Faculty Profiles - SAKAMOTO Shinji

Papers - SAKAMOTO Shinji

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A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis. Reviewed International journal

Diane E Peters, Lauren D Norris, Lukáš Tenora, Ivan Šnajdr, András K Ponti, Xiaolei Zhu, Shinji Sakamoto, Vijayabhaskar Veeravalli, Manisha Pradhan, Jesse Alt, Ajit G Thomas, Pavel Majer, Rana Rais, Christine McDonald, Barbara S Slusher

Science translational medicine 15 ( 708 ) eabn7491 2023.8

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

There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.

DOI： 10.1126/scitranslmed.abn7491

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Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Reviewed International journal

Xiaolei Zhu, Shinji Sakamoto, Chiharu Ishii, Matthew D Smith, Koki Ito, Mizuho Obayashi, Lisa Unger, Yuto Hasegawa, Shunya Kurokawa, Taishiro Kishimoto, Hui Li, Shinya Hatano, Tza-Huei Wang, Yasunobu Yoshikai, Shin-Ichi Kano, Shinji Fukuda, Kenji Sanada, Peter A Calabresi, Atsushi Kamiya

Nature immunology 24 ( 4 ) 625 - 636 2023.4

Authorship：Lead author 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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Inflamed brain: Targeting immune changes and inflammation for treatment of depression. Reviewed International journal

Shinji Sakamoto, Xiaolei Zhu, Yuto Hasegawa, Sadik Karma, Mizuho Obayashi, Emily Alway, Atsushi Kamiya

Psychiatry and clinical neurosciences 75 ( 10 ) 304 - 311 2021.10

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

Although there are a number of clinically effective treatments for depression, many patients exhibit treatment resistance. Recent clinical and preclinical studies reveal that peripheral and brain immune changes and inflammation are involved in the pathophysiology of depression. This 'Inflamed Brain' research provides critical clues for understanding of disease pathophysiology and many candidate molecules that are potentially useful for identifying novel drug targets for the treatment of depression. In this review, we will present clinical evidence on the role of inflammation in the pathophysiology of depression. We will also summarize current clinical trials which test drugs targeting inflammation for the treatment of patients with depression. Furthermore, we will briefly provide preclinical evidence demonstrating altered immune system function and inflammation in stress-induced animal models and will discuss the future potential of inflammation-related drug targets. Collectively, inflammatory signatures identified in clinical and preclinical studies may allow us to stratify depressive patients based on biotypes, contributing to the development of novel mechanism-based interventions that target specific patient populations.

DOI： 10.1111/pcn.13286

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Lamotrigine in the maintenance treatment of bipolar disorder. Reviewed International journal

Yasuhiko Hashimoto, Kazumasa Kotake, Norio Watanabe, Takashi Fujiwara, Shinji Sakamoto

The Cochrane database of systematic reviews 9 ( 9 ) CD013575 2021.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Bipolar disorder is a chronic mental disorder with repetitive mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health-related quality of life. A worldwide prevalence rate of 2.4% has been reported. The risk of suicide is higher in people with bipolar disorder than those with other mental disorders. Therefore, effective management of bipolar disorder in the maintenance period is warranted to minimize the risk of relapse or recurrence. Although lithium has been the standard treatment of bipolar disorder for many years, it is associated with adverse effects and teratogenicity. Lamotrigine is approved to be expected for prevention of recurrence for the maintenance treatment of bipolar disorder. In addition, lamotrigine is as effective as lithium. Therefore, we performed a systematic review to confirm the efficacy and safety of lamotrigine in the maintenance treatment of bipolar disorder. OBJECTIVES: To assess the efficacy and tolerability of lamotrigine in the maintenance treatment of bipolar disorder. SEARCH METHODS: We searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group's Specialized Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 21 May 2021. We also searched international trial registries and contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials enrolling adults with bipolar disorder who were treated with lamotrigine, placebo or lithium. DATA COLLECTION AND ANALYSIS: Two reviews authors independently checked the eligibility of studies and extracted data using a standardized form. Data extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in the term of efficacy and tolerability. Study information were then entered into RevMan web. MAIN RESULTS: We included 11 studies with a total of 2314 participants in this review; 1146 were randomized to lamotrigine, 869 were randomized to placebo and, 299 to lithium. We rated all studies as having an unclear risk of bias in at least one domain of Cochrane's tool for assessing risk of bias, with the most commonly observed weakness being selection bias (random sequence generation and allocation concealment). We judged five studies to be at a high risk of detection bias (blinding of outcome assessment). These potential biases pose as major threat to the validity of the included studies in this review. Outcomes of efficacy showed a possible advantage of lamotrigine over placebo. The estimated risk ratio (RR) for recurrence of manic symptom at one year as measured by the Young Mania Rating Scale (YMRS) was 0.67, (95% confidence interval (CI) 0.51 to 0.87; 3 studies, 663 participants; low-certainty evidence) in favor of lamotrigine. The RR of clinical worsening with the need for additional psychotropic treatment (RR 0.82, 95% CI 0.70 to 0.98; 4 studies, 756 participants) based on moderate-certainty evidence. The possible benefits of lamotrigine were also seen for the outcome of treatment withdrawal due to any reason at 6-12 months after treatment (RR 0.88, 95% CI 0.78 to 0.99; 4 studies, 700 participants; moderate-certainty evidence). Regarding tolerability, our analyses showed that the incidence rates of adverse effects were similar between the lamotrigine group and the placebo group (short-term effect: RR 1.07, 95% CI 0.81 to 1.42; 5 studies, 1138 participants; very low-certainty evidence; long-term effect: RR 0.97, 95% CI 0.77 to 1.23; 4 studies, 756 participants; moderate-certainty evidence). In the comparison between lamotrigine and lithium, efficacy was similar between groups except for recurrence of mania episode at one year. Recurrence of manic symptoms was higher in the lamotrigine group than that of the lithium group (RR 2.13, 95% CI 1.32 to 3.44; 3 studies, 602 participants; moderate-certainty evidence). Analysis of adverse effects at 6-12 months showed that a lower proportion of participants experienced at least one adverse effect when treated with lamotrigine compared to lithium (RR 0.70, 95% CI 0.51 to 0.96; 4 studies, 691 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Low- to moderate-certainty evidence collectively suggests that lamotrigine may be superior to placebo as a treatment modality for bipolar disorder. In comparison to lithium, people with bipolar disorder seem to tolerate lamotrigine better in the long run; however, the demonstrated efficacy in the maintenance of bipolar disorder was similar between the two groups.

DOI： 10.1002/14651858.CD013575.pub2

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Forgetfulness in adult attention‐deficit/hyperactivity disorder masks transient epileptic amnesia: a case report Reviewed

Takashi Fukao, Masaki Fujiwara, Yuto Yamada, Shinji Sakamoto, Yosuke Matsumoto, Manabu Takaki

Psychiatry and Clinical Neurosciences Reports 3 ( 3 ) 2024.8

Publishing type：Research paper (scientific journal) Publisher：Wiley

Abstract

Background

Inattention due to attention‐deficit/hyperactivity disorder (ADHD) can lead to forgetfulness. Transient epileptic amnesia (TEA) can cause forgetfulness, similar to ADHD. We report a patient with ADHD who developed TEA.

Case Presentation

The patient was a 40‐year‐old woman with ADHD. She has been prone to forgetfulness since childhood. Two years before visiting our outpatient clinic, she had begun to occasionally forget events that had occurred several days earlier. However, she was largely unaware of the emergence of new amnestic symptoms. She had also begun to experience various other amnestic symptoms 2 months before she visited our clinic, which prompted her to visit our outpatient clinic. The combination of a detailed interview, electroencephalography (EEG) examination, and consideration of TEA enabled us to diagnose her with TEA and provide treatment accordingly. In our patient, daily forgetfulness due to ADHD delayed the recognition of new additional forgetfulness attributed to TEA.

Conclusion

Psychiatrists need to consider TEA when patients with ADHD present with changes in or exacerbation of forgetfulness.

DOI： 10.1002/pcn5.70003

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Safe and Successful Electroconvulsive Therapy After an Ascending Aorta Replacement: A Case Report. Reviewed International journal

Yoshio Ohya, Shinji Sakamoto, Yuto Yamada, Shintaro Takenoshita, Yuji Higuchi, Norihito Yamada, Manabu Takaki

The journal of ECT 40 ( 2 ) e6-e7 2024.6

Comparison between olanzapine and aripiprazole treatment for 104 weeks after hospital discharge in schizophrenia spectrum disorders: a multicenter retrospective cohort study in a real-world setting Reviewed

Tomonari Hosokawa, Chikara Miyaji, Yusaku Yoshimura, Kenji Washida, Yuji Yada, Shinji Sakamoto, Yuko Okahisa, Soshi Takao, Akira Nomura, Yoshiki Kishi, Toshiki Harada, Manabu Takaki, Toshihiko Takeda, Norihito Yamada

Psychopharmacology 2023.7

Initial Outcomes of the Safe and Sound Protocol on Patients with Adult Autism Spectrum Disorder: Exploratory Pilot Study. Reviewed International journal

Hiroki Kawai, Makiko Kishimoto, Yuko Okahisa, Shinji Sakamoto, Seishi Terada, Manabu Takaki

International journal of environmental research and public health 20 ( 6 ) 2023.3

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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Late-Onset Neutropenia With Clozapine Associated With Lithium Carbonate–Related Hyperthyroidism Reviewed

Yuto Yamada, Masaki Fujiwara, Shuhei Tsujino, Satoru Edahiro, Shinji Sakamoto, Koichiro Yamamoto, Fumio Otsuka, Norihito Yamada, Manabu Takaki

Journal of Clinical Psychopharmacology 43 ( 1 ) 76 - 77 2023.1

The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms Reviewed

Kenji Hinotsu, Chikara Miyaji, Yuji Yada, Hiroki Kawai, Shinji Sakamoto, Yuko Okahisa, Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Soshi Takao, Yoshiki Kishi, Manabu Takaki, Norihito Yamada

Schizophrenia Research 248 292 - 299 2022.10

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice. Reviewed International journal

Benjamin J Bell, Kristen R Hollinger, Pragney Deme, Shinji Sakamoto, Yuto Hasegawa, David Volsky, Atsushi Kamiya, Norman Haughey, Xiaolei Zhu, Barbara S Slusher

Brain, behavior, & immunity - health 23 100478 - 100478 2022.8

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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精神医学のフロンティア甲状腺機能低下症によるPsychosis(Myxedema Psychosis)の臨床的特徴症例報告と文献レビュー Reviewed

山田裕士, 藤原雅樹, 宋龍平, 枝廣暁, 深尾貴志, 酒本真次, 高東祥一朗, 川田清宏, 和迩健太, 山本紘一郎, 大塚文男, 山田了士

精神神経学雑誌 124 ( 5 ) 293 - 299 2022.5

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

精神症状を呈した甲状腺機能低下症の患者の15%が精神病症状を生じると報告されており,「myxedema psychosis」と呼ばれる.しかし,わが国の精神科領域での報告は数例にとどまり,十分に認知されていない可能性がある.そこで,本症例報告では,精神科におけるmyxedema psychosis鑑別の重要性を改めて強調するため,自験例の詳細な臨床像を記述したうえで,系統的レビューで得られた症状,検査所見,治療経過の特徴を整理して呈示する.症例は50歳代の女性.X-2年に橋本病と診断され,レボチロキシンで治療されていた.X年5月にレボチロキシンを自己中断後,徐々に過敏になり,幻聴に左右されて家を飛びだすようになった.同月末に不安と動悸症状でA病院を受診し,著明な甲状腺機能低下が認められたため,内科に入院した.レボチロキシンを再開し,リスペリドンも開始されたが,精神病症状の改善に乏しく,精査を拒否するため,入院第7病日に当院当科へ転院した.転院時,幻聴は改善していたが,思路障害や焦燥は残存し,甲状腺機能低下も持続していた.脳波検査では徐波が混入しており,髄液検査ではタンパクの軽度高値を認めたことから,橋本脳症の可能性も考えたが,症状が改善傾向であったため,ステロイド投与は保留し,レボチロキシンを増量し経過観察した.すると,転院第7病日までに精神病症状は消失し,転院第16病日に退院した.12月にリスペリドンを中止後も精神病症状の再燃はなかった.X+1年8月にTSHの上昇とともに精神病症状が再発したが,レボチロキシンの増量により速やかに症状は改善した.Myxedema psychosisは甲状腺ホルモン補充により抗精神病薬中止が可能と系統的レビューが示すように,本症例もレボチロキシンの補充で症状は速やかに改善した.Myxedema psychosisは抗精神病薬の中止が可能な予後良好な病態であるため,精神病症状を呈した患者の治療においては,甲状腺機能の評価を行うことが望ましい.(著者抄録)

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Inconsistency of antibody testing in a patient with anti-N-methyl-D-aspartate receptor encephalitis. Reviewed International journal

Shori Mino, Kenji Hinotsu, Masaki Fujiwara, Shinji Sakamoto, Ryo Sasaki, Yuji Yada, Yuto Yamada, Takashi Fukao, Manabu Takaki, Norihito Yamada

Asian journal of psychiatry 72 103124 - 103124 2022.4

Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: An exploratory analysis. Reviewed International journal

Nozomu Hashimoto, Hiroshi Habu, Soshi Takao, Shinji Sakamoto, Yuko Okahisa, Keitaro Matsuo, Manabu Takaki, Yoshiki Kishi, Norihito Yamada

Drug and alcohol dependence 233 109365 - 109365 2022.4

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

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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Association between depression in chronic phase and future clinical outcome of patients with schizophrenia. Reviewed International journal

Yuto Yamada, Yusuke Yamauchi, Shinji Sakamoto, Masaki Fujiwara, Yuko Okahisa, Soshi Takao, Manabu Takaki, Norihito Yamada

Psychopharmacology 239 ( 3 ) 965 - 975 2022.2

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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A Decrease of Neutrophils After COVID-19 Vaccination in a Treatment-Resistant Patient With Schizophrenia Taking Clozapine. Reviewed International journal

Manabu Takaki, Yuji Yada, Shinji Sakamoto, Masaki Fujiwara, Yuko Okahisa, Norihito Yamada

Journal of clinical psychopharmacology 2022.2

Mirtazapine Was Effective for a Patient With Benzodiazepine Dependence. Reviewed International journal

Manabu Takaki, Ryo Ishikawa, Shinji Sakamoto, Nozomu Hashimoto, Yuko Okahisa, Norihito Yamada

Clinical neuropharmacology 2021.12

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

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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Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis. Reviewed International journal

Sojiro Okamoto, Manabu Takaki, Kenji Hinotsu, Hiroki Kawai, Shinji Sakamoto, Yuko Okahisa, Soshi Takao, Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Norihito Yamada

Psychopharmacology 239 ( 2 ) 525 - 531 2021.12

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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Causal impact of local inflammation in the nasal cavity on higher brain function and cognition. Reviewed International journal

Yuto Hasegawa, Ho Namkung, Amy Smith, Shinji Sakamoto, Xiaolei Zhu, Koko Ishizuka, Andrew P Lane, Akira Sawa, Atsushi Kamiya

Neuroscience research 172 110 - 115 2021.11

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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Alterations in circulating extracellular vesicles underlie social stress-induced behaviors in mice. Reviewed International journal

Shinji Sakamoto, Dania Mallah, Destynie J Medeiros, Eisuke Dohi, Takashi Imai, Indigo V L Rose, Ken Matoba, Xiaolei Zhu, Atsushi Kamiya, Shin-Ichi Kano

FEBS open bio 11 ( 10 ) 2678 - 2692 2021.10

Authorship：Lead author 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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Papers - SAKAMOTO Shinji