担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: To investigate the efficacy of tandospirone, an azapirone anxiolytic similar to buspirone that is used in Japan, for behavioral and psychological symptoms of dementia (BPSD), especially in oldest-old patients. Methods: This was an open-label observational study involving residents with BPSD in a special elderly nursing home between August 2013 and August 2018. The severity of dementia was assessed using the Clinical Dementia Rating (CDR) scale; as the main outcomes, the severity of BPSD was assessed using the Clinical Global Impressions-Severity scale (CGI-S) and Neuropsychiatric Inventory-12 (NPI-12) at baseline and 4 weeks after the maintenance dose of tandospirone was reached. The administration of tandospirone started at 30 mg, divided into three doses per day. Two weeks later, if the efficacy was sufficient based on the clinical nursing record, that dose was continued; if the efficacy was insufficient, the daily dose was increased from 40 mg/day to a maximum dose of 60 mg/day. Results: Thirty-three participants (25 females [76%], mean age 87.1 ± 5.4 years) completed the study. Twenty-three participants (70%) were oldest-old (18 females [78%], mean age 89.9 ± 3.4 years). The mean CDR score was 2.9 ± 0.3 in all participants. Tandospirone treatment showed few or no obvious adverse effects and significantly improved CGI-S scores, as well as total scores and many subscale scores on the NPI-12, in both the sample at large and the oldest-old participants. Conclusion: This study demonstrated the efficacy and safety of tandospirone for BPSD in oldest-old participants.

DOI： 10.9758/cpn.2021.19.3.514

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The pathophysiology of delayed carbon monoxide (CO) encephalopathy remains unclear. In this study, the effects of CO exposure on the dentate gyrus (DG) were investigated in a Wistar rat model by histochemical and molecular methods. Model rats showed significant cognitive impairment in the passive-avoidance test beginning 7 days after CO exposure. Immunohistochemistry showed that compared to the control, the cell number of SRY (sex-determining region Y)-box 2 (SOX2)+/brain lipid binding protein (BLBP)+/glial fibrillary acidic protein (GFAP)+ cells in the DG was significantly less, but the number of SOX2+/GFAP- cells was not, reflecting a decreased number of type 1 and type 2a neural precursor cells. Compared to the control, the numbers of CD11b+ cells and neuron glial antigen 2+ cells were significantly less, but the number of SOX2-/GFAP+ cells was not. Flow cytometry showed that the percent of live microglial cells isolated from the hippocampus in this CO rat model was significantly lower than in controls. Furthermore, mRNA expression of fibroblast growth factor 2 and glial cell-derived neurotrophic factor, which are neurogenic factors, was significantly decreased in that area. We conclude that, in this rat model, there is an association between delayed cognitive impairment with dysregulated adult hippocampal neurogenesis and glial changes in delayed CO encephalopathy.

添付ファイル： Scientific Reports 11, 6244 (2021).pdf

DOI： 10.1038/s41598-021-85860-9

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The testing of pathological biomarkers of Alzheimer's disease (AD), such as amyloid beta and tau, is time-consuming, expensive, and invasive. Here, we used 3xTg-AD mice to identify and validate putative novel blood transcriptome biomarkers of AD that can potentially be identified in the blood of patients. mRNA was extracted from the blood and hippocampus of 3xTg-AD and control mice at different ages and used for microarray analysis. Network and functional analyses revealed that the differentially expressed genes between AD and control mice modulated the immune and neuroinflammation systems. Five novel gene transcripts (Cdkn2a, Apobec3, Magi2, Parp3, and Cass4) showed significant increases with age, and their expression in the blood was collated with that in the hippocampus only in AD mice. We further assessed previously identified candidate biomarker genes. The expression of Trem1 and Trem2 in both the blood and brain was significantly increased with age. Decreased Tomm40 and increased Pink1 mRNA levels were observed in the mouse blood. The changes in the expression of Snca and Apoe mRNA in the mouse blood and brain were similar to those found in human AD blood. Our results demonstrated that the immune and neuroinflammatory system is involved in the pathophysiologies of aging and AD and that the blood transcriptome might be useful as a biomarker of AD.

DOI： 10.1007/s12035-020-02058-2

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Delayed carbon monoxide (CO) encephalopathy may occur following recovery from acute CO poisoning. However, the mechanism of delayed neuronal injury remains unknown. The nicotinic acetylcholine receptors (nAChRs) have been suggested to play a role in cognitive status in neurodegenerative diseases, including Alzheimer's disease. Therefore, in the current study, we investigated the effect of delayed neuronal CO poisoning on gene expression of nAChRs in the hippocampus of Wistar rats. Behavioral effects (measured by the passive-avoidance test) and histological analyses (hematoxylin-eosin-stained hippocampal cell counts and cell death observations) were also investigated, 21 days after CO exposure for I h (1000 ppm for 40 min + 3000 ppm for 20 min). Our findings show cognitive impairment and hippocampal cell death, suggesting our rat model is suitable for studying delayed CO encephalopathy. Expression of nAChR (Chrna3, Chrna4, Chnra7, and Chrnb2) mRNA was assessed using quantitative real-time polymerase chain reaction. Hippocampal Chrna3 expression was significantly decreased, and cerebellar Chrna7 expression significantly increased, in the delayed CO encephalopathy rat model. Thus, the nicotinic cholinergic system may be affected in delayed CO encephalopathy. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neu1et.2014.03.054

Web of Science

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Abstract

Aim

Constipation is one of the most common adverse effects in schizophrenia treatment, and it can sometimes cause severe gastrointestinal disease. However, the results of association studies between constipation and psychotropic medications in patients with schizophrenia are inconsistent. Therefore, we investigated the characteristics of psychotropic and laxative prescriptions at discharge in patients with schizophrenia to clarify the association between psychotropics and constipation.

Methods

We analyzed the data of 139 patients with schizophrenia with or without laxative prescriptions at discharge from eight institutions in 2020.

Results

Sixty‐two patients were prescribed laxatives at discharge. The prescription of benzodiazepines in the laxative use group (66.1%) was significantly higher than that in the non‐laxative use group (39.0%) (p = 1.4 × 10⁻³), and the mean number of benzodiazepines in the laxative use group (1.2 ± 1.1/day) was significantly higher than that in the non‐laxative use group (0.7 ± 0.9/day) (p = 2.6 × 10⁻³). Multivariate logistic regression analyses revealed that benzodiazepine prescriptions were significantly associated with laxative usage (odds ratio, 3.059; 95% confidence interval, 1.523–6.144; p = 2.0 × 10⁻³).

Conclusion

Benzodiazepines may be associated with constipation in patients with schizophrenia. Therefore, clinicians should be cautious when prescribing benzodiazepines for the treatment of schizophrenia.

DOI： 10.1002/npr2.12499

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Recent studies have implicated autophagy in both weight regulation and depression. This study aimed to investigate the relationship between stress-induced weight loss and autophagy-related gene expression in a mouse model of depression. METHOD: Male C57BL/6 mice were subjected to a chronic immobilization stress (CIS) protocol for 14 days to induce depressive-like behavior. Body weight was measured before and after the CIS, and depressive-like behavior was assessed using the tail suspension test (TST). The expression levels of autophagy-related genes (Atg5, Atg7, Atg12, Becn1, Mmp9, Fkbp5, and Map1lc3b) in the hippocampus and midbrain were evaluated using reverse transcription-quantitative PCR (RT-qPCR). Serum cortisol levels were also measured. RESULTS: The CIS resulted in significant weight loss and increased immobility time in the TST, indicating depressive-like behavior. Serum cortisol levels were not different between CIS-depression model and control mice. In the hippocampus, the expression levels of Fkbp5, Mmp9, and Map1lc3b were significantly higher in CIS-depression model mice than in control mice. In the midbrain, the expression levels of Fkbp5 and Mmp9 were significantly higher in CIS-depression model mice than in control mice. Increased autophagy-related gene expressions in CIS-depression model mice were consistent with the previous studies in the postmortem brains of patients with depression. A significant negative correlation was also found between Fkbp5 mRNA expression in the hippocampus and the weight change ratio before and after the CIS. CONCLUSION: The findings suggest that enhanced autophagy may be related to the pathology of depression and that Fkbp5, an autophagy regulator, mediates stress-induced weight loss.

DOI： 10.1002/npr2.12515

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担当区分：筆頭著者   記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The frequency of behavioral and psychological symptoms of dementia (BPSD) is high, and it is a challenge to elucidate its neural substrates underlying their development. In recent years, many findings have been reported on the relationship between BPSD and brain volume in dementia patients. However, the results are not fully conclusive. Furthermore, there have been few population-based studies. Therefore, the relationship between BPSD and brain volume was investigated as an exploratory study. Of the 927 older persons who participated in the fifth Nakayama study, 90 were included in this analysis, consisting of 52 patients with mild cognitive impairment and 38 patients with dementia, with head MRI and the Neuropsychiatric Inventory (NPI) data. Multiple regression analysis was used to examine the association between the total score of each BPSD score on the NPI and brain volume estimated by FreeSurfer. On multivariate adjustment, even after false discovery rate correction, insular cortical volumes decreased significantly as total scores for apathy/indifference increased (p value = 0.002, q-value = 0.01). Similarly, total brain volume decreased significantly as total scores for appetite and eating disturbance increased (p value = 0.03), and parietal, temporal, and hippocampal cortical volumes also decreased significantly as total scores for appetite and eating disturbance increased (all p and q values < 0.05). This study's results suggest that apathy is negatively correlated with insular cortical volume, and that appetite and eating disturbance are also correlated with brain regions, including parietal, temporal, and hippocampal volume in a community-dwelling older population.

DOI： 10.1038/s41598-024-77477-5

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞診療ガイドラインは臨床現場における課題について,治療者と患者の意思決定を行う際,それを支援する目的で作成されたものである。今回,個々の患者に対する治療のガイドライン一致率を評価するため,評価式として統合失調症版とうつ病版のindividual fitness score(IFS)を開発したため紹介する。治療内容をガイドライン一致率として数値化し可視化することで,具体的にどの要素がガイドラインの推奨治療に準じていないのかを把握することができる。この治療のガイドライン一致率は,日常臨床における治療方針決定のサポートツールとして役立つ可能性があると考えている。

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)星和書店  

カタトニアは,昏迷のような運動活動性の低下から,外的刺激の影響によらない興奮などの運動活動性の亢進まで幅がある複雑な臨床像を特徴とする精神運動性の障害であり,かつては「緊張病」として統合失調症の亜型の一つであったが,現在では,統合失調症を含め精神疾患に関連するもの,他の医学的な疾患に関連するもの,特定不能のものにわけられる症候群であるため,カタトニアを起こす原因疾患を鑑別することが重要である。カタトニアの治療は輸液などによる全身状態の管理に加え,原因となる疾患の治療を行うことが重要であるが,カタトニアに対してはbenzodiazepine受容体作動薬か電気けいれん療法がよく用いられる。統合失調症によるカタトニアに関してはこれらに加え,非定型抗精神病薬も治療の選択肢に上がりうるが,悪性症候群の出現やカタトニアの症状を悪化させる可能性もあるため注意する必要がある。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan. METHODS: The EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications. RESULTS: A total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients. CONCLUSION: This is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior.

DOI： 10.1186/s12888-024-05816-x

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)南山堂  

＜文献概要＞Point ●わが国の一般用医薬品(OTC薬)のなかには,ブロムワレリル尿素が含まれていることがある●睡眠薬を処方する前に,不眠をきたす各種疾患の鑑別や睡眠衛生指導を行う●睡眠薬の減量・中止には,十分な説明や睡眠衛生指導とともに時間をかけて行う

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00821&link_issn=&doc_id=20240408030010&doc_link_id=10.15104%2Fth.2024040005&url=https%3A%2F%2Fdoi.org%2F10.15104%2Fth.2024040005&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

掲載種別：研究論文（学術雑誌）  

Reports on polypharmacy strategies for patients with schizophrenia and major depressive disorder (MDD) are scarce. The nationwide Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project has been used to train psychiatrists on the guidelines for treatment of schizophrenia and MDD. This study aimed to determine whether the EGUIDE program enabled more appropriate evidence-based treatment of outpatients with schizophrenia and MDD. The types and doses of all psychotropics were analyzed in 174 and 147 patients with schizophrenia and MDD, respectively, in 2018 before the EGUIDE program and in 2019 and 2020 after the program. There were no significant differences in the rate of monopharmacy with antipsychotics for schizophrenia; however, the prescriptions of first-generation antipsychotics, anticholinergics, and benzodiazepines for schizophrenia decreased significantly after the program. There were also no significant differences in antidepressant monopharmacy rates for MDD; however, the prescriptions of benzodiazepines in patients with MDD decreased significantly after the program. Significant positive correlations were found between the number of psychotropic prescriptions and dosage of benzodiazepines. In conclusion, the EGUIDE project has improved the prescribing behavior for outpatients with schizophrenia and depression. Therefore, the guideline training program may be useful for regulating the prescribing behavior among physicians.

DOI： 10.1016/j.psycom.2024.100158

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Abnormal immunity in the periphery has been reported in the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: In this study, blood transcriptome analyses of patients with AD, those with mild cognitive impairment (MCI) due to AD, and heathy controls were performed to elucidate immune-related pathophysiology. METHODS: The sample included 63 participants from a complete enumeration study of elderly people in Nakayama town (the Nakayama Study), who were over 65 years of age, diagnosed as (1) healthy controls (N = 21, mean age: 83.8 years), (2) having MCI due to AD (N = 20, mean age: 82.6 years), or (3) having AD (N = 21, mean age: 84.2 years). Every participant underwent blood tests, magnetic resonance imaging, and questionnaires about lifestyle and cognitive function. With transcriptome analysis, differential gene expressions in the blood of the three groups were evaluated by gene ontology, pathway enrichment, and ingenuity pathway analyses, and quantitative real-time PCR was performed. RESULTS: Neutrophil extracellular trap signaling was increased, and lipid metabolism (FXR/RXR activation, triacylglycerol degradation) was decreased in AD, whereas MCI showed protective responses via decreased neutrophil extracellular trap signaling and mitochondrial functions such as upregulation of the sirtuin pathway and downregulation of oxidative stress. CONCLUSIONS: Based on these findings and consistent with other published studies, immune cells appear to have important roles in the pathogenesis of AD, and the transcriptome in blood may be useful as a biomarker for diagnosis via monitoring immunity in MCI and AD.

DOI： 10.1177/25424823241307878

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Antipsychotic treatment is vital for patients with schizophrenia even in the perinatal period, but the impact at the molecular biological level on offspring is unclear. The aim of the present study was to investigate the effects of intraperitoneal haloperidol injection to pregnant mice on glutamate and GABA receptors in the brain of offspring mice. Eight-week-old pregnant mice were treated with either intraperitoneal haloperidol or normal saline injection, and their offspring were defined as F1 mice. In addition, eight-week-old male mice were used as acute mice that were intraperitoneally injected with haloperidol or normal saline for 20 days. mRNA expression levels were measured by RT-qPCR. Western blotting was performed of the frontal lobes of F1 mice. In the hippocampi of F1 mice, Grik3 (p = 0.023) and Gabra3 (p = 0.004) mRNA expression levels were significantly higher in the haloperidol group than in the control group, whereas Gria2 (p < 0.001) and Grin2a (p < 0.001) mRNA expression levels were significantly lower in the haloperidol group than in the control group. Gria2 (p = 0.015), and Grik3 (p = 0.037), and Grin2a (p = 0.012) mRNA expression levels were significantly lower in the haloperidol group than in the control group in the frontal lobes of F1 mice. In the hippocampi of acute mice, Grik3 (p = 0.049) and Gabra3 (p = 0.007) mRNA expression levels were significantly decreased in the haloperidol group. Fetal exposure to haloperidol can affect glutamate and GABA receptors through mRNA expression changes in the brain of offspring.

DOI： 10.1016/j.ibneur.2023.09.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aims to examine the real-world effectiveness of education regarding clinical guidelines for psychiatric disorders using 'the Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)' project. METHODS: The EGUIDE project is a nationwide prospective implementation study of two clinical practice guidelines, i.e., the Guideline for Pharmacological Therapy of Schizophrenia and the Treatment Guidelines for Major Depressive Disorders, in Japan. Between 2016 and 2019, 782 psychiatrists belonging to 176 hospitals with psychiatric wards participated in the project and attended lectures on clinical practice guidelines. The proportions of guideline-recommended treatments in 7405 patients with schizophrenia and 3794 patients with major depressive disorder at participating hospitals were compared between patients under the care of psychiatrists participating in the project and those not participating in the project. Clinical and prescribing data on the patients discharged from April to September each year from participating hospitals of the project were also analyzed. RESULTS: The proportions of three quality indicators (antipsychotic monotherapy regardless of whether other psychotropics medication, antipsychotic monotherapy without other psychotropics and no prescription of anxiolytics or hypnotics) for schizophrenia were higher among participating psychiatrists than among nonparticipating psychiatrists. As similar results were obtained in major depressive disorder, the effectiveness of the project for the dissemination of guideline-recommended treatment has been replicated. CONCLUSION: This strategy of providing education regarding the clinical guidelines for psychiatric disorders was effective in improving the treatment-related behavior of psychiatrists. The use of this education-based strategy might contribute to resolving the mental health treatment gap.

DOI： 10.1111/pcn.13578

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

BACKGROUND: The number of patients with cognitive disorders is rapidly increasing in the world, becoming not only a medical problem, but also a social problem. There have been many reports that various factors are associated with cognitive dysfunction, but the factors have not yet been fully identified. This was a community-based complete enumeration study which aimed to identify risk and protective factors for dementia. METHODS: The first phase included all residents aged 65 years or older in a town in Japan. They completed many examinations, such as living conditions questionnaires, physical examination, Mini-Mental State Examination, and brain magnetic resonance imaging. The participants with suspected cognitive impairment underwent additional examinations for detailed evaluation in the second phase. Statistical analysis was performed to identify risk and protective factors for dementia after all participants were diagnosed. RESULTS: There were 927 participants in the baseline evaluation; 611 (65.9%) were healthy, 165 (17.8%) had mild cognitive impairment (MCI), and 151 (16.3%) had dementia. The age-standardised prevalence of dementia was 9.5%. Statistical analyses for amnestic MCI and Alzheimer's disease showed that risk factors for cognitive decline were diabetes mellitus, low activities of daily living, and living alone, and that protective factors were history of exercise and drinking habit. CONCLUSION: The present findings suggest that several lifestyle-related diseases and factors are associated with cognitive decline. These results support similar findings from previous studies and will be helpful for preventing dementia in the future.

DOI： 10.1111/psyg.13012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The onset of schizophrenia is associated with both genetic and environmental risks during brain development. Environmental factors during pregnancy can represent risk factors for schizophrenia, and we have previously reported that several microRNA and mRNA expression changes in fetal brains exposed to haloperidol during pregnancy may be related to the onset of this disease. This study aimed to replicate that research and focused on apoptotic-related gene expression changes. METHODS: Haloperidol (1mg/kg) or aripiprazole (1mg/kg) was injected into pregnant mice. Using RNA sequencing for the hippocampus of each offspring born from pregnant mice exposed to haloperidol, we analyzed genes identified as changed in our previous report and validated two apoptosis-related genes (Cdkn1a and Apaf1) using quantitative polymerase chain reaction (qPCR) methods. Furthermore, we attempted to elucidate the direct effects of haloperidol and aripiprazole on those mRNA expressions in in vitro experiments. RESULTS: RNA sequencing successfully replicated 16 up-regulated and 5 down-regulated genes in this study. Of those, up-regulations of Cdkn1a and Apaf1 mRNA expression were successfully validated by direct quantification. Moreover, haloperidol and aripiprazole dose-dependent upregulation of both mRNA expressions were confirmed in a Neuro2a cell line. CONCLUSIONS: In the hippocampus of offspring, intraperitoneal injection of haloperidol to pregnant mice induced up-regulation of apoptotic genes that representing the phenotypic change without apoptosis. These findings will be useful for understanding the molecular biological mechanisms underlying the effects of antipsychotics on the fetal brain.

DOI： 10.1016/j.brainresbull.2023.110662

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Polypharmacy of additional psychotropics alongside the main treatment drug (antipsychotics in schizophrenia and antidepressants in major depressive disorder) is common in Japan. Our goal is to align psychotropic prescription in Japan with international standards, while reducing the differences between facilities. To achieve this goal, we aimed to compare prescriptions at the time of hospital admission and discharge. METHODS: Data on prescriptions at admission and discharge from 2016 to 2020 were collected. We divided the patients into four groups: (1) mono_mono group, monotherapy of the main drug at admission and discharge; (2) mono_poly group, monotherapy at admission and polypharmacy at discharge; (3) poly_poly group, polypharmacy at admission and discharge; and (4) poly_mono group, polypharmacy at admission and monotherapy at discharge. We compared the changes in dosage and number of psychotropics among the four groups. RESULTS: For both schizophrenia and major depressive disorder, the patients who received monotherapy with the main drug at admission were likely to receive main drug monotherapy at discharge and vice versa. For schizophrenia, the polypharmacy was prescribed more often in the mono_poly group than that in the mono_mono group. The prescription was not changed at all for more than 10% of the patients. CONCLUSIONS: It is critical to avoid a polypharmacy regimen to ensure that guideline-compliant treatment is provided. We expect higher rates of monotherapy with the main drug after the EGUIDE lectures. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network Registry (UMIN000022645).

DOI： 10.1186/s12888-023-04908-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/jcp.0000000000001704

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We explored the gene expression levels in the brain of 3xTg-AD model mice to elucidate the molecular pathological changes from the early to end stages of Alzheimer's disease (AD). OBJECTIVE: We re-analyzed our previously published microarray data obtained from the hippocampus of 3xTg-AD model mice at 12 and 52 weeks of age. METHODS: Functional annotation and network analyses of the up- and downregulated differentially expressed genes (DEGs) in mice aged 12 to 52 weeks were performed. Validation tests for gamma-aminobutyric acid (GABA)-related genes were also performed by quantitative polymerase chain reaction (qPCR). RESULTS: In total, 644 DEGs were upregulated and 624 DEGs were downregulated in the hippocampus of both the 12- and 52-week-old 3xTg-AD mice. In the functional analysis of the upregulated DEGs, 330 gene ontology biological process terms, including immune response, were found, and they interacted with each other in the network analysis. In the functional analysis of the downregulated DEGs, 90 biological process terms, including several terms related to membrane potential and synapse function, were found, and they also interacted with each other in the network analysis. In the qPCR validation test, significant downregulation was seen for Gabrg3 at the ages of 12 (p = 0.02) and 36 (p = 0.005) weeks, Gabbr1 at the age of 52 weeks (p = 0.001), and Gabrr2 at the age of 36 weeks (p = 0.02). CONCLUSION: Changes in immune response and GABAergic neurotransmission may occur in the brain of 3xTg mice from the early to end stages of AD.

DOI： 10.3233/JAD-230078

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞本邦においても,日本神経精神薬理学会より,統合失調症の薬物治療ガイドラインが作成され,2022年には改訂版も上梓された。しかし,ガイドラインは,いまだ十分に利用されていないため,その普及と教育が必要である。精神科医療の普及と教育に対するガイドラインの効果に関する研究(EGUIDE)は,統合失調症薬物治療ガイドラインに関する講習を行い,ガイドラインの理解度,実践度,実際の処方行動をもとに,普及と教育と検証を行っている。さらにこれらのフィードバックによって講習内容や資料を適宜見直すことでよりよい講習ができるようにしている。また,ガイドラインの普及が進むことを検証するために実際の処方行動の調査研究や,ガイドラインをより利用しやすくするために,実際の処方がガイドラインの推奨内容にどれだけ適合しているかの適合度も作成することなどで,社会実装研究として患者のQOLの向上に寄与することを目指している。

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00749&link_issn=&doc_id=20230419060012&doc_link_id=10.11477%2Fmf.1405206894&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405206894&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/pcn.13489

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pcn.13489

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Several guidelines recommend monotherapy in pharmacotherapy for schizophrenia and major depressive disorder. The content of regular prescriptions has been reported in several studies, but not enough research has been conducted on the content of pharmacotherapy, including pro re nata (PRN) medications. The purpose of this study was to evaluate the content of pharmacotherapy, including PRN medications, and to clarify the relationship with regular prescriptions. METHODS: We used data from the "Effectiveness of Guidelines for Dissemination And Education in psychiatric treatment" (EGUIDE) project to investigate the presence or absence of PRN psychotropic medications at discharge for each drug category. We compared the PRN psychotropic prescription ratio at discharge by diagnosis for each drug category. The antipsychotic monotherapy ratio and no prescription ratio of other psychotropics for schizophrenia at discharge and the antidepressant monotherapy ratio and no prescription ratio of other psychotropics for major depressive disorder at discharge were calculated for each regular prescription, including PRN psychotropic medications, as quality indicators (QIs). Spearman's rank correlation test was performed for QI values of regular prescriptions and the QI ratio between regular prescriptions and prescriptions including PRN medications for each diagnosis. RESULTS: The PRN psychotropic prescription ratio at discharge was 28.7% for schizophrenia and 30.4% for major depressive disorder, with no significant differences by diagnosis. The prescription ratios of PRN antipsychotic medications and PRN antiparkinsonian medications were significantly higher for schizophrenia. The prescription ratios of PRN anxiolytic and hypnotic and PRN antidepressant medications were significantly higher for patients with major depressive disorder. For both schizophrenia and major depressive disorder, the QI was lower for discharge prescriptions, including PRN medications, than for regular prescriptions. QI values for regular prescriptions and the QI ratio were positively correlated. CONCLUSIONS: Considering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.

DOI： 10.1186/s12991-022-00429-8

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/pcn5.65

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pcn5.65

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To disseminate, educate, and validate psychiatric clinical practice guidelines, the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project was launched in 2016. In this study, we investigated whether the web-based courses offered by this project would be as effective as the face-to-face courses. We analyzed and compared survey answers about overall participant satisfaction with the course and answers regarding clinical knowledge of schizophrenia and major depressive disorder between 170 participants who took the web-based courses in 2020 and 689 participants who took the face-to-face courses from 2016 to 2019. The web-based course participants completed the survey questions about satisfaction with the web-based courses. The web-based courses were conducted using a combination of web services to make it as similar as possible to the face-to-face courses. The degree of satisfaction assessed by the general evaluation of the web-based courses was higher than what was expected from the face-to-face courses. The degree of satisfaction was similar for the courses on schizophrenia and major depressive disorder. In addition, there were no significant differences in overall satisfaction and clinical knowledge between web-based and face-to-face courses. In conclusion, the web-based courses on clinical practice guidelines provided by the EGUIDE project were rated as more satisfying than the face-to-face course that the participants expected to take and no differences in the effectiveness of either course. The results suggest that, after the COVID-19 pandemic, it would be possible to disseminate this educational material more widely by adopting web-based courses additionally face-to-face courses.

DOI： 10.1002/npr2.12300

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Treatment guidelines are designed to assist patients and health care providers and are used as tools for making treatment decisions in clinical situations. The treatment guidelines of the Japanese Society of Mood Disorders establish treatment recommendations for each severity of depression. The individual fitness score (IFS) was developed as a simple and objective indicator to assess whether individual patients are practicing treatment by the recommendations of the depression treatment guidelines of the Japanese Society of Mood Disorders. METHODS: The EGUIDE project members determined the IFS through the modified Delphi method. In this article, the IFS was calculated based on the treatment of depressed patients treated and discharged between 2016 and 2020 at facilities participating in the EGUIDE project. In addition, we compared scores at admission and discharge. RESULTS: The study included 428 depressed patients (mild n = 22, moderate/severe n = 331, psychotic n = 75) at 57 facilities. The mean IFS scores by severity were statistically significantly higher at discharge than at admission with moderate/severe depression (mild 36.1 ± 34.2 vs. 41.6 ± 36.9, p = 0.49; moderate/severe 50.2 ± 33.6 vs. 55.7 ± 32.6, p = 2.1 × 10-3; psychotic 47.4 ± 32.9 versus 52.9 ± 36.0, p = 0.23). CONCLUSION: We developed the IFS based on the depression treatment guideline, which enables us to objectively determine how close the treatment is to the guideline at the time of evaluation in individual cases. Therefore, the IFS may influence guideline-oriented treatment behavior and lead to the equalization of depression treatment in Japan, including pharmacotherapy.

DOI： 10.1002/npr2.12301

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The Guidelines for the Pharmacotherapy of Schizophrenia were established to improve the quality of medical care, and the EGUIDE project was conducted to train clinicians on guideline usage. A quality indicator (QI) was established to measure the prevalence of the guidelines, and a survey was conducted, which revealed a gap between the guidelines and actual clinical practice (evidence-practice-gap). The purpose of this study was to develop an individual fitness score (IFS) formula that expresses the degree to which prescribers adhere to the Guidelines for Pharmacological Therapy of Schizophrenia in a simple manner, and to determine the validity of this formula from a survey of the prescriptions of the EGUIDE project participants'. METHODS: To establish appropriate scores, members discussed the proposed formula and then voted on them. The IFS formula developed was set up so that antipsychotic monotherapy would be given 100 points, with points deducted if concomitant or adjunctive antipsychotic medications were used, and a minimum score of 0. To validate this formula, prescriptions of hospitalized schizophrenic patients at admission and at discharge were scored and compared. RESULT: IFS points vary and ranged from 0 to100. The average pre-admission score for all subjects was 45.6, and the average score at discharge was 54, those were significantly higher during discharge. CONCLUSIONS: We developed an IFS formula, a tool to easily visualize the degree to which current prescriptions conform to the guidelines for the pharmacological treatment of schizophrenia.

DOI： 10.1002/npr2.12293

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/JCP.0000000000001604

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Impaired synaptic plasticity has been linked to dynamic gene regulatory network changes. Recently, gene regulation has been introduced with the emerging concept of unique m 6A-based reversible transcript methylation. In this study, we tested whether m 6A RNA methylation may potentially serve as a link between the stressful insults and altered expression of plasticity-related genes. METHODS: Expression of plasticity genes Nr3c1, Creb1, Ntrk2; m6A modifying enzymes Fto, Mettl3, Mettl14; DNA methylation enzymes Dnmt1, Dnmt3a; transcription factor C/ebp-α; and miRNA-124-3p were determined by qPCR in the hippocampus of rats who showed susceptibility to develop stress-induced depression (learned helplessness, LH). M 6A methylation of plasticity-related genes was determined following m 6A mRNA immunoprecipitation. Chromatin immunoprecipitation was used to examine the endogenous binding of C/EBP-αto the Fto promoter. MiR-124-mediated post-transcriptional inhibition of Fto via C/EBPα was determined using an in-vitro model. RESULTS: Hippocampus of LH rats showed downregulation of Nr3c1, Creb1, and Ntrk2 along with enrichment in their m 6A methylation. A downregulation in demethylating enzyme Fto and upregulation in methylating enzyme Mettl3 were also noted. The Fto promoter was hypomethylated due to the lower expression of Dnmt1 and Dnmt3a. At the same time, there was a lower occupancy of transcription factor C/EBPα on the Fto promoter. Conversely, C/ebp-α transcript was downregulated via induced miR-124-3p expression. CONCLUSIONS: Our study mechanistically linked defective C/EBP-α-FTO-axis, epigenetically influenced by induced expression of miR-124-3p, in modifying m 6A enrichment in plasticity-related genes. This could potentially be linked with abnormal neuronal plasticity in depression.

DOI： 10.1093/ijnp/pyac068

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担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/pcn5.33

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pcn5.33

担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：(株)星和書店  

感染症による精神疾患においては、感染症が直接引き起こす器質性精神障害と、既知の精神障害が感染症によって影響される場合とがある。前者の代表例として神経梅毒が挙げられる。一方、新型コロナウイルス感染症(COVID-19)では、双方が引き起こされる可能性がある。また、抗菌薬など身体治療による精神症状の発現や向精神薬との薬物相互作用にも気をつけなければならない。この稿では、これら感染症による精神障害の捉え方、そこで注意することに触れた後に、最後に、薬物以外で心に留めなければいけないことについても概説する。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Schizophrenia is a mental disorder caused by both environmental and genetic factors. Prenatal exposure to antipsychotics, an environmental factor for the fetal brain, induces apoptotic neurodegeneration and cognitive impairment of offspring similar to schizophrenia. The aim was to investigate molecular biological changes in the fetal hippocampus exposed to haloperidol (HAL) by RNA expression as a model of the disorder. METHODS: HAL (1 mg/kg/day) was administered to pregnant mice. Upregulated and downregulated gene expressions in the hippocampus of offspring were studied with RNA-seq and validated with the qPCR method, and miRNA regulating mRNA expressional changes was predicted by in silico analysis. An in vitro experiment was used to identify the miRNA using a dual-luciferase assay. RESULTS: There were significant gene expressional changes (1,370 upregulated and 1,260 down regulated genes) in the HAL group compared to the control group on RNA-seq analysis (p < 0.05 and q < 0.05). Of them, the increase of Nr3c1 mRNA expression was successfully validated, and in silico analysis predicted that microRNA-137-3p (miR-137-3p) possibly regulates that gene's expression. The expression of miR-137-3p in the hippocampus of offspring was significantly decreased in the first generation, but it increased in the second generation. In vitro experiments with Neuro2a cells showed that miR-137-3p inversely regulated Nr3c1 mRNA expression, which was upregulated in the HAL group. CONCLUSIONS: These findings will be keys for understanding the impact of the molecular biological effects of antipsychotics on the fetal brain.

DOI： 10.1093/ijnp/pyac044

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The number of dementia patients is increasing worldwide, especially in Japan, which has the world's highest ageing population. The increase in the number of older people with dementia is a medical and socioeconomic problem that needs to be prevented, but the actual situation is still not fully understood. METHODS: Four cross-sectional studies on dementia were conducted in 1997, 2004, 2012, and 2016 for complete enumeration of all residents aged 65 years and older. We examined the secular trends in the prevalence of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and other/unclassified dementia. RESULTS: The age-standardised prevalence of all-cause dementia significantly increased (4.5% in 1997, 5.7% in 2004, 5.3% in 2012, 9.5% in 2016; P for trend <0.05). Similar trends were observed for AD (1.7%, 3.0%, 2.5% and 4.9%, respectively; P for trend <0.05) and other/unclassified dementia (0.8%, 1.0%, 1.0% and 2.2%, respectively; P for trend <0.05), whereas no significant change in VaD was seen (2.1%, 1.8%, 1.8%, 2.4%, respectively; P for trend = 0.77). The crude prevalence of all-cause dementia and AD increased from 1997 to 2016 among participants aged 75-79 years and ≥85 years (all P for trend <0.05). Similar trends were observed for other/unclassified dementia among participants aged ≥80 years (all P for trend <0.05), but not in VaD. CONCLUSIONS: The prevalence of dementia has increased beyond the ageing of the population, suggesting that factors in addition to ageing are involved in the increase in the number of older people with dementia. To control the increase in the number of older people with dementia, elucidation of secular trends in the incidence, mortality, and prognosis of dementia as well as the factors that promote and protect against dementia, and development of preventive strategies are necessary.

DOI： 10.1111/psyg.12865

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: In the treatment guidelines for major depressive disorder (MDD), the recommended treatment differs based on the severity. However, the type of treatment provided based on the severity of MDD in real-world clinical practice has not been investigated. In this study, we clarified the actual situation of MDD treatment in clinical practice and compared the treatment based on the severity of MDD. METHODS: We used data from 1484 patients with MDD at discharge from October 2016 to March 2020. RESULTS: The number of psychotropic prescriptions tended to be lower in those diagnosed with MDD in the severe group compared to in the non-severe group. There were significant differences among the three groups (mild, moderate/severe, and psychotic) in the percentage of patients who were not prescribed antipsychotics (p = 1.9 ×10-6), a combination of antipsychotics and antidepressants (p = 5.0 ×10-4), and the implementation rate of modified electroconvulsive therapy (m-ECT) (p = 3.4 ×10-9). The percentage of patients with a severe diagnosis who underwent m-ECT was higher, which corresponded to the severity. CONCLUSION: Our findings showed that the use of psychotropics decreased when the severity of MDD was diagnosed, and the rate of a combination of antipsychotics and antidepressants and the implementation rate of m-ECT increased with the severity. However, this study suggests that there is still an evidence-practice gap in the treatment of MDD in Japan, and guidelines are only partially adhered to in the treatment of depression.

DOI： 10.1016/j.ajp.2022.103174

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Clinical practice guidelines for schizophrenia and major depressive disorder have been published. However, these have not had sufficient penetration in clinical settings. We developed the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project as a dissemination and education programme for psychiatrists. AIMS: The aim of this study is to assess the effectiveness of the EGUIDE project on the subjective clinical behaviour of psychiatrists in accordance with clinical practice guidelines before and 1 and 2 years after participation in the programmes. METHOD: A total of 607 psychiatrists participated in this study during October 2016 and March 2019. They attended both 1-day educational programmes based on the clinical practice guidelines for schizophrenia and major depressive disorder, and answered web questionnaires about their clinical behaviours before and 1 and 2 years after attending the programmes. We evaluated the changes in clinical behaviours in accordance with the clinical practice guidelines between before and 2 years after the programme. RESULTS: All of the scores for clinical behaviours in accordance with clinical practice guidelines were significantly improved after 1 and 2 years compared with before attending the programmes. There were no significant changes in any of the scores between 1 and 2 years after attending. CONCLUSIONS: All clinical behaviours in accordance with clinical practice guidelines improved after attending the EGUIDE programme, and were maintained for at least 2 years. The EGUIDE project could contribute to improved guideline-based clinical behaviour among psychiatrists.

DOI： 10.1192/bjo.2022.44

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Late-onset Alzheimer's disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested. OBJECTIVE: Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population. METHODS: A blood expression study (45 AD subjects, 54 controls) in which total RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2*2 frequency and the risk of LOAD. RESULTS: ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p = 0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2*2 allele, with an increased AD risk (OR = 1.38; 95% CI = 1.02-1.85; p = 0.0348, I2 = 81.1%). CONCLUSION: There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2*2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population.

DOI： 10.3233/JAD-215627

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE) project, which is a nationwide dissemination and implementation program for clinical practice guidelines (CPGs) in the field of psychiatry, is currently ongoing. In the current study, a subjective assessment of the participants in the EGUIDE programs was assessed using a questionnaire. Then, the relationships between the subjective assessment, the characteristics of the participants, and the clinical knowledge of the CPGs were evaluated. More than 90% of the participants gave a high rating for the components of content, recommendation, knowledge, skill, and adherence, but not for the component of confidence. A positive correlation was found between years of professional experience and the score of confidence. These results suggest that it may be necessary to apply the knowledge and skills of CPGs obtained in the education programs into practice to increase confidence in the proper use of psychiatric therapies based on CPGs.

DOI： 10.1002/npr2.12245

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although several guidelines indicate that daily pharmacotherapy is an important part of the treatment of schizophrenia and major depressive disorder, there are few reports regarding pro re nata (PRN) prescriptions. The purpose of this study is to clarify the characteristics of patients receiving psychotropic PRN prescription for the treatment of schizophrenia and major depressive disorder. METHOD: We used data from 'the effectiveness of guideline for dissemination and education in psychiatric treatment' (EGUIDE) project to evaluate the presence or absence of psychotropic PRN prescription at the time of discharge, the age and sex of patients receiving PRN prescription for each diagnosis, and the association between PRN prescription and regular daily psychotropics. RESULTS: The psychotropic PRN prescription ratio was 29.9% among 2617 patients with schizophrenia and 31.1% among 1248 patients with major depressive disorder at discharge. In schizophrenia, the psychotropic PRN prescription ratio was 21.6% for patients aged 65 years or older, which was lower than that of all other age groups. In major depressive disorder, the psychotropic PRN prescription ratio was 34.2% for female patients, which was significantly higher than that for male patients (25.5%). In schizophrenia, there was an association between psychotropic PRN prescription and regular use of multiple psychotropic medications. CONCLUSIONS: Psychotropic PRN prescription was less common in elderly patients with schizophrenia and more common in female patients with major depressive disorder. In schizophrenia, psychotropic PRN prescription led to polypharmacy of psychotropics. Further studies are needed to accumulate evidence and to provide education on appropriate PRN prescriptions.

DOI： 10.1016/j.ajp.2022.103007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

STUDY OBJECTIVES: To investigate the proportion of inpatients with schizophrenia and major depressive disorder prescribed hypnotic medication, and the association between such medication and the use of other antipsychotic agents. METHODS: This was a nationwide cross-sectional study performed as part of the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment' (EGUIDE) project. Data from 2146 inpatients with schizophrenia and 1031 inpatients with major depressive disorder were analyzed. All types and dosages of psychotropic drugs were recorded and the data at the time of discharge were analyzed. Associations between the use of hypnotic medication and other antipsychotic agents were evaluated using multivariate logistic regression analyses. RESULTS: The proportions of schizophrenia patients who were prescribed any and two or more hypnotic agents were 55.7% and 17.6%, respectively, and the corresponding proportions for patients with major depressive disorder were 63.6% and 22.6%, respectively. In schizophrenia patients, multivariate logistic regression analyses showed that two or more antipsychotics, anticholinergic drugs, anxiolytics, and mood stabilizers/antiepileptic drugs were positively associated with the use of any hypnotic agent. In patients with major depressive disorder, multivariate logistic regression analyses revealed that two or more antidepressants, two or more antipsychotics, anxiolytics, and mood stabilizers/antiepileptic drugs were positively associated with the use of any hypnotic agent. CONCLUSIONS: Prescription of hypnotic agents was found to be highly frequent among inpatients with psychiatric disorders. Prescription of two or more main antipsychotic agents was commonly associated with the use of hypnotic medication for both schizophrenia and major depressive disorder.

DOI： 10.1016/j.sleep.2021.11.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups-low rate group (LG), medium rate group (MG), and high rate group (HG)-according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.

DOI： 10.3389/fpsyt.2022.823826

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) has various influences on physical abilities. Identification of specific physical abilities of people with ADHD/ASDs as biomarkers for diagnosing these conditions is necessary. Therefore, in the present review, we aimed firstly to extract the difference in physical abilities of people with ADHD or ASDs compared to those of normal individuals. Secondly, we aimed to extract the specific physical ability characteristics for identifying potential diagnostic biomarkers in people with ADHD/ASDs. Methods: A systematic literature review was performed. The databases were searched for relevant articles on motor function deficits and characteristics of ADHD or ASD. Results: Forty-one cross-sectional studies and three randomized controlled trials were identified, comprising 33 studies of ADHD, 10 studies of ASDs, and 1 study of both ADHD and ASDs. The quality of studies varied. Three types of physical activities/exercises were identified, including coordinated movement, resistance-type sports, and aerobic-type sports. People with ADHD/ASDs generally exhibited poorer physical abilities for all types of activities, possibly because of low levels of physical activity. Specifically, we found temporal discoordination of movement in ADHD and integration or synchronization of separate movements in ASDs. Conclusion: Specific deficits in physical ability may be attributed to ADHD/ASDs. However, there is not enough research on the physical abilities of people with ADHD and ASDs to clarify the specific deficits. Investigation of specific motor functions that characterize ADHD/ASDs should be facilitated.

DOI： 10.2147/NDT.S369845

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment-resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine. METHODS: After attending a 1-day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty-nine facilities in 2017 were included in the study. RESULTS: There were dichotomous distributions in the examination rate of TRS and a non-normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (rs  = 0.531, P = 1.032 × 10-4 ). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS. CONCLUSION: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families.

DOI： 10.1002/npr2.12218

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Monopharmacy with antipsychotics and antidepressants is the first-line treatment for schizophrenia and major depressive disorder (MDD) in most clinical guidelines, while polypharmacy with psychotropic agents in the treatment of schizophrenia is common in clinical practice. There are no detailed data on the prescription patterns for inpatients with mental illness with reliable diagnoses made by treating psychiatrists. METHODS: We gathered prescription data at discharge from 2177 patients with schizophrenia and 1238 patients with MDD from October 2016 to March 2018. RESULTS: The patients with schizophrenia aged between 60 and 79 were prescribed lower doses of antipsychotics and hypnotics/anxiolytics than those aged between 40 and 59. There were significant differences between the prescription rate of antipsychotics in the patients with schizophrenia and that of antidepressants in the patients with MDD. The frequency of concomitant drugs such as anti-Parkinson drugs, anxiolytics/hypnotics and mood stabilizers in the subjects with schizophrenia prescribed antipsychotic polypharmacy was significantly higher than that with monotherapy. For the patients with schizophrenia, olanzapine, risperidone, aripiprazole, quetiapine, and blonanserin were the five most prescribed antipsychotics. For the patients with MDD, mirtazapine, duloxetine, escitalopram, trazodone and sertraline were the five most prescribed antidepressants. CONCLUSIONS: Our results showed the use of high doses of antipsychotics, high percentages of antipsychotic polypharmacy and concurrent use of hypnotics/anxiolytics in patients with schizophrenia. Notably, these data were collected before intensive instruction regarding the guidelines; therefore, we need to assess the change in the prescription pattern post guideline instruction.

DOI： 10.1016/j.ajp.2021.102744

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/npr2.12193

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：(株)医学書院  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To implement clinical practice guidelines (CPGs), it is necessary for psychiatrists to deepen their understanding of the CPGs. The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide dissemination and implementation study of two sets of CPGs for schizophrenia and major depressive disorder (MDD). METHODS: A total of 413 psychiatrists (n = 212 in 2016; n = 201 in 2017) learned the two CPGs in the education program of the EGUIDE project, and clinical knowledge of these CPGs was evaluated at baseline and after the programs. To improve the correct answer rate for clinical knowledge after the programs, we revised the lecture materials associated with items that had a low correct answer rate in 2016 and used the revised lecture materials with the CPGs in 2017. The rates of correct answers after the programs between the 2016 and 2017 groups were compared. RESULTS: The correct answer rate of one item on the schizophrenia CPG and one item on the MDD CPG tended to be improved (S-D5 and D-C6) and that of one on the MDD CPG was significantly improved (D-D3, P = 0.0008) in the 2017 group compared to those in the 2016 group. CONCLUSIONS: We reported improvements in clinical knowledge of CPGs after the EGUIDE program in the 2017 group following revision of the lecture materials based on results from the 2016 group. These attempts to improve the degree of understanding of CPGs may facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice.

DOI： 10.1002/npr2.12173

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cyclin-dependent kinase inhibitor 2A (CDKN2A) is an important gene in cellular senescence and aging. OBJECTIVE: This study assessed the utility of blood CDKN2A mRNA expression levels and methylation status as a potential biomarker for aging and the pathogenesis of Alzheimer's disease (AD). METHODS: The correlation between CDKN2A mRNA expression levels and age was examined in 45 healthy subjects, after which mRNA expression levels were compared among 46 AD patients, 20 mild cognitive impairment due to AD patients, 21 Parkinson's disease patients, 21 dementia with Lewy bodies patients, and 55 older healthy controls. The methylation rates of the second exon of the CDKN2A gene, known to influence its expression levels, was also examined. RESULTS: A significant correlation between CDKN2A mRNA expression levels and age was found (Spearman's rank correlation coefficient: r = 0.407, p = 0.005). CDKN2A mRNA expression levels in blood were significantly decreased in AD patients, although those of healthy controls were significantly increased with age. Further, only in AD patients were CDKN2A mRNA expression levels significantly and positively correlated with methylation rates. CONCLUSION: Although further research with a larger sample size is needed to elucidate the relationships between CDKN2A gene expression in blood and the development of other neurodegenerative diseases, CDKN2A mRNA expression in blood may be a biomarker for differentiating AD from normal aging and other neurodegenerative diseases.

DOI： 10.3233/JAD-210483

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. OBJECTIVE: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. METHODS: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. RESULTS: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. CONCLUSION: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD.

DOI： 10.3233/JAD-201046

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記述言語：英語  

DOI： 10.1111/pcn.13143

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：(株)じほう  

＜Points＞▼意識障害やけいれん発作ではてんかん以外にも薬剤性に引き起こされるものも存在するため、意識障害やけいれん発作を来しうる薬物中毒の可能性を鑑別として考慮しておく必要がある。▼原因不明の意識障害やけいれん発作に加え、難治性、再発性の皮疹を認めるときはブロムワレリル尿素による薬物中毒も鑑別にあげる必要がある。▼血中のブロムにより、偽性高Cl血症および負のアニオンギャップを認めることがある。▼近年、ブロムワレリル尿素は医師が睡眠薬として処方することはなくなってきているが、現在でも用いられる例は少なからず存在し、また抗てんかん薬として処方されることもあるため、慢性投与による中毒の可能性に留意する必要がある。▼わが国では特に規制がないため、多くの市販の解熱鎮痛薬や鎮静薬の成分中にもブロムワレリル尿素が含まれていることに留意し、それら一般用医薬品(OTC薬)の常用歴や過量服薬の有無にも気をつける必要がある。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01465&link_issn=&doc_id=20200708110003&doc_link_id=%2Fan1yakgl%2F2020%2F006209%2F006%2F1712-1714%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fan1yakgl%2F2020%2F006209%2F006%2F1712-1714%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We recently reported that older patients with schizophrenia (SZ) show possible idiopathic normal pressure hydrocephalus (iNPH) more frequently than the general population. In this study, we estimated the prevalence of iNPH in a larger number of older SZ patients and explored useful examination values for diagnosis in the SZ population. METHODS: We enrolled older inpatients with SZ (n = 39, mean age = 68.6 ± 7.7 years) from several psychiatric hospitals in Ehime, Japan and acquired brain imaging data using computed tomography. We evaluated three iNPH symptoms (dementia, gait disturbance, and urinary incontinence). In addition, we combined these data with our previous data to elucidate the relationship between iNPH and characteristics of SZ symptoms. RESULTS: In total, five (12.8%) patients were diagnosed with possible iNPH. Evans' index for patients with iNPH was significantly higher than for those without iNPH (p = 0.002). The number of disproportionately enlarged subarachnoid space hydrocephalus (DESH) findings was significantly higher in patients with iNPH than in those without iNPH (p <  0.001). Using combined data, Drug-Induced Extra-pyramidal Symptoms Scale (DIEPSS) subscales of gait and bradykinesia showed an increasing trend in the SZ with iNPH group. CONCLUSIONS: We reconfirmed that older inpatients with SZ experienced possible iNPH more frequently than the general population. We should pay attention to the DIEPSS subscales of gait and bradykinesia and DESH findings in addition to the three main symptoms of iNPH and Evans' index so as to not miss SZ patients with iNPH.

DOI： 10.1186/s12888-020-02690-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CTL-associated antigen 4 (CTLA4) and its downstream signals compose an important mechanism that suppresses immune activity. Recent studies have shown that immune abnormalities are associated with the pathogenesis of schizophrenia (SCZ), but little research has been performed on the relevance of CTLA4 and SCZ. In the present study, we investigated the relationship between CTLA4 mRNA expression and SCZ. We examined the expression of CTLA4 mRNA in blood from patients with SCZ, bipolar disorder (BD), and major depressive disorder (MDD). We compared 50 SCZ subjects, 46 BD subjects, and 63 MDD subjects with age- and sex-matched healthy controls (HCs). Quantitative real-time PCR was performed to examine CTLA4 mRNA expression in peripheral blood using TaqMan probes. Levels of CTLA4 mRNA expression were significantly lower in patients with SCZ compared with HCs (p < 0.001), whereas no differences were found between affective disorder (BD and MDD) patients and HCs. We analyzed the correlation between CTLA4 mRNA expression and clinical parameters, but no significant correlation was found. The expression of CTLA4 mRNA was lower specifically in SCZ, suggesting that abnormal CTLA4 expression may be particularly related to the pathogenesis of SCZ. CTLA4 may be a useful diagnostic marker and a potential therapeutic target of SCZ.

DOI： 10.1016/j.ajp.2020.102112

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担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.5234/cnpt.11.5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68+ phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms.

DOI： 10.1016/j.neuint.2020.104672

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The aim was to clarify whether DRD2 methylation changes in leukocytes of dementia with Lewy bodies (DLB) or Parkinson's disease (PD) patients are seen and can be used to discriminate between them. METHODS: Methylation rates were examined in 23 DLB subjects and 23 age- and sex-matched healthy controls and 37 PD patients and 37 age- and sex-matched healthy controls. RESULTS: Significant DRD2 DNA methylation changes were found in leukocytes of DLB and PD patients compared with healthy subjects. Discriminant analysis between DLB and PD using seven CpG sites demonstrated sensitivity and specificity of 83.8% and 90.9%, respectively. None of the CpG sites were associated with sex, age, age of onset, disease duration, and any of the neuropsychological tests in DLB and PD patients. CONCLUSION: This is the first report showing that DRD2 DNA methylation rates in leukocytes were increased in DLB patients and decreased in PD patients. These results may be an important step in understanding epigenetic mechanisms underlying DLB and PD pathogenesis and providing a novel biomarker for discriminating between them.

DOI： 10.1111/ane.13186

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Few studies have explored school refusal in children with autism spectrum disorder (ASD), despite being considered a serious problem. One of the leading causes of school refusal is bullying, which is defined by the feelings of students who are bullied or not, and psychological suffering caused by a psychological or physical attack. This study investigated the characteristics of school refusal in children with ASD. Methods: A total of 94 outpatients with school refusal and ASD and 143 outpatients with school refusal without ASD aged 6-18 years were included. Chi squared tests and Mann-Whitney tests were used to compare the characteristics of school refusal in children with and without ASD. Univariate and multivariate logistic regression analyses were performed to analyze the reasons for school refusal in children with ASD by sex. Results: School refusal significantly occurred earlier in children with ASD than in those without. In addition, "bullying" was significantly associated with school refusal in both boys and girls with ASD. Conclusions: These findings suggest that school refusal should be monitored early in children with ASD. The importance of recognizing bullying among children with ASD should be highlighted as an opportunity for early intervention.

DOI： 10.1186/s13034-020-00325-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Although ATP-binding cassette sub-family A member 7 gene (ABCA7) is known to be associated with Alzheimer's disease, the relationship between ABCA7 and schizophrenia has been unknown. Methods: Schizophrenia patients (n = 50; 24 males, 62.1 ± 0.50 years old) and age- and sex-matched healthy controls (n = 50) were recruited for the mRNA analysis. Additionally, a case-control study for the rs3764650 genotypes was performed with 1308 samples (control subjects; n = 527, schizophrenia patients; n = 781). All participants were Japanese, unrelated to each other, and living in the same area. Results: The distributions of the rs3764650 genotypes in schizophrenia patients were not different from that of controls. However, the ABCA7 mRNA expression levels in schizophrenia patients were significantly higher than those in controls by a logistic regression analysis. Additionally, the ABCA7 mRNA expression levels in schizophrenia patients were correlated with the rs3764650 genotypes in a dose-dependent manner. Discussion: The ABCA7 mRNA expression levels in peripheral blood with the rs3764650 genotypes may be related to pathological mechanisms in schizophrenia and may be a biological marker for schizophrenia.

DOI： 10.2147/NDT.S238471

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記述言語：日本語   出版者・発行元：日本神経心理学会  

典型的な語義失語像を呈した54歳右利き男性の意味性認知症例の経過中,全般的な能力は保たれていたが,意味記憶障害の進展に伴い,当初は目立たなかった常同行動の出現を認めた.「休職中に早朝から用紙作成のために会社の複写機を独占する」と社会的行動障害を認めたが,行動異常型前頭側頭型認知症よりも強迫的であった.固執的な常同行動の背景に,語義失語による語彙の喪失に対する自覚とそれに伴う不安から対処行動に対する強迫化の傾向,意味記憶障害の進行に伴う対象の意味理解の狭小化と言語に関連する実行機能障害による行動目標の狭小化,早期から現れる他者視点の消失と次第に強まる自己の障害への無関心の3要素の関与を推定した.(著者抄録)

DOI： 10.20584/neuropsychology.17077

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01877&link_issn=&doc_id=20200108090006&doc_link_id=10.20584%2Fneuropsychology.17077&url=https%3A%2F%2Fdoi.org%2F10.20584%2Fneuropsychology.17077&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Schizophrenic patients resistant to antipsychotics are diagnosed as having treatment-refractory schizophrenia, and they are treated with clozapine. However, clozapine is sometimes combined with electroconvulsive therapy (ECT) if clozapine monotherapy fails. In this report, a severe treatment-refractory schizophrenic patient who did not respond to clozapine even with ECT, but who recovered with asenapine monotherapy, is presented. Asenapine, considered a serotonin spectrum dopamine modulator, is a new atypical antipsychotic with unique pharmacological features that is used not only for schizophrenia, but also for bipolar disorder. The unique features of asenapine may be effective for some treatment-refractory schizophrenic patients.

DOI： 10.9758/cpn.2019.17.4.559

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The gene for dopamine receptor D2 (DRD2) is associated with schizophrenia (SCZ). Epigenetic changes may be related to SCZ pathology. The -141C Ins/Del polymorphism in DRD2 (rs1799732) is functional and associated with SCZ. Fifty SCZ patients and 50 control subjects were newly recruited and analyzed in addition to 50 previously reported SCZ samples and 50 previously reported control samples. Genomic DNA from peripheral leukocytes was analyzed. We replicated analysis of DNA methylation rates at seven CpG sites (CpG 1-1 to 1-7) and also analyzed five additional sites (CpG 2-1 to 2-5) in the upstream region of DRD2. We also performed genotyping of -141C IIns/Del and analyzed the effects of -141C Ins/Del on methylation of DRD2. Methylation rates were significantly lower in SCZ patients compared to control subjects, respectively. In control subjects, the methylation rates were significantly lower in individuals with the Ins/Ins genotype than in Del allele carriers. We replicated hypomethylation of the DRD2 promoter region in SCZ patients compared to age-matched control subjects. The -141C Ins/Del polymorphism affected the methylation rates in regions of DRD2. Hypomethylation and the -141C Ins/Del polymorphism of DRD2 may be biomarkers for SCZ.

DOI： 10.1016/j.psychres.2019.06.001

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：医歯薬出版(株)  

健康寿命を伸ばすためには身体的活動を保つことが重要であり、そのためには身体的な視点に加え精神・心理的な視点を持たなければならない。高齢者では、加齢により、生物・心理・社会的にすべての能力が低下することから、自己肯定感を損ねがちで、それがさらに閉じこもりを引き起こすという悪循環を導く可能性もある。高齢者に起こる身体的活動が低下する精神疾患の代表であるうつ病は、うつ症状に加え、不定愁訴が多いこと、認知症と間違えられる認知機能低下がみられること、加えて自殺率が高いことから、早期に診断し適切な治療的介入を行わなければいけない病気である。高齢者のうつ病の治療においても、若年者と同様に安静・休養は大事であるが、早期に改善させることにより身体不活動をできるだけ予防すべきで、高齢とはいえ抗うつ薬は副作用に留意しつつも十分量・十分期間使わなければならない。施行できる機関は限られるが、電気痙攣療法も有効な治療法のひとつである。そして、精神療法においては、常に礼節を持って接し、若年者以上に自己肯定感を高めるようにしなければならない。(著者抄録)

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担当区分：筆頭著者,　責任著者   記述言語：英語  

DOI： 10.1097/JCP.0000000000000998

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.psychres.2018.12.135

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The neuroprotective effect of ghrelin has recently been reported in Alzheimer's disease (AD). Ghrelin is converted from des-acyl ghrelin to the activated form, acyl ghrelin, by membrane bound o-acyltransferase 4 (MBOAT4), and then binds to growth hormone secretagogue receptor (GHS-R). We examined the levels of plasma acyl/des-acyl ghrelin in 75 AD subjects and age- and sex-matched controls, as well as the DNA methylation and mRNA expression of MBOAT4 and GHS-R in peripheral leukocytes. The acyl ghrelin concentration was significantly higher in AD subjects than in controls (2.18 ± 1.25 vs. 1.49 ± 2.3, p = 0.001). The methylation rate of MBOAT4 CpG 2 was significantly lower in AD subjects than in controls (4.0 ± 0.9 vs. 4.7 ± 1.2, p < 0.001). The mRNA expression levels of MBOAT4 and GHS-R1b were significantly higher in AD subjects than in controls (MBOAT4: 1.10 ± 0.48 vs. 1.0 ± 0.55, p = 0.049; GHS-R1b: 1.76 ± 3.18 vs. 1.0 ± 1.56, p = 0.030). These changes in the ghrelin cascade in peripheral blood may reflect those in the brain, and may be a neuroprotective biomarker in AD.

DOI： 10.1016/j.jpsychires.2018.10.011

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担当区分：筆頭著者  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

DOI： 10.1097/FTD.0000000000000506

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing  

Aim: Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory pathways. Myocyte-enhancer factor 2C (MEF2C) is one such candidate gene for AD. Methods: We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age- and sex-matched control subjects. Results: In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 ± 0.25 vs 0.99 ± 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = −0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects. Conclusion: MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD.

DOI： 10.1111/pcn.12618

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3233/JAD-180418

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：愛媛医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Objectives: Recent genome-wide association studies revealed that Triggering receptor expressed on myeloid cells 2 (TREM2) was associated with Alzheimer's disease (AD) and other neurodegenerative diseases. We previously reported that TREM2 mRNA is highly expressed in leukocytes of AD patients compared to those in healthy controls. However, the mechanism of TREM2 expression change is still not known. In this study, we examined the involvement of the DNA methylation status of TREM2 in its high gene expression.
Materials and methods: Fifty AD subjects and age- and sex-matched control subjects were recruited (25 males, 25 females; 79.9 +/- 5.27 and 79.4 +/- 3.92 years old, respectively). TREM2 mRNA expression and the percentage of DNA methylation at four CpG sites in intron 1 of TREM2 were studied using their peripheral leukocytes.
Results: We confirmed that TREM2 mRNA expression in leukocytes was significantly higher in AD patients than in controls (p = 0.007). The percentage methylation at three CpG sites in TREM2 intron 1 was significantly lower in AD subjects than in control: CpG1, 9.4 +/- 3.2 vs 11.9 +/- 4.0 (p = 0.001); CpG2, 15.4 +/- 4.9 vs 19.1 +/- 4.8 (p = 0.001); CpG3, 20.8 +/- 5.5 vs 25.5 +/- 5.4 (p &lt; 0.001); and the average percentage methylation of all CpG sites: 13.5 +/- 3.7 vs 16.1 +/- 3.8 (p = 0.002), respectively. In addition, there were significant negative correlations between TREM2 mRNA expression and the percentage DNA methylation of each of CpG sites (CpG1, r = -0.416, p &lt; 0.001; CpG2, r = -0.510, p &lt; 0.001; CpG3, r = -0.504, p &lt; 0.001; CpG4, r = -0.356, p &lt; 0.001).
Conclusions: Lower DNA methylation at TREM2 intron 1 caused higher TREM2 mRNA expression in the leukocytes of AD subjects versus controls and may be a biomarker for AD. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jpsychires.2017.04.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Background
Nitric oxide (NO) is a neurotransmitter that may be related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces a dose-dependent antidepressant-like effect. NO modulates major neurotransmitters involved in the neurobiology of MDD, such as norepinephrine, serotonin, dopamine, and glutamate. In this study, we investigated the effects of antidepressants as NO modulators in acute and sub-chronic treatments.
Methods
Rats were injected with the SSRI paroxetine (PAR, 10 mg/kg), the SNRI milnacipran (MIL, 30 mg/kg), or the NaSSA mirtazapine (MIR, 10 mg/kg) for acute (1 h) or sub-chronic (3 weeks) treatment prior to analysis of nine brain regions (frontal cortex, temporal cortex, striatum, thalamus, hippocampus, midbrain, pons, cerebellum, and olfactory bulb). The mRNA expression levels of three NOS subtypes (neuronal: nNOS, inducible: iNOS, and endothelial: eNOS) were analyzed using real-time PCR with Taqman probes.
Results
Acute MIR treatment significantly increased nNOS mRNA expression in the hippocampus, midbrain, cerebellum and olfactory bulb, and iNOS mRNA expression in the frontal cortex and midbrain. Acute PAR and MIR treatments significantly increased eNOS mRNA expression in most brain regions. Conversely, sub-chronic treatment with all types of antidepressants resulted in significant decreases of eNOS mRNA expression in most brain regions.
Conclusions
Sub-chronic treatment with the three types of antidepressants consistently decreased eNOS mRNA expression levels in the rat brain. These effects may be associated with the involvement of the NO system in the mechanism of action of antidepressants.

DOI： 10.1007/s00213-017-4567-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [ c.30 C &gt; G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and beta-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/beta-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions.

DOI： 10.1038/s41598-017-02792-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Research Foundation  

A hypothesis for schizophrenia (SCZ) called the "microglia hypothesis" has been suggested. In SCZ, expression of triggering receptor expressed on myeloid cell 2 (TREM2) mRNA is higher in leukocytes than in healthy individuals. Here, the methylation rates of four CpG sites in TREM2 intron 1 that may bind important transcription factors and the correlation between the methylation rate and mRNA expression were determined. We compared the methylation rates in SCZ patients and age-matched controls (n = 50 each). SCZ patients had significantly lower methylation rates of CpG 2 (17.0 ± 6.7 vs. 20.2 ± 5.0
p = 0.02) and CpG 3 (23.8 ± 8.2 vs. 28.1 ± 6.2
p = 0.01). The average methylation rate (15.3 ± 5.2 vs. 17.6 ± 3.9
p = 0.009) was also lower. A significant negative correlation was found between TREM2 mRNA expression and the methylation rate of CpG 2 (r = -0.252, p = 0.012). SCZ susceptibility markers may include low methylation at TREM2 intron 1 and increased TREM2 mRNA levels. Our pilot study requires validation with higher numbers of participants and with other myeloid cell types.

DOI： 10.3389/fnins.2017.00275

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FRONTIERS MEDIA SA  

A hypothesis for schizophrenia (SCZ) called the microglia hypothesis has been suggested. In SCZ, expression of triggering receptor expressed on myeloid cell 2 (TREM2) mRNA is higher in leukocytes than in healthy individuals. Here, the methylation rates of four CpG sites in TREM2 intron 1 that may bind important transcription factors and the correlation between the methylation rate and mRNA expression were determined. We compared the methylation rates in SCZ patients and age-matched controls (n = 50 each). SCZ patients had significantly lower methylation rates of CpG 2 (17.0 +/- 6.7 vs. 20.2 +/- 5.0; p = 0.02) and CpG 3 (23.8 +/- 8.2 vs. 28.1 +/- 6.2; p = 0.01). The average methylation rate (15.3 +/- 5.2 vs. 17.6 +/- 3.9; p = 0.009) was also lower. A significant negative correlation was found between TREM2 mRNA expression and the methylation rate of CpG 2 (r = -0.252, p = 0.012). SCZ susceptibility markers may include low methylation at TREM2 intron 1 and increased TREM2 mRNA levels. Our pilot study requires validation with higher numbers of participants and with other myeloid cell types.

DOI： 10.3389/fnins.2017.00275

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)星和書店  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J03168&link_issn=&doc_id=20170424290013&doc_link_id=issn%3D1343-3474%26volume%3D20%26issue%3D5%26spage%3D585&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D1343-3474%26volume%3D20%26issue%3D5%26spage%3D585&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimIt is difficult to diagnose dementia with Lewy bodies (DLB) because it exhibits clinical and neuropathological overlap with both Alzheimer's disease and Parkinson's disease. The -synuclein protein is a major component of Lewy bodies, and accumulation of -synuclein aggregates causes synaptic dysfunction in DLB. Epigenetic changes at the synuclein alpha (SNCA) gene may be involved in DLB pathogenesis.
MethodsWe examined DNA methylation rates at 10 CpG sites located in intron 1 of SNCA and SNCA mRNA expression in peripheral leukocytes to compare DLB patients (n=20; nine men, 11 women; age=78.87.7years) with healthy controls (n=20; eight men, 12 women; age=77.0 6.9years).
ResultsThe methylation rate at CpG 4 (P=0.002) and the overall mean methylation rate at these sites (P&lt; 0.001) were significantly lower in DLB patients than in healthy controls after Bonferroni correction. Although SNCA126, a partial form of SNCA mRNA expression, was significantly increased in DLB (P=0.017), there was no significant difference in total SNCA mRNA expression between DLB patients and healthy controls (P=0.165). No correlation was observed between SCNA mRNA expression levels and blood DNA methylation rates in either DLB or healthy controls.
ConclusionOur findings indicated that lower methylation rates may be a biomarker for DLB.

DOI： 10.1111/pcn.12462

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Microglial dysfunction and inflammation have recently been shown to be related to the development of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase (INPP5D) functions broadly as a negative regulator of immune signaling, and its locus was associated with development of AD in a large-scale genome-wide association study. Thus, we examined INPP5D mRNA expression and methylation rates of the CpG sites in the upstream region of INPP5D exon 1 in peripheral leukocytes in 50 AD and age- and sex-matched control subjects. INPP5D mRNA expression in AD subjects was significantly higher than that in control subjects (1.16 +/- 0.39 versus 1.0 +/- 0.23, p = 0.049) and was correlated with the Mini-Mental State Examination score (p = 0.002, r = 0.426) and the total score of the Alzheimer's Disease Assessment Scale (p &lt; 0.001, r = -0.697). Methylation rates in the upstream region of INPP5D exon 1 were not significantly different between AD and control subjects (average rate: 3.5 +/- 3.0 versus 2.8 +/- 1.3, p = 0.551). Our results suggested that INPP5D mRNA expression was elevated in the early stage and decreased with cognitive decline in AD. INPP5D mRNA expression in leukocytes may be a useful biomarker for the early stage of AD.

DOI： 10.3233/JAD-161211

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Background/Objective: The aim of this study was to examine the blood gene expression and methylation of ATP-binding cassette sub-family A member 7 gene (ABCA7) as a biological marker of AD.
Methods: AD subjects (n = 50; 11 males, 77.7 +/- 6.05 years old) and age-and sex-matched healthy controls (n = 50) were recruited. A single nucleotide polymorphism in ABCA7 (rs3764650), methylation rates of CpG sites in the ABCA7 promoter region, and ABCA7 mRNA expression levels in peripheral blood were examined.
Results: The distribution of the rs3764650 polymorphism in AD subjects was not different from that of controls. Although the methylation rates of AD subjects were not significantly different from those of controls, the ABCA7 mRNA expression level in AD subjects was significantly higher than that in controls. Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer's Disease Assessment Scale total score, and the Clinical Dementia Rating score. We also found a significant correlation between the ABCA7 mRNA expression level and duration of illness.
Conclusion: The ABCA7 mRNA expression level in peripheral blood may be a marker for early stages of AD and disease progression regardless of rs3764650 and the methylation rate of its promoter.

DOI： 10.3233/JAD-161195

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Background: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), and is reported in several genome-wide association studies to be associated with Alzheimer's disease (AD).
Objective: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD.
Methods: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age-and sex-matched control subjects.
Results: TOMM40 mRNA expression was significantly lower in AD subjects (0.87 +/- 0.18 versus 1.0 +/- 0.23, p = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5 +/- 0.61 versus 1.0 +/- 0.52, p &lt; 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r = 0.290, p = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p = 0.32). Methylation rates in the upstream region of TOMM40exon 1 were not different between AD and control subjects (average rate: 1.37 +/- 0.99 versus 1.39 +/- 1.20, p = 0.885), and TOMM40523 polyT genotypes were also not different between AD and control subjects (p = 0.67).
Conclusion: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction.

DOI： 10.3233/JAD-170361

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Anorexia nervosa (AN) is a complex psychiatric disorder, which is not yet fully understood. Several studies reported that AN was associated with disruption of cytokine network. Carcinoembryonic antigen (CEA) is a glycoprotein related to its network, used as a tumor marker of adenocarcinoma, and suggested to stimulate monocytes and macrophages to release proinflammatory cytokines. Here, we report a 41-year-old male suffering from AN who was suspected of having a malignant tumor due to markedly elevated serum CEA levels. However, on further examinations, he was discovered to have no malignant tumors, and, interestingly, his CEA levels actually decreased as his clinical state of AN improved. Furthermore, it was found that his CEA levels were elevated proportionally to his clinical state of AN and that his body mass index was significantly correlated with serum CEA levels. Therefore, it is suggested that inflammatory responses may be associated with the clinical state of AN. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:428-431).

DOI： 10.1002/eat.22474

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記述言語：英語   出版者・発行元：KOREAN COLL NEUROPSYCHOPHARMACOLOGY  

Nasu-Hakola disease (NHD) is a rare autosomal recessive neuropsychiatric disorder characterized by bone cysts, fractures, and cognitive impairment. Two genes are responsible for the development of NHD; TYROBP and TREM2. Although it presents with typical signs and symptoms, diagnosing this disease remains difficult, This case report describes a male with NHD with no family or past history of bone fractures who was diagnosed using exome sequencing. His frontal lobe psychiatric symptoms recovered partially following treatment with sodium valproate, but not with an antipsychotic,

DOI： 10.9758/cpn.2015.13.3.324

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

TREM2 and TYROBP are causal genes for Nasu-Hakola disease (NHD), a rare autosomal recessive disease characterized by bone lesions and early-onset progressive dementia. TREM2 forms a receptor signaling complex with TYROBP, which triggers the activation of immune responses in macrophages and dendritic cells, and the functional polymorphism of TREM2 is reported to be associated with neurodegenerative disorders such as Alzheimer's disease (AD). The objective of this study was to reveal the involvement of TYROBP and TREM2 in the pathophysiology of AD and schizophrenia. Methods: We investigated the mRNA expression level of the 2 genes in leukocytes of 26 patients with AD and 24 with schizophrenia in comparison with age-matched controls. Moreover, we performed gene association analysis between these 2 genes and schizophrenia. Results: No differences were found in TYROBP mRNA expression in patients with AD and schizophrenia; however, TREM2 mRNA expression was increased in patients with AD and schizophrenia compared with controls (P &lt; 0.001). There were no genetic associations of either gene with schizophrenia in Japanese patients. Conclusion: TREM2 expression in leukocytes is elevated not only in AD but also in schizophrenia. Inflammatory processes involving TREM2 may occur in schizophrenia, as observed in neurocognitive disorders such as AD. TREM2 expression in leukocytes may be a novel biomarker for neurological and psychiatric disorders.

DOI： 10.1371/journal.pone.0136835

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Nitric oxide (NO) may be a neurotransmitter related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces dose-dependent antidepressant-like effects. However, its role in MDD is not yet known. The purpose of our study was to determine if antidepressants improve depression via the NO pathway using an acute depressive rat model induced by L-arginine (AR). Three types of antidepressants were examined, fluoxetine (FLX, 10 mg/kg), milnacipran (MIL, 30 mg/kg), and mirtazapine (MIR, 10 mg/kg), in a depressive model that used AR (750 mg/kg) pretreatment. mRNA expression levels of three NOS subtypes were analyzed by real-time PCR, as well as serum NO levels. Significant increases in iNOS mRNA expression levels were found in brain regions after AR treatment, although the eNOS gene tended to decrease with AR injection. After antidepressant treatment, there were no mRNA expression changes in either nNOS or iNOS. However, eNOS mRNA expression significantly increased with FLX (cerebellum, P = 0.011; hippocampus, P = 0.011; midbrain, P = 0.011; pons, P = 0.013; striatum, P = 0.011; and thalamus, P &lt; 0.001). There was a statistically significant increase in serum NO levels with MIL treatment (P = 0.011). We conclude that changes in eNOS mRNA levels in the brain with FLX treatment, and amount of serum NO with MIL treatment may be related to antidepressant effects of both agents, but further experiments are needed to confirm involvement of the NO system in MDD. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2015.05.043

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER WIEN  

Abnormal hexanucleotide repeat expansion of C9ORF72 is known to cause neurodegenerative disorders such as frontotemporal dementia. Additionally, patients with psychotic symptoms are more likely to have abnormal hexanucleotide repeat expansion than are patients without them. We investigated the hexanucleotide repeat sizes of C9ORF72 in 466 Japanese schizophrenia patients. We found no abnormal hexanucleotide repeat expansion. In conclusion, C9ORF72 may not be responsible for schizophrenia susceptibility in the Japanese population.

DOI： 10.1007/s00702-014-1295-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Common adverse effects of atypical antipsychotic treatments for schizophrenia are weight gain and lipid metabolism abnormality. We aimed to identify the signs of metabolic problems with continuous atypical antipsychotic treatment for schizophrenia over a 2-year period. The participants were 68 schizophrenic patients (29 males, 39 females
ages 53.4 ± 13.5 years old). Changes in carbohydrate metabolism and changes in physical characteristics were studied over a 2-year period. In addition, functional single nucleotide polymorphisms in the transcriptional regulatory region of the resistin gene were examined. We found no changes in the mental state of the participants over a 2-year period. Patients did show a significant decrease in total cholesterol and hemoglobin A1c levels, although physical changes such as body mass index and abdominal girth, were not observed. The amount of resistin may not be associated with mental states and physical parameters. We could not find physical factors related to metabolic changes of antipsychotics in this 2-year study. However, several psychological factors, such as health-related thoughts and behaviors, should be studied in the future. © 2015, SAGE Publications. All rights reserved.

DOI： 10.1177/2045125315596697

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KOREAN COLL NEUROPSYCHOPHARMACOLOGY  

Clozapine is well known for successful use in schizophrenic patients treatment resistant to other antipsychotics. However, even with clozapine, 25% of schizophrenic patients are not in remission. Recently, as adjunctive treatment with clozapine, electroconvulsive therapy has been reported to be an effective and safe adjunctive treatment. We report a Japanese schizophrenic woman who was not in remission with clozapine alone but with both clozapine and electroconvulsive therapy.

DOI： 10.9758/cpn.2014.12.2.160

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Alanine:glyoxylate aminotransferase 2 (AGXT2) is the only enzyme that degrades D-3-aminoisobutyrate (D-AIB), which is an intermediate product of thymine, and 30-40% of Japanese lack AGXT2 activity genetically and excrete high amounts of D-AIB in their urine. Recently, AGXT2 is reported to metabolize asymmetric dimethyl arginine (ADMA), a competitive inhibitor of nitric oxide (NO) synthase. Since AGXT2 is expressed in the central nervous system, the loss of AGXT2 activity will be related to the vulnerability for neuropsychiatric disorders related to the NO system. In this study, we recruited 85 Japanese subjects to discover loss variants of the AGXT2 gene with the amount of D-AIB excretion in their urine. From the statistical relevance between them, we found three missense polymorphisms (rs37370, rs37369, and rs180749) independently related to AGXT2 activity (P &lt; 0.0001). Then, we performed a case-control association analysis of its missense polymorphisms with 1136 schizophrenia and 1908 control subjects because the NO system may be involved in the vulnerability of schizophrenia processes. We could not find any associations of three functional SNPs with schizophrenia pathogenesis in the analyses of either genotypic or allelic models. We concluded that the AGXT2 gene is not associated with schizophrenia in Japanese subjects. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2014.04.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: D-3-aminoisobutyrate, an intermediary product of thymine, is converted to 2-methyl-3-oxopropanoate using pyruvate as an amino acceptor by D-3-aminoisobutyrate-pyruvate aminotransferase (D-AIB AT; EC 2.6.1.40). A large amount of D-AIB AT is distributed in the kidney and liver; however, small amounts are found in the brain. Recently, D-AIB AT was reported to metabolize asymmetric dimethylarginine (ADMA) in vivo and was suggested to be an important enzyme for nitric oxide metabolism because ADMA is a competitive inhibitor for nitric oxide synthase. In this study, we examined the distribution of D-AIB AT in the rat brain further to understand its role. We measured D-AIB AT mRNA and protein expression using quantitative RT-PCR and Western blotting, and monitored its distribution using immunohistochemical staining.
Results: D-AIB AT was distributed throughout the brain, with high expression in the cortex and hippocampus. Immunohistochemical staining revealed that D-AIB AT was highly expressed in the retrosplenial cortex and in hippocampal neurons.
Conclusion: Our results suggest that D-AIB AT is distributed in the examined-just the regions and may play an important role there.

DOI： 10.1186/1471-2202-15-53

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

症例は60歳男性で、本人は特に困ることはないと述べており、家族は認知症の精査と体が動くようにして欲しいと望んでいた。50歳頃から近時記憶障害が出現し、近医受診されるが異常は指摘されなかった。56歳頃から失見当識が出現し、59歳時には幻視や着衣失行、散歩中警察に保護された。つじつまの合わない言動や易怒性から精神科病院に入院し、診断および治療目的で転院となった。遺伝子検査においてアミロイド前駆体タンパク遺伝子変異(APPV7171)を認め、若年発症のAlzheimer病と診断した。診断後、抗精神病薬を減量中止し、過鎮静や錐体外路兆候が消失した。donepezilを10mgまで増量し、意欲、活動性が改善した。家族歴が明らかでなく、多彩な精神神経症状を認める若年発症の認知症の診断には、遺伝子検査を行うことで、有益な結果がもたらされる可能性が示唆された。

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記述言語：英語   出版者・発行元：日本臨床精神神経薬理学会  

We present the case of an epileptic patient who experienced risperidone-induced hyperprolactinemia with chronic renal failure under hemodialysis. Her prolactin level was 1058 ng/ml, which was unexpectedly high. Because prolactin is mainly excreted in the urine, clinicians should pay more attention to chronic renal failure as one of the risk factors of hyperprolactinemia when prescribing risperidone.

DOI： 10.5234/cnpt.4.20

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Alzheimer's disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD.
Case presentation: In this study, we report a 275341 G &gt; C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 +/- 3.1 years old (n = 9; range, 42-52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations.
Conclusion: We conclude that the clinical features of Alzheimer's disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes.

DOI： 10.1186/1471-2377-12-38

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記述言語：日本語   出版者・発行元：(一社)日本医療薬学会  

外来精神科チーム医療における患者情報の共有ツール「私のお薬連絡帳」について検討した。お薬連絡帳により収集した患者情報を基に、薬剤師が処方変更提案を行った患者は50例中29例で、総件数は47件であった。内容は、ふらつき10件、服用忘れが多いタイミングの処方9件、起床困難7件、便秘7件、薬剤性錐体外路症状6件、性機能障害5件、中途覚醒3件であった。薬剤師からの処方変更提案に対する医師の受諾率は74.5%(35件)であった。処方変更後の患者の症状は、ふらつき8件、服用忘れが多いタイミングの処方7件、起床困難5件、便秘7件、薬剤性錐体外路症状2件、性機能障害4件、中途覚醒2件で改善を認めた。お薬連絡帳を介して患者情報の提供を受けた8例の医師にアンケートを行い、すべての医師がお薬連絡帳は有用であったと答えた。また、お薬連絡帳を使用して問題発生なしとすべての医師が答えた。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J03520&link_issn=&doc_id=20111214470002&doc_link_id=%2Fdb5pharm%2F2011%2F003712%2F002%2F0675-0680%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdb5pharm%2F2011%2F003712%2F002%2F0675-0680%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)星和書店  

薬物の標的臓器での作用は、薬物の体内での血液循環を介した系である薬物動態(pharmacokinetics:PK)、薬物が標的臓器に取り込まれ、その効果を発揮する応答性である薬物感受性(pharmacodynamics:PD)の2つの要素によって決定される。本稿では抗精神病薬のPKについて概説する。PKに関する最も重要な反応の1つはチトクロムP-450(cytochrome P-450:CYP)による酸化反応である。全CYPの中でも最も研究が進んでいるCYP2D6活性は、超代謝型、高代謝型、中間代謝型、低代謝型と分けられるが、それらは70種類以上の遺伝子多型によって決定される。日本人の約30〜50%は中間代謝型(intermediate metabolizers:IMs)のCYP2D6*10を持つ、抗精神病薬では、risperidoneやaripiprazoleなど、CYP2D6を主要な代謝経路として持つ薬物が多く、この遺伝子多型と薬物投与量や副作用との関連が報告されている。抗精神病薬の使用にあたっては、CY-P2D6に限らずその他の代謝酵素活性の個人差、薬物による酵素誘導や阻害など薬物相互作用にまで留意していく必要があると思われる。(著者抄録)

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We present a schizophrenic patient who experienced neuroleptic malignant syndrome with risperidone treatment due to variants of the CYP2D6 gene with reduced function. Clinicians need to be aware of this potential complication. © 2011 Elsevier Inc.

DOI： 10.1016/j.genhosppsych.2011.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

The atypical antidepressant, mirtazapine enhances noradrenergic transmission, but its effects on serotonergic transmission remain to be clarified. The present study determined the effects of acute and chronic administration of mirtazapine on serotonergic transmissions in raphe nuclei and their innervation regions, frontal and entorhinal cortex, using multiple-probes microdialysis with real-time PCR and western blotting. Acute administration of mirtazapine did not affect extracellular serotonin level in raphe nuclei or cortex; however, chronic administration increased extracellular serotonin level in raphe nuclei without affecting that in cortex. Blockade of 5-HT1A receptor, but not that of the 5-HT2A/2C receptor, enhanced the effects of acute administration of mirtazapine on extracellular serotonin level in raphe nuclei. Chronic mirtazapine administration reduced the inhibitory function associated with somatodendritic 5-HT1A receptor in raphe nuclei, but enhanced postsynaptic 5-HT1A receptor in serotonergic innervated cortical regions. Chronic administration reduced the expression of mRNA and protein of serotonin transporter and 5-HT1A receptor in raphe nuclei, but not in the cortices. These results suggested that acute administration of mirtazapine probably activated serotonergic transmission, but its stimulatory action was abolished by activated inhibitory 5-HT1A receptor. Chronic administration of mirtazapine resulted in increased extracellular serotonin level via reduction of serotonin transporter with reduction of somatodendritic 5-HT1A autoreceptor function in raphe nuclei. These pharmacological actions of mirtazapine include its serotonergic profiles as noradrenergic and specific serotonergic antidepressant (NaSSA). (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuropharm.2010.12.025

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記述言語：日本語   出版者・発行元：(株)星和書店  

トゥレット障害の主な薬物療法は、haloperidolやpimozide、risperidoneなどの抗精神病薬が使用されるが、近年、トゥレット障害に対するaripiprazoleの使用についての報告が散見される。AripiprazoleはドーパミンD2受容体部分アゴニストであり、多くの抗精神病薬がドーパミンD2受容体アンタゴニストであることから、特殊な薬理学特性を持つ抗精神病薬と言える。Aripiprazoleは、また、強力な抗精神病作用を有し、錐体外路症状、代謝異常や過鎮静をきたしにくい安全性の高い抗精神病薬のため、統合失調症の第一選択薬として国内で認識され、広く使われている。今回、我々は、トゥレット障害と診断し、多彩なチック症状に対してaripiprazoleの使用により改善に至った2症例を経験したので報告する。1例目は14歳男性、risperidoneによる治療を開始したが、過鎮静と効果不十分のためaripiprazoleに置換して6mg/日から開始、24mg/日まで増量し、奏効した。2例目は12歳男性、広汎性発達障害が併存していた。Aripiprazole 3mg/日から開始し、12mg/日まで増量したところ、チック症状は改善した。2症例とも副作用は眠気のみであった。以上から、aripiprazoleは、継続投与が可能で忍容性が高く、効果が期待でき、トゥレット障害に用いることのできる薬物治療の選択肢の1つであると判断した。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Purpose: Although olanzapine may have advantages over other second-generation antipsychotics (SGAs) regarding longer time to treatment discontinuation among chronically ill patients, little evidence has been provided for the comparative effectiveness of SGAs in the acute phase. We aimed to determine if any of four SGAs were more effective in treating newly admitted acute schizophrenic patients. We performed a rater-blinded, randomized controlled trial of four SGAs in 15 psychiatric emergency sites. Eligible patients were 18-64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A final total of 78 patients were randomly assigned by means of sealed envelopes to receive risperidone (3-12 mg/day; n = 20), olanzapine (10-20 mg/day; n = 17), quetiapine (300-750 mg/day; n = 20), or aripiprazole (12-30 mg/day; n = 21), with follow-up at 8 weeks. The primary outcome measure was all-cause treatment discontinuation.
Results: Overall, 37% (29/78) of patients discontinued the study medication before 8 weeks: 25% for risperidone; 12% for olanzapine; 55% for quetiapine; and 52% for aripiprazole. Time to treatment discontinuation for any cause was significantly longer in the olanzapine group than in the quetiapine (p = 0.006) or aripiprazole (p = 0.008) groups, but not compared to the risperidone group (p = 0.32). Time to treatment discontinuation was significantly longer in the risperidone group than in the quetiapine group (p=0.048), but not compared to the aripiprazole group (p = 0.062). However, the rate of p.r.n. intramuscular haloperidol use was significantly higher in the aripiprazole group than in other groups (p = 0.029).
Conclusion: Olanzapine and risperidone are superior to quetiapine and aripiprazole for the acute treatment of psychosis in hospitalized patients. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2009.05.030

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：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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記述言語：日本語   出版者・発行元：日本スポーツ精神医学会  

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記述言語：日本語   出版者・発行元：日本スポーツ精神医学会  

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記述言語：英語   出版者・発行元：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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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞読者の皆様は診療に役立つ知識をどう学んでいくかということに関心をお持ちだと思います.今日は,明日に活かせる技術や知識をどのように学んでいくか,現場での困難な状況でどのように活路を切り開くかなど,最終的には後輩の指導にもつながるようなお話を専門の異なる同世代の先生方から伺い共有したいと思います.

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：日本語   出版者・発行元：(一社)日本臨床薬理学会  

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記述言語：日本語   出版者・発行元：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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CiNii Books

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記述言語：日本語  

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