Details of a Researcher - Uchida, Hiroyuki

Papers - Uchida, Hiroyuki

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Predicting relapse from the time to remission during the acute treatment of depression: A re-analysis of the STAR*D data

Kubo K., Sakurai H., Tani H., Watanabe K., Mimura M., Uchida H.

Journal of Affective Disorders (Journal of Affective Disorders) 320 710 - 715 2023.01

ISSN 01650327

Background: Predicting relapse during maintenance treatment for depression is challenging. The objective of this analysis was to investigate the association between the time taken to achieve remission in the acute phase, and the subsequent relapse rate or time to relapse using the Sequenced Treatment Alternatives to Relieve Depression dataset. Method: Data of 1296 outpatients with nonpsychotic depression who entered a 12-month naturalistic follow-up period after achieving remission with citalopram for up to 14 weeks were analyzed. One-way analysis of variance and the Jonckheere-Terpstra trend test were performed to compare the relapse rates and days to relapse during the follow-up period among those who achieved remission at weeks 2, 4, 6, 9, 12, and 14. Remission and relapse were defined as scores of ≤5 and ≥11, respectively, on the 16-Item Quick Inventory of Depressive Symptomatology and Self-Report. Results: The relapse rates were significantly different among those who achieved remission each week (F(5, 1087) = 4.995, p < 0.001). The lowest and highest relapse rates were observed in those who achieved remission at weeks 4 (25.7 %) and 12 (42.4 %), respectively, with a significant difference (p = 0.006). There was also a significant negative trend between the weeks taken to achieve remission and the days to relapse (z = −6.13, p < 0.001). Conclusions: Patients with depression who show a faster response to antidepressant treatment are more likely to maintain remission in the long term. This finding suggests that, to prevent relapse, close attention should be paid to patients who require a relatively long time to achieve remission.

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Antipsychotic Monotherapy for Major Depressive Disorder: A Systematic Review and Meta-Analysis

Nishi A., Sawada K., Uchida H., Mimura M., Takeuchi H.

Pharmacopsychiatry (Pharmacopsychiatry) 56 ( 1 ) 5 - 17 2023.01

ISSN 01763679

Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

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Comparable Psychotropic Prescription Rates after Hospital Discharge between Patients with COVID-19 and Those with Non-COVID-19-Related Respiratory Infection

Takahashi Y., Yatomi T., Yamaguchi N., Yoshimura K., Hori S., Uchida H.

Pharmacopsychiatry (Pharmacopsychiatry) 2023

ISSN 01763679

Introduction Whether psychiatric symptoms after recovery from coronavirus disease 2019 (COVID-19) are specific to this illness remains unclear. Methods In this retrospective study, the Diagnosis Procedure Combination data and outpatient clinic data were used for patients who received inpatient treatment in Saiseikai-affiliated hospitals for COVID-19 or other respiratory tract infections (non-COVID) from 2020 to 2022. The primary outcome was new prescriptions of psychotropic drugs after discharge (i. e., prescriptions of psychotropics to patients who had not received them before or during their hospitalization). Values of interest were compared between groups using the chi-square test or Fisher's exact test. A COX proportional-hazards model was used to examine factors associated with psychotropic prescriptions after discharge in age- and sex-matched COVID-19 and non-COVID patients. Results Of 31,993 chart records, 19,613 were excluded due to a positive history with psychiatric disorders (n = 2,445), prescriptions of psychotropics (n = 744), and no follow-ups (n = 16,424). Thus, 3,648 COVID-19 and 8,732 non-COVID patients were included (mean [range] duration of follow-up, days: 146.9 [1-727] and 239.2 [1-729], respectively). Two hundred and four (5.6 %) of the 3,648 patients with COVID-19 received psychotropic prescriptions after discharge. No statistically significant differences were observed in the prescription rates of any psychotropic category between the COVID-19 and non-COVID groups. An increase in severity during hospitalization was significantly associated with more frequent psychotropic prescriptions (hazard ratio 1.83, p < 0.001). Discussion The development of psychiatric symptoms should be closely observed, especially in patients who experienced increased severity during hospitalization, regardless of whether they suffered from COVID-19.

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Predictors of response to pharmacotherapy in children and adolescents with psychiatric disorders: A combined post hoc analysis of four clinical trial data

Tsujii T., Sakurai H., Takeuchi H., Suzuki T., Mimura M., Uchida H.

Neuropsychopharmacology Reports (Neuropsychopharmacology Reports) 42 ( 4 ) 516 - 520 2022.12

Objective: The prediction of response to pharmacotherapy has not been sufficiently explored in children and adolescents with psychiatric disorders, which was addressed in this study. Methods: Data from four double-blind, placebo-controlled studies (sertraline and fluvoxamine for anxiety disorders, risperidone for autistic disorder, and fluoxetine for major depressive disorder) in children and adolescents funded by the National Institute of Mental Health were used. The response was defined as a score of 1 or 2 on the Clinical Global Impression-Global Improvement (CGI-I) at the endpoint. Logistic regression analysis was performed to evaluate associations between response status and the following variables: sex, diagnosis, treatment allocation, and CGI-Severity of Illness (CGI-S) score at baseline. Moreover, the presence of early improvement (a score of ≤3 in the CGI-I) at Week 1 was added to the independent variables in an additional binary logistic regression analysis, using the data from two studies. Results: A total of 599 patients were included in the analysis. In the binary logistic regression analysis, active drug use (odds ratio [OR] = 8.64, P < 0.001) and female sex (OR = 1.89, P = 0.002) were significantly associated with treatment response. In the second binary logistic regression, the presence of early improvement in the CGI-I (OR = 3.47, P = 0.009), as well as active drug use (OR = 15.05, P < 0.001) and female sex (OR = 2.87, P = 0.016), were associated with subsequent responses. Conclusion: Allocation to active drugs, female sex, and early improvement may predict treatment response to pharmacotherapy among children and adolescents with psychiatric disorders.

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Patterns of functional connectivity alterations induced by alcohol reflect somatostatin interneuron expression in the human cerebral cortex

Ochi R., Ueno F., Sakuma M., Tani H., Tsugawa S., Graff-Guerrero A., Uchida H., Mimura M., Oshima S., Matsushita S., Nakajima S.

Scientific Reports (Scientific Reports) 12 ( 1 ) 7896 2022.12

Acute alcohol administration affects functional connectivity, yet the underlying mechanism is unknown. Previous work suggested that a moderate dose of alcohol reduces the activity of gamma-aminobutyric acidergic (GABAergic) interneurons, thereby leading to a state of pyramidal disinhibition and hyperexcitability. The present study aims to relate alcohol-induced changes in functional connectivity to regional genetic markers of GABAergic interneurons. Healthy young adults (N = 15, 5 males) underwent resting state functional MRI scanning prior to alcohol administration, immediately and 90 min after alcohol administration. Functional connectivity density mapping was performed to quantify alcohol-induced changes in resting brain activity between conditions. Patterns of differences between conditions were related to regional genetic markers that express the primary GABAergic cortical interneuron subtypes (parvalbumin, somatostatin, and 5-hydroxytryptamine receptor 3A) obtained from the Allen Human Brain Atlas. Acute alcohol administration increased local functional connectivity density within the visual cortex, sensorimotor cortex, thalamus, striatum, and cerebellum. Patterns of alcohol-induced changes in local functional connectivity density inversely correlated with somatostatin cortical gene expression. These findings suggest that somatostatin-expressing interneurons modulate alcohol-induced changes in functional connectivity in healthy individuals.

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Trazodone and Mianserin for Delirium: A Retrospective Chart Review

Kawano S., Ide K., Kodama K., Kikuchi Y., Sugihara H., Fujisawa D., Uchida H., Mimura M., Takeuchi H.

Journal of Clinical Psychopharmacology (Journal of Clinical Psychopharmacology) 42 ( 6 ) 560 - 564 2022.11

ISSN 02710749

Background Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium. Methods Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared. Results Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n=45) for trazodone and 89.1% (n=41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups (P=0.17 and P=0.13, respectively). Conclusion Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

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Clinical Outcomes after Clozapine Discontinuation in Patients with Schizophrenia: A Systematic Review

Miura G., Tanaka K., Kemuriyama T., Misawa F., Uchida H., Mimura M., Takeuchi H.

Pharmacopsychiatry (Pharmacopsychiatry) 55 ( 4 ) 181 - 192 2022.07

ISSN 01763679

Introduction Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation. Methods A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation∗ OR cease∗ OR withdraw∗ OR discontinu∗ OR halt∗ OR stop∗ OR switch*) AND (schizophreni∗ OR schizoaffective)). Results A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-Arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group. Discussion Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

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Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry

Sakurai H., Yonezawa K., Tani H., Mimura M., Bauer M., Uchida H.

Pharmacopsychiatry (Pharmacopsychiatry) 55 ( 4 ) 193 - 202 2022.07

ISSN 01763679

Introduction There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis. Methods We systematically searched the US Clinical Trials registry for antidepressant compounds with completed phase II and III trials. Compounds that demonstrated significant superiority over placebo in the primary outcome measure in the latest phase of phase II and III trials were identified. The collateral information was gathered via a PubMed search and press releases. Results Nine compounds were identified. AXS-05 (a combination of dextromethorphan and bupropion) and ansofaxine hydrochloride showed a positive result over placebo in a phase III study for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, facial injection of botulinum toxin A, prasterone, and casopitant demonstrated at least one positive result in phase II trials. Ayahuasca showed a greater response rate than placebo at week one, indicating the rapid antidepressant effect. Discussion These new compounds with novel mechanisms of action are expected to provide a greater variety of treatment options for depression if preliminary positive results are confirmed.

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Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment

Wada M., Noda Y., Iwata Y., Tsugawa S., Yoshida K., Tani H., Hirano Y., Koike S., Sasabayashi D., Katayama H., Plitman E., Ohi K., Ueno F., Caravaggio F., Koizumi T., Gerretsen P., Suzuki T., Uchida H., Müller D.J., Mimura M., Remington G., Grace A.A., Graff-Guerrero A., Nakajima S.

Molecular Psychiatry (Molecular Psychiatry) 27 ( 7 ) 2950 - 2967 2022.07

ISSN 13594184

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

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MAP Bayesian modelling combining striatal dopamine receptor occupancy and plasma concentrations to optimize antipsychotic dose regimens in individual patients

Ismail M., Straubinger T., Uchida H., Graff-Guerrero A., Nakajima S., Suzuki T., Caravaggio F., Gerretsen P., Mamo D., Mulsant B.H., Pollock B.G., Bies R.

British Journal of Clinical Pharmacology (British Journal of Clinical Pharmacology) 88 ( 7 ) 3341 - 3350 2022.07

ISSN 03065251

Aims: Develop a robust and user-friendly software tool for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone, in order to facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods: Previously developed population pharmacokinetic models for olanzapine and risperidone were combined with a pharmacodynamic model for D2 RO and implemented in the R programming language. Maximum a posteriori Bayesian estimation was used to provide predictions of plasma concentration and RO based on sparse concentration sampling. These predictions were then compared to observed plasma concentration and RO. Results: The average (standard deviation) response times of the tools, defined as the time required for the application to predict parameter values and display the output, were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (95% confidence interval) of predicted vs. observed concentrations were 3.73 ng/mL (−2.42–9.87) and 10.816 ng/mL (6.71–14.93) for olanzapine, and 0.46 ng/mL (−4.56–5.47) and 6.68 ng/mL (3.57–9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and root mean squared error of RO were −1.47% (−4.65–1.69) and 5.80% (3.89–7.72) for olanzapine and −0.91% (−7.68–5.85) and 8.87% (4.56–13.17) for risperidone. Conclusion: Our monitoring software predicts concentration–time profiles and the corresponding D2 RO from sparsely sampled concentration measurements in an accessible and accurate form.

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Drug Combinations for Mood Disorders and Physical Comorbidities That Need Attention: A Cross-Sectional National Database Survey

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

Pharmacopsychiatry (Pharmacopsychiatry) 55 ( 3 ) 157 - 162 2022.05

ISSN 01763679

Introduction This study investigated combined prescriptions of drugs for mood disorders and physical comorbidities that need special attention in the light of frequent physical comorbidities in patients with mood disorders. Methods We used the claims sampling data of 581,990 outpatients in January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Fisher's exact test was performed to compare the prescription rates of non-steroidal anti-inflammatory drugs (NSAIDs), loop/thiazide diuretics, angiotensin-converting enzyme inhibitors, and/or angiotensin II receptor blockers between lithium users and age- and sex-matched non-lithium users; NSAIDs, antiplatelet drugs, and/or anticoagulants between selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) users and non-users; warfarin between mirtazapine users and non-users; and the proportions of patients in the two groups with a diagnosis of somatic conditions for which these medications were indicated and actually received them. A Bonferroni corrected p-value of<0.05/3 was considered statistically significant. Results Prescriptions of the above-mentioned medications were less frequent in lithium and mirtazapine users and comparable in SSRI/SNRI users, compared to non-users (18.3 vs. 31.9%, p=7.6×10 -10; 0.78 vs. 1.65%, p=0.01; 23.1 vs. 24.1%, p=0.044). In a subgroup of patients with somatic diseases for which these medications were indicated, the prescription rates were comparable in lithium and mirtazapine users and higher in SSRI/SNRI users compared to non-users (28.0 vs. 29.4%, p=0.73; 4.7 vs. 7.4%, p=0.28; 35.6 vs. 33.4%, p=0.0026). Discussion Pharmacotherapy with drugs for mood disorders and physical comorbidities that require attention was commonly observed in clinical practice.

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AMPA receptors in schizophrenia: A systematic review of postmortem studies on receptor subunit expression and binding

Yonezawa K., Tani H., Nakajima S., Nagai N., Koizumi T., Miyazaki T., Mimura M., Takahashi T., Uchida H.

Schizophrenia Research (Schizophrenia Research) 243 98 - 109 2022.05

ISSN 09209964

Background: While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia. Methods: A systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase. Results: A total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences. Conclusion: Published data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.

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Influence of alcohol and acetaldehyde on cognitive function: findings from an alcohol clamp study in healthy young adults

Ueno F., Matsushita S., Hara S., Oshima S., Roh S., Ramchandani V.A., Mimura M., Uchida H.

Addiction (Addiction) 117 ( 4 ) 934 - 945 2022.04

ISSN 09652140

Aims: To investigate the acute effects of intravenous alcohol and its metabolite acetaldehyde on cognitive function in healthy individuals. Design: Experimental pre-test/post-test design. Setting: Kurihama Medical and Addiction Center, Japan. Participants: A total of 298 healthy Japanese people age 20 to 24 years. Measurements: Participants underwent an intravenous alcohol infusion with a target blood alcohol concentration (BAC) of 0.50 mg/mL for 180 minutes. Participants completed the continuous performance test (CPT) for sustained attention, the paced auditory serial addition test (PASAT) for working memory, and the reaction time test (RTT) for speed/accuracy, along with the blood test for BAC and blood acetaldehyde concentration (BAAC) at baseline, 60 and 180 minutes. Findings: Although the target BAC was maintained during the infusion, BAAC peaked at 30 minutes and then gradually declined (η2 = 0.18, P < 0.01). The CPT scores worsened, and the changes between 0 and 60 minutes were correlated with BAAC (correct detection, η2 = 0.09, P < 0.01; r = −0.34, P < 0.01; omission errors, η2 = 0.08, P < 0.01; r = 0.34, P < 0.01). PASAT scores improved through 180 minutes, whereas the changes between 0 and 60 minutes were negatively correlated with BAAC (task one, η2 = 0.02, P < 0.01; r = −0.25, P < 0.01; task two, η2 = 0.03, P < 0.01; r = −0.28, P < 0.01). Although RTTs worsened, they were not associated with BAC or BAAC. None of these comparisons maintained the time effect after controlling for body height. Conclusions: Acetaldehyde exposure following acute intravenous alcohol appears to have a negative impact on sustained attention and working memory, whereas there seems to be only a minor effect of moderate alcohol concentration on speed and accuracy.

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Decision tree classification of cognitive functions with D<inf>2</inf> receptor occupancy and illness severity in late-life schizophrenia

Kusudo K., Ochi R., Nakajima S., Suzuki T., Mamo D., Caravaggio F., Mar W., Gerretsen P., Mimura M., Pollock B.G., Mulsant B.H., Graff-Guerrero A., Rajji T.K., Uchida H.

Schizophrenia Research (Schizophrenia Research) 241 113 - 115 2022.03

ISSN 09209964

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Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels

Ochi R., Plitman E., Patel R., Tarumi R., Iwata Y., Tsugawa S., Kim J., Honda S., Noda Y., Uchida H., Devenyi G.A., Mimura M., Graff-Guerrero A., Chakravarty M.M., Nakajima S.

Journal of Psychiatry and Neuroscience (Journal of Psychiatry and Neuroscience) 47 ( 1 ) E1 - E10 2022.01

ISSN 11804882

Background: Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia. Methods: This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels. Results: We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose. Limitations: Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study. Conclusion: This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.

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Comorbid Psychiatric Disorders in Patients Hospitalized for Pulmonary Embolism and Acute Myocardial Infarction: A Japanese Nationwide Database Study

Takahashi K., Uchida H., Suzuki T., Mimura M., Ishida T.

Journal of Clinical Psychiatry (Journal of Clinical Psychiatry) 83 ( 1 ) 2022.01

ISSN 01606689

Objective: While the most common cause of sudden cardiac arrest (SCA) in the general population is ischemic cardiac disease including acute myocardial infarction (AMI), previous preliminary data highlighted pulmonary embolism (PE) as a common cause of SCA among psychiatric patients. The aim of this study was to examine the proportion of patients with comorbid psychiatric disorders among patients hospitalized for either AMI or PE using a Japanese nationwide database. Methods: This study used Diagnosis Procedure Combination (DPC) data between April 2013 and March 2018 provided by the Ministry of Health, Labor, and Welfare. The DPC data included information on the causes of hospitalization and comorbidities of psychiatric diseases among inpatients in all acute care hospitals in Japan. The proportions of patients with schizophrenia (ICD-10 code F20), mood disorders (F31 or F32), and no psychiatric disorders were analyzed among patients who were hospitalized for AMI and PE. Results: The data from 351,159 AMI patients (mean age = 70.3 years) and 52,036 PE patients (mean age = 69.2 years) were used. Mortality rates were 8.0%–14.4% in AMI patients and 4.3%–9.8% in PE patients. The AMI group was predominantly male. The proportions of patients with schizophrenia and mood disorder were significantly higher in the PE group than in the AMI group (schizophrenia: 2.53% [1,314/52,036] vs 0.55% [1,922/351,159], P< .001; mood disorder: 2.94% [1,532/52,036] vs 0.60% [2,099/351,159], P< .001). Conclusions: The results highlight the importance of PE as a major cause of SCA in this specific population and the need for preventive measures to mitigate the mortality gap among patients with psychiatric disorders.

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Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of <sup>1</sup>H-magnetic resonance spectroscopy studies

Nakahara T., Tsugawa S., Noda Y., Ueno F., Honda S., Kinjo M., Segawa H., Hondo N., Mori Y., Watanabe H., Nakahara K., Yoshida K., Wada M., Tarumi R., Iwata Y., Plitman E., Moriguchi S., de la Fuente-Sandoval C., Uchida H., Mimura M., Graff-Guerrero A., Nakajima S.

Molecular Psychiatry (Molecular Psychiatry) 27 ( 1 ) 744 - 757 2022.01

ISSN 13594184

Background: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. Results: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01). Conclusions: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

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Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan

Kitagawa K., So R., Nomura N., Tsukahara M., Misawa F., Kodama M., Uchida H., Bies R., Straubinger T., Banker C., Mizuno Y., Mimura M., Takeuchi H.

Journal of Clinical Psychopharmacology (Journal of Clinical Psychopharmacology) 42 ( 2 ) 163 - 168 2022

ISSN 02710749

Objective Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine. Methods We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine. Results The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies. Conclusions Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.

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Clinical features of catatonic non-convulsive status epilepticus: A systematic review of cases

Ogyu K., Kurose S., Uchida H., Kanemoto K., Mimura M., Takeuchi H.

Journal of Psychosomatic Research (Journal of Psychosomatic Research) 151 110660 2021.12

ISSN 00223999

Objective: Non-convulsive status epilepticus (NCSE) can manifest as catatonia, although it is unclear how frequently such cases have been reported. The common clinical features of these two conditions are also unclear. Methods: Using the MEDLINE and Embase databases, we performed a systematic literature search to identify cases diagnosed with both catatonia, according to the Bush-Francis Catatonia Rating Scale, and NCSE, according to the Salzburg Consensus Criteria (last search: March 29, 2021). We extracted data on demographics, clinical features of catatonia, EEG findings, and treatments. Results: A total of 66 patients with catatonic NSCE (men, 49%; mean age, 42.0 years) were identified from our search. Of the 66 cases described: 30 (46%) showed motor symptoms; 35 (38%) occurred in patients with preceding episodes of epileptic seizures; 19 (29%) showed subtle ictal clinical phenomena, such as minor twitching of the mouth, periorbital region, and extremities; 22 (33%) presented with psychiatric symptoms prior to the onset of catatonia; 17 (26%) had a history of psychiatric diseases; and in 10 cases (15%), NSCE was confirmed by intentional or non-intentional long-term EEG monitoring. Benzodiazepines were used as the initial treatment for NCSE in 30 cases (49%), of which 20 cases (73%) improved with monotherapy. Discussion: A substantial number of cases included in the present review involved catatonia without any symptoms indicative of epilepsy, suggesting that NCSE may be misdiagnosed as a psychiatric disease, and highlighting the importance of the accurate diagnosis and treatment of NCSE in patients presenting with catatonia.

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Cancellation of outpatient appointments in patients with attention-deficit/hyperactivity disorder

Nomura K., Tarumi R., Yoshida K., Sado M., Suzuki T., Mimura M., Uchida H.

PLoS ONE (PLoS ONE) 16 ( 11 November ) e0260431 2021.11

Background Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge. Methods A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of 15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group. Results We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0–15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8–8.3) and DCD-CD (5.3%, 95% CI: 3.6–7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39–0.95 and 0.49, 95% CI: 0.25–0.95, respectively), although these significances did not find in the subgroup analysis including only patients with 6 years old. Conclusions Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations.

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