研究者詳細 - 内田　裕之

論文 - 内田　裕之

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Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication

Tani H., Moxon-Emre I., Forde N.J., Neufeld N.H., Bingham K.S., Whyte E.M., Meyers B.S., Alexopoulos G.S., Hoptman M.J., Rothschild A.J., Uchida H., Flint A.J., Mulsant B.H., Voineskos A.N.

Brain Imaging and Behavior （Brain Imaging and Behavior） 18 （ 1 ） 117 - 129 2024年02月

ISSN 19317557

Background: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. Methods: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. Results: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25–1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71–2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. Conclusions: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

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Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults

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

Alcohol: Clinical and Experimental Research （Alcohol: Clinical and Experimental Research） 48 （ 1 ） 58 - 71 2024年01月

Background: To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. Methods: Eighteen healthy Japanese participants (7 males/11 females) aged 20–30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Results: Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. Conclusions: Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

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Comparison of changes in stress coping strategies between cognitive behavioral therapy and pharmacotherapy

Ihara S., Katayama N., Nogami W., Amano M., Noda S., Kurata C., Kobayashi Y., Sasaki Y., Mitsuda D., Ozawa M., Matsuoka J., Takemura R., Uchida H., Nakagawa A.

Frontiers in Psychiatry （Frontiers in Psychiatry） 15 1343637 2024年

ISSN 1664-0640

Background: Coping refers to conscious responses to negative circumstances, with the intention of ameliorating these situations. Few studies have compared the differences between psychotherapy and medication treatment for coping strategies for depression. In this study, we investigated the differences in coping strategies between cognitive behavioral therapy (CBT) combined with medication (CBT group) and medication alone (pharmacotherapy group) among outpatients with depression. Methods: A prospective observational study was conducted among 50 patients with major depression (24 and 26 in the CBT and pharmacotherapy groups, respectively). Stress coping strategies (Coping Inventory for Stressful Situations [CISS]) and depression severity (Beck Depression Inventory-Second Edition [BDI-II]) were assessed at baseline and 16 weeks later. Changes in the CISS and BDI-II scores in both groups were tested using repeated analysis of variance. Inverse probability weighting with propensity score analysis was applied to address potential selection bias. Results: At 16 weeks, the CBT group exhibited increased CISS task-oriented coping, distraction, and social diversion scores, which differed from those of the pharmacotherapy group. The CBT group exhibited a significantly greater reduction in depressive symptoms than the pharmacotherapy group. Limitations: This study was not a randomized controlled trial and thus may have selection bias. Conclusion: Gaining adaptive coping skills, including task-oriented coping, distraction, and social diversion skills, by combining CBT with medication may lead to greater improvement in depression symptoms. These findings suggest that clinicians should evaluate coping strategies and facilitate the acquisition of adaptive coping strategies in patients with depression to reduce their symptoms.

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Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments

Komatsu Y., Takehara M., Hart X., Takahashi Y., Hori S., Ueno F., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 57 （ 5 ） 221 - 231 2024年

ISSN 01763679

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia.

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Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics

Hart X.M., Gründer G., Ansermot N., Conca A., Corruble E., Crettol S., Cumming P., Frajerman A., Hefner G., Howes O., Jukic M., Kim E., Kim S., Maniscalco I., Moriguchi S., Müller D.J., Nakajima S., Osugo M., Paulzen M., Ruhe H.G., Scherf-Clavel M., Schoretsanitis G., Serretti A., Spina E., Spigset O., Steimer W., Süzen S.H., Uchida H., Unterecker S., Vandenberghe F., Verstuyft C., Zernig G., Hiemke C., Eap C.B.

World Journal of Biological Psychiatry 25 （ 9 ） 451 - 536 2024年

ISSN 15622975

Background: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. Methods: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). Results: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. Conclusion: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.

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Efficacy and Safety of Dose Increase from 40 mg/d to 80 mg/d of Lurasidone in Patients with Schizophrenia: A Post Hoc Analysis of Extension Trial

Takeuchi H., Uchida H.

Journal of Clinical Psychopharmacology 45 （ 1 ） 16 - 19 2024年

ISSN 02710749

Objectives The primary objective of this study was to evaluate the efficacy and safety of increasing the dose of lurasidone from 40 mg/d to 80 mg/d in patients with schizophrenia. Methods This post hoc analysis focused on patients who completed a 6-week double-blind, placebo-controlled trial of lurasidone and transitioned to a subsequent 12-week open-label extension trial. Patients initially assigned to lurasidone (40 mg/d) or placebo during the double-blind trial (DBT-LUR group or DBT-PLA group, respectively) received lurasidone (40 mg/d) during the extension. Clinicians could increase the dose to 80 mg/d based on clinical judgment. The efficacy outcomes included the change in the Positive and Negative Syndrome Scale (PANSS) total score from the start to the end of the lurasidone (80 mg/d) treatment period. Safety outcome was the rate of newly emergent adverse events. Results Of 287 patients in the intention-to-treat population, 153 received an increased dose of lurasidone from 40 mg/d to 80 mg/d. Significant reductions in the PANSS total scores were observed in both groups (all P values, ≤0.001). Additionally, 35.9% of the DBT-LUR group and 40.0% of the DBT-PLA group achieved a ≥20% reduction in the PANSS total score. New adverse events emerged in 47.4% of the DBT-LUR group and 48.0% of the DBT-PLA group during the lurasidone (80 mg/d) treatment period. Conclusions Increasing the dose of lurasidone from 40 mg/d to 80 mg/d may be effective and well tolerated in patients with schizophrenia. Because of the lack of a control group and blinding, the results should be interpreted with caution.

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α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor density underlies intraregional and interregional functional centrality

Yatomi T., Tomasi D., Tani H., Nakajima S., Tsugawa S., Nagai N., Koizumi T., Nakajima W., Hatano M., Uchida H., Takahashi T.

Frontiers in Neural Circuits 18 1497897 2024年

ISSN 16625110

Local and global functional connectivity densities (lFCD and gFCD, respectively), derived from functional magnetic resonance imaging (fMRI) data, represent the degree of functional centrality within local and global brain networks. While these methods are well-established for mapping brain connectivity, the molecular and synaptic foundations of these connectivity patterns remain unclear. Glutamate, the principal excitatory neurotransmitter in the brain, plays a key role in these processes. Among its receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is crucial for neurotransmission, particularly in cognitive functions such as learning and memory. This study aimed to examine the association of the AMPAR density and FCD metrics of intraregional and interregional functional centrality. Using [11C]K-2, a positron emission tomography (PET) tracer specific for AMPARs, we measured AMPAR density in the brains of 35 healthy participants. Our findings revealed a strong positive correlation between AMPAR density and both lFCD and gFCD-lFCD across the entire brain. This correlation was especially notable in key regions such as the anterior cingulate cortex, posterior cingulate cortex, pre-subgenual frontal cortex, Default Mode Network, and Visual Network. These results highlight that postsynaptic AMPARs significantly contribute to both local and global functional connectivity in the brain, particularly in network hub regions. This study provides valuable insights into the molecular and synaptic underpinnings of brain functional connectomes.

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Metabolites for monitoring symptoms and predicting remission in patients with depression who received electroconvulsive therapy: a pilot study

Uchida T., Sugiura Y., Sugiyama E., Maeda R., Tanaka K.F., Suematsu M., Mimura M., Uchida H.

Scientific Reports （Scientific Reports） 13 （ 1 ） 13218 2023年12月

The lack of biomarkers to monitor and predict the efficacy of electroconvulsive therapy (ECT) has hindered its optimal use. To establish metabolomic markers for monitoring and predicting the treatment efficacy of ECT, we comprehensively evaluated metabolite levels in patients with major depressive disorder (MDD) by performing targeted and non-targeted metabolomic analyses using plasma samples before and after the first, third, and final ECT sessions, and 3–7 days after the final session. We compared the plasma metabolomes of age- and sex-matched healthy controls (HCs). Thirteen hospitalized patients with MDD and their corresponding HCs were included in this study. We observed that patients with MDD exhibited lower levels of amino acids, including gamma-aminobutyric acid (GABA), and metabolites involved in tryptophan metabolism and the kynurenine pathway, and higher levels of cortisol at baseline. Furthermore, we investigated the relationship between metabolite levels and depression severity across seven measurement timepoints along with one correlation analysis and found that amino acids, including GABA and tryptophan catabolites, were significantly correlated with the severity of depression. Despite the exploratory nature of this study due to the limited sample size necessitating further validation, our findings suggest that the blood metabolic profile has potential as a biomarker for ECT.

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[Psychedelic Drugs: Past, Present, and Future].

Uchida H

Brain and nerve = Shinkei kenkyu no shinpo 75 （ 12 ） 1355 - 1359 2023年12月

ISSN 1881-6096

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Highly endorsed screening and assessment scales for alcohol problems: A systematic review

Ohtani Y., Ueno F., Kimura M., Matsushita S., Mimura M., Uchida H.

Neuropsychopharmacology Reports （Neuropsychopharmacology Reports） 43 （ 4 ） 470 - 481 2023年12月

Background: Problems associated with alcohol use are multidimensional with psychiatric, psychological, physical, and social aspects, which makes it challenging to choose appropriate assessment scales. However, there has been no systematic evaluation of existing alcohol scales. Methods: A systematic literature search was conducted for articles that assessed the psychometric properties of scales for alcohol use disorder on March 19, 2023, using Medline, EMBASE, and PsycINFO. Only scales whose original development papers were cited more than 20 times were included. The methodological quality and psychometric properties of the scales were evaluated using COnsensus-based Standards for the selection of health Measurement INstruments. The overall rating of the scales were assessed with a score ranging from 0 to 18. Results: In total, 314 studies and 40 scales were identified. These scales differ widely in measurement methods, target populations, and psychometric properties. The overall mean score was 6.3, and only the following three scales received >9 points suggesting a moderate level of evidence: Alcohol Use Disorders Identification Test (AUDIT), Alcohol Dependence Scale (ADS), and Short Alcohol Dependence Data Questionnaire (SADD). Measurement error and responsiveness were not evaluated or reported in the included scales. Conclusions: Although the AUDIT, ADS, and SADD were rated the highest among the 40 scales, they showed, at most, a moderate level of evidence. These findings underscore the need to accumulate further evidence to assure the quality of the scales. It may be advisable to select and combine scales to meet the purpose of the assessment.

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New-onset addictions in patients with alcohol dependence: A cross-sectional study

Ohtani Y., Asano K., Ueno F., Den R., Hisae H., Kimura M., Matsushita S., Uchida T., Tani H., Nakajima S., Mimura M., Uchida H.

Drug and Alcohol Dependence （Drug and Alcohol Dependence） 252 110966 2023年11月

ISSN 03768716

Background: Individuals who are addicted to one addiction are at an increased risk for developing another new addiction. New-onset addictions among patients with alcohol dependence needs to be considered for more effective treatment of alcohol dependence. Methods: In this cross-sectional study, Japanese outpatients with alcohol dependence were assessed using a comprehensive, originally designed questionnaire to determine whether they were addicted to substances or behaviors other than alcohol. The prevalence rates of new-onset addictions were compared between alcohol-dependent patients who had abstained from alcohol for a year or more and those who had not. Multiple regression analysis was performed to examine the association between the number of new-onset addictions and the demographic and clinical characteristics. Results: One hundred and nine outpatients with alcohol dependence (54.6±11.0 years; 97 men) participated in the study. The prevalence of new-onset addictions was 41.3%. No significant differences were found in the prevalence of new-onset addictions between the patients who had abstained for a year or more and those who had not. Multiple regression analysis revealed that the number of new-onset addictions was positively associated with the presence of psychiatric comorbidity (β = 0.24; p = 0.02) and use of benzodiazepines (β = 0.20; p = 0.04) with a R2 of 0.153. Conclusion: Alcohol dependent patients with characteristics such as psychiatric comorbidity and use of benzodiazepines should be given more attention to the development of new-onset addictive behaviors. On the other hand, those behaviors could be acceptable for harm-reduction unless excessive and loss of control.

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Caution to psychiatry ward: COVID-19 pneumonia can manifest weeks or months after testing positive with a PCR test in individuals on preexisting immune-suppressing medication

Nakano M., Funayama M., Wakisaka R., Takata T., Kudo S., Kuramochi S., Koreki A., Ogino S., Ishida T., Uchida H., Mimura M.

Psychiatry and Clinical Neurosciences Reports （Psychiatry and Clinical Neurosciences Reports） 2 （ 3 ） e135 2023年09月

Background: Some patients are reported to develop depression immediately after COVID-19 infection. Typically, hospitalization is arranged a week to 10 days after symptom onset to avoid outbreak in the psychiatric ward when infectivity is almost eliminated. However, in patients on immunosuppressive drugs, infection is known to persist beyond the 10th day after testing positive with a polymerase chain reaction (PCR) test. Case Presentation: We present a patient with follicular lymphoma who was receiving immune-suppressing medication and contracted a COVID-19 infection; she developed severe depression and eventually required hospitalization 10 days after symptom onset or 5 days after the COVID-19 infection-related symptoms disappeared. Although the patient did not exhibit any symptom of pneumonia upon admission, she developed COVID-19 pneumonia 3 weeks after the initial positive test. She received intravenous infusion of the antiviral drug remdesivir, which led to the improvement of pneumonia, and she was discharged on day 32 from testing COVID-19 positive. However, COVID-19 pneumonia recurred on days 64 and 74. Conclusion: This is the first report of COVID-19 pneumonia developing in a psychiatric ward in a patient on immunosuppressive drugs, weeks to months after testing positive with a PCR test. When patients with compromised immune function, such as those on immunosuppressant medication or those with human immunodeficiency virus disease, are admitted to a psychiatric ward, careful monitoring of the risk of recurrence and sufficient consideration for infection control measures are necessary to avoid outbreaks.

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Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree Analysis

Hart X.M., Mitsukura Y., Bies R.R., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry） 57 （ 2 ） 53 - 60 2023年08月

ISSN 01763679

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D 2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D 2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D 2 occupancy.

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Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression

Yonezawa K., Uchida H., Yatomi T., Ohtani Y., Nomoto-Takahashi K., Nakajima S., Mimura M., Tani H.

Pharmacopsychiatry （Pharmacopsychiatry） 57 （ 1 ） 35 - 40 2023年07月

ISSN 01763679

Introduction Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials. Methods Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score. Results This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration. Discussion Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response.

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Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy

Eiro T., Miyazaki T., Hatano M., Nakajima W., Arisawa T., Takada Y., Kimura K., Sano A., Nakano K., Mihara T., Takayama Y., Ikegaya N., Iwasaki M., Hishimoto A., Noda Y., Miyazaki T., Uchida H., Tani H., Nagai N., Koizumi T., Nakajima S., Mimura M., Matsuda N., Kanai K., Takahashi K., Ito H., Hirano Y., Kimura Y., Matsumoto R., Ikeda A., Takahashi T.

Cell Reports Medicine （Cell Reports Medicine） 4 （ 5 ） 101020 2023年05月

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

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[Drugs in the Developmental Stage (Psychotropics)].

Uchida H

Brain and nerve = Shinkei kenkyu no shinpo 75 （ 5 ） 437 - 440 2023年05月

ISSN 1881-6096

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Intravenous pulse methylprednisolone and corticosteroid-induced psychiatric disorders: A retrospective study

Ogyu K., Mashima Y., Nishi A., Kusudo K., Kato H., Kurose S., Uchida H., Fujisawa D., Mimura M., Takeuchi H.

Journal of Psychosomatic Research 167 111179 2023年04月

ISSN 00223999

Objective: Corticosteroids can cause psychiatric symptoms known as corticosteroid-induced psychiatric disorders (CIPDs). Little is known regarding the relationship between intravenous pulse methylprednisolone (IVMP) and CIPDs. Therefore, we aimed to examine the relationship between corticosteroid use and CIPDs in this retrospective study. Methods: Patients who were prescribed corticosteroids during their hospitalization at a university hospital and referred to our consultation-liaison service were selected. Patients diagnosed with CIPDs according to the ICD-10 codes were included. The incidence rates were compared between patients receiving IVMP and those receiving any other corticosteroid treatment. The association between IVMP and CIPDs was examined by classifying patients with CIPD into three groups according to the use of IVMP and timing of CIPD onset. Results: Of the 14,585 patients who received corticosteroids, 85 were diagnosed with CIPDs, with an incidence rate of 0.6%. Among the 523 patients who received IVMP, the incidence rate of CIPDs was 6.1% (n = 32), which was significantly higher than that in patients receiving any other corticosteroid treatment. Among the patients with CIPDs, 12 (14.1%) developed CIPDs during IVMP, 19 (22.4%) developed CIPDs after IVMP, and 49 (57.6%) developed CIPDs without IVMP. There was no significant difference in the doses at the time of CIPD improvement among the three groups when we excluded one patient whose CIPD improved during IVMP. Conclusion: Patients receiving IVMP were more likely to develop CIPDs than those who did not receive IVMP. Furthermore, corticosteroid doses at the time of improvement of CIPDs were constant, regardless of IVMP use.

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Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia

Ogyu K., Matsushita K., Honda S., Wada M., Tamura S., Takenouchi K., Tobari Y., Kusudo K., Kato H., Koizumi T., Arai N., Koreki A., Matsui M., Uchida H., Fujii S., Onaya M., Hirano Y., Mimura M., Nakajima S., Noda Y.

Schizophrenia Research （Schizophrenia Research） 252 129 - 137 2023年02月

ISSN 09209964

Background: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. Method: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. Results: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. Conclusion: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

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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年01月

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年01月

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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