype frequencies of rs77434921 and rs1800762 and in the frequencies of GC haplotypes corresponding to rs77434921-rs1800762. Our findings suggest that common genetic variations of DRD5 are likely to contribute to genetic susceptibility to paranoid schizophrenia in Han Chinese. Further studies in larger samples are needed to replicate this association.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese

Zhao¹,

Ding²,

Pang³

et al. 2014

Genet. Mol. Res.

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“…As for the DRD3 gene, a possible role was suggested for the Ser allele of the Ser9Gly polymorphism (rs6280) to be associated with poorer response to clozapine in a metaanalysis by Hwang et al (68). The DRD4 variants have been found to have a minor contribution to clozapine response using 18-item BPRS scale, while DRD5 showed none (69). A study by Miura et al, investigated the Taq1A polymorphism (rs1800497), in linkage disequilibrium and related to the DRD2 receptor, in relation to response to aripiprazole treatment, using the PANSS and CGI scales.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

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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“…Zhao et al 29 and Hwang et al 30 found significant associations between polymorphisms in DRD4 and response to clozapine. However, most studies were unable to detect this significant association.…”

Section: Genetic Variants In Drug Target Proteins and Response To Trementioning

confidence: 99%

“…113 Two studies analyzed DRD1 and found a significant association with clozapine response in African Americans 22 and Caucasians, 23 but another study was unable to replicate this association. 106 Hwang et al 30 evaluated the importance of DRD5 and found no significant association with clozapine response.…”

Section: -98mentioning

confidence: 99%

Pharmacogenetics in schizophrenia: a review of clozapine studies

Kohlrausch

2013

Rev. Bras. Psiquiatr.

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Objectives: Clozapine is quite effective to treat schizophrenia, but its use is complicated by several factors. Although many patients respond to antipsychotic therapy, about 50% of them exhibit inadequate response, and ineffective medication trials may entail weeks of unremitted illness, potential adverse drug reactions, and treatment nonadherence. This review of the literature sought to describe the main pharmacogenetic studies of clozapine and the genes that potentially influence response to treatment with this medication in schizophrenics. Methods: We searched the PubMed database for studies published in English in the last 20 years using keywords related to the topic. Results and Conclusions: Our search yielded 145 studies that met the search and selection criteria. Of these, 21 review articles were excluded. The 124 studies included for analysis showed controversial results. Therefore, efforts to identify key gene mechanisms that will be useful in predicting clozapine response and side effects have not been fully successful. Further studies with new analysis approaches and larger sample sizes are still required.

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Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: Replication and exploration

Cited by 36 publications

References 91 publications

Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese

Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese

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

Pharmacogenetics in schizophrenia: a review of clozapine studies

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