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BACKGROUND: Cognitive impairment is common in people with mental disorders, leading to transdiagnostic classification based on cognitive characteristics. However, few studies have used this approach for intellectual abilities and functional outcomes. AIMS: The present study aimed to classify people with mental disorders based on intellectual abilities and functional outcomes in a data-driven manner. METHOD: Seven hundred and forty-nine patients diagnosed with schizophrenia, bipolar disorder, major depression disorder or autism spectrum disorder and 1030 healthy control subjects were recruited from facilities in various regions of Japan. Two independent k-means cluster analyses were performed. First, intelligence variables (current estimated IQ, premorbid IQ, and IQ discrepancy) were included. Second, number of work hours per week was included instead of premorbid IQ. RESULTS: Four clusters were identified in the two analyses. These clusters were specifically characterised in terms of IQ discrepancy in the first cluster analysis, whereas the work variable was the most salient feature in the second cluster analysis. Distributions of clinical diagnoses in the two cluster analyses showed that all diagnoses were unevenly represented across the clusters. CONCLUSIONS: Intellectual abilities and work outcomes are effective classifiers in transdiagnostic approaches. The results of our study also suggest the importance of diagnosis-specific strategies to support functional recovery in people with mental disorders.

DOI： 10.1192/bjo.2022.50

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BACKGROUND: Nalmefene is the only medication marketed to reduce the consumption of alcohol in patients with alcohol dependence, but it remains unclear which patients could most benefit from it. This study aimed to identify clinical moderators that affect treatment response to nalmefene in patients with alcohol dependence. METHODS: In a multicenter, randomized, controlled, double-blind, phase 3 study of nalmefene on Japanese patients with alcohol dependence, the relationship between the reduction of heavy drinking days (HDD) and total alcohol consumption (TAC) at 12 and 24 weeks of treatment and baseline variables of the participants were analyzed in a linear regression and multiple adjusted analysis. RESULTS: Age < 65, no family history of problem drinking, age at onset of problem drinking ≥ 25, and not currently smoking were possible positive moderators. Nalmefene showed a significant HDD reduction in patients with age < 65 or no family history of problem drinking, and a significant TAC reduction in patients with age at onset of problem drinking ≥ 25 or who were not currently smoking. After multiple adjusted analyses, age < 65 (p = .028), no family history of problem drinking (p = .047), and age at onset of problem drinking ≥ 25 (p = .030) were statistically significant. Not currently smoking (p = .071) was marginally significant. In combination, these moderators indicated synergistic effects. CONCLUSIONS: Alcohol-dependent patients with favorable prognostic factors such as non-smoking status, no family history of problem drinking, and a late-onset of problem drinking selectively benefit from nalmefene. Further research is needed to validate these exploratory results.

DOI： 10.1016/j.drugalcdep.2022.109365

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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RATIONALE: Depression in schizophrenia is an important symptom. We investigated whether depression and suicidal symptoms in the chronic phase are related to remote future clinical outcomes in patients with schizophrenia and whether psychotropics improved clinical outcomes. OBJECTIVES: The subjects included 462 outpatients of working age (15 to 64 years old) with schizophrenia treated at Okayama University Hospital from January 2010 to December 2011. We investigated the relationship between the Clinical Global Impression-Severity score at the last visit (average 19.2 years) and the existence of previous depression, suicidal ideas, and suicide attempts. We adjusted by several possible confounders including medical history using multiple regression analysis or logistic regression analysis. RESULTS: Of 462 patients, 168 (36.4%) presented with depression 2 years after schizophrenia onset. A history of suicidal ideas and attempts was related to worse clinical outcome. In males, a history of depression was related to worse clinical outcome, but not in females. Lithium carbonate was related to better clinical outcome in all schizophrenia patients with depression, especially in males. Treatment with antidepressants was related to better clinical outcome only in males. CONCLUSIONS: A history of depression or suicidal symptoms in the chronic phase predicted the future worse clinical outcome in patients with schizophrenia. The administration of lithium carbonate or antidepressants might be recommended, especially to male schizophrenia patients with depression.

DOI： 10.1007/s00213-022-06099-4

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DOI： 10.1097/JCP.0000000000001527

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OBJECTIVE: Benzodiazepine (BZD) dependence has become a social problem and results in poor outcomes. Only a few evidence-based treatments for pharmacotherapy, including antidepressants, are recommended. METHODS: We reported about a 71-year-old man with onset of blindness at 50 years of age due to pigmentary degeneration of the retina developed insomnia at age 59 years, characterized by nocturnal and early morning awakenings. RESULTS: Mirtazapine was effective to not only treat sleep disturbance but also a craving for BZD. CONCLUSIONS: The increases of dopamine, norepinephrine, and serotonin signaling by mirtazapine may be related to the effectiveness in reducing BZD dependence.

DOI： 10.1097/WNF.0000000000000488

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Rationale Adequate immunotherapies for anti-NMDAR encephalitis during pregnancy produce a relatively good clinical outcome for pregnant mothers and their infants, but there are no reports about the future growth of their babies. The damage of anti-NMDAR antibodies to early neuronal development is still unknown. Objectives Serum or cerebrospinal fluid from one patient with anti-NMDAR encephalitis (the index patient) and one patient with schizophrenia (the control patient) was administered to primary cultures of dissociated rat cortical neurons, and dendritic outgrowth, centrosome elimination, and branching of dendrites were investigated. For rescue experiments, serum of the index patient was replaced with normal culture media after 3 days' administration of the index patient. Results Serum and cerebrospinal fluid of the index patient statistically significantly impaired dendritic outgrowth of cultured rat cortical primary neurons. Serum of the index patient also statistically significantly delayed centrosome elimination. Impaired dendritic outgrowth and delayed centrosome elimination were not perfectly rescued by changing to normal culture media. Serum of the index patient also statistically significantly reduced the branching of dendrites. Conclusions This is the first demonstration of the damage by anti-NMDAR antibodies on early dendritic development in vitro. As a strategy to protect embryonic neurons, our findings may support the efficacy of early immunotherapy for anti-NMDAR encephalitis in pregnancy.

DOI： 10.1007/s00213-021-06036-x

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objective There is no report that statistically evaluates the therapeutic reference (350-600 ng/ml) and adverse drug reaction (ADR) range (>1000 ng/ml) of clozapine (CLZ) recommended by the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) consensus guidelines in an isolated and large sampling study.Methods We administered CLZ to 131 Japanese patients with treatment-resistant schizophrenia in a multicenter cross-sectional study. Plasma CLZ concentrations were assayed by high-performance liquid chromatography using trough sampling. The Brief Psychiatric Rating Scale (BPRS) and severe dose-dependent ADR (sedation, myoclonus, and seizures) were analyzed statistically after adjusting for possible confounders.Results The daily CLZ dosage showed a moderately positive relationship with the plasma concentration (r = 0.49, p 0.001). Every 100 ng/ml increase in plasma CLZ concentration improved the total BPRS score 1.95% (95% CI: 0.89-3.01, p 0.001) and the odds ratio (OR) 1.38 (95% CI: 1.14-1.66, p = 0.001) for BPRS response. Compared with concentrations below 350 ng/ml CLZ, 350-600 ng/ml (11.12%; 95% CI: 2.52-19.72, p = 0.012) and 600-1000 ng/ml (11.05%; 95% CI: 2.40-19.71, p = 0.013) showed significant improvement in the total BPRS score. Dosages above 1000 ng/ml showed greater improvement (25.36%; 95% CI: 13.08-37.64, p 0.001) of the total BPRS score but more severe ADRs than dosages below 1000 ng/ml (OR: 31.72; 95% CI: 1.04-968.81, p = 0.048).Conclusion The AGNP therapeutic reference range (350-600 ng/ml) is useful, and a dose above 1000 ng/ml is potentially more effective but carries the risk of severe ADRs in the central nervous system.

DOI： 10.1111/acps.13264

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The mortality rate of patients with schizophrenia is high, and life expectancy is shorter by 10 to 20 years. Metabolic abnormalities including type 2 diabetes mellitus (T2DM) are among the main reasons. The prevalence of T2DM in patients with schizophrenia may be epidemiologically frequent because antipsychotics induce weight gain as a side effect and the cognitive dysfunction of patients with schizophrenia relates to a disordered lifestyle, poor diet, and low socioeconomic status. Apart from these common risk factors and risk factors unique to schizophrenia, accumulating evidence suggests the existence of common susceptibility genes between schizophrenia and T2DM. Functional proteins translated from common genetic susceptibility genes are known to regulate neuronal development in the brain and insulin in the pancreas through several common cascades. In this review, we discuss common susceptibility genes, functional cascades, and the relationship between schizophrenia and T2DM. Many genetic and epidemiological studies have reliably associated the comorbidity of schizophrenia and T2DM, and it is probably safe to think that common cascades and mechanisms suspected from common genes' functions are related to the onset of both schizophrenia and T2DM. On the other hand, even when genetic analyses are performed on a relatively large number of comorbid patients, the results are sometimes inconsistent, and susceptibility genes may carry only a low or moderate risk. We anticipate future directions in this field.

DOI： 10.1093/ijnp/pyaa097

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<title>Abstract</title>Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (<italic>KDM4C</italic>) have been suggested to confer a risk for such disorders. However, rare genetic variants in <italic>KDM4C</italic> have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in <italic>KDM4C</italic> and SCZ (<italic>p</italic> = 0.003) and ASD (<italic>p</italic> = 0.04). We also observed a significant association between deletions in <italic>KDM4C</italic> and SCZ (corrected <italic>p</italic> = 0.04). Next, to explore the contribution of single nucleotide variants in <italic>KDM4C</italic>, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with <italic>KDM4C</italic> deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between <italic>KDM4C</italic> CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

DOI： 10.1038/s41398-020-01107-7

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Other Link： http://www.nature.com/articles/s41398-020-01107-7

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
<sec>
<title>Background</title>
Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in <italic>NRXN1</italic>, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.


</sec>
<sec>
<title>Methods</title>
To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced <italic>NRXN1</italic> coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.


</sec>
<sec>
<title>Results</title>
Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of <italic>NRXN1</italic>α isoform<italic>,</italic> as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.


</sec>
<sec>
<title>Conclusions</title>
The combined data suggest that missense variants in <italic>NRXN1</italic> could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.


</sec>

DOI： 10.1186/s11689-020-09325-2

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Other Link： http://link.springer.com/article/10.1186/s11689-020-09325-2/fulltext.html

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Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

DOI： 10.1038/s41439-020-00125-7

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Rationale Changing antipsychotics of patients with chronic schizophrenia involves several risks. Switching to aripiprazole is especially difficult. We investigated switching methods and related factors for successful switching patients with chronic schizophrenia to aripiprazole. Objectives This study was a multi-center historical cohort study and approved by the research ethics committee of Okayama University Hospital and Okayama Psychiatric Medical Center. We compared survival proportions of 178 chronic schizophrenia patients who continued aripiprazole monotherapy for 6 months after non-direct switching (add-on switching (n = 45), cross switching (n = 62)) or direct switching (n = 71). We adjusted possible confounders using a Cox proportional hazards model. Results Of patients with chronic schizophrenia, 56.7% (101/178) were switched to aripiprazole monotherapy, and 55.0% (98/178) showed improvement in symptoms as demonstrated by the Clinical Global Impression Severity score. Kaplan-Meier survival curves showed that non-direct switching had a higher survival proportion than direct switching (log-rank test, p = 0.012). Even after adjusting for several variables using a Cox proportional hazards model, add-on switching had a significantly lower hazard at 6 months than direct switching (hazard ratio 0.42, 95% confidence interval 0.21-0.82, P = 0.01). In cases of switching to aripiprazole for psychiatric symptoms, non-direct switching had a lower hazard than direct switching (hazard ratio 0.41, 95% confidence interval 0.21-0.81, P = 0.01) but was not significant for adverse reaction. When aripiprazole was switched from olanzapine, add-on switch showed the lowest hazard ratio for continuation (hazard ratio 0.29, 95% confidence interval 0.07-1.11, P = 0.07). Conclusions Flexibility in strategies when switching to aripiprazole may induce a better outcome for patients with chronic schizophrenia.

DOI： 10.1007/s00213-019-05352-7

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.euroneuro.2019.07.137

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Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

DOI： 10.1093/schbul/sby140

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DOI： 10.18926/AMO/56860

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Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

DOI： 10.1097/YPG.0000000000000204

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Three types of antipsychotics, typical (e.g. haloperidol), atypical (e.g. clozapine), and dopamine partial agonist (e.g. aripiprazole), are administered for treatment of schizophrenia. These antipsychotics have different efficacy and side-effect profiles. We investigated whether aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine through the AKT-GSK-3 beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidol was administered to the rat cortical neurons. The levels of PSD95 protein and AKT-GSK-3 beta cascade-related proteins were investigated by Western blot. The number of spines and PSD95 puncta were investigated by immunofluorescence cell staining. Aripiprazole (1 µM or 10 µM) and clozapine (1 µM) increased the levels of PSD95 protein, the number of spines, phosphorylated Akt Thr308 and Ser473, and phosphorylated GSK-3 beta Ser9. On the other hand, haloperidol (1 µM or 10 µM) or an inappropriate concentration of clozapine (10 µM) decreased them. A GSK inhibitor also increased the levels of PSD-95 protein and caused the same morphology. Aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine, and this effect may occur through the AKT-GSK-3 beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spines in patients with schizophrenia.

DOI： 10.1016/j.euroneuro.2018.03.004

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In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

DOI： 10.1038/s41398-017-0061-y

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Language：English   Publisher：ELSEVIER SCIENCE BV  

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Aim: Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning.
Methods: A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants' current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ.
Results: Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were -16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls.
Conclusion: These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

DOI： 10.1111/pcn.12474

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Disturbances of synaptic connectivity during perinatal and adolescent periods have been hypothesized to be related to the pathophysiology of schizophrenia. Rho guanine nucleotide exchange factor 11 (ARHGEF11) is a specific guanine nucleotide exchange factors (GEF) for RhoA, which is a critical regulator of actin cytoskeleton dynamics and organization of dendritic spines and inhibitor of spine maintenance. ARHGEF11 variants are reported to be associated with a higher risk for the onset of schizophrenia in a Japanese population; however, how ARHGEF11 contributes to the pathogenesis of schizophrenia in dendritic spines is unknown. Therefore, we first studied the distribution, binding, and function of ARHGEF11 in the dendritic spines of the rat cerebral cortex. After subcellular fractionation of the rat cerebral cortex, ARHGEF11 was detected with synaptophysin and post-synaptic density protein 95 (PSD-95) in the P2 fractions including synaptosomal fractions containing presynaptic and postsynaptic density proteins. Endogenous ARHGEF11 was coimmunoprecipitated with synaptophysin or PSD-95. In cortical primary neurons at 28 days in vitro, immunostaining revealed that ARHGEF11 located in the dendrites and dendritic spines and colocalized with PSD-95 and synaptophysin. Overexpression of exogenous ARHGEF11 significantly decreased the number of spines (p = 0.008). These results indicate that ARHGEF11 is likely to be associated with synaptic membranes and regulation of spine.

DOI： 10.3390/ijms18010067

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DOI： 10.1038/mp.2016.259

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Other Link： http://orcid.org/0000-0001-7856-3952

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP-like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases and 20 Braak NFT stage-matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas-positive tau-positive tufted astrocytes (TAs) and Gallyas-negative tau-positive TA-like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology was sequentially and significantly greater in AGD cases lacking these tau-positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68- and 64-kDa bands and 33-kDa low-molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP.

DOI： 10.1111/bpa.12319

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Many patients with schizophrenia have poor clinical and social outcomes. Some risk alleles closely related to the onset of schizophrenia have been reported to be associated with their clinical phenotypes, but the direct relationship between genetic vulnerability to schizophrenia and clinical/social outcomes of schizophrenia, as evaluated by both practical clinical scales and 'real-world' function, has not been investigated. We evaluated the clinical and social outcomes of 455 Japanese patients with schizophrenia by severity of illness according to the Clinical Global Impression-Severity Scale (CGI-S) and social outcomes by social adjustment/maladjustment at 5 years after the first visit. We examined whether 46 single nucleotide polymorphisms (SNPs) selected from a Japanese genome-wide association study of susceptibility to schizophrenia were associated with clinical and social outcomes. We also investigated the polygenic risk scores of 46 SNPs. Allele-wise association analysis detected three SNPs, including rs2623659 in the CUB and Sushi multiple domains-1 (CSMD1) gene, associated with severity of illness at end point. The severity of illness at end point was associated with treatment response, but not with the severity of illness at baseline. Three SNPs, including rs2294424 in the C6orf105 gene, were associated with social outcomes. Point estimates of odds ratios showed positive relationships between polygenic risk scores and clinical/social outcomes; however, the results were not statistically significant. Because these results are exploratory, we need to replicate them with a larger sample in a future study.

DOI： 10.1038/jhg.2015.153

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

Functional outcomes in individuals with schizophrenia suggest recovery of cognitive, everyday, and social functioning. Specifically improvement of work status is considered to be most important for their independent living and self-efficacy. The main purposes of the present study were 1) to identify which outcome factors predict occupational functioning, quantified as work hours, and 2) to provide cut-offs on the scales for those factors to attain better work status. Forty-five Japanese patients with schizophrenia and 111 healthy controls entered the study. Cognition, capacity for everyday activities, and social functioning were assessed by the Japanese versions of the MATRICS Cognitive Consensus Battery (MCCB), the UCSD Performance-based Skills Assessment-Brief (UPSA-B), and the Social Functioning Scale Individuals' version modified for the MATRICS-PASS (Modified SFS for PASS), respectively. Potential factors for work outcome were estimated by multiple linear regression analyses (predicting work hours directly) and a multiple logistic regression analyses (predicting dichotomized work status based on work hours). ROC curve analyses were performed to determine cut-off points for differentiating between the better- and poor work status. The results showed that a cognitive component, comprising visual/verbal learning and emotional management, and a social functioning component, comprising independent living and vocational functioning, were potential factors for predicting work hours/status. Cut-off points obtained in ROC analyses indicated that 60-70% achievements on the measures of those factors were expected to maintain the better work status. Our findings suggest that improvement on specific aspects of cognitive and social functioning are important for work outcome in patients with schizophrenia.

DOI： 10.1016/j.scog.2015.07.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

ObjectiveAlthough a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations.DesignTo discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-epsilon 4 status to eliminate the established effect of APOE region.ResultsOur data indicated that 18p11.32 (rs1992269, P=9.77x10(-7)), CNTNAP2 (rs802571, P=1.26x10(-6)), and 12q24.23 (rs11613092, P=6.85x10(-6)) were suggestive loci for susceptibility to LOAD.ConclusionWe identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.

DOI： 10.1097/YPG.0000000000000090

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Care for the disabled elderly can be stressful and exhausting, especially in cases of dementia. There have been a number of studies on the dementia caregiver burden, but studies focusing on differences by stages of the disease are rare. The caregiver burden of 85 caregivers of patients with amnestic mild cognitive impairment (aMCI) and 106 caregivers of patients with mild Alzheimer's disease (AD) was evaluated by the short version of the Japanese version of the Zarit Burden Interview (sZBI). The caregiver burden in mild AD was more severe than that in aMCI. In mild AD, the risk factors of caregiver burden were neurobehavioral symptoms and disturbances instrumental activities of daily living (IADL), whereas the risk factors in aMCI were neurobehavioral symptoms and memory dysfunction. The severity of dementing disease affects the caregiver burden, and somewhat different factors contribute to the burden at different stages. We should pay attention to different factors in evaluating and reducing the caregiver burden in aMCI and mild AD. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2014.12.055

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ObjectiveThe human Rho guanine nucleotide exchange factor 11 (ARHGEF11) gene is one of the candidate genes for type 2 diabetes mellitus (T2DM). ARHGEF11 is mapped to chromosome 1q21, which has susceptible risk loci for T2DM and schizophrenia. We hypothesized that ARHGEF11 contributes to the pathogenesis of schizophrenia.
MethodWe selected eight single nucleotide polymorphisms of ARHGEF11 that had significant associations with T2DM for a case-control association study of 490 patients with schizophrenia and 500 age-matched and sex-matched controls.
ResultsWe did not find any differences in allelic, genotypic associations, or minor allele frequencies with schizophrenia. Analysis of the rs6427340-rs6427339 haplotype and the rs822585-rs6427340-rs6427339 haplotype combination provided significant evidence of an association with schizophrenia (global permutations p=0.00047 and 0.0032, respectively). C-C of the rs6427340-rs6427339 haplotype and A-C-C of the rs822585-rs6427340-rs6427339 haplotype carried higher risk factors for schizophrenia (permutation p=0.0010 and 0.0018, respectively). A-C-T of the rs822585-rs6427340-rs6427339 haplotype had a possible protective effect (permutation p=0.031).
ConclusionThese results provide new evidence that ARHGEF11 may constitute a risk factor for schizophrenia. Copyright (c) 2014 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2435

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Language：English   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.psychres.2014.02.006

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Language：Japanese   Publisher：(株)星和書店  

非鎮静系抗精神病薬aripiprazole(APZ)122例、blonanserin(BNS)46例が、統合失調症以外の疾患に対し適応外使用された背景と理由、半年後の転帰(継続、効果、副作用)を検討した。使用理由は、他の抗精神病薬以外の薬物療法が無効83.9%、1年以上の経過で慢性かつ難治64.3%、他の抗精神病薬が無効64.3%、少ない副作用を期待47.6%、重症の入院症例45.2%、精神病症状31.0%であった。APZは53.3%、BNSは43.5%が有効と判断された。副作用は、APZ 26.2%、BNS 23.9%と高率であった。抗精神病薬のエビデンスレベルの高いF0、F3圏内で有効性は高く、強迫性障害を除くと、エビデンスレベルが低いF4圏内で低い有効性かつ高頻度の副作用となった。非鎮静系抗精神病薬の統合失調症以外での可能性も部分的に示唆されたが、不適切な使用が行われている現状も明らかとなった。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

The UCSD Performance-based Skills Assessment Brief (the UPSA-B) has been widely used for evaluating functional capacity in patients with schizophrenia. The utility of the battery in a wide range of cultural contexts has been of concern among developers. The current study investigated the validity of the Japanese version of the UPSA-B as a measure of functional capacity and as a co-primary for neurocognion. Sixty-four Japanese patients with schizophrenia and 83 healthy adults entered the study. The Japanese version of the UPSA-B (UPSA-B Japanese version) and the MATRICS Cognitive Consensus Battery Japanese version (MCCB Japanese version) were administered. Normal controls performed significantly better than patients, with large effect sizes for the Total and the subscale scores of the UPSA-B. Receiver Operating Characteristic (ROC) curve analysis revealed that the optimal cut-off point for the UPSA-B Total score was estimated at around 80. The UPSA-B Total score was significantly correlated with the MCCB Composite score and several domain scores, indicating the relationship between this co-primary measure and overall cognitive functioning in Japanese patients with schizophrenia. The results obtained here suggest that the UPSA-B Japanese version is an effective tool for evaluating disturbances of daily-living skills linked to cognitive functioning in schizophrenia, providing an identifiable cut-off point and relationships to neurocognition. Further research is warranted to evaluate the psychometrical properties and response to treatment of the Japanese version of the UPSA-B.

DOI： 10.1016/j.scog.2014.08.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Methamphetamine (METH) use can provoke psychotic reactions requiring immediate treatment, namely METH-induced psychosis. Although the distinction between METH-induced and primary psychosis is important for understanding their clinical courses, we do not have clear diagnostic procedure by their symptoms. Not only are there similarities between the clinical features of METH-induced psychosis and schizophrenia (SCZ), but there is also epidemiological evidence of a shared genetic risk between 'METH-related' disorders and SCZ, which makes the differentiation of these two conditions difficult. In this study, we conducted a genome-wide association study (GWAS) targeting METH-dependent patients. The METH sample group, used in the METH-dependence GWAS, included 236 METH-dependent patients and 864 healthy controls. We also included a 'within-case' comparison between 194 METH-induced psychosis patients and 42 METH-dependent patients without psychosis in a METH-induced psychosis GWAS. To investigate the shared genetic components between METH dependence, METH-induced psychosis, and SCZ, data from our previous SCZ GWAS (total N = 1108) were re-analyzed. In the SNP-based analysis, none of the SNPs showed genome-wide significance in either data set. By performing a polygenic component analysis, however, we found that a large number of 'risk' alleles for METH-induced psychosis are over-represented in individuals with SCZ (P-best = 0.0090). Conversely, we did not detect enrichment either between METH dependence and METH-induced psychosis or between METH dependence and SCZ. The results support previous epidemiological and neurobiological evidence for a relationship between METH-induced psychosis and SCZ. These also suggest that the overlap between genes scored as positive in these data sets can have higher probability as susceptibility genes for psychosis.

DOI： 10.1038/npp.2013.94

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim This preliminary study was performed to test the reliability and validity of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), developed by the National Institute of Mental Health MATRICS initiative, as an assessment tool in a Japanese-language version (MCCB-J). Methods The subjects for the present study were 37 patients with schizophrenia. Each subject gave written informed consent to participate in the research. In order to examine the validity of the MCCB-J, the correlation between the MCCB-J and the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) was determined. Results Cronbach's alpha for the MCCB-J was 0.72. The MCCB-J composite score was significantly correlated with all subtests of the MCCB-J. There was a significant correlation between the MCCB-J and the BACS composite score. Conclusion This preliminary study indicates that the MCCB-J has good psychometric properties and validity.

DOI： 10.1111/pcn.12029

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DOI： 10.1176/appi.neuropsych.12070166

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Takaki M, Okahisa Y, Kodama M, Mizuki Y, Sakamoto S, Ujike H, Uchitomi Y. Efficacy and tolerability of blonanserin in 48 patients with intractable schizophrenia. Background: Blonanserin is effective for the treatment of schizophrenia in Korea and Japan. Methods: We administered blonanserin to 48 Japanese patients with schizophrenia for whom other atypical antipsychotics were not sufficiently effective or tolerated. Results: Previous antipsychotics were replaced with blonanserin because of its effectiveness (54.2%; 26/48) or tolerability (45.8%; 22/48). Blonanserin was more effective in 65.4% (17/26) of the and better tolerated in 95.5% (21/22) of the patients. Of 48 patients, 33 continued blonanserin for 1 year. The mean Clinical Global Impression of Severity scores improved from 4.60 to 2.48. The mean Global Assessment of Functioning score improved from 29.8 to 51.7. Nineteen patients (39.6%; 19/48) had a social role. The reasons for discontinuation of blonanserin were ineffectiveness against psychosis (27.1%; 13/48) or intolerability (4.2%; 2/48). The ratio of discontinuation for intolerability versus ineffectiveness was 0.15, which was the lowest among atypical psychotics. Conclusions: Blonanserin may be effective and safe for the treatment of intractable schizophrenia.

DOI： 10.1111/j.1601-5215.2012.00663.x

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Several studies have suggested that the endocannabinoid system plays significant roles in the vulnerability to psychiatric disorders including drug abuse. To examine the possible association of the CNR1 and CNR2 genes, which encode cannabinoid receptors CB1 and CB2, with methamphetamine dependence, we investigated three single nucleotide polymorphisms (SNPs) (rs806379, rs1535255, rs2023239) in intron 2 of the CNR1 gene and a nonsynonymous SNP, Q63R, in the CNR2 gene. The study samples consisted of 223 patients with methamphetamine dependence and 292 age- and sex- matched controls. There were no significant differences between the patients and controls in genotypic or allelic distribution of any SNP of the CNR1 and CNR2 genes. We also analyzed the clinical features of methamphetamine dependence. Rs806379 of the CNR1 gene showed a significant association with the phenotype of latency of psychosis after the first consumption of methamphetamine. Patients with the T allele or T-positive genotypes (T/T or A/T) may develop a rapid onset of psychosis after methamphetamine abuse. The present study suggests a possibility that genetic variants of the CNR1 gene may produce a liability to the complication of psychotic state after abuse of methamphetamine; however, our findings need to be confirmed by future replications.

DOI： 10.2174/157015911795017191

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The regulator of G-protein signaling (RGS) modulates the functioning of heterotrimeric G protein. RGS9-2 is highly expressed in the striatum and plays a role in modulating dopaminergic receptor-mediated signaling cascades. Previous studies suggested that the RGS9 gene might contribute to the susceptibility to psychotic diseases. Therefore, we investigated the association between the RGS9 gene and two related dopamine psychoses, schizophrenia and methamphetamine use disorders. The subjects comprised 487 patients of schizophrenia and 464 age- and sex-matched healthy controls and 220 patients of methamphetamine use disorder and 289 controls. We genotyped two nonsynonymous polymorphisms, rs12452285 (Leu225Ser) and rs34797451 (His498Arg), of the RGS9 gene. Rs34797451 showed monomorphism in the present Japanese population, but rs12452285 showed polymorphism. There were no significant differences in genotypic or allelic distributions of rs12452285 between patients with schizophrenia and the corresponding control or between patients with methamphetamine use disorder and the corresponding control. We also analyzed the clinical features of methamphetamine use disorder. We found a significant association in allelic distribution with the phenotypes of age at first consumption (p=0.047). The present study suggested that the RGS9 gene is unlikely to play a major role in schizophrenia and methamphetamine dependence liability and/or the development of methamphetamine induced psychosis, at least in a Japanese population.

DOI： 10.2174/157015911795017029

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Several lines of evidence implicate serotonergic dysfunction in diverse psychiatric disorders including anxiety, depression, and drug abuse. Mice with a knock-out of the 5HT1b receptor gene (HTR1B) displayed increased locomotor response to cocaine and elevated motivation to self-administer cocaine and alcohol. Previous genetic studies showed significant associations of HTR1B with alcohol dependence and substance abuse, but were followed by inconsistent results. We examined a case-control genetic association study of HTR1B with methamphetamine-dependence patients in a Japanese population. The subjects were 231 patients with methamphetamine dependence, 214 of whom had a co-morbidity of methamphetamine psychosis, and 248 age- and sex-matched healthy controls. The three single nucleotide polymorphisms (SNPs), rs130058 (A-165T), rs1228814 (A-700C) and rs1228814 (A+1180G) of HTR1B were genotyped. There was no significant difference in allelic and genotypic distributions of the SNPs between methamphetamine dependence and the control. Genetic associations of HTR1B were tested with several clinical phenotypes of methamphetamine dependence and/or psychosis, such as age at first abuse, duration of latency from the first abuse to onset of psychosis, prognosis of psychosis after therapy, and complication of spontaneous relapse of psychotic state. There was, however, no asscocation between any SNP and the clinical phenotypes. Haplotype analyses showed the three SNPs examined were within linkage disequilibrium, which implied that the three SNPs covered the whole HTR1B, and distribution of estimated haplotype frequency was not different between the groups. The present findings may indicate that HTR1B does not play a major role in individual susceptibility to methamphetamine dependence or development of methamphetamine-induced psychosis.

DOI： 10.2174/157015911795017137

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Experimental studies have demonstrated that not only dopaminergic signaling but also glutamatergic/NMDA receptor signaling play indispensable roles in the development of methamphetamine psychosis. Our recent genetic studies provided evidence that genetic variants of glutamate-related genes such as DTNBP1, GLYT1, and G72, which are involved in glutamate release and regulation of co-agonists for NMDA receptors, conferred susceptibility to methamphetamine psychosis. Serine racemase converts l-serine to d-serine, which is an endogenous co-agonist for NMDA receptors. Three single nucleotide polymorphisms (SNPs) in the promoter region of the serine racemase gene (SRR), rs224770, rs3760229, and rs408067, were proven to affect the transcription activity of SRR. Therefore, we examined these SNPs in 225 patients with methamphetamine psychosis and 291 age- and sex-matched controls. There was no significant association between methamphetamine psychosis and any SNP examined or between the disorder and haplotypes comprising the three SNPs. However, rs408067 was significantly associated with the prognosis for methamphetamine psychosis and multi-substance abuse status. The patients with C-positive genotypes (CC or CG) of rs408067 showed better prognosis of psychosis after therapy and less abuse of multiple substances than the patients with GG genotypes. Because the C allele of rs408067 reduces the expression of SRR, a lower d-serine level or reduced NMDA receptor activation may affect the prognosis of methamphetamine psychosis and multiple substance abuse. Our sample size is, however, not large enough to eliminate the possibility of a type I error, our findings must be confirmed by replicate studies with larger samples.

DOI： 10.2174/157015911795017092

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A genetic component in etiology of substance dependence is very large, and the estimated hereditary rates by twin and family studies are 70% or more. Extensive classical linkage analyses for alcohol and substance dependence revealed numerous but weak susceptibility loci on every chromosomes. Genetic association studies including whole genome examination showed many shared genomic risks for substance dependence of diverse classes, e.g., alcohol, nicotine, opioids, cocaine, amphetamines and cannabinoids. In contrast, some specific genetic risks or protective factors for individual drug are also found. This paper reviews the current status of research into the genetics of substance dependence.

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family, regulates the neuronal phenotype and coordinates astrocyte, oligodendrocyte, microglia, and inflammatory cell responses. The LIF gene is located on 22q12.1-q12.2, a hot spot for schizophrenia. Three polymorphisms of the LIF gene (rs929271, rs737812, and rs929273) were examined in a case-control association study of 390 patients with schizophrenia and 410 age- and sex-matched controls. Effects of a risk genotype of LIF on cognitive domains were evaluated by the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, and Wisconsin Card Sorting Test (WCST) in 355 healthy volunteers. The LIF gene showed significant associations with schizophrenia at rs929271 and a haplotype consisting of rs929271-rs737812. After stratification by subtype of schizophrenia, the hebephrenic, but not paranoid, type was associated with the LIF gene at rs929271 (allele, P=0.014) and the haplotype (permutation P=0.013). Having the T-allele and T-carrier genotypes (TT and TG) of rs929271 were risks for hebephrenic schizophrenia, and the odds ratios were 1.38 (95% CI: 1.21-1.56) and 1.54 (95%CI: 1.19-1.98), respectively. Subjects with T-carrier genotypes made significantly more errors on the WCST compared with those without (P=0.04). The present study indicated that the LIF gene variant may produce susceptibility to hebephrenic schizophrenia and deterioration of working memory function. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2009.10.020

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To investigate the biological mechanism of gender identity disorder (GID), five candidate sex hormone-related genes, encoding androgen receptor (AR), estrogen receptors alpha (ER alpha) and beta (ER beta), aromatase (CYP19), and progesterone receptor (PGR) were analyzed by a case-control association study. Subjects were 242 transsexuals (74 male-to-female patients (MTF) and 168 female-to-male patients (FTM)), and 275 healthy age- and geographical origin-matched controls (106 males and 169 females). The distributions of CAG repeat numbers in exon 1 of AR, TA repeat numbers in the promoter region of ER alpha CA repeat numbers in intron 5 of ER beta, TTTA repeat numbers in intron 4 of CYP19, and six polymorphisms (rs2008112, rs508653, V660L, H770H, rs572698 and PROGINS) of PGR were analyzed. No significant difference in allelic or genotypic distribution of any gene examined was found between MTFs and control males or between FTMs and control females. The present findings do not provide any evidence that genetic variants of sex hormone-related genes confer individual susceptibility to MTF or FTM transsexualism. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2009.07.008

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes cl-serine, an NMIDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (Fs778293) showed a significant association with methamphetamine psychosis (genotype: p = 0.00016, allele: p = 0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p = 0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p = 0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2009.05.017

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D2-like receptors are key targets for methamphetamine in the CNS, and their activation is an initial and indispensable effect in the induction of dependence and psychosis. It is possible that genetic variants of D2-like receptors may affect individual susceptibility to methamphetamine dependence and psychosis. To test this hypothesis, 6 putatively functional polymorphisms of D2-like receptors, -141C Ins/Del, Ser311Cys and TaqIA of the DRD2 gene, Ser9Gly of the DRD3 gene, and -521C&gt;T and a variable number of tandem repeats in exon 3 of the DRD4 gene, were analyzed in 202 patients with methamphetamine dependence and/or psychosis and 243 healthy controls in a Japanese population. No polymorphism examined showed significant association with methamphetamine dependence, but two polymorphisms of DRD2 were associated with the clinical course and prognosis of methamphetamine psychosis. The A1/A1 homozygote of DRD2 was a negative risk factor for a poorer prognosis of psychosis that continues for more than I month after the discontinuance of methamphetamine abuse and the beginning of treatment with neuroleptics (p=0.04, odds ratio (OR) = 0.42, 95% CI: 0.27-0.65) and the complication of spontaneous relapse of methamphetamine psychosis after remission (p = 0.014, OR = 0.34,95% CI; 0.22-0.54). The genotype of -141C Del positive (Del/Del and Del/Ins) was at risk for rapid onset of methamphetamine psychosis that develops into a psychotic state within 3 years after initiation of methamphetamine abuse (p = 0.00037, OR = 3.62, 95% CI 2.48-5.28). These findings revealed that genetic variants of DRD2, but not DRD3 or DRD4, confer individual risks for rapid onset, prolonged duration, and spontaneous relapse of methamphetamine psychosis. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2009.02.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Aims: Neuropeptide Y (NPY) is a 36-amino acid peptide that is widely distributed in the brain, adrenal medulla, and sympathetic nervous system. Several lines of evidence suggest a possible involvement of the NPY system in the physiological effects of several classes of abused substances including alcohol, phencyclidine, cocaine, and marijuana and in endogenous psychosis. Accordingly, it was hypothesized that the NPY system may also be involved in methamphetamine dependence or psychosis.
Methods: The single nucleotide polymorphisms rs16147 of the NPY gene (-485C&gt;T) and rs7687423 of the NPY receptor Y1 (NPY1R) gene were analyzed in 222 patients with methamphetamine dependence and psychosis and 288 age-and gender-matched controls.
Results: Genotypic distribution of the NPY1R gene showed a significant association with methamphetamine dependence and psychosis (P = 0.04), whereas the NPY gene had no significant association with them.
Conclusion: It is possible that genetic variants of the NPY1R gene affect the NPY-NPY receptor type Y1 signaling system in the brain, which may result in susceptibility to methamphetamine dependence or the development of methamphetamine psychosis, but the present findings need to be confirmed on replication.

DOI： 10.1111/j.1440-1819.2009.01961.x

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Casein kinase 1 epsilon (CKIepsilon) is a component of the DARPP-32 in second-messenger pathway. CKIepsilon phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence. A recent clinical study showed that rs135745, a noncoding single nucleotide polymorphism of the 3'-untranslated region of the CSNK1E gene, was associated with the intensity of the subjective response to an oral amphetamine dose in normal volunteers. Differences in sensitivity to the drug should affect development of dependence to it. Hence, we genotyped rs135745 of the CSNK1E (MIM 600863) gene in 215 patients with methamphetamine dependence and 274 age- and gender-matched normal controls. No significant differences in genotype and allele frequencies were observed between the patients with methamphetamine dependence and controls. There was also no significant association between rs135745 and the clinical characteristics of methamphetamine dependence and co-morbid methamphetamine psychosis (e.g., age of first consumption, latency of psychosis, prognosis of psychosis after therapy, spontaneous relapse of psychotic symptoms, and poly-substance abuse status). The present findings suggest that having a genetic variant of the CSNK1E gene did not affect susceptibility to methamphetamine dependence or psychosis, at least in a Japanese population.

DOI： 10.1196/annals.1432.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHYSICIANS POSTGRADUATE PRESS  

Objective: One of the clinically significant adverse effects of olanzapine treatment is weight gain, which shows substantial inter-individual differences and may be influenced by genetic variation. The aim of this investigation was identification of genetic risk factors associated with olanzapine-induced weight gain.
Method: Inpatients with DSM-IV-TR schizophrenia (N = 164) were administered olanzapine for 8 to 24 (mean +/- SD = 17.9 +/- 9.4) weeks. The clinical background, body mass index (BMI), and clinical response to olanzapine were investigated. Twenty-one loci of diverse candidate genes encoding dopamine, serotonin (5-HT), histamine, and adrenergic receptors, tumor necrosis factor-alpha, ghrelin, adiponectin, and peroxisorne proliferator-activated receptor gamma-2, were analyzed. The study was conducted from June 2001 to June 2003 at 4 psychiatric hospitals in Japan.
Results: BMI increased by a mean +/- SD 4.3 +/- 10.7% after treatment with olanzapine (mean +/- SD dose = 15.5 +/- 5.8 mg/day). Olanzapine-induced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment (p &lt; .0001), but it did not correlate with the daily dose of olanzapine, concomitant antipsychotics, sex, age, or smoking. Four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis revealed that the baseline BMI predicted 12.5% of the weight gain, and the 2 latter genetic factors added 6.8%. The patients with double and triple genetic risk factors showed 5.1% and 8.8% BMI increases, respectively, during olanzapine treatment, whereas the patients with a single or no risk factor showed approximately a 1% BMI increase.
Conclusions: We identified genetic variants of 5-HT2A and 5-HT,, receptors, the G-protein beta-3 subunit, and the adrenergic receptor beta-3, as genetic risk factors for olanzapine-induced weight gain, and they showed additive genetic effects on weight gain.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Frizzled 3 (Fzd3) is a receptor required for the Wnt-signaling pathway, which has been implicated in the development of the central nervous system, including synaptogenesis and structural plasticity. We previously found a significant association between the FZD3 gene and susceptibility to schizophrenia, but subsequent studies showed inconsistent findings. To understand the roles of the FZD3 gene in psychotic disorders further, it should be useful to examine FZD3 in patients with methamphetamine psychosis because the clinical features of methamphetamine psychosis are similar to those of schizophrenia.
Methods: Six SNPs of FZD3, rs3757888 in the 3&apos; flanking region, rs960914 in the intron 3, rs2241802, a synonymous SNP in the exon5, rs2323019 and rs352203 in the intron 5, and rs880481 in the intron 7, were selected based on the previous schizophrenic studies and analyzed in 188 patients with methamphetamine psychosis and 240 age- and gender-matched controls.
Results: A case-control association analyses revealed that two kinds of FZD3 haplotypes showed strong associations with methamphetamine psychosis (p &lt; 0.00001). Having the G-A-T-G or A-G-C-A haplotype of rs2241802-rs2323019rs352203- rs880481 was a potent negative risk factor (odds ratios were 0.13 and 0.086, respectively) for methamphetamine psychosis.
Conclusion: Our present and previous findings indicate that genetic variants of the FZD3 gene affect susceptibility to two analogous but distinct dopamine-related psychoses, endogenous and substance-induced psychosis.

DOI： 10.1186/1744-9081-4-37

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Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p = 0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p = 0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2008.01.033

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Glycine transporter (GlyT)-1 plays a pivotal role in maintaining the glycine level at the glutamatergic synapse. Glycine is an allosteric agonist of N-methyl-D-aspartate (NMDA) receptors. Because activation of NAIDA receptors is an essential step for induction of methamphetamine dependence and psychosis, differences in the functioning of GlyT-l due to genetic variants of the GlyT-1 gene (GLYT1) may influence susceptibility. A case-control genetic association study of the GLYT1 gene examined 204 patients with methamphetamine-use disorder and 210 healthy controls. We examined three single nucleotide polymorphisms (SNPs), SNP1, IVS3 + 411C &gt; T, rs2486001; SNP2, 1056G &gt; A, rs2248829; and SNP3, IVS11 + 22G &gt; A rs2248632, of the GLYT1 gene and found that SNP1 showed a significant association in both genotype (P = 0.0086) and allele (P = 0.0019) with methamphetamine-use disorder. The T-G haplotype at SNP1 and SNP2 was a significant risk factor for the disorder (P = 0.000039, odds ratio: 2.04). The present findings indicate that genetic variation of the GLYT1 gene may contribute to individual vulnerability to methamphetamine dependence and psychosis. (C) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.30565

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: The dysbindin (DTNBP1 [dystrobrevin-binding protein 1])gene has repeatedly been shown to be associated with schizophrenia across diverse populations. One study also showed that risk haplotypes were shared with a bipolar disorder subgroup with psychotic episodes, but not with all cases. DTNBP1 may confer susceptibility to psychotic symptoms in various psychiatric disorders besides schizophrenia.
Methods: Methamphetamine psychosis, the psychotic symptoms of which are close to those observed in schizophrenia, was investigated through a case (n = 197)-control (n = 243) association analyses of DTNBP1.
Results: DTNBP1 showed significant associations with methamphetamine psychosis at polymorphisms of P1635 (rs3213207, p = .00003) and SNPA (rs2619538, p = .049) and the three-locus haplotype of P1655 (rs2619539)-P1635-SNPA (permutation p = .0005). The C-A-A haplotype, which was identical to the protective haplotype previously reported for schizophrenia and psychotic bipolar disorders, was a protective factor (p = .0013, odds ratio [OR] = .62, 95% confidence interval [CI] .51-.77) for methamphetamine psychosis. The C-G-T haplotype was a risk for methamphetamine psychosis (p = .0012, OR = 14.9, 95% CI 3.5-64.2).
Conclusions: Our genetic evidence suggests that DTNBP1 is involved in psychotic liability not only for schizophrenia but also for other psychotic disorders, including substance-induced psychosis.

DOI： 10.1016/j.biopsych.2007.03.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: Serine racemase (SRR) is a brain-enriched enzyme that converts L-serine to D-serine, which acts as an endogenous ligand of N-methyl D-aspartate (NMDA) receptors. Dysfunction of SRR may reduce the function of NMDA receptors and susceptibility to schizophrenia.
Methods: We genotyped three single-nucleotide polymorphisms (SNPs) of the 5' region of the SRR gene in 525 patients with schizophrenia and 524 healthy controls. Effects of SNPs on the promoter activity and on serum levels of total and D-serine were examined.
Results: We found a significant excess of the IVS1 a+465C allele of the SRR gene in schizophrenia, especially in the paranoid subtype (p=.0028). A reporter assay showed that the IVS1a+465C allele had 60% lower promoter activity than did the IVS1a+465G allele.
Conclusions: The IVS1 a+465C allele of the SRR gene, which reduces expression of the gene, is a risk factor for schizophrenia, especially the paranoid subtype.

DOI： 10.1016/j.biopsych.2006.07.025

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Language：English   Publishing type：Research paper (scientific journal)  

Dihydropyrimidinase-related protein 2 (DRP-2 or DPYSL-2)mediates the intracellular response to collapsin, a repulsive extracellular guidance cue or axonal outgrowth. DRP-2 is also referred to as collapsin response mediator protein 2 (CRMP-2). We have previously demonstrated that the DRP-2 gene is associated with susceptibility to schizophrenia, but not to bipolar disorders. In addition, a genetic association was observed with paranoid-type schizophrenia, but not with hebephrenic-type schizophrenia. It has been well documented that repeated abuse of methamphetamine (METH) for a long period frequently produces psychotic symptoms, such as auditory hallucinations and delusions that are hardly distinguishable from those of paranoid-type schizophrenia. Therefore, we hypothesized that a certain genetic variant of the DRP-2 gene may affect individual vulnerability to the development of METH-induced psychosis. We examined the genetic association by a case-control method. The polymorphism *2236T>C in the 3' untranslated region of the DRP-2 gene, which has been shown to be a negative genetic risk factor for paranoid-type schizophrenia, was analyzed in 198 patients with METH psychosis and 221 corresponding healthy controls in a Japanese population. No significant association of the DRP-2 gene with METH psychosis was found. Neither did we find an association with the clinical phenotype of METH psychosis, such as the age of first consumption of METH, latency to development of psychosis after METH abuse, prognosis of psychosis after detoxification from METH use, complication of spontaneous relapse of psychosis without reconsumption of the drug, or multisubstance abuse status. These findings indicate that a genetic variant of the DRP-2 gene may not affect the risk of METH psychosis or any clinical phenotype of the disorder.

DOI： 10.1196/annals.1369.008

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会  

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Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

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Language：Japanese   Publisher：(株)星和書店  

脳神経系の構造に対する自己抗体が引き起こす自己免疫性脳炎は、受容体やイオンチャンネルに関連する神経細胞表面抗原に対する抗体によるものと、細胞内抗原への抗体によるものとに大別される。近年、前者の神経細胞表面抗原に対する様々な抗体による脳炎が相次いで報告され注目されている。なかでも、抗N-methyl-D-aspartate(NMDA)受容体抗体脳炎は精神症状を初発症状とし、早期の免疫療法が奏効することから、初期診断における精神科医の役割が非常に大きい疾患である。他にも電位依存性カリウムチャンネル複合体抗体に関連する脳炎など、精神科鑑別診断において念頭に置くべき様々な疾患が知られている。本稿では、抗NMDA受容体抗体脳炎を中心に、精神科診療との関連を交えて概説する。(著者抄録)

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

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Language：Japanese   Publisher：日本精神神経学会  

統合失調症患者では,個々の患者で程度はさまざまであるものの,認知機能の低下が生じることが報告されてきた.本研究の目的は,統合失調症患者の病前知能と現在の知的機能から推定された認知機能障害の程度を調査することである.11の大学病院などからリクルートされた,446名の統合失調症患者と686名の健常者に日本版WAIS-III成人知能検査,知的機能の簡易評価(JART)の25項目短縮版を実施し,現在の知的能力と病前推定知能を評価した.現在の知的能力と病前推定知能の差から認知機能障害スコアを算出した.統合失調症患者での推定認知機能障害スコアは-16.3,現在の知的機能が84.2,病前推定知能は100.5であり,いずれの項目においても,健常者と比較して有意に低かった.さらに,推定認知機能障害スコアで20以上の低下を示した患者の割合は39.7%であった.推定認知機能障害スコアを用いると,81.6%の患者と健常者を正しく判別することができた.本研究によって,統合失調症患者の認知機能障害の程度とその分布が明らかとなった.このような知見は,認知機能障害をもつ患者を同定し,認知機能障害の重症度の評価をするうえで寄与しうるものである.(著者抄録)

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Language：Japanese   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1038/tp.2017.170

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DOI： 10.1038/tp.2017.173

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Language：Japanese   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

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Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(公社)日本心理学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：Japanese   Publisher：(株)星和書店  

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Language：Japanese   Publisher：(一社)日本アルコール・アディクション医学会  

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Language：Japanese   Publisher：(株)医学書院  

認知機能障害は統合失調症の中核症状であり,患者の社会機能予後に対して精神病症状以上に大きな影響を及ぼすと考えられている。我々は簡便で鋭敏な認知機能評価のため,統合失調症認知機能簡易評価尺度(Brief Assessment of Cognition in Schizophrenia;BACS)の日本語版(BACS-J)を作成した。このたび,BACS-J標準化のため健常者709名のデータを収集し,その内,性別および学歴を考慮した292名のデータを解析したので報告する。平均年齢(標準偏差)は36.7(13.5)歳,平均教育年数は14.6(2.2)年であった。結果として,年齢とすべてのBACS-J各下位検査およびcomposite scoreとの間に統計学的に有意な相関を認めた。また,言語性記憶課題においてのみ,女性のほうが男性よりも得点が統計学的に有意に高かった。さらに,教育年数と言語性記憶課題,言語流暢性,ロンドン塔検査,そしてcomposite scoreとの間に統計学的に有意な相関を認めた。本研究結果に基づき,年代および性別を考慮したz-score/T-scoreの算出が可能である。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00749&link_issn=&doc_id=20130225060011&doc_link_id=10.11477%2Fmf.1405102387&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405102387&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：Japanese   Publisher：(株)星和書店  

非鎮静系抗精神病薬aripiprazole(APZ)またはblonanserin(BNS)を服薬した、維持期、慢性期の難治例を含む統合失調症患者138例を対象とし、半年後の比較を行った。両群とも70%に有効、平均CGI-Sは1点低下、CGI-S:1が10%程度となり、悪化はAPZ群に多かった。APZは気分の安定、BNSは抗幻覚妄想と疎通性の改善が多かった。両群とも性機能障害など副作用の改善を認め、高プロラクチン血症は全例低下した。鎮静、アカシジアの改善はBNS群に多かった。半年後の継続率は両群60%で、社会機能を持つ患者が約60%であった。APZはアカシジアによる脱落が多かった。APZ群で単剤化が多く、気分調節薬の併用率が低かった。非定型抗精神病薬の変更理由を調査し、副作用÷効果不足の比をとると、鎮静系は大きくolanzapineが最高、非鎮静系は小さくBNSが最小となった。これらを薬理学的特性より考察した。(著者抄録)

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Lamotrigineは新規の気分安定薬であるが、特にうつ病相の予防効果を有する薬剤として期待されている。我々は、lamotrigineのうつ状態への急性効果を調べるため、当院におけるlamotrigineの使用状況を調査した。対象は2008年12月上市後から2011年8月の間にうつ状態に対してlamotrigineが処方された全36例とし、診療録から後ろ向きに調査した。投与開始後8週間の改善度をClinical Global Impression-Improvement scale(CGI-I)を用いて評価した。Lamotrigineは双極性障害、単極性うつ病、その他の疾患において処方されており、うつ状態に対する急性効果を持つことが示唆された。また、双極I型&gt;双極II型&gt;単極性うつ病&gt;その他の疾患の順で有効性の高い結果が得られた。Lamotrigineは双極性の強い疾患において、よりうつ状態に対する効果の高い可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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遷延性の経過をたどる難治性うつ病性障害に対して、mirtazapineが投与早期から有効であった3症例を経験した。3症例ともに、ベンゾジアゼピン系抗不安薬、睡眠薬への依存傾向がみられた。Mirtazapineにより、抗不安薬、睡眠薬を減量、または中止し、維持療法が可能となった。副作用の眠気は、初回用量に注意し、説明を加えることで、体重増加は適切な用量設定で防ぐことができ、mirtazapineの脱落率が下がる可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

Mirtazapine(MIR)は、Noradrenergic and Specific Serotonergic Antidepressant(NaSSA)と呼ばれる新規抗うつ薬である。今回、我々はMIRによるせん妄が強く疑われた4例を経験した。全例、身体疾患の治療を目的として入院中の高齢女性であり、不眠を伴ううつ状態に対してMIR15mg/日が処方された。4例中3例では、MIR内服開始から3日以内にせん妄が出現した。中止後の経過は良好であり、4例全例において速やかにせん妄は改善した。せん妄が惹起された機序としては、前頭前野におけるドーパミン量の増大が関与している可能性を指摘した。身体合併症を有する高齢患者にMIRを使用する場合には、十分な注意が必要である。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

非定型抗精神病薬を鎮静の強弱により、risperidone(RIS)、olanzapine(OLZ)を鎮静系、aripiprazole(APZ)、blonanserin(BNS)を非鎮静系抗精神病薬に分類する報告がある。本稿では、鎮静系のRIS、OLZが継続できず、非鎮静系のAPZ、BNSが有効であった、難治の経過をたどっていた統合失調症4例について経過を報告し、APZ、BNSの使い分けについて考察した。入院の2症例は、BNSが陰性症状に有効であった1例と、APZが強迫症状を中心とした思路障害に著効した1例であった。外来の2症例は、APZまたはBNSに変更後の副作用の改善に加え、鎮静が少なくなったことで集中力が増し、社会性の向上に繋がった。鎮静系抗精神病薬が無効である難治例に対して、非鎮静系抗精神病薬APZ、BNSは、急性期、維持期の治療において期待できる可能性が示された。(著者抄録)

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.schres.2010.02.836

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全ゲノム解析の主役が連鎖解析から全ゲノム相関解析(GWAS)に移り、数十万の一塩基置換多型(SNP)の解析が可能となり、薬物依存脆弱性に関与する可能性のある多くの遺伝子が発見されるようになった。アルコール依存症、ニコチン依存症、違法性薬物依存症の全ゲノム解析について概説した。また、薬物依存関連遺伝子のデータベース、遺伝子解析から推定される薬物依存神経機序を図に示した。

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

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Language：Japanese   Publisher：(株)世論時報社  

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

当院で経験した更年期の全般性不安障害4例について報告した.4例はいずれも50歳代女性で,不安とそれに伴う体調不良,動悸,食欲低下,不眠などの不定愁訴がみられた.きっかけは家族の病気や死亡,介護,子供の進学・就職や夫の単身赴任,自分自身の病気や退職などであった.4例中3例では家族の協力が十分に得られ,心理療法・薬物療法を導入でき,比較的早期に症状の軽快がみられたが,残り1例では夫や子供の協力が皆無で家庭環境の調節は難しく,心理療法や薬物療法の導入は困難で,通院を中断してしまった.更年期女性の全般性不安障害は,患者の環境変化や性格背景を把握し,心理療法と薬物療法を併用して治療を行うことが必要であると考えられた

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Language：Japanese   Publisher：(一社)山口県医師会  

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Language：Japanese   Publisher：(株)医学書院  

24歳女.5歳時に精神遅滞を指摘された.成績は不良で,高校中退後は家事手伝いをしていた.自発性の低下がみられ,何かしている途中でボーッと止まってしまうようになった.「首や目が勝手にキョロキョロ動かされる」との訴えも出現し,入院した.心血管奇形,特異顔貌,低カルシウム血症,鼻咽腔閉鎖不全,精神遅滞,血小板減少がみられることより22q11.2欠失症候群を疑い,FISH法により確定診断した.クエチアピンを開始し,約2週間頃より次第に対人緊張が軽減し表情が穏やかになり,母親以外の者とも談笑できるようになった.精神遅滞のため病棟の規則などの了解が悪く,食事時間に戻ってこなかったり,夜遅く大声でしゃべったりと,時に問題行動がみられることもあった.病的精神症状がほぼ消失したため入院約3ヵ月後に退院した.バセドウ病は抗甲状腺剤で治療を行っていたが退院時に甲状腺機能はまだ正常域には戻ってはいなかった

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2004&ichushi_jid=J00749&link_issn=&doc_id=20040217080014&doc_link_id=10.11477%2Fmf.1405100438&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405100438&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(一社)日本総合病院精神医学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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