Japanese Schizophrenic Patients Research Articles

Cytochrome P450 II D6 gene polymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japanese schizophrenic patients.

The purpose of this study was to examine whether the neuroleptic-induced extrapyramidal symptoms are associated with the CYP2D6 activity. The CYP2D6 gene polymorphisms (CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*10, and CYP2D6*12) were genotyped in 196 normal controls and 320 schizophrenic patients receiving neuroleptics. The relationships with susceptibility to extrapyramidal symptoms (EPS) and tardive dyskinesia, and with steady-state serum haloperidol levels in maintenance therapy, were investigated. The allele frequency of CYP2D6*2 was significantly higher, while that of CYP2D6*10 tended to be higher in the schizophrenic patients susceptible to acute EPS. The steady-state serum haloperidol levels per daily dosage were observed to be significantly higher in schizophrenic patients with the mutant-type homozygote of CYP2D6*2, while this difference was trend level in those of CYP2D6*10. However, no significant difference was observed in the distribution of both CYP2D6*2 (C2938T) and CYP2D6*10 (C188T) polymorphisms between schizophrenic patients with or without tardive dyskinesia. The present results suggest that the homozygotes of CYP2D6*2 and CYP2D6*10 appear to be a susceptibility factor for developing acute EPS in schizophrenic patients and for impaired neuroleptic metabolism in Japanese schizophrenic patients.

NAD(P)H: quinone oxidoreductase (NQO1) gene polymorphism and schizophrenia

NAD(P)H: quinone oxidoreductase (NQO1), an obligate two-electron reductase of quinones, prevents their participation in redox cycling and subsequent generation of reactive oxygen species (ROS). Reduced or negative activity of NQO1 would lead to an excess of neurotoxic compounds of cathecolamine o-quinones and ROS. Recently, there has been increasing evidence that catecholamine o-quinones and ROS might contribute to the development of schizophrenia. We investigated the genetic association between a functional polymorphism (Pro187Ser) in the human NQO1 gene and schizophrenia (244 Japanese schizophrenic patients and 204 healthy controls). No significant differences in the allelic and genotypic distribution between patients and controls were observed. In addition, our results revealed no association between the genotypes of the polymorphism and any characteristics of patients such as gender, age at onset, family history or current neuroleptic dosage. Our results suggest that the NQO1 gene polymorphism does not confer increased susceptibility for schizophrenia in the present sample.

Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia.

The effects of various CYP2D6 genotypes on the steady-state plasma concentrations (Css) of risperidone and its active metabolite, 9-hydroxyrisperidone, were studied in 85 Japanese schizophrenic patients (27 men and 58 women) treated with 6 mg/d risperidone for at least 2 weeks. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry. The patients had the following CYP2D6 genotypes: wild-type (wt)/wt (40 patients), CYP2D6*10 (*10)/wt ( 28), CYP2D6*5 (*5)/wt ( 8), *10/*10 ( 5), *5/*10 ( 3), and CYP2D6*4/CYP2D6*14 ( 1), respectively. The Css values of risperidone and 9-hydroxyrisperidone were corrected to the median body weight of 58 kg. The medians (ranges) of the Css of risperidone in the aforementioned genotype groups were 2.2 (0.37-35.7), 6.4 (2.1-26.5), 12.3 (4.7-39.5), 19.4 (13.4-26.4), 64.0 (41.6-68.8), and 91.8 nmol/L. Those values for risperidone-to-9-hydroxyrisperidone ratio were 0.03 (0.01-0.33), 0.06 (0.03-0.19), 0.14 (0.07-0.29), 0.28 (0.25-0.38), 0.48 (0.38-0.58), and 2.35, respectively. The Css of risperidone was significantly (P < 0.05 or P < 0.001) different among the four genotype groups (wt/wt, *10/wt, *5/wt, and *10/*10), except between the *5/wt and *10/*10 groups. Also, the risperidone-to-9-hydroxyrisperidone ratio significantly (P < 0.005 or P < 0.001) differed among these genotype groups. No significant differences were found in the Css of 9-hydroxyrisperidone and the active moiety (the Css of risperidone plus 9-hydroxyrisperidone) among these genotype groups. This study confirms previous findings that the CYP2D6 status affects the Css of risperidone via its strong regulation of 9-hydroxylation of risperidone. However, similar active moiety of risperidone among different genotype groups suggests that the determination of the CYP2D6 genotype has little importance for clinical situations.

Extrapyramidal symptom profiles in Japanese patients with schizophrenia treated with olanzapine or haloperidol

Previous clinical trials have clearly shown the superiority of olanzapine to haloperidol in the improvement of extrapyramidal symptoms (EPS) in schizophrenic patients. The primary purpose of this study was to compare EPS profiles in Japanese schizophrenic patients treated with an atypical antipsychotic, olanzapine, or a typical antipsychotic, haloperidol, as measured by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The DIEPSS, which consists of eight individual parameters and one global assessment (overall severity), was used to evaluate 182 patients enrolled in this 8-week study. The primary safety analysis was maximum change (that could be either a decrease or increase) from baseline in DIEPSS total score. Secondary analyses included change from baseline to maximum in DIEPSS total score, change from baseline to endpoint (LOCF) in DIEPSS total score, and the rank sum of the maximum change (that could be either a decrease or increase) from baseline in the DIEPSS individual items. Incidence of treatment-emergent EPS adverse events using the DIEPSS scale was also analyzed. The olanzapine group showed statistically significant superiority to the haloperidol group on the primary analysis ( p<0.001). Secondary analyses also demonstrated olanzapine's superiority in DIEPSS total, parkinsonism, akathisia and overall severity scores (all p≤0.014). Categorical analysis of treatment-emergent akathisia and parkinsonism syndromes at endpoint showed improvement in the olanzapine group but worsening in the haloperidol group. The results from this study suggest that olanzapine, as in Caucasian populations, is a safe treatment in Japanese patients chronically ill with schizophrenia.

An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia.

Morphological alterations in the brains of schizophrenia patients suggest that neurodevelopmental dysfunction is involved in the etiology of the disease.(1) Such dysfunction may be due to functional alterations of cell adhesion molecules, which play important roles in cell migration, axonal growth, fasciculation, synaptogenesis, and synaptic remodeling. We screened for mutations in the coding region of the close homologue to L1 gene (CHL1), which is located on human chromosome 3p26, in 24 Japanese patients with schizophrenia. A missense polymorphism (Leu17Phe) in the signal peptide region was identified. A case-control comparison revealed significantly higher frequencies of the Leu/Leu genotype (P = 0.004) and the Leu allele (P = 0.006) in 282 Japanese schizophrenic patients than in 229 Japanese control subjects. The estimated odds ratio for schizophrenia was 1.83 (95% CI, 1.28-2.26) for the Leu/Leu genotype compared with the other genotypes. An association between this CHL1 gene polymorphism and schizophrenia supports the notion that cell adhesion molecules are involved in the etiology of schizophrenia.

Exon 3 of tyrosine hydroxylase gene: lack of association with Japanese schizophrenic patients.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine (DA) biosynthesis. Exon 3 of the human TH gene encodes the sequence from Ser31 to Glu104 of type 1 enzyme, which contains the critical parts for regulation of the catalytic activity. The amino acid residues Gly36-Arg37-Arg38 were identified as a key sequence for DA to exert its inhibitory effect on catalytic activity. Therefore, we screened the nucleotide sequences of exon 3 from 201 Japanese patients with schizophrenia to explain the elevation in the synaptic or presynaptic DA concentrations in the schizophrenic brain, based on the hypothesis that any mutation changing the amino acid sequence Gly36-Arg37-Arg38 would result in the elevation of DA synthesis, due to a reduced inhibitory effect of DA on the catalytic activity. However, no mutated sequences of exon 3 and both exon-intron boundaries were detected in any of the patients examined. Polymorphisms generating Val81 and Met81 were compared of the distributions of genotype and allele between the patients and 175 Japanese healthy controls, which did not suggest an association between the polymorphism and schizophrenia. These results indicate that exon 3 of the human TH gene lacks association with schizophrenia in Japanese patients.

Clara cell secretory protein (CC16) gene polymorphism and schizophrenia in humans

An increasing amount of evidence suggests that the pathophysiology of schizophrenia is associated with activation of the inflammatory response system, as indicated by lower serum concentrations of Clara cell secretory protein (CC16), an endogenous anti-inflammatory protein in patients with schizophrenia. In the present study, we investigated the genetic association between a functional polymorphism (A38G) in human CC16 gene and schizophrenia (248 Japanese schizophrenic patients and 206 healthy controls). No significant positive association between the CC16 gene polymorphism and schizophrenia was observed. In addition, even when schizophrenic patients were divided into those with a positive family history for schizophrenia and with a negative family history for schizophrenia, no significant association with A38G polymorphism of the CC16 gene was observed. Our results suggest that the CC16 gene polymorphism do not confer increased susceptibility for schizophrenia.

Apolipoprotein E ε3 Allele Is Not a Risk Factor of Schizophrenia: A Study of 314 Japanese Patients

The association between apolipoprotein E (ApoE) alleles and schizophrenia has remained controversial. A recent report claiming that ApoE ε3 Taiwan Chinese carriers have an increased risk of schizophrenia prompted us to investigate the allele frequency in a large group of Japanese schizophrenic patients. Serum samples were obtained from 314 schizophrenic patients and 188 controls in Japan and examined using isoelectric focusing/immunoblotting. There were no significant differences in ApoE allele frequencies between schizophrenic patients and controls and in the odds ratios for schizophrenia among the ε2, ε3 and ε4 carriers. In contrast to the report from Taiwan, our findings and results of the majority of previous studies suggest no effects of ApoE alleles on the development of schizophrenia.

The Human Serotonin Receptor Gene (HTR2) MspI Polymorphism in Japanese Schizophrenic and Alcoholic Patients

Epidemiological and genetic studies of alcoholism and schizophrenia have been performed, and in this study, the human serotonin receptor (HTR2) polymorphism was examined in 75 alcoholics and 31 schizophrenic patients. We found that there might not be a significant difference between these psychiatric disease patients and controls in the frequency of the C1/C2 HTR2 gene (MspI polymorphism). The results suggest that the human HTR2 MspI polymorphism might not be associated with a risk factor for developing alcohol dependence or susceptibility to schizophrenia. It is possible that there may be a racial difference in the frequency of the C1/C2 gene between Japanese and Caucasians. Further studies are required to determine whether or not the novel serotonin receptor polymorphism reflects the pathogenesis of alcoholism or schizophrenia.

Genetic association analysis between CYP2D6*2 allele and tardive dyskinesia in schizophrenic patients

Previous studies have shown a possible association between tardive dyskinesia (TD) and debrisoquine 4-hydroxylase (CYP2D6) polymorphisms, which result in absent enzyme activity. We have recently found a positive association between TD and the CYP2D6*10 allele, which codes for the intermediate metabolizer (IM) phenotype and is characterized by decreased but not absent CYP2D6 activity in Japanese schizophrenic patients. In addition, the CYP2D6*2 allele with the HhaI site mutation in exon 6 has also been reported to be an IM allele and a risk factor for Parkinson’s disease (PD) in the Japanese population. In the present study, we investigated potential contributions of the CYP2D6*2 allele to TD using case-control and regression analysis in 99 schizophrenic patients. No significant differences in genotypic and allelic frequencies were found between patients with and without TD. Even after using regression analysis to adjust for the confounding variables, there was no significant association of the CYP2D6*2 genotype with either outcome variable, the occurrence of TD or the total AIMS score. These results suggest that the CYP2D6*2 allele may not contribute to the pathogenesis of TD.

Social cue perception in Japanese schizophrenic patients

Although abnormal social cue perception in schizophrenia is thought to be a factor in impairing the acquisition of social skills, there have been no studies on social cue perception in Japanese schizophrenics. In order to clarify the characteristics of social cue perception in Japanese schizophrenic patients, 46 schizophrenics and 41 normal controls were presented 12 videotaped vignettes of interpersonal situations, and then they were asked true–false questions about the interaction viewed. Additionally, schizophrenics were administered the Bech version of the Brief Psychiatric Rating Scale. The results showed that the schizophrenic group showed a poorer performance on the cue recognition task than the normal group, and in particular, schizophrenics exhibiting false alarm errors were seen more often than schizophrenics exhibiting omission errors. This suggests that false recognition of information that does not actually exist in social situation is an important characteristic of social cue perception in schizophrenic patients. The false alarm rates on the cue recognition task in schizophrenics were related to the severity of positive-thought disorder, but not to that of negative symptoms. There was no significant relationship between the omission error rates and the two symptom scores in schizophrenics. Faulty cue recognition and positive-thought disorder may be due to a common factor.

Attention deficits assessed by continuous performance test and span of apprehension test in Japanese schizophrenic patients

To examine whether attention deficits in the Continuous Performance Test (CPT) and in the Span of Apprehension Test (SPAN) are observed in Japanese schizophrenics, 49 chronic medicated schizophrenics and 43 normal controls were administered the UCLA version of CPT and SPAN. To investigate whether each measure of the CPT and the SPAN is independently correlated to symptoms, a hierarchical multiple regression was conducted with the attentional measures and age as independent variables and with the conceptual disorganization scores on the Brief Psychiatric Rating Scale (BPRS) as a dependent variable in schizophrenic subjects. Decreased performance on the CPT and SPAN measures was observed in the Japanese patients. This indicates that the CPT and the SPAN can detect the attention deficits of schizophrenics in Japan as well as Europe and the US. The SPAN scores in the present study were lower than in previous studies. This may be due to a lower level of familiarity of Japanese subjects with the Roman alphabet. Each measure of the CPT and the SPAN was significantly correlated with the conceptual disorganization scores after controlling for the other measure and age. We concluded that each deficit in sustained attention and processing capacity was independently related to formal thought disorder in schizophrenia.

Association of dopamine D2 receptor molecular variant with schizophrenia

We have examined a variant of the dopamine D2 receptor gene (Ser311→Cys) in 156 Japanese schizophrenic patients and 300 controls. The allele frequency of Cys311 was significantly higher in the whole patient group (0·054), among patients with onset before age 25 (0 090), and among those with a family history (0·35) than in the controls (0·18). 3 patients were homozygous for Cys311. The patients with Cys311 showed significantly less severe thought disorder and negative symptoms of schizophrenia than those without Cys311. The Cys311 variant of the D2 receptor may be a genetic risk factor for some types of schizophrenia.

Schizophrenic Neologism versus Aphasic Neologism: Characteristics in Writings of Japanese Schizophrenic Patients

Three cases of schizophrenia with ideographic neologisms in Japanese are presented and compared with aphasic neologisms reported in Japanese literature. Schizophrenic neologisms are different from aphasic neologisms in nature. The contrast becomes obvious when both are compared in Japanese writing based on the dual writing system of kanji (Chinese characters, ideogram) and kana (phonetic characters, syllabogram).