RESUMO
Although the advent of atypical, second-generation antipsychotics (SGAs) has resulted in reduced likelihood of akathisia, this adverse effect remains a problem. It is known that extrapyramidal adverse effects are associated with increased drug occupancy of the dopamine 2 receptors (DRD2). The A1 allele of the DRD2/ANKK1, rs1800497, is associated with decreased striatal DRD2 density. The aim of this study was to identify whether the A1(T) allele of DRD2/ANKK1 was associated with akathisia (as measured by Barnes Akathisia Rating Scale) in a clinical sample of 234 patients who were treated with antipsychotic drugs. Definite akathisia (a score ≥ 2 in the global clinical assessment of akathisia) was significantly less common in subjects who were prescribed SGAs (16.8%) than those prescribed FGAs (47.6%), p < 0.0001. Overall, 24.1% of A1+ patients (A1A2/A1A1) who were treated with SGAs had akathisia, compared to 10.8% of A1- (thus, A2A2) patients. A1+ patients who were administered SGAs also had higher global clinical assessment of akathisia scores than the A1- subjects (p = 0.01). SGAs maintained their advantage over FGAs regarding akathisia, even in A1+ patients who were treated with SGAs. These results strongly suggested that A1+ variants of the DRD2/ANKK1 Taq1A allele do confer an associated risk for akathisia in patients who were treated with SGAs, and these variants may explain inconsistencies found across prior studies, when comparing FGAs and SGAs.
Assuntos
Acatisia Induzida por Medicamentos/genética , Antipsicóticos/efeitos adversos , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Esquizofrenia/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Adulto , Acatisia Induzida por Medicamentos/epidemiologia , Acatisia Induzida por Medicamentos/metabolismo , Antidepressivos de Segunda Geração/efeitos adversos , Antidepressivos de Segunda Geração/uso terapêutico , Antipsicóticos/uso terapêutico , Centros Comunitários de Saúde Mental , Estudos Transversais , Manual Diagnóstico e Estatístico de Transtornos Mentais , Antagonistas dos Receptores de Dopamina D2 , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Hospitais de Ensino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Serina-Treonina Quinases/metabolismo , Queensland/epidemiologia , Receptores de Dopamina D2/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêuticoRESUMO
Catechol-O-methyl transferase (COMT) encodes an enzyme involved in the metabolism of dopamine and maps to a commonly deleted region that increases schizophrenia risk. A non-synonymous polymorphism (rs4680) in COMT has been previously found to be associated with schizophrenia and results in altered activity levels of COMT. Using a haplotype block-based gene-tagging approach we conducted an association study of seven COMT single nucleotide polymorphisms (SNPs) in 160 patients with a DSM-IV diagnosis of schizophrenia and 250 controls in an Australian population. Two polymorphisms including rs4680 and rs165774 were found to be significantly associated with schizophrenia. The rs4680 results in a Val/Met substitution but the strongest association was shown by the novel SNP, rs165774, which may still be functional even though it is located in intron five. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. This association was slightly improved when males were analysed separately possibly indicating a degree of sexual dimorphism. Our results confirm that COMT is a good candidate for schizophrenia risk, by replicating the association with rs4680 and identifying a novel SNP association.
Assuntos
Catecol O-Metiltransferase/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Austrália , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Projeto HapMap , Haplótipos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Dystrobrevin binding protein 1 (DTNBP1), or dysbindin, is thought to be critical in regulating the glutamatergic system. While the dopamine pathway is known to be important in the aetiology of schizophrenia, it seems likely that glutamatergic dysfunction can lead to the development of schizophrenia. DTNBP1 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and a DTNBP1 polymorphism has been associated with reduced brain expression. Despite numerous genetic studies no DTNBP1 polymorphism has been strongly implicated in schizophrenia aetiology. Using a haplotype block-based gene-tagging approach we genotyped 13 SNPs in DTNBP1 to investigate possible associations with DTNBP1 and schizophrenia. Four polymorphisms were found to be significantly associated with schizophrenia. The strongest association was found with an A/C SNP in intron 7 (rs9370822). Homozygotes for the C allele of rs9370822 were more than two and a half times as likely to have schizophrenia compared to controls. The other polymorphisms showed much weaker association and are less likely to be biologically significant. These results suggest that DTNBP1 is a good candidate for schizophrenia risk and rs9370822 is either functionally important or in disequilibrium with a functional SNP, although our observations should be viewed with caution until they are independently replicated.