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Risperidone (RIS) is a frequently used efficacious psychotropic drug. However, it prolongs the QTc interval and may cause fatal arrhythmia. Little is known on the determinants of this RIS side effect. RIS is metabolized by CYP2D6, and is subject to drug efflux by P-glycoprotein (P-gp) encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene. P-gp removes both RIS and its metabolite 9-OH-RIS from cardiac tissue. To investigate the effect of RIS metabolism and ABCB1 gene polymorphisms on QTc, steady-state plasma RIS and 9-OH-RIS levels, and QTc were measured. CYP2D6, ABCB1 C3435T and G2677T/A genotypes were determined in 66 schizophrenia patients on RIS. QTc was significantly longer in patients with ABCB1 3435CT+3435 TT than in those with 3435CC (P=0.006). ABCB1 G2677T/A genotype did not affect QTc. Multiple regression analysis showed that C/T or T/T genotypes at the ABCB1 C3435T locus, lower weight, and older age prolonged QTc. In summary, the T allele of the ABCB1 C3435T genotype should be considered in future diagnostic development efforts for RIS-associated QT. [ABSTRACT FROM AUTHOR]

Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic β cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics. [ABSTRACT FROM AUTHOR]

Neuregulin- 1 ( NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1β1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients ( n = 40) and healthy volunteers ( n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 ± 0.40 ng/mL, ~213 ± 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles. [ABSTRACT FROM AUTHOR]

We investigated the effect of 5-hydroxytryptamine 3A and 3B receptor (HTR3A and HTR3B) gene polymorphisms on nausea induced by paroxetine in Japanese psychiatric patients. Blood samples were collected from 78 individuals after at least 2 weeks treatment with the same daily dose of paroxetine. The patients visited every 2 weeks and the paroxetine dose was changed in response to their clinical symptoms. Nausea was assessed at each visit. The Tyr129Ser polymorphism of the HTR3B gene had a significant effect on the incidence of nausea (P=0.038). Logistic regression analysis also showed that patients with the Tyr/Tyr genotype had a 3.95-fold (P=0.048) higher risk of developing nausea than patients with the Ser allele. HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea. The mean score of nausea severity was corrected by the Bonferroni test. HTR3B gene polymorphisms are significant predictors of paroxetine-induced nausea.The Pharmacogenomics Journal (2006) 6, 351–356. doi:10.1038/sj.tpj.6500382; published online 14 March 2006 [ABSTRACT FROM AUTHOR]

We investigated the effects of a 5-hydroxytryptamine (5-HT) 1A receptor gene polymorphism on the clinical response to fluvoxamine (FLV) in 65 depressed outpatients who gave written consent to participate in the study. Patients visited every 2 weeks after the first examination until the week 12 end point and were evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17) at each visit. FLV dose was changed in response to their clinical symptoms. The Gly272Asp polymorphism of the 5-HT1A receptor gene was identified by a PCR method. The subjects with the Asp allele had a significantly higher % reduction in the HAM-D-17 score than those with the Gly/Gly genotype at week 2 (P=0.009), week 6 (P=0.036), and week 12 (P=0.031). There was a significant difference in the genotype distribution between the responders and nonresponders. These results suggest that the Gly272Asp polymorphism of the 5-HT1A receptor gene may predict the response to FLV.The Pharmacogenomics Journal (2004) 4, 283-286. doi:10.1038/sj.tpj.6500256 Published online 18 May 2004 [ABSTRACT FROM AUTHOR]

The biological activity of interferon (IFN) is mediated by the induction of intracellular antiviral proteins, such as 2'-5' oligoadenylate synthetase, dsRNA-activated protein kinase and MxA protein. Among these, MxA protein is assumed to be the most specific surrogate parameter for IFN action. This study was performed to elucidate whether a single nucleotide polymorphism (SNP) (GIT at nt-88) in the promoter region of the MxA gene influences the response to IFN therapy in patients with chronic hepatitis C virus (HCV) infection. Polymorphisms of the MxA gene in 235 HCV patients were determined by polymerase chain reaction- restriction fragment length polymorphism. The frequency of SNP was compared between sustained-responders (n = 78) and nonresponders (n = 1 57), as determined by biochemical and virological responses to IFN. Multivariate analysis showed that among all patients, HCV genotype, HCV RNA level and the SNP of the MxA gene were independent and significant determinants of the outcome of IFN therapy [odds ratio 3.8 (95% confidence interval 2.0-7.0), P < 0.0001; 0.27 (0.15-0.50), P < 0.0001; 1.8 (1.0-3.4), P - 0.0464, respectively]. Furthermore, among patients with a low viral load (≤2.0 Meq/mL), MxA-T-positive patients were more likely to show a sustained response compared with MxA-T- negative patients [2.87 (1.3-6.3); 62% vs 36%; P = 0.0075]. Our findings suggested that the SNP of the MxA gene is one of the important host factors that independently influences the response to IFN in patients with chronic HCV infection, especially those with a low viral load. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the use of prolactin concentration to explore functional polymorphisms in the dopamine receptor D2 gene in healthy individuals.

Abstract: The protein interacting with C-kinase 1 (PICK1) has been implicated in the susceptibility to schizophrenia. PICK1 interacts with enzymes and receptors that play roles in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two studies reported associations between schizophrenia and two PICK1 gene polymorphisms, rs3952 in Chinese and Japanese populations and rs2076369 in a Japanese population. We attempted to confirm these associations in a case–control study of 1765 Japanese patients with schizophrenia and 1851 Japanese control subjects. Neither polymorphism was associated with schizophrenia (rs3952, p =0.755; rs2076369, p =0.997). A haplotype block with these polymorphisms spanning the 5′ region of the PICK1 gene showed high linkage disequilibrium in the Japanese population (D′=0.98, r 2 =0.34); however, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and polymorphisms of the PICK1 gene identified thus far are unlikely to contribute to genetic susceptibility to schizophrenia in the Japanese population. [Copyright &y& Elsevier]

Abstract: The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p =0.92; SNP 4 (rs951436), p =0.91; SNP 7 (rs951439), p =0.27; and SNP 18 (rs2661319), p =0.43. A haplotype block constructed by these SNPs spans the 5′ flanking region to the 5′ mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population. [Copyright &y& Elsevier]