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

DOI： 10.1007/s00213-023-06407-6

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Other Link： https://link.springer.com/article/10.1007/s00213-023-06407-6/fulltext.html

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1405207008

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

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

The intestinal immune system interacts with commensal microbiota to maintain gut homeostasis. Furthermore, stress alters the microbiome composition, leading to impaired brain function; yet how the intestinal immune system mediates these effects remains elusive. Here we report that colonic γδ T cells modulate behavioral vulnerability to chronic social stress via dectin-1 signaling. We show that reduction in specific Lactobacillus species, which are involved in T cell differentiation to protect the host immune system, contributes to stress-induced social-avoidance behavior, consistent with our observations in patients with depression. Stress-susceptible behaviors derive from increased differentiation in colonic interleukin (IL)-17-producing γδ T cells (γδ17 T cells) and their meningeal accumulation. These stress-susceptible cellular and behavioral phenotypes are causally mediated by dectin-1, an innate immune receptor expressed in γδ T cells. Our results highlight the previously unrecognized role of intestinal γδ17 T cells in the modulation of psychological stress responses and the importance of dectin-1 as a potential therapeutic target for the treatment of stress-induced behaviors.

DOI： 10.1038/s41590-023-01447-8

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

Sensory impairments are common features of autism spectrum disorder (ASD) and are associated with its social impairments. However, there is no established treatment for these impairments in adults with ASD. The Safe & Sound Protocol (SSP) is a listening program designed to improve social communication skills by reducing auditory hypersensitivity. We investigated the effectiveness of the SSP for adults with ASD. We administered the SSP to six participants with ASD aged 21-44 years old, and the effects were assessed using the Social Responsiveness Scale, Second Edition (SRS-2). Secondary outcomes were assessed using the Center for Epidemiological Studies Depression Scale (CES-D), State-Trait Anxiety Inventory (STAI), WHO Quality of Life 26 (WHOQOL-BREF), and Adolescent/Adult Sensory Profile (A/ASP). In this study, only the Social Awareness scale of the SRS-2 Family-Report showed a significant improvement after the intervention. In addition, it was significantly correlated with physical health of WHOQOL-BREF (r = -0.577, p = 0.012), state and trait anxiety of STAI (r = 0.576, p = 0.012; r = 0.708, p = 0.00009, respectively), and CES-D (r = 0.465, p = 0.05). In conclusion, the SSP has a partial effect on social impairments in adults with ASD, specifically on the Social Awareness subscale of the SRS-2.

DOI： 10.3390/ijerph20064862

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/jcp.0000000000001646

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

DOI： 10.1016/j.schres.2022.08.024

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

Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences. Our lab has developed a brain-penetrant prodrug of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), JHU083, that potently inhibits brain GLS activity in mice following oral administration. To assess the therapeutic potential of JHU083, we infected mice with EcoHIV and characterized their neurobehavioral phenotypes. EcoHIV-infected mice exhibited decreased social interaction, suppressed sucrose preference, disrupted sleep during the early rest period, and increased sleep fragmentation, similar to what has been reported in PLH but not yet observed in murine models. At doses shown to inhibit microglial GLS, JHU083 treatment ameliorated all of the abnormal neurobehavioral phenotypes. To explore potential mechanisms underlying this effect, hippocampal microglia were isolated for RNA sequencing. The dysregulated genes and pathways in EcoHIV-infected hippocampal microglia pointed to disruptions in immune functions of these cells, which were partially restored by JHU083 treatment. These findings suggest that upregulation of microglial GLS may affect immune functions of these cells. Thus, brain-penetrable GLS inhibitors like JHU083 could act as a potential therapeutic modality for both glutamate excitotoxicity and aberrant immune activation in microglia in chronic HIV infection.

DOI： 10.1016/j.bbih.2022.100478

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

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Language：English  

DOI： 10.1016/j.ajp.2022.103124

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

DOI： 10.1016/j.drugalcdep.2022.109365

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

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

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

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

DOI： 10.1007/s00213-022-06099-4

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

DOI： 10.1097/JCP.0000000000001527

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

DOI： 10.1097/WNF.0000000000000488

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

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

DOI： 10.1007/s00213-021-06036-x

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

Epidemiological evidence suggests that adverse environmental factors in the nasal cavity may increase the risk for neuropsychiatric diseases. For instance, air pollution and nasal viral infection have been underscored as risk factors for Parkinson's disease, schizophrenia, and mood disorders. These adverse factors can elicit local inflammation in the nasal cavity, which may in turn influence higher brain function. Nevertheless, evidence that directly supports their causal link is missing. To fill this knowledge gap, we used an inducible mouse model for olfactory inflammation and showed the evidence that this local pathological factor can elicit behavioral abnormalities.

DOI： 10.1016/j.neures.2021.04.009

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

Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression. Although the pathological implication of many peripheral factors such as pro-inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here, we report that chronic social defeat stress (CSDS)-induced social avoidance phenotype, assessed by a previously untested three-chamber social approach test, can be distinguished by multiple pro-inflammatory cytokines and EV-associated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS-susceptible mice from the CSDS-resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV-associated miRNAs. We also demonstrated that EVs enriched from the CSDS-susceptible mouse sera upregulated the production of pro-inflammatory cytokines in the LPS-stimulated microglia-like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro-inflammatory mechanisms underlying stress-induced neurobehavioral outcomes.

DOI： 10.1002/2211-5463.13204

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

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

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

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

DOI： 10.1093/ijnp/pyaa097

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/wnf.0000000000000443

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

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

DOI： 10.1111/acps.13264

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

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

DOI： 10.1097/YCT.0000000000000686

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

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

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

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

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

DOI： 10.1007/s00213-019-05352-7

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

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

電気けいれん療法(ECT)は、統合失調症患者においても緊張病状態や薬物治療抵抗例に対して考慮される重要な治療法である。ECTにおいて本邦で頻用される麻酔薬のpropofolは、強い抗けいれん作用を有するため、高い発作閾値が問題になるケースでは麻酔に工夫を要する。発作閾値上昇効果がないとされるketamineへの切り替え、または併用によるpropofolの減量は有効な方法の1つで、うつ病患者では抗うつ効果の増強も期待したketamineによるECTの報告が多い。一方でketamineは、その作用機序から統合失調症の精神症状を悪化させる懸念もある。今回、高い発作閾値が問題化したが、ketamineの併用によりpropofolを減量したECTで有効な発作が得られ、精神病症状の悪化を認めることなく有効かつ安全に治療し得た統合失調症の2例を経験したため報告する。(著者抄録)

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Language：Japanese   Publisher：(一社)日本心身医学会  

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

電気けいれん療法(ECT)は、統合失調症患者においても緊張病状態や薬物治療抵抗例に対して考慮される重要な治療法である。ECTにおいて本邦で頻用される麻酔薬のpropofolは、強い抗けいれん作用を有するため、高い発作閾値が問題になるケースでは麻酔に工夫を要する。発作閾値上昇効果がないとされるketamineへの切り替え、または併用によるpropofolの減量は有効な方法の1つで、うつ病患者では抗うつ効果の増強も期待したketamineによるECTの報告が多い。一方でketamineは、その作用機序から統合失調症の精神症状を悪化させる懸念もある。今回、高い発作閾値が問題化したが、ketamineの併用によりpropofolを減量したECTで有効な発作が得られ、精神病症状の悪化を認めることなく有効かつ安全に治療し得た統合失調症の2例を経験したため報告する。(著者抄録)

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

DOI： 10.1016/j.euroneuro.2019.07.137

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

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently-discovered autoimmune disorder in which antibodies target NMDAR in the brain. The number of reported cases of anti-NMDAR encephalitis has increased rapidly. Anti-NMDAR encephalitis can be mistakenly diagnosed as psychiatric disorders because many patients present with prominent psychiatric symptoms and visit psychiatric institutions first. Thus, psychiatrists should cultivate a better understanding of anti-NMDAR encephalitis. In this review, we present the mechanisms, epidemiology, symptoms and clinical course, diagnostic tests, treatment and outcomes of patients with anti-NMDAR encephalitis. Furthermore, we discuss the diversity of clinical spectra of anti-NMDAR encephalitis, and demonstrate a differential diagnosis of psychiatric disease from the perspective of psychiatry.

DOI： 10.18926/AMO/56860

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

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RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear. OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES). METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia. RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027). CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.

DOI： 10.1007/s00213-018-5101-7

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

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

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

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

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

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

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

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

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

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

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

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

DOI： 10.1038/s41398-017-0061-y

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Language：English   Publisher：ELSEVIER SCIENCE BV  

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

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

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

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

DOI： 10.3390/ijms18010067

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

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Language：English   Publisher：WILEY-BLACKWELL  

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

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Other Link： http://search.jamas.or.jp/link/ui/2016381558

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/JCP.0000000000000439

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

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

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DOI： 10.1002/hup.2435

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

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

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

DOI： 10.1002/hup.2435

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

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier  

DOI： 10.1016/j.psychres.2014.02.006

CiNii Article

CiNii Books

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

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

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

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

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

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

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Language：English  

DOI： 10.1176/appi.neuropsych.12070166

PubMed

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

DOI： 10.1111/j.1601-5215.2012.00663.x

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Language：English   Publisher：ELSEVIER SCIENCE BV  

Web of Science

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Language：English   Publisher：OXFORD UNIV PRESS  

Web of Science

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

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Language：Japanese   Publisher：医歯薬出版(株)  

自己免疫性脳炎のなかで最も頻度が高い抗N-methyl-D-aspartic acid受容体(NMDAR)抗体脳炎は、精神症状が初発症状、早期の免疫療法が奏効する、抗精神病薬による副作用を生じやすいなどの特徴を持ち、精神疾患との鑑別が非常に重要な疾患である。神経細胞膜自己抗体によって、精神症状のみを呈する(神経症状をまったく、または微細にしか認めない)患者群は、典型的な自己免疫性脳炎とは区別して自己免疫性精神病(autoimmune psychosis)とよばれる。抗NMDAR抗体脳炎の疫学、診断と臨床症状、検査法と検査所見、発症機序、治療について概説する。加えて、抗NMDAR抗体を中心とした神経細胞膜自己抗体が精神疾患に与える影響についての知見をまとめ、本分野の将来の展望を考察する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00060&link_issn=&doc_id=20210614020004&doc_link_id=%2Faa7ayuma%2F2021%2F027711%2F005%2F0964b0969%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2021%2F027711%2F005%2F0964b0969%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Language：Japanese   Publisher：(株)羊土社  

近年、精神疾患の病態生理メカニズムとして、免疫システムと炎症の関与が注目されている。しかしながら、さまざまな遺伝リスク因子や環境要因、あるいはその相互作用が、いかに神経免疫系の障害や脳内炎症を引き起こし、精神疾患発症に関与するのかは不明である。本稿では、統合失調症と自閉症スペクトラム障害に焦点をあて、脳発達の観点から脳炎症に関連する臨床所見とモデルマウスを用いた最新の知見を紹介する。さらに炎症とそれにかかわる免疫細胞が神経発達に果たす役割を明らかにすることで、新たな病態生理メカニズム、治療薬が開発される可能性について展望する。(著者抄録)

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

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

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

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

統合失調症患者の抑うつ症状は発現頻度の高い精神症状のひとつであり、自殺傾向とも関連すると言われている。日常臨床において、陽性症状のみならず、抑うつ症状を適切に評価し治療を行うことが、統合失調症患者の長期予後の改善につながると考える。本稿では、岡山大学病院における維持期の統合失調症圏患者における後ろ向き研究を紹介し、エビデンスを交えながら、統合失調症の抑うつ症状や自殺企図に関連する要因や薬物治療について検討した。(著者抄録)

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

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Language：Japanese   Publisher：(株)星和書店  

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

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Language：Japanese   Publisher：(株)星和書店  

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

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

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

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

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