Poster

Poster 13 Schizophrenia 2 ポスター 13 統合失調症2

P13-1 Review of the findings which suggest Niemann-Pick disease type C in the pati ents with schizophrenia 統合失調症と診断された症例を対象とした成人型ニーマンピック病C型を示唆する所見の検討 Fujii Kumiko（藤井久彌子）¹，前川正充²，衞藤義勝³，尾関祐二^1,4，齋藤尚大⁵，有銘預世布⁶，永島隆秀^7,8，岡安寛明¹，篠崎隆央¹，秋山一文⁶，下田和孝¹ ¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan ²Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan ³Advanced Clinical Research Center, Institute for Neurological Disorders, Kaw asaki, Japan ⁴Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan ⁵Yokohama Camellia Hospital, Yokohama, Japan ⁶Department of Biological Psychiatry and Neuroscience, Dokkyo Medical Univers ity School of Medicine, Tochigi, Japan ⁷Department of Neurology, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan ⁸Department of Neurology, Dokkyo Medical University School of Medicine, Tochi gi, Japan 【Abstract】Once dystonia or dysmetria happens in patient with schizophrenia (SZ), we usually recognize that antipsychotics could induce such involuntary movement.　However, some of the patients have too severe neurological symptoms to be considered as adverse effects. In fact, we have experienced the patient with probable Niemann-Pick disease type C (NPC) in such kinds of patients. In this study, we measured some biological markers of NPC in plasma. Furthermore, mRNA expression level of NPC1 and NPC2, which are pathological genes of NPC, were compared between the patients with SZ and normal controls (NC) in blood. 【Objective】We got the written informed consent by all participants. We selected the patients with neurological symptoms that are included in NPC Suspicion Index and measured possible biological markers. In addition, mRNA expression level of NPC1 and NPC2 was measured in the patients with SZ and NC. 【Methods】We measured some bile acids in their urine with LC/MS/M S and serum oxysterol with Q-TOF LC/MS in five patients with neurological symptoms. In addition, one patient was analyzed whole-genome sequences by the particular company. We measured mRNA expression level of NPC1 and NPC2 with the TaqMan method and performed semi-quantitative assessment with beta-actin. 【Results】No patients have significantly high biological markers as the disease. However, one participant revealed intermediate values and another one patient showed very low values. One patient who analyzed whole-genome sequences has no known mutations in NPC1 or NPC2. mRNA expression level of NPC1 and NPC2 of the patients with SZ are significantly high compared with NC. To realize the implication of the results, further investigation requires including resequencing of NPC1 and NPC2.		P13-2 The comparison of the trazodone monotherapy with the ramelteon and trazodone combination therapy on the management of delirium: A retrospective study せん妄に対するトラゾドン単剤療法とトラゾドン・ラメルテオン併用療法の後方視的検討 Ishii Takao（石井貴男）¹，橋本恵理¹，鵜飼渉¹，森元隆文²，出利葉健太¹，河西千秋¹ ¹The Department of Neuropsychiatry, School of Medicine, Sapporo Medical University, Sapporo, Japan ²Department of Occupational therapy, School of Health Sciences, Sapporo Medical University, Sapporo, Japan Background: Extrapyramidal symptoms caused by antipsychotic medications represent a major concern in the pharmacotherapy of delirium, meaning that therapeutic alternatives using drugs other than antipsychotics are required. The aim of this study was to compare the efficacy and tolerability of trazodone monotherapy with ramelteon and trazodone combination therapy for the management of the symptoms of delirium. Methods: A retrospective study was conducted in a general hospital setting. Delirium Rating Scale-revised-98 (DRS-R-98) scores were measured at the initial examination and at 3-7 days after starting the study drugs. Adverse drug reactions were also assessed. Results: Thirty-three patients were retrospectively enrolled to the trazodone monotherapy group (T group) and 59 patients were enrolled to the ramelteon and trazodone combination therapy group (RT group). Following treatment, the total DRS-R-98 scores were significantly reduced in both groups (22.0 ± 5.5 to 13.5 ± 8.5 in the T group and 23.7 ± 6.1 to 11.4 ± 8.6 in the RT group). However, the proportion of patients meeting the remission criteria was significantly higher in the RT group than in the T group (71% vs. 48%; chi-square=4.681, p=0.030). The most commonly reported side effect was somnolence, in the RT group (3%). Conclusion: Our findings indicate that both trazodone monotherapy and combination therapy of ramelteon and trazodone were effective in managing the symptoms of delirium. However, more patients met the remission criteria following combination therapy with ramelteon and trazodone. In both groups, the incidence of adverse drug reactions was very low.

P13-3 Glutathione Levels in Patients with Schizophrenia - A Systematic Review and Meta-analysis 統合失調症におけるグルタチオン濃度に関する体系的レビューとメタ解析 Tsugawa Sakiko（津川幸子）¹，垂水良介¹，野田賀大¹，三村悠¹，吉田和生^1,2，岩田祐輔³，Elsalhy Muhammad¹，黒宮みの里¹，増田史¹，尾久守侑¹，和田真孝¹，宮崎貴浩¹，三村將¹，中島振一郎^1,3 ¹Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan ²Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada ³Centre for Addiction and Mental Health, Toronto, ON, Canada Background: Accumulating evidence has suggested that oxidative stress and N-methyl-D-aspartate receptor (NMDAR) hypofunction may contribute to the pathophysiology of schizophrenia (SZ). Glutathione (GSH) is the most abundant antioxidant which plays an important role in preventing oxidative stress. Further, GSH deficits could be one causal factor implicated in NMDAR hypofunction. Previous studies have noted abnormal GSH levels in patients with SZ, however, their findings were inconsistent. Thus, we conducted a meta-analysis to investigate whether any differences in GSH levels may exist between patients with SZ and healthy controls (HCs). Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies, in which GSH, GSH disulfide (GSSG), or GSH + GSSG (total GSH) levels were measured with any techniques in both patients with SZ and HCs, were included. The following variables were extracted: the levels of GSH, GSSG and total GSH, diagnoses, age, sex, antipsychotic treatment status, duration of illness, symptom severity, and methods of GSH measurement. Standardized mean differences were calculated to determine the differences in the GSH levels between the groups, with a random-effects model. Results: Out of 1273 initial records, 40 articles were identified for the further analyses. GSH, GSSG, and total GSH levels were reported in 33 studies, 9 studies, and 17 studies, respectively. GSH and total GSH levels were significantly lower in patients with SZ than in HCs, whereas GSSG did not exhibit any significant differences between the groups. Conclusion: This meta-analysis generated the finding that patients with SZ may have decreased level of GSH and total GSH with a large effect size.		P13-4 Classification of treatment resistant to antipsychotics in schizophrenia using resting-state functional magnetic resonance imaging 安静時脳機能結合データを用いた治療抵抗性統合失調症と寛解統合失調症の判別 Ochi Ryo（越智涼）¹，中島振一郎²，垂水良介^2,3，本多栞⁴，松下佳鈴¹，加藤彩¹，津川幸子²，野田賀大²，三村將²，藤井進也¹ ¹Faculty of Environment and Information Studies, Keio University, Kanagawa, Japan ²Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan ³Seikei-kai Komagino Hospital, Tokyo, Japan ⁴Graduate School of Media and Governance, Keio University, Kanagawa, Japan Introduction: About 30 percent of patients with schizophrenia show treatment resistance to antipsychotics. The neural basis related to treatment resistance has not fully been clarified yet. Thus, identifying the neural basis for treatment resistance is crucial not only for elucidation of this pathophysiology but also for development of novel therapeutic methods in this devastating disorder. Here, we aimed to develop a method to distinguish patients with treatment-resistant schizophrenia (TRS) from all patients with schizophrenia by using the functional connectivity (FC) computed from the resting-state functional magnetic resonance imaging (rs-fMRI).Methods: rs-fMRI data were recorded from 13 patients with TRS and 21 patients with non-TRS. The TRS and non-TRS were defined based on the TRRIP guideline. The Probabilistic Independent Component Analysis (PICA) was performed to extract the FC from the all patients by using the FSL software. We used the random-forest pattern recognition method to classify TRS from non-TRS. This research was in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Results: We identified the patients with TRS with the accuracy of 66.7% and the Area Under the Curve of 0.786. Conclusion: Our findings suggest that rs-fMRI data may have a potential to distinguish patients with TRS and non-TRS. Furthermore, the FCs of DMN and cerebellum are suggested to be useful classifiers as they may represent the neurobiological differences between TRS and non-TRS patients.

P13-5 Impairment of Beat Production Ability Relates to Language Disturbance in Patients with Schizophrenia 統合失調症患者の言語的認知機能と音楽リズム生成能力の関係性 Matsushita Karin（松下佳鈴）¹，野田賀大²，垂水良介^2,4，本多栞³，越智涼¹，津川幸子²，加藤彩¹，中島進一郎²，三村將²，藤井進也¹ ¹Faculty of Environment and Information Studies, Keio University ²Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan ³Graduate School of Media and Governance, Keio University, Kanagawa, Japan ⁴Seikei-kai Komagino Hospital, Tokyo, Japan Background: It has been noted that patients with schizophrenia have language impairments including deterioration of verbal communication. Recent studies have shown that the ability to synchronize movements to musical beat relates to neural encoding of speech and language metrics. Thus, we hypothesized that the beat processing ability would be associated with the neural basis supporting the linguistic ability in this disorder. Methods: Forty-six patients with schizophrenia participated in this study. To assess the beat processing ability, we employed the Harvard Beat Assessment Test (H-BAT), a test to measure individuals’ abilities of beat perception and production. Further, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Japanese Adult Reading Test (JART) were used to assess cognitive function and premorbid intelligence levels. Correlation coefficients were calculated among scores of the H-BAT, RBANS, and JART, controlling for the Simpson-Angus Scale (SAS) score and chlorpromazine equivalent daily dose. This research was in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Results: We found significant correlations between the H-BAT and RBANS (r = -0.38, p = 0.012) as well as JART scores (r = 0.36, p = 0.019). Notably, a robust relationship was observed between the beat production score in the H-BAT and RBANS language score (r = -0.45, p = 0.003). Conclusion: Our results indicate that decreased ability of beat production may relate to the deteriorated linguistic ability in patients with schizophrenia. There may be a shared neural mechanism between beat production and language disturbances underlying the pathophysiology in this disorder.		P13-6 The relationship between volumetric alteration and glutamatergic neurometabolite levels in precommissural caudate in patients with chronic schizophrenia 慢性期統合失調症における交連前尾状核の体積およびグルタミン酸濃度の関係 Tsugawa Sakiko（津川幸子）¹，垂水良介¹，野田賀大¹，和田真孝¹，本多栞²，藤井進也³，Chakravarty Mallar^4,5，Plitman Eric⁶，Graff-Guerrero Ariel⁶，宮崎貴浩¹，内田裕之¹，三村將¹，中島振一郎^1,6 ¹Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan ²Graduate School of Media and Governance, Keio University ³Faculty of Environment and Information Studies, Keio University ⁴Douglas Mental Health University Institute, Montreal, Canada ⁵Department of Biomedical Engineering at McGill University, Montreal, Canada ⁶Centre for Addiction and Mental Health, Toronto, ON, Canada Background: Dopaminergic and glutamatergic dysfunctions in the precommissural caudate (PC) is implicated in the pathophysiology of schizophrenia. One previous study found decreased PC volumes and increased glutamate levels in the PC in patients with first-episode psychosis. However, such a relationship has not been elucidated in patients with chronic schizophrenia, which was investigated in this study. Methods: Forty-eight patients with chronic schizophrenia were examined, which consisted of 22 patients with treatment-resistant schizophrenia (TRS) and 26 non-TRS. TRS or non-TRS was defined based on the TRRIP guideline. Glutamatergic neurometabolite levels in the right PC were assessed with 3T 1H-MRS. The PC volume was calculated, using the MAGeT-Brain algorithm. The total brain volume (TBV) was computed by the SPM software. Multiple regression analyses were performed to examine relationships between glutamatergic neurometabolite levels and the right PC volumes, controlling for the TBV. Results: In the right PC, glutamate levels were associated with its volume (standardized β=0.33, p=0.011). Furthermore, this positive association was observed in TRS patients (standardized β=3.25, p=0.004), but not in non-TRS patients. Conclusion: Contrary to the reported negative relationship between glutamate levels and the volume in the right PC in patients with first-episode psychosis, patients with chronic TRS showed a positive relationship between glutamate levels and the volume in the right PC, which represents a possibility that effects of the glutamatergic system to the striatal neuroanatomy depend on the illness stage and treatment response. Further research is needed to characterize the glutamatergic excitotoxicity throughout the illness course.

P13-7 Micro-structural volumes of the limbic system in patients with treatment-resistant schizophrenia 治療統合失調症における大脳辺縁系領域の脳体積 Tsugawa Sakiko（津川幸子）¹，垂水良介¹，野田賀大¹，和田真孝¹，本多栞²，藤井進也³，Chakravarty Mallar^4,5，Plitman Eric⁶，Graff-Guerrero Ariel⁶，宮崎貴浩¹，内田裕之¹，三村將¹，中島振一郎^1,6 ¹Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan ²Graduate School of Media and Governance, Keio University, Tokyo, Japan ³Faculty of Environment and Information Studies, Keio University, Tokyo, Japan ⁴Douglas Mental Health University Institute, Montreal, Canada ⁵Department of Biomedical Engineering at McGill University, Montreal, Canada ⁶Centre for Addiction and Mental Health, Toronto, ON, Canada Background: One third of patients with schizophrenia do not show response to antipsychotic treatment. Previous studies showed decreased volumes of the limbic system in patients with schizophrenia. However, no study has examined the relationships between treatment resistance and volumetric differences in the limbic system among patients with schizophrenia. Thus, we aimed to investigate volumetric differences of the limbic micro-structures between patients with treatment-resistant schizophrenia (TRS) and non-TRS. Methods: Twenty-two patients with TRS and 26 patents with non-TRS were enrolled in this study. TRS or non-TRS was defined based on the TRRIP guideline. A T1 image was acquired with a 3.0T MRI scanner. MAGeT-Brain segmentation algorithm was used to segment each limbic region (hippocampus, mammillary body, and amygdala) into subdivisions and acquire these volumes. The volumes of the limbic subdivisions were compared between the groups using analyses of covariance controlling for total brain volume (TBV), duration of illness (DOI), or chlorpromazine (CPZ) equivalents. This research was in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Results: Patients with TRS had a significantly larger volume of the left mammillary body compared to patients with non-TRS. This significance remained after controlling TBV or DOI, while it did not survive when controlling for the CPZ dose. In contrast, there were no significant group differences in the hippocampus or amygdala volume. Conclusion: The left mammillary body volume may be associated with the neural basis of the antipsychotic treatment resistance in patients with schizophrenia. On the other hand, impact of antipsychotic dosage on the volume also warrants further investigations.		P13-8 Glutamate levels in patients with treatment-resistant schizophrenia: a cross-sectional proton magnetic resonance spectroscopy study 治療抵抗性統合失調症における脳内グルタミン酸濃度：1H-MRSを用いた横断研究 Tarumi Ryosuke（垂水良介）¹，野田賀大¹，津川幸子¹，ピットマンエリック²，本多栞⁴，三村悠¹，藤井進也³，内田裕之¹，三村將¹，グラフゲレーロアリエル²，中島振一郎^1,2 ¹Department of Neuropsychiatry, Keio University School of Medicine ²Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto ³Faculty of Environment and Information Studies, Keio Universit ⁴Graduate School of Media and Governance, Keio University Background: Approximately 30% of patients with schizophrenia do not respond to antipsychotics, suggesting that schizophrenia may be classified as treatment-resistant schizophrenia (TRS) and nonTRS. Evidence suggests that the glutamate hypothesis accounts for their different pathophysiology. According to previous studies employing proton magnetic resonance spectroscopy (MRS), striatal glutamate levels are higher in patients with schizophrenia than healthy controls. However, no study has examined the relationship between antipsychotic treatment resistance and striatal glutamate levels in TRS.Method: This study enrolled patients with TRS and patients with nonTRS. Optimal antipsychotic treatment was defined as having taken antipsychotics at chlorpromazine equivalent daily dose of >400 mg for a duration of >6 consecutive weeks. TRS was defined by a Clinical Global Impression Severity (CGI) score of >4 and a score of >4 on 2 positive symptom items in the Positive and Negative Syndrome Scale (PANSS) after the optimal treatment with >2 different antipsychotics. NonTRS was defined as a CGI score of <3, scores of <3 on all positive symptom items of PANSS, and no symptomatic relapse for the previous 3 months. Glutamatergic neurometabolite levels were assessed in the caudate and anterior cingulate cortex (ACC). demographic characteristics, spectrum quality indices, and glutamate levels were compared between the groups. Result: We included 25 TRS patients and 25 nonTRS patients. No significant differences were found in the clinico-demographic characteristics, spectrum quality indices or glutamatergic neurometabolite levels in the caudate and ACC between the groups. Discussion: The results suggest that the striatal glutamate levels may not differ between TRS and non-TRS patients.

P13-9 The investigation of ALDH4A1 expression in the postmortem brains from patients with schizophrenia-genetic neuropathology 統合失調症死後脳におけるALDH4A1についてのジェネティックニューロパソロジー Nagaoka Atsuko（長岡敦子）¹，國井泰人^1,2，日野瑞城¹，泉竜太¹，松本純弥¹，丹羽真一²，竹島明³，那波宏之⁴，柿田明美³，矢部博興¹ ¹Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan ²Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan ³Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan ⁴Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan The molecular mechanisms underlying schizophrenia remain largely unclear. We have investigated the functional correlations between schizophrenia risk alleles and molecular expression profiles of postmortem brains from patients with schizophrenia as intermediate phenotypes. We previously identified multiple proteins significantly altered in postmortem prefrontal cortex with schizophrenia using focused quantitative proteomics. Among these proteins, aldehyde dehydrogenase 4 family member A1(ALDH4A1) was especially elevated in schizophrenia. ALDH4 is enzyme that dehydrogenize the metabolites of proline into glutamate. There were only a few reports focused on association between ALDH4A1 and schizophrenia. A previous microarray study showed the increased expression of ALDH4A1 gene in peripheral blood cells of schizophrenia. Also, a postmortem study using nano LC-MS/MS indicated increased ALDH4A1 expression in corpus callosum of schizophrenia. Therefore, in this study, we investigated the expression levels of ALDH4A1 protein in prefrontal cortex and superior temporal gyrus, which have been extensively examined in schizophrenia in 64 postmortem samples from subjects with schizophrenia, bipolar disorder, and control subjects using ELISA which enables us to determine expression levels more precisely. Moreover, we explored the associations between these expressions and genetic variants of ALDH4A1 gene in a much larger set of postmortem samples. In this conference, we show the results of this study with some discussion. This study was approved by the Ethics Committee of Fukushima Medical University and complied with the Declaration of Helsinki. All procedures were carried out with the informed written consent of the next of kin, and conducted anonymously and kept confidential.		P13-10 The relationship between electroencephalography delta activity and cognitive function among in patients with chronic schizophrenia 統合失調症における脳波デルタ波と高次脳機能の関連性 Wada Masataka（和田真孝）¹，垂水良介¹，宮崎貴浩¹，津川幸子¹，本多栞²，三村悠¹，藤井進也³，中島振一郎¹，三村將¹，野田賀大¹ ¹Department of Neuropsychiatry, Keio University School of Medicine ²Graduate School of Media and Governance, Keio University ³Faculty of Environment and Information Studies, Keio University Background: In patients with schizophrenia, electroencephalography (EEG) delta activity is increased compared to healthy controls. However, the role of EEG delta activity has not been fully elucidated in terms of cognitive function in patients with schizophrenia. Thus, we aimed to investigate the relationship between delta activity and cognitive function in this population. Methods: Forty-eight patients with chronic schizophrenia underwent resting-state EEG recording. Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The EEG data were pre-processed and 2 second epochs were extracted. The epoched data were band-pass filtered at delta, theta, alpha, beta, and gamma frequencies and Hilbert-transformed to obtain the amplitude values for delta frequency band. The relationship between neuropsychological examination and root-mean-squared amplitudes for delta frequency bin was tested with the linear regression.This research was in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Results: The delta amplitude was negatively associated with the RBANS total score (p=0.001). In terms of cognitive domains, the delta amplitude was also negatively related to the Immediate memory score, (p=0.006), and Visuospatial/constructional score (p=0.007) Conclusion: This research revealed that increased EEG delta power was associated with a greater cognitive impairment in chronic patients with schizophrenia, suggesting that delta activity could contribute to the pathophysiology of the cognitive impairment of schizophrenia.