Japanese Schizophrenic Patients Research Articles

CYP1A2*F Polymorphism Contributes at Least Partially to the Variability of Plasma Levels of Dehydroaripiprazole, an Active Metabolite of Aripiprazole, in Schizophrenic Patients.

The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients. It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported. The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A), and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients. All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis. The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2*C genotype. The absence of the A allele of CYP1A2*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis. The findings of this study suggest that the CYP1A2*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.

Metabolic changes of Japanese schizophrenic patients transferred from hospitalization to outpatients.

It is well known that schizophrenic patients have high incidence of metabolic syndrome and life-style related diseases. There are reports that the rates of these diseases are increased more in outpatients than inpatients, but are also reports that the rates are not different between both patient groups. These differences might be related to the length of hospitalization. Hospitalization of Japanese psychiatric patients is about 300 days, much longer than western countries (below 50 days). Therefore, we investigated lipid and glucose metabolism of schizophrenic patients transferred from hospitalization to outpatients at Kohnodai hospital with a mean of 80 days hospitalization period to clarify metabolic characteristics in Japanese patients. Study participants were 144 schizophrenia inpatients and 109 outpatients at Kohnodai Hospital. These 109 outpatients were followed for approximately 2 years, without changes of administrated drugs, and from 144 inpatients. Data from outpatients were obtained at 6 months, 1 year and 2 years after their discharge. Outpatients 2 years after discharge had significantly higher levels of total cholesterol, triglyceride and non-high density lipoprotein (non-HDL) cholesterol than inpatients, accompanied with an increase of body weight. Serum HDL-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels had no significant difference between both groups. These lipids and glucose levels also showed the same tendency in outpatients 0.5 year and 1 year after discharge as those after 2 years. We found that schizophrenic patients in our study appeared to have changes of lipid metabolism 2 years after their discharge, but no significant changes of glucose metabolism, such as FPG and HbA1c.

Definition and refinement of the 7q36.3 duplication region associated with schizophrenia

Using a very high-resolution oligonucleotide array for copy number variant (CNV) screening of samples comprising schizophrenic patients, we detected a novel CNV within the critical region (NCBI36/hg18, Chr7: 158,630,410–158,719,410) previously shown to be associated with schizophrenia. We investigated the association between the novel CNV identified in the current study and schizophrenia. Three independent samples were used: (1) Screening set, 300 Japanese schizophrenic patients (53.28 ± 14.66 years); (2) Confirmation set, 531 schizophrenic patients (46.03 ± 12.15 years); and (3) 711 healthy controls (47.12 ± 11.03 years). All subjects enrolled in the study were Japanese. Chromosomal position was determined using fluorescence in situ hybridization. We identified a novel duplication within the region associated with schizophrenia identified on 7q36.3 that is adjacent to VIPR2 and is not associated with schizophrenia. In the Japanese population, the 35-kb region that harbors the common, novel CNV should be excluded from the region associated with schizophrenia on 7q36.3.

The Prevalence of Glucose Intolerance in Japanese Schizophrenic Patients With a Normal Fasting Glucose Level

The prevalence of diabetes in patients with schizophrenia is 2- to 3-fold higher than in the general population. Glucose abnormalities were detected in 11.9% of Japanese schizophrenic patients in a recent cross-sectional study that included fasting glucose monitoring. However, detailed studies of glucose intolerance using the glucose tolerance test have been limited in Japanese patients with schizophrenia. We investigated the prevalence of abnormal glucose tolerance after glucose loading among Japanese inpatients with schizophrenia, with normal fasting glucose levels. A total of 258 inpatients with schizophrenia participated in this study after giving their written informed consent. A 75-g oral glucose tolerance test was conducted in the morning after a 12-hour overnight fast. Among patients with normal fasting glucose, 81.3% had normal glucose tolerance, 17.3% had impaired glucose tolerance, and 1.3% were diagnosed with diabetes. This study showed that the frequency of impaired glucose tolerance in patients with schizophrenia with normal fasting glucose levels might be higher than in the general population. Careful monitoring and screening of patients with schizophrenia for abnormal glucose metabolism might therefore be necessary.

Excessive Insulin Secretion in Japanese Schizophrenic Patients Treated With Antipsychotics Despite Normal Fasting Glucose Levels

The development of impaired glucose tolerance induced by antipsychotics (APs) is of concern as a serious adverse effect of psychiatric drug therapy. However, the mechanism by which APs cause dysfunction of the glucose-insulin response is not fully understood. Recent studies have shown that patients treated with APs for schizophrenia were more likely to exhibit impaired glucose tolerance after a glucose load compared with healthy control subjects, even if fasting glucose levels were within the reference range. To explain these findings, we hypothesized that insulin secretion is increased in schizophrenic patients treated with AP, even those normal fasting glucose (NFG) levels. Therefore, oral glucose tolerance tests were conducted in 159 Japanese inpatients with AP-treated schizophrenia and in 90 healthy subjects without schizophrenia. Plasma glucose and serum insulin concentrations were measured before (0 minute) and at 30, 60, 90, and 120 minutes after the oral glucose load. Although insulin levels at 0 minute were similar in both groups of subjects, insulin levels were significantly higher in the patients treated with AP at all times after the glucose load than in the healthy subjects. In analyses of NFG subjects, insulin levels were significantly higher in the patients treated with AP compared with the healthy subjects at all times after glucose loading. Overall, we found that insulin secretion in response to a glucose load was significantly higher in the patients treated with AP, irrespective of NFG. These results suggest that APs affect the glucose-insulin response, which may lead to subclinical insulin resistance before the onset of overt glucose intolerance.

Sexual dysfunction and hyperprolactinemia in Japanese schizophrenic patients taking antipsychotics

This study aimed to estimate the prevalence of sexual dysfunction, evaluated by the Nagoya Sexual Function Questionnaire (NSFQ), and hyperprolactinemia in patients with schizophrenia and examine a relationship between sexual dysfunction and serum prolactin levels. This cross-sectional, comparative study was performed using a sample comprising 195 Japanese schizophrenic in- and outpatients treated with antipsychotics (117 males and 78 females). Data were collected from October 2009 to January 2010 using single, cross-sectional ratings of sexual function assessed by the NSFQ and concurrent measurement of serum prolactin levels. The prevalence of sexual dysfunction in patients with schizophrenia was high (males 66.7%; females 79.5%). Hyperprolactinemia (>25ng/ml) was highly prevalent among schizophrenia patients, affecting 53.8% of females and 51.3% of males. Among female patients, 16.7% had prolactin levels>100ng/ml. There was no relationship between sexual dysfunction and serum prolactin levels. The present study demonstrated a higher prevalence of sexual dysfunction and hyperprolactinemia in Japanese schizophrenia patients. Clinicians should keep these problems in mind and discuss potential solutions with patients to improve patients' quality of life and adherence to therapy.

Different patterns of longitudinal changes in plasma levels of catecholamine metabolites and brain-derived neurotrophic factor after administration of atypical antipsychotics in first episode untreated schizophrenic patients

In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18–46 years; mean±SD: 25±16 years). The patients were treated with risperidone (n=32) in a dose range of 2–6 mg/day (mean±SD=3.4±1.9), olanzapine (n=18) in a dose range of 5–20 mg/day (mean±SD=12.1±5.8), or aripiprazole (n=9) in a dose range of 12–30 mg/day (mean±SD=22.8±10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment.

Investigation of clinical factors influencing cognitive function in Japanese schizophrenia

Several investigators have reported cognitive dysfunction in chronic schizophrenia that was associated with insight and social skills. Such cognitive dysfunction seriously hinders an immediate return to normal life. Recently, Kaneda et al. reported that the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) was superior in the evaluation of the cognitive function. We investigated which clinical factors (age, sex, duration of illness, level of education, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage) affected cognitive dysfunction in 115 Japanese schizophrenic patients, with the use of multiple regression analysis. We detected an association between composite score, verbal memory, working memory and executive function and PANSS total score. Moreover, most cognitive tasks were associated with a negative PANSS score but not a positive PANSS score or general score. We also showed an association between age and verbal fluency and attention in schizophrenia. In addition, anxiolytics/hypnotics (diazepam-equivalent) were associated with composite score, working memory and motor speed. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Because anxiolytics/hypnotics might have a detrimental influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible.

Prepulse inhibition of the startle response with chronic schizophrenia: A replication study

Prepulse inhibition (PPI) deficit, the acoustic startle reflex (ASR) and habituation (HAB) impairment are considered to be endophenotypes for schizophrenia. The recent two studies have reported that a PPI deficit was detected in Japanese schizophrenic patients. We replicated that study using larger samples (115 schizophrenic patients and 111 normal controls) than the original study and a method same as original study. A startle response monitoring system was used to deliver acoustic startle stimuli, and to record and score the electromyographic activity of the orbicularis oculi muscle. We evaluated the startle measures of mean magnitude of ASR, HAB, and PPI at prepulse sound pressure intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90). ASR was significantly different between schizophrenic patients and controls. HAB and all PPI session data from schizophrenic patients were significantly lower than in controls. In addition, we detected significant differences for ASR, HAB and each PPI (82, 86 and 90 dB) between schizophrenic patients and controls with the use of multiple regression analysis. The gender and smoking state were not correlated with ASR, HAB or any PPI in multiple regression analysis. In conclusion, we were able to replicate the finding of HAB impairment and PPI deficit in chronic Japanese schizophrenic patients.

Analysis of mitochondrial DNA variants in Japanese patients with schizophrenia

To test the hypothesis that mitochondrial DNA (mtDNA) variants contribute to the susceptibility to schizophrenia, we sequenced the entire mtDNAs from 93 Japanese schizophrenic patients. Three non-synonymous homoplasmic variants in subunit six of the ATP synthase (MT-ATP6) gene that were detected only in patients but not in controls were suggested to be slightly deleterious, because (1) their original amino acid residues (AA) were highly conserved and (2) the physicochemical differences between the original and altered AA were relatively high. In addition, we detected three novel heteroplasmic variants that were potentially pathogenic. Although functional analysis is needed, rare variants in the mtDNA may convey susceptibility to schizophrenia.

No Association Between Polymorphisms of Neuronal Oxide Synthase 1 Gene (NOS1) and Schizophrenia in a Japanese Population

The neuronal nitric oxide synthase gene (NOS1) is located on 12q24, in a susceptibility region for schizophrenia, and produces nitric oxide (NO) in the brain. NO plays a role in neurotransmitter release and is the second messenger of the N-methyl-D-aspartate (NMDA) receptor. Furthermore, it is connected to the dopaminergic and serotonergic neural transmission systems. Therefore, abnormalities in the NO pathway are thought to be involved in the pathophysiology of schizophrenia. Several genetic studies showed an association of NOS1 with schizophrenia. However, results of replication studies have been inconsistent. Therefore, we conducted a replication study of NOS1 with schizophrenia in a Japanese sample. We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs2682826, and rs6490121) in NOS1 that were positively associated with schizophrenia in previous studies. Two SNPs showed an association with Japanese schizophrenic patients (542 cases and 519 controls, rs3782219: P allele = 0.0291 and rs3782206: P allele = 0.0124, P genotype = 0.0490), and almost these significances remained with an increased sample size (1154 cases and 1260 controls, rs3782219: P allele = 0.0197 and rs3782206: P allele = 0.0480). However, these associations also might have resulted from type I error on account of multiple testing (rs3782219: P allele = 0.133 and rs3782206: P allele = 0.168). In conclusion, we could not replicate the association between seven SNPs in NOS1 and schizophrenia found in several earlier studies, using larger Japanese schizophrenia and control samples.

Fluctuating plasma levels of the active moiety of risperidone is related to occurrence of extrapyramidal symptoms

In the present study, we compared the plasma levels of the active moiety (i.e. risperidone plus 9-hydroxyrisperidone) in a steady state in 54 Japanese schizophrenic patients with or without emerging extrapyramidal symptoms (EPS and non-EPS groups, respectively) who were treated with 4 mg/day risperidone. No differences were observed in the plasma levels of the active moiety at 4 and 8 weeks after risperiodne administration in both groups. However, the EPS group patients showed a greater number of fluctuations/larger fluctuations in the plasma active moiety levels than those in the non-EPS group. These results suggest that a stable plasma active moiety level maybe important for preventing EPSs during treatment with risperidone.

The Relationship Between the Response of Clinical Symptoms and Plasma Olanzapine Concentration, Based on Pharmacogenetics

The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics.

Direct metabolic effects of risperidone and olanzapine in Japanese schizophrenic patients

Direct metabolic effects of risperidone and olanzapine in Japanese schizophrenic patients

Questionnaire on animal-assisted therapy (AAT): The expectation for AAT as a day-care program for Japanese schizophrenic patients

Animal-assisted therapy (AAT) was developed to promote human social and emotional functioning as a day-care program for psychiatric patients. In this study, we determined which animals 481 schizophrenic patients liked and what they thought about AAT, using an original questionnaire. It was found that more than 80% of the present patients liked animals and that they thought contact with animals was useful as a novel therapy. They had much interest in, and many hopes, for AAT.

Body Mass Index among Japanese Inpatients with Schizophrenia

Many studies have emphasized the high frequency of obesity in schizophrenic patients. However, the characteristics of the Body Mass Index (BMI) distribution in Japanese schizophrenic patients remain unknown, and the aim of this study was to clarify these characteristics in a Japanese schizophrenic inpatient population. The subjects were 273 inpatients (males: 141, females: 132) with schizophrenia. The patient BMI distribution was compared with normal control data obtained from the 2003 Japanese National Health and Nutrition Survey. The mean patient BMI was 23.0 +/- 4.3, and the BMI showed a normal distribution. The proportion of patients who were obese, of normal weight and underweight was 30.8%, 53.1%, and 16.1%, respectively. No statistical evidence of a higher frequency of obesity was found in male patients, compared to normal controls, but a higher frequency of underweight patients and a lower frequency of normal-weight patients were apparent in most decades of age. In female schizophrenia patients, a higher prevalence of obesity occurred in patients aged 50-59 years old, compared to controls. A higher rate of underweight elderly patients and a lower rate of normal-weight patients aged 40 to more than 70 years old were also apparent. The results suggest that not only obesity but also weight problems related to an underweight condition occur more frequently in Japanese schizophrenic inpatients than in normal controls. The deviation of the BMI distribution in Japanese schizophrenic inpatients may have a relationship with higher mortality and sudden death in schizophrenia.

Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in Japanese schizophrenic patients

The aim of the present study is to examine the relationship between dopamine D2-receptor gene (DRD2) polymorphisms (Taq1A, Taq1B, -141C Ins/Del) and the risk of extrapyramidal adverse effects (EPS), assessed according to the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), or the maintenance dose of antipsychotics in schizophrenic patients. The DIEPSS score was significantly higher in patients bearing the -141C Del allele than in those without it. Taq1A and Taq1B restriction fragment length polymorphisms (RFLPs) did not significantly affect the DIEPSS score. On the other hand, maintenance doses of neuroleptics and antiparkinsonian drugs were significantly higher in patients with the B1 allele of Taq1B RFLP than in those without it, while the Taq1A RFLP and -141C Ins/Del polymorphisms were not significantly related to the maintenance doses. In conclusion, the risk of EPS may be increased in patients with the -141C Del allele of the DRD2 gene. In these patients, antipsychotics should be administered with caution.

Quality of life of schizophrenic patients living in the community: The relationships with personal characteristics, objective indicators and self‐esteem

The relationship of personal characteristics, objective indicators, and self-esteem to quality of life (QOL) was investigated cross-sectionally in 73 Japanese schizophrenic patients, and the question of how objective conditions affect subjective evaluation was evaluated. Depressive mood and uncooperativeness were negatively correlated with self-esteem, and self-esteem was positively correlated with QOL. Self-esteem was considered to directly affect QOL, and depressive mood and uncooperativeness to affect QOL via self-esteem. Findings suggest that, in order to improve the QOL of schizophrenia patients, interventions to help alleviate psychiatric symptoms (e.g. depressive mood, uncooperativeness) must be utilized. A change in Japanese society itself must occur so that the consequences of stigma may be reduced and patient coping skills improved.

Association between chromogranin b gene polymorphisms and schizophrenia in the japanese population

Background We found in previous work a significant association between schizophrenia and D20S95 on chromosome 20p12.3. In this study, we analyzed 10 microsatellite markers and found an association of schizophrenia with D20S882 and D20S905 that flank D20S95. The chromogranin B gene ( CHGB) is 30 kb from D20S905. The chromogranin B (secretogranin I) belongs to a series of acidic secretory proteins that are widely expressed in endocrine and neuronal cells, and its cerebrospinal fluid levels have been reported to decrease in patients with chronic schizophrenia. Methods We screened for polymorphisms in CHGB with polymerase chain reaction direct sequencing methods in 24 Japanese schizophrenic patients and identified a total of 22 polymorphisms. Allelic and genotypic distributions of detected polymorphisms were compared between unrelated Japanese schizophrenic patients ( n = 192) and healthy control subjects ( n = 192). Results Statistically significant differences in the allelic distributions were found between schizophrenic patients and control subjects for 1058C/G (A353G) (corrected p = 7.7 × 10 −5) and 1104A/G (E368E) (corrected p = 8.1 × 10 −6). The 1058C/G and 1104A/G alleles were in almost complete linkage disequilibrium and were in linkage disequilibrium with D20S95. Conclusions Results suggest that the CHGB variations are involved in the susceptibility to schizophrenia in our study population.

Psychopharmacogenetic study regarding risperidone in Japanese schizophrenic patients

Kakihara, Shingo; Yoshimura, Reiji; Matsumoto, Chima; Kaji, Kyouko; Shinkai, Koji; Yamada, Yasuhisa; Goto, Makiko; Ueda, Nobuhisa; Ohmori, Osama; Nakamura, Jun Author Information