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Alzheimer's disease (AD) is a progressive disease, and the number of AD patients is increasing every year as the population ages. One of the pathophysiological mechanisms of AD is thought to be the effect of metabolomic abnormalities. There have been several studies of metabolomic abnormalities of AD, and new biomarkers are being investigated. Metabolomic studies have been attracting attention, and the aim of this study was to identify metabolomic biomarkers associated with AD and mild cognitive impairment (MCI). Of the 927 participants in the Nakayama Study conducted in Iyo City, Ehime Prefecture, 106 were selected for this study as Control (n = 40), MCI (n = 26), and AD (n = 40) groups, matched by age and sex. Metabolomic comparisons were made across the three groups. Then, correlations between metabolites and clinical symptoms were examined. The blood mRNA levels of the ornithine metabolic enzymes were also measured. Of the plasma metabolites, significant differences were found in ornithine, uracil, and lysine. Ornithine was significantly decreased in the AD group compared to the Control and MCI groups (Control vs. AD: 97.2 vs. 77.4; P  = 0.01, MCI vs. AD: 92.5 vs. 77.4; P  = 0.02). Uracil and lysine were also significantly decreased in the AD group compared to the Control group (uracil, Control vs. AD: 272 vs. 235; P  = 0.04, lysine, Control vs. AD: 208 vs. 176; P  = 0.03). In the total sample, the MMSE score was significantly correlated with lysine, ornithine, thymine, and uracil. The Barthel index score was significantly correlated with lysine. The instrumental activities of daily living (IADL) score were significantly correlated with lysine, betaine, creatine, and thymine. In the ornithine metabolism pathway, the spermine synthase mRNA level was significantly decreased in AD. Ornithine was decreased, and mRNA expressions related to its metabolism were changed in the AD group compared to the Control and MCI groups, suggesting an association between abnormal ornithine metabolism and AD. Increased betaine and decreased methionine may also have the potential to serve as markers of higher IADL in elderly persons. Plasma metabolites may be useful for predicting the progression of AD.

There is growing evidence that glutamatergic signaling may be involved in major depressive disorder (MDD). In regard to peripheral blood glutamate changes in MDD, inconsistent findings have been reported. The purpose of the present study was to evaluate whether blood glutamate levels differed between MDD patients and control participants. We conducted a systematic review and meta-analysis of 12 association studies between blood glutamate levels and MDD in a total of 529 MDD patients and 590 controls. Subsequently, we conducted subgroup analyses and a meta-regression analysis to examine the sources of potential heterogeneity. A random effects model showed that blood glutamate levels were significantly higher in MDD patients than in controls (standardized mean difference=0.54, 95% CI=0.27-0.82, =8.5×10 ) with high heterogeneity ( =75.0%, <0.05). Subgroup analyses showed elevated glutamate levels in MDD patients compared with controls in plasma, but not serum studies, and in studies using high-performance liquid chromatography but not with mass spectrometry for glutamate assay. A meta-regression analysis showed no effects of age, gender, medication use, sample size, and published year on blood glutamate levels. Our findings suggest that altered glutamate levels may be implicated in MDD, which provides further evidence of glutamatergic dysfunction in MDD.

There is high mortality among patients with bipolar disorder (BD). Studies have reported accelerated biological aging in patients with BD. Recently, Horvath and Hannum et al. independently developed DNA methylation (DNAm) profiles as “epigenetic clocks,” which are the most accurate biological age estimate. This led to the development of two accomplished measures of epigenetic age acceleration (EAA) using blood samples, namely, intrinsic and extrinsic EAA (IEAA and EEAA, respectively). IEAA, which is based on Horvath’s clock, is independent of blood cell counts and indicates cell-intrinsic aging. On the other hand, EEAA, which is based on Hannum’s clock, is associated with age-dependent changes in blood cell counts and indicates immune system aging. Further, Lu et al. developed the “GrimAge” clock, which can strongly predict the mortality risk, and DNAm-based telomere length (DNAmTL). We used a DNAm dataset from whole blood samples obtained from 30 patients with BD and 30 healthy controls. We investigated Horvath EAA, IEAA, Hannum EAA, EEAA, Grim EAA, DNAmTL, and DNAm-based blood cell composition. Compared with controls, there was a decrease in Horvath EAA and IEAA in patients with BD. Further, there was a significant decrease in Horvath EAA and IEAA in patients with BD taking medication combinations of mood stabilizers (including lithium carbonate, sodium valproate, and carbamazepine) than in those taking no medication/monotherapy. This study provides novel evidence indicating decelerated epigenetic aging associated with mood stabilizers in patients with BD.

English translation team: (affiliation as of May 2021) Ryota Hashimoto, Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry Junichi Iga, Department of Neuropsychiatry, Ehime University Graduate School of Medicine Ken Inada, Department of Psychiatry, Tokyo Women’s Medical University Taro Kishi, Department of Psychiatry, Fujita Health University School of Medicine Hiroshi Kimura, Department of Psychiatry, International University of Health and Welfare/Gakuji-kai Kimura Hospital Yuki Matsuda, Department of Psychiatry, Jikei University School of Medicine Nobumi Miyake, Department of Neuropsychiatry, St. Marianna University School of Medicine Kiyotaka Nemoto, Department of Psychiatry, Faculty of Medicine, University of Tsukuba Shusuke Numata, Department of Psychiatry, Graduate School of Biomedical Science, Tokushima University Shinichiro Ochi, Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine Hideki Sato, National Center Hospital, National Center of Neurology and Psychiatry Seiichiro Tarutani, Department of Psychiatry, Shin-Abuyama Hospital, Osaka Institute of Clinical Psychiatry Hiroyuki Uchida, Department of Neuropsychiatry, Keio University School of Medicine English translation team: (COI as of 2018-2020) Ryota Hashimoto: Received research grants from Otsuka Pharmaceutical Co., Ltd., Japan Tobacco Inc., and Takeda Pharmaceutical Company Ltd.; rewards for lectures from Takeda Pharmaceutical Company Ltd., Lundbeck Japan K.K., Dainippon Sumitomo Pharma Co., Ltd., and Mochida Pharmaceutical.Co., Ltd.; manuscript fees for writing from Dainippon Sumitomo Pharma Co., Ltd. Junchi Iga: Received rewards for lectures from Otsuka Pharmaceutical Co. Ltd., Meiji Seika Pharma Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Kyowa Pharmaceutical Industry Co. Ltd., Shionogi & Co. Ltd., Mochida Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mylan Inc., Sawai Pharmaceutical Co. Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., Sanofi K.K., Viatris Inc., and Yoshitomiyakuhin Co. Ken Inada: Received research grants, rewards for lectures, manuscript fees for writing, and donations from Astellas Pharma Inc., Eisai Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Pfizer Inc., Meiji Seika Pharma Co. Ltd., Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., and Yoshitomiyakuhin Co. Taro Kishi: Received speaker’s honoraria from Sumitomo Dainippon, Otsuka, Eisai, Daiichi Sankyo, Janssen, Takeda, Kyowa, Kissei, Meiji, Pfizer, Mochida, Eli Lilly, MSD, Janssen, and Tanabe-Mitsubishi (Yoshitomi); as well as research grants from Eisai, the Japanese Ministry of Health, Labour and Welfare, Grant-in-Aid for Scientific Research, and Fujita Health University School of Medicine. Before reading this guideline (For experts, patients, families, and supporters) This guideline was written for specialists in the treatment of schizophrenia, but patients, as well as their families and supporters, may also use this guideline. [...]a very simple explanation will first be given on the aims of this guideline. [...]one may have the impression from reading the individual texts that it is recommended to treat schizophrenia with pharmacological therapy alone, or that pharmacological therapy has a larger effect than other therapies. [...]the available drugs and their administration and the medical system can vary between Japan and other countries. [...]a clinical guideline that is aligned with the medical circumstances in Japan was needed.

Background Although antidepressant monotherapy is recommended for patients with major depressive disorder (MDD), they often do not respond to it, necessitating alternatives such as electroconvulsive therapy (ECT). However, maintenance pharmacotherapy after ECT has remained unestablished. This study, conducted at 240 facilities throughout Japan, aimed to explore maintenance pharmacotherapy after ECT for 3,749 inpatients with MDD. Methods The patients were divided into two groups, one that underwent ECT (ECT group, N  = 521) and another that did not (non-ECT group, N  = 3,273), for the comparison of clinical characteristics and prescription details at discharge. The primary outcome of this study was the prescription rate of antidepressant monotherapy at discharge, while the secondary outcomes included prescription rates of specific combination regimens, such as antidepressant plus lithium. Results We identified 198 prescription patterns involving antidepressants in the ECT group. Analysis by drug category revealed distinctive patterns: there was no statistically significant difference in prescription rates for antidepressant monotherapy between the ECT and non-ECT groups ( N  = 118, 22.6% vs. N  = 932, 28.4%). In contrast, the prescription rate for the combination of antidepressant and antipsychotic medications was significantly higher in the ECT group ( N  = 188, 36.0% vs. N  = 941, 28.7%). The combination of antidepressant and mood stabilizer was also more frequent in the ECT group ( N  = 35, 6.7% vs. N  = 130, 3.9%), although this difference did not reach statistical significance after Bonferroni correction. At the drug level, additional distinctive patterns emerged: among antidepressant monotherapies, nortriptyline use was significantly more common in the ECT group ( N  = 9, 1.7% vs. N  = 11, 0.3%). For mood stabilizers, restricting the analysis to lithium revealed a markedly higher rate in the ECT group ( N  = 30, 5.7% vs. N  = 35, 1.0%). Conclusions These findings highlight the complexity of treatment decisions managing of MDD after ECT and emphasize the need for structured prospective research on the effectiveness of specific maintenance pharmacotherapies after ECT.

Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS) is a comprehensive, quantitative, and high throughput tool used to analyze metabolite profiles. In the present study, we used CE-TOFMS to profile metabolites found in the blood plasma of 33 medication-free patients with major depressive disorder (MDD) and 33 non-psychiatric control subjects. We then investigated changes which occurred in the metabolite levels during an 8-week treatment period. The medication-free MDD patients and control subjects showed significant differences in their mean levels of 33 metabolites, including kynurenine (KYN), glutamate (Glu), glutamine (Gln), methionine sulfoxide, and methionine (Met). In particular, the ratios of KYN to tryptophan (TRP), Gln to Glu, and Met to methionine sulfoxide were all significantly different between the two groups. Among the 33 metabolites with altered levels in MDD patients, the levels of KYN and Gln, as well as the ratio of Gln to Glu, were significantly normalized after treatment. Our findings suggest that imbalances in specific metabolite levels may be involved in the pathogenesis of MDD, and provide insight into the mechanisms by which antidepressant agents work in MDD patients.

Many observational studies have shown elevated blood CRP levels in schizophrenia compared with controls and one population-based prospective study has reported that elevated plasma CRP levels were associated with late- and very-late-onset schizophrenia. Furthermore, several clinical studies have reported the efficacy of anti-inflammatory drugs on the symptoms in patients with schizophrenia. However, whether elevated CRP levels are causally related to schizophrenia is not still established because of confounding factors and reverse causality. In the present study, we demonstrated that serum CRP levels were significantly higher in patients with schizophrenia than in the controls by conducting a case-control study and a meta-analysis of case-control studies between schizophrenia and serum CRP levels. Furthermore, we provided evidence for a causal association between elevated CRP levels and increased schizophrenia risk by conducting a Mendelian randomization analysis. Our findings suggest that elevated CRP itself may be a causal risk factor for schizophrenia.

Cryopreservation of whole blood is useful for DNA collection, and clinical and basic research. Blood samples in ethylenediaminetetraacetic acid disodium salt (EDTA) tubes stored at − 80 °C are suitable for DNA extraction, but not for high-quality RNA extraction. Herein, a new methodology for high-quality RNA extraction from human blood samples is described. Quickly thawing frozen whole blood on aluminum blocks at room temperature could minimize RNA degradation, and improve RNA yield and quality compared with thawing the samples in a 37 °C water bath. Furthermore, the use of the NucleoSpin RNA kit increased RNA yield by fivefold compared with the PAXgene Blood RNA Kit. Thawing blood samples on aluminum blocks significantly increased the DNA yield by ~ 20% compared with thawing in a 37 °C water bath or on ice. Moreover, by thawing on aluminum blocks and using the NucleoSpin RNA and QIAamp DNA Blood kits, the extraction of RNA and DNA of sufficient quality and quantity was achieved from frozen EDTA whole blood samples that were stored for up to 8.5 years. Thus, extracting RNA from frozen whole blood in EDTA tubes after long-term storage is feasible. These findings may help advance gene expression analysis, as well as biomarker research for various diseases.

Clozapine is an efficacious atypical antipsychotic for treatment-refractory schizophrenia. Clinical response and appearance of adverse events vary among individual patients receiving clozapine, with genetic and non-genetic factors potentially contributing to individual variabilities. Pharmacogenetic studies investigate associations between genetic variants and drug efficacy and toxicity. To date, most pharmacogenetic studies of clozapine have been conducted through candidate gene approaches. A recent advance in technology made it possible to perform comprehensive genetic mapping underlying clinical phenotypes and outcomes, which allow novel findings beyond biological hypotheses based on current knowledge. In this paper, we will summarize the studies on clozapine pharmacogenetics that have extensively examined clinical response and agranulocytosis. While there is still limited evidence on clozapine efficacy, recent genome-wide studies provide further evidence of the involvement of the human leukocyte antigen (HLA) region in clozapine-induced agranulocytosis.