研究者詳細 - 三村　将

論文 - 三村　将

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Discrepancies between Nomenclature and Indications of Psychotropics

Minami F., Zohar J., Suzuki T., Koizumi T., Mimura M., Yagi G., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 52 （ 4 ） 175 - 179 2019年05月

ISSN 01763679

© Georg Thieme Verlag KG Stuttgart · New York. Introduction While the current nomenclature of psychotropic drugs is disease-based, their approved indications do not always match their classifications. Methods Information on approved indications of second-generation antipsychotics and newer antidepressants that are available in the United States (US), the United Kingdom (UK), France, Germany, and Japan were extracted from their packet inserts. Results A significant proportion of atypical antipsychotics were approved for psychiatric conditions other than psychotic disorders (i. e., bipolar disorder, major depressive disorder, and autistic disorder) as follows: 76.9% in the US, 66.7% in the UK, 66.7% in France, 60.0% in Germany, and 44.4% in Japan. Likewise, more than half of newer antidepressants had approved indications for psychiatric conditions other than depression (e. g., panic disorder, obsessive compulsive disorder, social anxiety disorder, general anxiety disorder, and post-traumatic stress disorder): 56.3% in the US, 69.2% in the UK, 69.2% in France, 50.0% in Germany, and 62.5% in Japan. Conclusions Our results raise concerns regarding generic terminologies of antipsychotics and antidepressants since the conventional indication-based nomenclature does not fit well with the official indication.

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Serotonin-mediated inhibition of ventral hippocampus is required for sustained goal-directed behavior

Yoshida K., Drew M., Mimura M., Tanaka K.

Nature Neuroscience （Nature Neuroscience） 22 （ 5 ） 770 - 777 2019年05月

ISSN 10976256

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. The ability to sustain goal-directed action is essential for success in many domains, but little is known about the corresponding neural substrates. Using fiber photometry to monitor population neural activity, we demonstrate that engagement in sustained food- or punishment-motivated behavior is associated with suppression of ventral but not dorsal hippocampal activity. Using optogenetic stimulation, we demonstrate that this suppression is required for goal-directed behavior, whereas optogenetic suppression of the ventral hippocampus (vHP) enhances the ability to sustain goal-directed behavior. Suppression of vHP during sustained goal-directed behavior was accompanied by increased activity in median but not dorsal raphe, implicating serotonergic signaling through Htr3a as a mechanism of vHP suppression during successful goal-directed behavior. Sustainment of goal-directed action may require suppression of vHP because of the structure’s well-documented role in behavioral inhibition.

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Etiology of out-of-hospital cardiac arrest in psychiatric patients: Chart review

Ishida T., Miyazaki K., Yukawa T., Yamagishi T., Sugiyama K., Tanabe T., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 5 ） 243 - 247 2019年05月

ISSN 13231316

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: Although sudden cardiac deaths are more common in psychiatric patients than the general population, data on their causes are very limited. The aim of this study was to investigate initial rhythms and causes of out-of-hospital cardiac arrest (OHCA) in patients with psychiatric disorders. Methods: We conducted a systematic chart review of patients resuscitated after OHCA and hospitalized in the Tertiary Emergency Medical Center of Tokyo Metropolitan Bokutoh Hospital in Japan between January 2010 and December 2017. The initial rhythms and causes of OHCA were compared between psychiatric patients and non-psychiatric patients. Parameters of interest were compared using chi-squared test, Fisher's exact test, or the Mann–Whitney U-test, as appropriate. Results: A total of 49 psychiatric and 600 non-psychiatric patients were eligible for this study. Fatal but shockable arrhythmias (i.e. ventricular fibrillation and ventricular tachycardia) were less frequently observed as initial rhythms in patients with psychiatric disorders than the others (22.4% vs 49.7%, P < 0.001). Cardiac origin was less common as the cause of OHCA (26.5% vs 58.5%, P < 0.01), while airway obstruction and pulmonary embolism were more frequent in psychiatric versus non-psychiatric patients (24.5% vs 6.5%, P < 0.01; and 12.2% vs 1.5%, P < 0.01, respectively). The results were similar when psychiatric patients were compared with sex- and age-matched controls selected from the non-psychiatric patient group. Conclusion: Although fatal arrhythmias may be less common, non-cardiac causes such as pulmonary embolism and airway obstruction need to be treated with high clinical suspicion in an event of sudden cardiac arrest in psychiatric patients.

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Remarkable behavioural signs and progressive non-fluent aphasia in a patient with adult-onset leucoencephalopathy with axonal spheroids and pigmented glia

Funayama M., Sugihara M., Takata T., Mimura M., Ikeuchi T.

Psychogeriatrics （Psychogeriatrics） 19 （ 3 ） 282 - 285 2019年05月

ISSN 13463500

© 2018 Japanese Psychogeriatric Society Adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leucoencephalopathy with spheroids (HDLS), is a progressive neurocognitive disorder that predominantly affects the cerebral white matter, mainly the frontal subcortical areas and the corpus callosum. Patients with ALSP are clinically characterized by a gradual onset of cognitive and behavioural dysfunction and personality changes, followed by motor impairments such as gait disturbance and bradykinesia. Given the disease-related degenerative changes of the frontal white matter, it is no wonder that patients with ALSP present with behavioural symptoms and non-fluent aphasia, which are found in patients with frontotemporal lobar degeneration. However, behavioural symptoms and non-fluent aphasia in a patient with ALSP have rarely reported in detail. Here, we describe a patient with ALSP who initially presented with remarkable behavioural signs and non-fluent primary progressive aphasia, which resembled symptoms of frontotemporal lobar degeneration. The present case suggests that ALSP should be included in the differential diagnosis for frontotemporal lobar degeneration.

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Neuroimaging correlates of narcolepsy with cataplexy: A systematic review

Wada M., Mimura M., Noda Y., Takasu S., Plitman E., Honda M., Natsubori A., Ogyu K., Tarumi R., Graff-Guerrero A., Nakajima S.

Neuroscience Research （Neuroscience Research） 142 16 - 29 2019年05月

ISSN 01680102

© 2018 Elsevier B.V. and Japan Neuroscience Society Recent developments in neuroimaging techniques have advanced our understanding of biological mechanisms underpinning narcolepsy. We used MEDLINE to retrieve neuroimaging studies to compare patients with narcolepsy and healthy controls. Thirty-seven studies were identified and demonstrated several replicated abnormalities: (1) gray matter reductions in superior frontal, superior and inferior temporal, and middle occipital gyri, hypothalamus, amygdala, insula, hippocampus, cingulate cortex, thalamus, and nucleus accumbens, (2) decreased fractional anisotropy in white matter of fronto-orbital and cingulate area, (3) reduced brain metabolism or cerebral blood flow in middle and superior frontal, and cingulate cortex (4) increased activity in inferior frontal gyri, insula, amygdala, and nucleus accumbens, and (5) N-acetylaspartate/creatine-phosphocreatine level reduction in hypothalamus. In conclusion, all the replicated findings are still controversial due to the limitations such as heterogeneity or size of the samples and lack of multimodal imaging or follow-up. Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets.

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A content analysis of multidimensional support needs regarding fertility among cancer patients: How can nonphysician health care providers support?

Takeuchi E., Shimizu M., Miyata K., Shimizu R., Matsunaga N., Moroi N., Fujisawa D., Mimura M., Kato M.

Journal of Adolescent and Young Adult Oncology （Journal of Adolescent and Young Adult Oncology） 8 （ 2 ） 205 - 211 2019年04月

ISSN 21565333

© Copyright 2019, Mary Ann Liebert, Inc., publishers 2019. Purpose: This study aimed to identify support needs among young cancer patients regarding fertility-related issues to describe multidimensional support provided by nonphysician health care providers. Methods: Participants were cancer patients and their families who contacted the Hotline for Cancer Treatment and Reproduction at National Cancer Center Hospital in Japan. Medical charts were analyzed through content analysis. Results: A total of 51 participants met the inclusion criteria, of which 32 cases (63%) involved patients themselves, 13 (25%) patients' family members, and 6 (12%) both patients and their families. About patients' demographic status, 40% of the patients were female and 28% were in their thirties. Gynecological and breast cancer patients were the majority, and 24 patients (47%) had not yet started cancer treatment. As a result of content analysis regarding support needs, 9 categories and 55 codes were extracted. The categories included information about risk of infertility, information about means to maintain reproductive function, referral to specialists, support for economic burden, support for worry about cancer progression, support for psychological distress upon facing the risk of infertility, support for communication with oncologists, support for family relationships, and decisional aid. Conclusions: This study suggests that nonphysician health care providers should acquire knowledge about fertility preservation and provide psychological support within their specialties.

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Brief Report: Evaluating the Utility of Varied Technological Agents to Elicit Social Attention from Children with Autism Spectrum Disorders

Kumazaki H., Warren Z., Swanson A., Yoshikawa Y., Matsumoto Y., Yoshimura Y., Shimaya J., Ishiguro H., Sarkar N., Wade J., Mimura M., Minabe Y., Kikuchi M.

Journal of Autism and Developmental Disorders （Journal of Autism and Developmental Disorders） 49 （ 4 ） 1700 - 1708 2019年04月

ISSN 01623257

© 2018, The Author(s). Technological agents could be effective tools to be used in interventions for enhancing social orienting for some young children with ASD. We examined response to social bids in preschool children with ASD and typical development (TD) at a very early age (i.e., around 3 years) using social prompts presented by technological agents of various forms and human comparisons. Children with ASD demonstrated less response overall to social bids compared to TD controls, across agents or human. They responded more often to a simple humanoid robot and the simple avatar compared to the human. These results support the potential utilization of specific robotic and technological agents for harnessing and potentially increasing motivation to socially-relevant behaviors in some young children with ASD.

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Brief Report: A Novel System to Evaluate Autism Spectrum Disorders Using Two Humanoid Robots

Kumazaki H., Muramatsu T., Yoshikawa Y., Yoshimura Y., Ikeda T., Hasegawa C., Saito D.N., Shimaya J., Ishiguro H., Mimura M., Kikuchi M.

Journal of Autism and Developmental Disorders （Journal of Autism and Developmental Disorders） 49 （ 4 ） 1709 - 1716 2019年04月

ISSN 01623257

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. We investigated the feasibility of our novel evaluation system for use with children with autism spectrum disorders (ASD). We prepared the experimental setting with two humanoid robots in reference to the birthday party scene in the Autism Diagnostic Observational Schedule (ADOS). We assessed the relationship between social communication ability measured in the ADOS condition (i.e., with a human clinician) and in a robotic condition for children with ASD. There were significant correlations between the social communication scores in the gold-standard ADOS condition and the robotic condition for children with ASD. The current work provides support for a unique application of a robotic system (i.e., two robot-mediated interaction) to evaluate the severity of autistic traits for children with ASD.

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Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

Iwata Y., Nakajima S., Plitman E., Caravaggio F., Kim J., Shah P., Mar W., Chavez S., De Luca V., Mimura M., Remington G., Gerretsen P., Graff-Guerrero A.

Biological Psychiatry （Biological Psychiatry） 85 （ 7 ） 596 - 605 2019年04月

ISSN 00063223

© 2018 Society of Biological Psychiatry Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F 3,96 = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ.

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Subiculum volumes associated with memory function in the oldest-old individuals aged 95 years and older

Eguchi Y., Noda Y., Nakajima S., Tsugawa S., Kida H., Plitman E., Graff-Guerrero A., Chakravarty M.M., Takayama M., Arai Y., Matsuda H., Mimura M., Niimura H.

Geriatrics and Gerontology International （Geriatrics and Gerontology International） 19 （ 4 ） 347 - 351 2019年04月

ISSN 14441586

© 2019 Japan Geriatrics Society Aim: Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods: A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results: There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F 1, 8 = 8.67, adjusted R 2 = 0.46). Conclusions: The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347–351.

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Predictive factors of the duration of sick leave due to mental disorders

Sakakibara S., Sado M., Ninomiya A., Arai M., Takahashi S., Ishihara C., Miura Y., Tabuchi H., Shirahase J., Mimura M.

International Journal of Mental Health Systems （International Journal of Mental Health Systems） 13 （ 1 ） 2019年03月

© 2019 The Author(s). Background: This study aimed to examine potential predictors of duration of sick leave due to mental disorders in Japan. Methods: A total of 207 employees at a manufacturing company in Japan with a past history of sick leave due to mental disorders participated in this study. Mental disorders were defined as those listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). All of the participants used the mental health program that the company provided. The predictive power of the variables was tested using a Cox proportional hazard analysis. The hazard ratios in the final model were used to identify the predictor variables of the duration of sick leave. We included socio-demographic (age, sex, tenure), clinical (diagnosis and number of previous sick leave), and work-related factors (employment rank) as possible predictors. Data on these variables were obtained through the psychiatrists and psychologists in the company's mental health program. Results: The results of the univariate analyses showed that the number of previous sick leave episodes, diagnosis and employee rank were significant predictors of the duration of sick leave due to mental disorders. A multivariate analysis indicated that age, number of previous sick leave and employee rank were statistically significant predictors of return to work. Conclusions: Diagnosis, number of previous sick leave episodes, and employee rank are predictors of the duration of sick leave due to mental disorders. This study's findings have implications in the development of effective interventions to prevent protracted sick leave.

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Impact of subjective vs. objective remission status on subjective cognitive impairments in depression

Sawada K., Yoshida K., Ozawa C., Mizuno Y., Rubinstein E.B., Suzuki T., Mimura M., Uchida H.

Journal of Affective Disorders （Journal of Affective Disorders） 246 99 - 104 2019年03月

ISSN 01650327

© 2018 Elsevier B.V. Objective: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. Methods: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery–Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. Results: 102 participants were included (45 men; mean ± SD age, 50.5 ± 14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0–12.0] vs. 3.0 [range: 2.0–4.0], p < 0.001). Conclusions: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.

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Comparison of emotional processing assessed with fear conditioning by interpersonal conflicts in patients with depression and schizophrenia

Tani H., Tada M., Maeda T., Konishi M., Umeda S., Terasawa Y., Mimura M., Takahashi T., Uchida H.

Psychiatry and Clinical Neurosciences （Psychiatry and Clinical Neurosciences） 73 （ 3 ） 116 - 125 2019年03月

ISSN 13231316

© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology Aim: While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. Methods: We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors’ faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. Results: Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. Conclusion: Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.

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Electroconvulsive therapy modulates resting-state EEG oscillatory pattern and phase synchronization in nodes of the default mode network in patients with depressive disorder

Takamiya A., Hirano J., Yamagata B., Takei S., Kishimoto T., Mimura M.

Frontiers in Human Neuroscience （Frontiers in Human Neuroscience） 13 2019年02月

© 2019 Takamiya, Hirano, Yamagata, Takei, Kishimoto and Mimura. Introduction: Electroconvulsive therapy (ECT) has antidepressant effects, but it also has possible cognitive side effects. The effects of ECT on neuronal oscillatory pattern and phase synchronization, and the relationship between clinical response or cognitive change and electroencephalogram (EEG) measurements remain elusive. Methods: Individuals with unipolar depressive disorder receiving bilateral ECT were recruited. Five minutes of resting, eyes-closed, 19-lead EEG recordings were obtained before and after a course of ECT. Non-overlapping 60 artifact-free epocs of 2-s duration were used for the analyses. We used exact low resolution electromagnetic tomography (eLORETA) to compute the whole-brain three-dimensional intracortical distribution of current source density (CSD) and phase synchronization among 28 regions-of-interest (ROIs). Paired t-tests were used to identify cortical voxels and connectivities showing changes after ECT. Montgomery Asberg Depression Rating Scale (MADRS) and Mini-Mental State Examination (MMSE) were used to evaluate the severity of depression and the global cognitive function. Correlation analyses were conducted to identify the relationship between changes in the EEG measurements and changes in MADRS or MMSE. Results: Thirteen depressed patients (five females, mean age: 58.4 years old) were included. ECT increased theta CSD in the anterior cingulate cortex (ACC), and decreased beta CSD in the frontal pole (FP), and gamma CSD in the inferior parietal lobule (IPL). ECT increased theta phase synchronization between the posterior cingulate cortex (PCC) and the anterior frontal cortex, and decreased beta phase synchronization between the PCC and temporal regions. A decline in beta synchronization in the left hemisphere was associated with cognitive changes after ECT. Conclusion: ECT modulated resting-state EEG oscillatory patterns and phase synchronization in central nodes of the default mode network (DMN). Changes in beta synchronization in the left hemisphere might explain the ECT-related cognitive side effects.

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Placebo effects in adult and adolescent patients with schizophrenia: combined analysis of nine RCTs

Kubo K., Fleischhacker W.W., Suzuki T., Yasui-Furukori N., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica） 139 （ 2 ） 108 - 116 2019年02月

ISSN 0001690X

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. Method: Data of 672 patients with schizophrenia randomized to placebo in nine double-blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5-Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. Results: Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per-protocol analysis or a 15% reduction in last-observation-carried-forward analysis in the PANSS total score at week 1 showed the highest predictive power. Conclusion: These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia.

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Suicide and microglia: Recent findings and future perspectives based on human studies

Suzuki H., Ohgidani M., Kuwano N., Chrétien F., Lorin de la Grandmaison G., Onaya M., Tominaga I., Setoyama D., Kang D., Mimura M., Kanba S., Kato T.A.

Frontiers in Cellular Neuroscience （Frontiers in Cellular Neuroscience） 13 1 - 10 2019年01月

ISSN 16625102

© 2019 Suzuki, Ohgidani, Kuwano, Chrétien, Lorin de la Grandmaison, Onaya, Tominaga, Setoyama, Kang, Mimura, Kanba and Kato. Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

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Effectiveness of the prefrontal repetitive transcranial magnetic stimulation on cognitive profiles in depression, schizophrenia, and Alzheimer's disease: A systematic review

Iimori T., Nakajima S., Miyazaki T., Tarumi R., Ogyu K., Wada M., Tsugawa S., Masuda F., Daskalakis Z., Blumberger D., Mimura M., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry） 88 31 - 40 2019年01月

ISSN 02785846

© 2018 Elsevier Inc. Repetitive transcranial magnetic stimulation (rTMS) is an effective clinical intervention for various neuropsychiatric diseases. However, it is still unclear whether rTMS has an effect on cognitive functioning. In this review, we aimed to systematically evaluate the cognitive effects of rTMS in depression, schizophrenia, and Alzheimer's disease. We searched PubMed (1996–2018) under the set terms to review randomized controlled trials (RCT) to examine the effectiveness of rTMS administered to the dorsolateral prefrontal cortex (DLPFC) and evaluated cognitive functions in patients with depression, schizophrenia, and Alzheimer's disease. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 579 articles, 31 of which met inclusion and exclusion criteria. Among them, 15 were conducted in patients with depression, 11 in patients with schizophrenia, and 5 in patients with Alzheimer's disease. Specifically, 6 studies demonstrated a significant improvement of executive function across these diseases. Further, no evidence for cognitive adverse effects was found in these included rTMS studies. Although the heterogeneity between studies in terms of cognitive measures applied, stimulation parameters, and participants limits the ability to generalize conclusions, this review demonstrated that prefrontal rTMS could exert pro-cognitive effects on executive function and attention in some patients with depression but inconsistent cognitive impacts in any of the examined domains especially in patients with schizophrenia and Alzheimer's disease. The results warrant further rTMS studies that include systematic assessment of cognition across various neuropsychiatric diseases.

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The association between midlife serum high-density lipoprotein and mild cognitive impairment and dementia after 19 years of follow-up

Svensson T., Sawada N., Mimura M., Nozaki S., Shikimoto R., Tsugane S.

Translational Psychiatry （Translational Psychiatry） 9 （ 1 ） 2019年01月

© 2019, The Author(s). A third of dementia cases could be attributable to modifiable risk-factors. Midlife high-density lipoprotein cholesterol (HDL-C) is a measure which could help identify individuals at reduced risk of developing age-related cognitive decline. The Japan Public Health Centre-based prospective (JPHC) Study is a large population-based cohort which started in 1990. This study included 1299 participants from Saku area in Nagano prefecture. Participants had HDL-C measured in 1995–1996, and underwent a mental health screening in 2014–2015. Of these, 1114 participants were included in MCI analyses, and 781 participants were included in dementia analyses. Logistic regression models were used to determine odds ratios (OR) and 95% confidence intervals (CI) for the association between HDL-C quartiles and MCI and dementia, respectively. For dementia analysis, quartiles 2–4 were collapsed due to low number of cases. Missing data was addressed through multiple imputations. There were 386 cases of MCI and 53 cases of dementia. Compared to the lowest HDL-C quartile, the highest HDL-C quartile was significantly inversely associated with MCI (OR = 0.47, 95% CI, 0.28–0.79) in the multivariable analysis. High HDL-C (quartiles 2–4) was inversely associated with dementia compared to low HDL-C (quartile 1) (OR = 0.37, 95% CI, 0.16–0.88). This study has found that high midlife HDL-C levels are inversely associated with both late-life MCI and dementia in a Japanese population.

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Early placebo improvement is a marker for subsequent placebo response in long-acting injectable antipsychotic trials for schizophrenia: Combined analysis of 4 RCTs

Kumagai F., Suzuki T., Fleischhacker W., Yasui-Furukori N., Mimura M., Uchida H.

Journal of Clinical Psychiatry （Journal of Clinical Psychiatry） 80 （ 1 ） 2019年01月

ISSN 01606689

© Copyright 2018 Physicians Postgraduate Press, Inc. Objective: Placebo effects remain largely unexplored in clinical trials of long-acting injectable (LAI) antipsychotics for schizophrenia. This study aims to characterize patients showing improvements after placebo injections and to search for criteria for the prediction of subsequent response based on the magnitude of score changes after the first week of treatment. Methods: Data from 450 patients with schizophrenia (DSM-IV) who received placebo injections in 4 double-blind randomized controlled trials evaluating efficacy of LAI paliperidone palmitate obtained through the Yale University Open Data Access (YODA) project were analyzed. These 4 studies were conducted from October 2003 to March 2008. Multiple logistic regression analyses were conducted to examine associations between placebo response and demographic and clinical characteristics. The predictive power of improvement at week 1 for response at week 9 was investigated; sensitivity and specificity of incremental 5% cutoff points between a 5% and 25% reduction in Positive and Negative Syndrome Scale (PANSS) total score at week 1 were calculated. Results: Percent reduction in the PANSS total score at week 1 and a lower PANSS G12 item score (ie, better in judgment and insight) at baseline were significantly associated with placebo response at week 9 (odds ratio [OR] = 1.063; 95% CI, 1.040-1.087, P < .001; and OR= 0.739; 95% CI, 0.553-0.986, P = .040, respectively, in the per-protocol analysis). Cutoffs of a 10% (accuracy = 0.724 in the per-protocol analysis) and 15% (accuracy = 0.722 in the last-observation-carried-forward analysis) reduction in the PANSS total score at week 1 showed the highest predictive power. Conclusions: The appreciation that longer-term response following placebo injections can be predicted by a 10%-15% PANSS total score reduction at week 1 could guide the design of future clinical trials of LAI antipsychotics in schizophrenia to identify and exclude potential placebo responders early during the course of the study.

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Regional brain volume reductions in major depressive disorder and bipolar disorder: An analysis by voxel-based morphometry

Niida R., Yamagata B., Matsuda H., Niida A., Uechi A., Kito S., Mimura M.

International Journal of Geriatric Psychiatry （International Journal of Geriatric Psychiatry） 34 （ 1 ） 186 - 192 2019年01月

ISSN 08856230

© 2018 John Wiley & Sons, Ltd. Objectives: The present study investigated the usefulness of evaluating the existence of volume reduction in brain regions using voxel-based morphometry (VBM) to dissociate major depressive disorder (MDD) from bipolar disorder (BD). Methods/Design: This study enrolled 92 individuals with MDD, 32 individuals with BD, and 43 healthy controls (HCs). We focused on gray matter volume (GMV) of the subgenual anterior cingulate cortex (sgACC), subcallosal area (SCA), and hippocampus. The degree of volume reduction in these brain regions was calculated as the z score, and the differences of z scores in these regions were investigated among the MDD, BD, and HC groups. We then performed a receiver operating characteristic curve analysis to dissociate the individuals with MDD and BD from the HCs based on the z scores in the GMV of these brain regions. Results: While there were no significant differences in the z scores of the hippocampus among the three groups, the z score of the sgACC was significantly higher in the MDD group than in the BD and HC groups, and the SCA z score was significantly higher in the MDD and BD groups than in the HC group. Conclusions: Our findings suggest that VBM evaluation of GMV reduction in the sgACC may be useful as an objective adjunctive tool to distinguish between MDD and BD.

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