論文 - 内田　裕之

Delivery of Acetaminophen to the Central Nervous System and the Pharmacological Effect after Intranasal Administration with a Mucoadhesive Agent and Absorption Enhancer.

Ogawa K, Uchida M, Yamaki T, Matsuzaki H, Kimura M, Okazaki M, Uchida H, Natsume H

International journal of pharmaceutics    120046 2020年12月

ISSN  0378-5173

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Towards safer risperidone prescribing in Alzheimer's disease.

Reeves S, Bertrand J, Uchida H, Yoshida K, Otani Y, Ozer M, Liu KY, Bramon E, Bies R, Pollock BG, Howard R

The British journal of psychiatry : the journal of mental science    1 - 8 2020年11月

ISSN  0007-1250

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Diffuse Large B-Cell Lymphoma of the Central Nervous System Manifesting with Intratumoral Hemorrhage: A Case Report and Literature Review.

Bureta C, Higa N, Makino R, Takajo T, Yonezawa H, Uchida H, Yoshimoto K

World neurosurgery 143   490 - 494 2020年11月

ISSN  1878-8750

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Lower mortality from suicidal trauma among patients with a psychiatric diagnosis upon admission: Nationwide japanese retrospective cohort study

Ishida T., Kuwahara Y., Shibahashi K., Okura Y., Sugiyama K., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Psychiatry Research （Psychiatry Research）  293   113456 2020年11月

ISSN  01651781

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© 2020 Suicide and self-harm are major public health issues. Few studies have compared mortality from suicidal trauma between patients with and without contact with psychiatric services. This study aimed to compare the in-hospital mortality of suicidal trauma between patients with and without a psychiatric diagnosis upon hospital admission. Data on 15- to 90-year-old patients with suicidal trauma between 2004 and 2015 was extracted from the Japan Trauma Data Bank. In-hospital mortality were compared between patients with and without a psychiatric diagnosis. A total of 9,803 patients were included. The median age was 42 years (interquartile range: 29–59), and 5,010 patients (51.1%) were male. The most frequent method of injury was falling from a height (53.4%), followed by stabbing (32.3%) and burns (6.2%). In total, 4,878 patients (49.8%) had a psychiatric diagnosis upon admission. The proportion of patients with a psychiatric diagnosis was significantly lower among males, teenagers, and older people. In-hospital mortality was significantly lower among patients with a psychiatric diagnosis than those without (10.9%vs18.7%). Contact with psychiatric services might be protective among people with suicidal trauma. However, the proportion of psychiatric service use was generally low. These findings show the importance of delivering appropriate psychiatric services to high-risk patients.

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Inappropriate sales of hypochlorous acid solution in Japan: An online investigation.

Mitsuboshi S, Yamaguchi R, Uchida H, Kamoshida S, Hashi H

Infection control and hospital epidemiology    1 - 2 2020年10月

ISSN  0899-823X

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A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

Higa N, Akahane T, Yokoyama S, Yonezawa H, Uchida H, Takajo T, Kirishima M, Hamada T, Matsuo K, Fujio S, Hanada T, Hosoyama H, Yonenaga M, Sakamoto A, Hiraki T, Tanimoto A, Yoshimoto K

Cancer science 111 （ 10 ） 3902 - 3911 2020年10月

ISSN  1347-9032

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Gap between patients with schizophrenia and their psychiatrists on the needs to psychopharmacological treatment: A cross-sectional study

Takahashi K., Yamazawa R., Suzuki T., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports）  40 （ 3 ） 232 - 238 2020年09月

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© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology. Aim: Psychopharmacological treatment is indispensable in patients with schizophrenia but data on needs, preferences, and complaints about their medications are limited. Moreover, there has been no study to assess the degree of awareness of their psychiatrists (gap in needs) regarding these issues. Methods: Ninety-seven Japanese patients with schizophrenia (ICD-10) were asked to fill in the questionnaire consisting of multiple-choice questions regarding (a) their needs and complaints about psychopharmacological treatment that they were receiving, and (b) their preference of dosage form, dosing frequency, and timing of dosing. Additionally, their psychiatrists in charge were asked to predict their patients’ response to the above questions. Results: Both the most frequently endorsed need and complaints about the current psychopharmacological treatment were “nothing in particular” (n = 14, 16.7% and n = 17, 20.2%); merely 23.1% and 15.4% of their psychiatrists correctly predicted these responses, respectively. “Once a day” (n = 56, 65.1%), “at bedtime” (n = 53, 61.6%), and “tablet” (n = 51, 59.3%) were the patients’ most favorite dosing frequency, timing, and dosage form, respectively; 59.8% (n = 49), 54.9% (n = 45), and 64.6% (n = 53) of their psychiatrists predicted them. Conclusions: These findings suggest that there is substantial room for improvement on the side of psychiatrists to capture their patients’ needs and complaints about psychopharmacological treatment.

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Prescription patterns of psychotropics in patients receiving synthetic glucocorticoids

Yatomi T., Uchida T., Takeuchi H., Kuramochi S., Yoshimura K., Mimura M., Uchida H.

Acta Psychiatrica Scandinavica （Acta Psychiatrica Scandinavica）  142 （ 3 ） 242 - 248 2020年09月

ISSN  0001690X

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© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. Methods: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. Results: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10−7); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10−30); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10−75); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10−10) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. Conclusion: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.

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An iPad application-based intervention for improving post-stroke depression symptoms in a convalescent rehabilitation ward: A pilot randomized controlled clinical trial protocol.

Uchida H, Hiragaki Y, Nishi Y, Nakahara S, Koumoto J, Onmyoji Y, Fujimoto N, Kawakami K, Ishii M, Hirao K

Internet interventions 21   100340 2020年09月

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How mental health care should change as a consequence of the COVID-19 pandemic

Moreno C., Wykes T., Galderisi S., Nordentoft M., Crossley N., Jones N., Cannon M., Correll C.U., Byrne L., Carr S., Chen E.Y.H., Gorwood P., Johnson S., Kärkkäinen H., Krystal J.H., Lee J., Lieberman J., López-Jaramillo C., Männikkö M., Phillips M.R., Uchida H., Vieta E., Vita A., Arango C.

The Lancet Psychiatry （The Lancet Psychiatry）  7 （ 9 ） 813 - 824 2020年09月

ISSN  22150366

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© 2020 Elsevier Ltd The unpredictability and uncertainty of the COVID-19 pandemic; the associated lockdowns, physical distancing, and other containment strategies; and the resulting economic breakdown could increase the risk of mental health problems and exacerbate health inequalities. Preliminary findings suggest adverse mental health effects in previously healthy people and especially in people with pre-existing mental health disorders. Despite the heterogeneity of worldwide health systems, efforts have been made to adapt the delivery of mental health care to the demands of COVID-19. Mental health concerns have been addressed via the public mental health response and by adapting mental health services, mostly focusing on infection control, modifying access to diagnosis and treatment, ensuring continuity of care for mental health service users, and paying attention to new cases of mental ill health and populations at high risk of mental health problems. Sustainable adaptations of delivery systems for mental health care should be developed by experts, clinicians, and service users, and should be specifically designed to mitigate disparities in health-care provision. Thorough and continuous assessment of health and service-use outcomes in mental health clinical practice will be crucial for defining which practices should be further developed and which discontinued. For this Position Paper, an international group of clinicians, mental health experts, and users of mental health services has come together to reflect on the challenges for mental health that COVID-19 poses. The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery. Thus, the COVID-19 pandemic could be an opportunity to improve mental health services.

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Prefrontal cortex hypoactivity distinguishes severe from mild-to-moderate social anxiety as revealed by a palm-sized near-infrared spectroscopy system.

Uchida H, Hirao K

Journal of neural transmission (Vienna, Austria : 1996) 127 （ 9 ） 1305 - 1313 2020年09月

ISSN  0300-9564

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Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review

Kurose S., Mimura Y., Uchida H., Takahata K., Kim E., Suzuki T., Mimura M., Takeuchi H.

The Journal of clinical psychiatry （The Journal of clinical psychiatry）  81 （ 5 ）  2020年07月

ISSN  0160-6689

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© Copyright 2020 Physicians Postgraduate Press, Inc. OBJECTIVE: The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. DATA SOURCES: MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). STUDY SELECTION: The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. DATA EXTRACTION: The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. RESULTS: Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. CONCLUSIONS: The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

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White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study

Ochi R., Noda Y., Tsuchimoto S., Tarumi R., Honda S., Matsushita K., Tsugawa S., Plitman E., Masuda F., Ogyu K., Wada M., Miyazaki T., Fujii S., Chakravarty M.M., Graff-Guerrero A., Uchida H., Mimura M., Nakajima S.

Progress in Neuro-Psychopharmacology and Biological Psychiatry （Progress in Neuro-Psychopharmacology and Biological Psychiatry）  100   109871 2020年06月

ISSN  02785846

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© 2020 Elsevier Inc. Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p <.05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

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Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia

Ogyu K., Noda Y., Yoshida K., Kurose S., Masuda F., Mimura Y., Nishida H., Plitman E., Tarumi R., Tsugawa S., Wada M., Miyazaki T., Uchida H., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports）  40 （ 2 ） 138 - 149 2020年06月

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© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology Aim: It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods: This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6-week double-blind, placebo-controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results: Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2:.51,.42 and.55,.54, respectively). Conclusion: Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.

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Reliability of the glasgow antipsychotic side-effects scale for Clozapine Japanese version (GASS-C-J)

Kitagawa K., So R., Nomura N., Mizuno Y., Misawa F., Kodama M., Uchida H., Mimura M., Takeuchi H.

PLoS ONE （PLoS ONE）  15 （ 6 ） e0234864 2020年06月

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Copyright: © 2020 Kitagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The purpose of this study was to develop the Glasgow Antipsychotic Side effects Scale for Clozapine Japanese version (GASS-C-J) and examine its reliability to assess clozapine-related side effects. We developed the GASS-C-J using forward and backward translation. Semantic equivalence of the GASS-C-J to the GASS-C was confirmed by the original author. We then administered the GASS-C-J twice to 109 patients on clozapine treatment at two psychiatric hospitals in Japan. We assessed the internal consistency and test-retest reliability of the GASS-C-J using Cronbach's alpha and weighted kappa coefficient, respectively. We also examined if discrepancies in each GASS-C-J item score between the first and second rating were correlated with items of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD). The Cronbach's alpha coefficient of the GASS-C-J at the first and second rating was 0.78 (95% CI: 0.72 to 0.84) and 0.82 (95% CI: 0.76 to 0.88), respectively. The weighted kappa coefficient of individual and total GASS-C-J item scores ranged from 0.45 to 0.88. Some symptom domains were correlated with discrepancies in specific items of the GASS-C-J: psychotic symptoms and nausea/vomiting (rs = 0.27), thirst (rs = 0.31), and appetite/weight gain (rs = 0.27); disorganized thinking and urinary incontinence (rs = 0.26); depression/anxiety and myoclonus (rs = 0.25), hypersalivation (rs = -0.27), and blurred vision (rs = -0.22). These findings demonstrate that the GASS-C-J can be used in clinical and research settings as a reliable scale to assess clozapine-related side effects.

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Life-Threatening Serotonin Syndrome Precipitated by Discontinuation of Serotonin-Dopamine Antagonist in the Presence of Serotonergic Agents: A Case Report

Ishida T., Uchida H., Kaneko S., Sugiyama K., Hamabe Y., Mimura M., Suzuki T.

Clinical Neuropharmacology （Clinical Neuropharmacology）  43 （ 3 ） 81 - 83 2020年05月

ISSN  03625664

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© Wolters Kluwer Health, Inc. All rights reserved. Introduction Serotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far. Case Presentation A 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful. Conclusions Discontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.

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Factors associated with successful antipsychotic dose reduction in schizophrenia: a systematic review of prospective clinical trials and meta-analysis of randomized controlled trials

Tani H., Takasu S., Uchida H., Suzuki T., Mimura M., Takeuchi H.

Neuropsychopharmacology （Neuropsychopharmacology）  45 （ 5 ） 887 - 901 2020年04月

ISSN  0893133X

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© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only 8 studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration < 1 year, age > 40 years, duration of illness > 10 years, and post-reduction chlorpromazine equivalent (CPZE) dose > 200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23–3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25–1.12). A subgroup analysis indicated that only a post-reduction CPZE dose ≤ 200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29–6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.

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Pharmacological management of depression: Japanese expert consensus

Sakurai H., Uchida H., Kato M., Suzuki T., Baba H., Watanabe K., Inada K., Kikuchi T., Katsuki A., Kishida I., Sugawara Kikuchi Y., Yasui-Furukori N.

Journal of Affective Disorders （Journal of Affective Disorders）  266   626 - 632 2020年04月

ISSN  01650327

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© 2020 Background: Clinically relevant issues in the real-world treatment of depression have not always been captured by conventional treatment guidelines. Methods: Certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology were asked to evaluate treatment options regarding 23 clinical situations in the treatment of depression using a 9-point Likert scale (1=“disagree” and 9=“agree”). According to the responses of 114 experts, the options were categorized into first-, second-, and third-line treatments. Results: First-line antidepressants varied depending on predominant symptoms: escitalopram (mean ± standard deviation score, 7.8 ± 1.7) and sertraline (7.3 ± 1.7) were likely selected for anxiety; duloxetine (7.6 ± 1.9) and venlafaxine (7.2 ± 2.1) for loss of interest; mirtazapine for insomnia (8.2 ± 1.6), loss of appetite (7.9 ± 1.9), agitation and severe irritation (7.4 ± 2.0), and suicidal ideation (7.5 ± 1.9). While first-line treatment was switched to either an SNRI (7.7 ± 1.9) or mirtazapine (7.4 ± 2.0) in the case of non-response to an SSRI, switching to mirtazapine (7.1 ± 2.2) was recommended in the case of non-response to an SNRI, and vice versa (switching to an SNRI (7.0 ± 2.0) in the case of non-response to mirtazapine). Augmentation with aripiprazole was considered the first-line treatment for partial response to an SSRI (7.1 ± 2.3) or SNRI (7.0 ± 2.5). Limitations: The evidence level of expert consensus is considered low. All included experts were Japanese. Conclusions: Recommendations made by experts in the field are useful and can supplement guidelines and informed decision making in real-world clinical practice. We suggest that pharmacological strategies for depression be flexible and that each patient's situational needs as well as the pharmacotherapeutic profile of medications be considered.

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Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study

Tarumi R., Tsugawa S., Noda Y., Plitman E., Honda S., Matsushita K., Chavez S., Sawada K., Wada M., Matsui M., Fujii S., Miyazaki T., Chakravarty M.M., Uchida H., Remington G., Graff-Guerrero A., Mimura M., Nakajima S.

Neuropsychopharmacology （Neuropsychopharmacology）  45 （ 4 ） 632 - 640 2020年03月

ISSN  0893133X

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© 2019, The Author(s), under exclusive licence to American College of Neuropsychopharmacology. Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

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Visualization of AMPA receptors in living human brain with positron emission tomography

Miyazaki T., Nakajima W., Hatano M., Shibata Y., Kuroki Y., Arisawa T., Serizawa A., Sano A., Kogami S., Yamanoue T., Kimura K., Hirata Y., Takada Y., Ishiwata Y., Sonoda M., Tokunaga M., Seki C., Nagai Y., Minamimoto T., Kawamura K., Zhang M.R., Ikegaya N., Iwasaki M., Kunii N., Kimura Y., Yamashita F., Taguri M., Tani H., Nagai N., Koizumi T., Nakajima S., Mimura M., Yuzaki M., Kato H., Higuchi M., Uchida H., Takahashi T.

Nature Medicine （Nature Medicine）  26 （ 2 ） 281 - 288 2020年02月

ISSN  10788956

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© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

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