Details of a Researcher - Uchida, Hiroyuki

Papers - Uchida, Hiroyuki

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Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Siskind D., Northwood K., Pillinger T., Chan S., Correll C., Cotes R.O., Every-Palmer S., Hahn M., Howes O.D., Kane J.M., Kelly D., Korman N., Lappin J., Mena C., Myles N., McCutcheon R.A., Siskind D., McCutcheon R.A., Pillinger T., Chan S., Correll C.U., Cotes R., Every-Palmer S., Hahn M., Howes O., Kane J.M., Kelly D.L., Korman N., Lappin J., Mena C., Agid O., Arango C., Asmal L., Ayinde O.O., Baptiste T., Béchard L., Bitter I., Bittner R.A., Breznoscakova D., Chen E., Chkonia E., Citrome L., Clark S.R., Corbeil O., Cordoba R., Crossley N., de Bartolomeis A., Ebdrup B.H., Fernandez-Egea E., Elkis H., Eltorki Y., Šimunović Filipčić I., de Filippis R., Fleischhacker W., Freudenreich O., Gadelha A., Gama C.S., Gaughran F., Gee S., Guinart D., Hallak J.E.C., Harris A., Hasan A., Honer W., Jayaram M., Kanazawa T., Kawashima H., Keating D., Kim S.H., Kwon J.S., Lane H.Y., Lee J., Lennox B., de Leon J., Leung J.G., Luykx J.J., MacCabe J., Murray G., Nielsen J., O'Donoghue B., Oloyede E., Qubad M., Remington G., Roy M.A., Rubio J., Sagud M., Schulte P.F.J., Selten J.P., Si T., Smith L., Sommer I., Sundram S., Taipale H., Takeuchi H., Tandon R., Tanzer T., Taylor D., Thirthalli J.

Lancet Psychiatry 2025

ISSN 22150366

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

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Acute and long-term effects of repeated ketamine infusions in treatment-resistant depression and associated metabolite changes

Sakurai H., Setoyama D., Kato T.A., Tachimori H., Murao M., Matsumoto Y., Tada T., Imamura Y., Seki H., Tsuboi T., Uchida H., Watanabe K.

Psychiatry and Clinical Neurosciences 2025

ISSN 13231316

Aim: This study aims to investigate the acute and sustained antidepressant effects of repeated ketamine infusions in patients with treatment-resistant depression (TRD), and to identify early metabolomic changes predictive of treatment outcomes using metabolome analyses. Methods: This open-label study investigated the effects of four intravenous ketamine infusions (0.5 mg/kg) administered over 2 weeks in 30 patients with TRD. Clinical outcomes, including the Montgomery-Åsberg Depression Rating Scale (MADRS), were evaluated at baseline, 1–2 h after each infusion, and monthly during a 12-month follow-up. Plasma levels of 11 depression-associated metabolites were measured at baseline and 1.5–2 h after the first infusion. A general linear model was employed to analyze the association between metabolite changes after the first infusion and the MADRS score percent improvements after the fourth infusion and at 12 months. Remission was defined as a MADRS score of ≤10. Results: All participants completed the four infusions. The MADRS score decreased from 30.6 ± 6.1 at baseline to 20.3 ± 11.5 after the fourth infusion, with a remission rate of 26.7%. At 12 months, 13.3% of participants remained in remission. Changes in 3-hydroxybutyrate levels after the first infusion predicted the MADRS score percent improvements after the fourth infusion (β = 1.35, 95% CI: 0.41–2.30, P = 0.005) and at 12 months (β = 1.38, 95% CI: 0.37–2.39, P = 0.007). Conclusion: While repeated ketamine infusions demonstrated rapid antidepressant effects, sustained remission was achieved in a minority of patients with TRD. 3-Hydroxybutyrate may serve as a biomarker for predicting treatment response. These findings underscore the potential for individualized strategies using ketamine infusions. Clinical Trial Registration: jRCTs031210648 (Japan Registry of Clinical Trials).

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Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia

Shibukawa S., Kan H., Honda S., Wada M., Tarumi R., Tsugawa S., Tobari Y., Maikusa N., Mimura M., Uchida H., Nakamura Y., Nakajima S., Noda Y., Koike S.

Translational Psychiatry (Translational Psychiatry) 14 ( 1 ) 164 2024.12

Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues’ magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility–volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group’s nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.

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Caution for psychiatrists: malignant hyperthermia risks with the anesthetic agent succinylcholine (Suxamethonium) during electroconvulsive therapy

Nakano M., Funayama M., Takata T., Wakisaka R., Koyama G., Koreki A., Ishida T., Uchida H., Mimura M.

BMC Psychiatry (BMC Psychiatry) 24 ( 1 ) 411 2024.12

Background: Malignant hyperthermia is a potentially lethal condition triggered by specific anesthetic drugs, especially a depolarizing muscle relaxant of succinylcholine (Suxamethonium). Despite the frequent use of succinylcholine with electroconvulsive therapy (ECT), there has been no reported case of potentially lethal malignant hyperthermia following ECT. In addition, the time interval between the administration of succinylcholine and the onset of malignant hyperthermia has not been outlined in the context of ECT. Case presentation: We present the case of a 79-year-old woman suffering from severe depression, who experienced severe malignant hyperthermia due to succinylcholine administration during an ECT session. She presented with a high fever of 40.2 °C, tachycardia of 140/min, hypertension with a blood pressure exceeding 200 mmHg, significant muscle rigidity, and impaired consciousness. These symptoms emerged two hours after ECT, which occurred in a psychiatric ward rather than an operating room, and reached their peak in less than 24 h. She was given 60 mg of dantrolene, which quickly reduced the muscular rigidity. Subsequently, she received two additional doses of 20 mg and 60 mg of dantrolene, which brought her fever down to 36.2 °C and completely eased her muscle rigidity within two days after ECT. Conclusions: This is the first reported case of potentially lethal malignant hyperthermia after ECT. In addition, it highlights the delayed onset of malignant hyperthermia following an ECT procedure, emphasizing the necessity for psychiatrists to recognize its onset even after the treatment. In the light of potentially lethal consequences of malignant hyperthermia, it is critically important for psychiatrists to closely monitor both intraoperative and postoperative patient’s vital signs and characteristic physical presentations, promptly identify any symptomatic emergence, and treat it immediately with dantrolene.

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Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder

Sano Y., Yamamoto Y., Kubota M., Moriguchi S., Matsuoka K., Kurose S., Tagai K., Endo H., Yamagata B., Suzuki H., Tarumi R., Nomoto K., Takado Y., Kawamura K., Zhang M.R., Tabuchi H., Mimura M., Uchida H., Higuchi M., Takahata K.

Translational Psychiatry 14 ( 1 ) 403 2024.12

Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [18F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = –0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.

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Efficacy and safety of intravenous ketamine treatment in Japanese patients with treatment-resistant depression: A double-blind, randomized, placebo-controlled trial

Ohtani Y., Tani H., Nomoto-Takahashi K., Yatomi T., Yonezawa K., Tomiyama S., Nagai N., Kusudo K., Honda S., Moriyama S., Nakajima S., Yamada T., Morisaki H., Iwabuchi Y., Jinzaki M., Yoshimura K., Eiro T., Tsugawa S., Ichijo S., Fujimoto Y., Miyazaki T., Takahashi T., Uchida H.

Psychiatry and Clinical Neurosciences 78 ( 12 ) 765 - 775 2024.12

ISSN 13231316

Aim: Although the antidepressant effect of ketamine on treatment-resistant depression (TRD) has been frequently reported in North American and European countries, evidence is scarce among the Asian population. We aimed to evaluate the efficacy and safety of intravenous ketamine in Japanese patients with TRD. Methods: In this double-blind randomized placebo-controlled trial, 34 Japanese patients with TRD were randomized to receive either intravenous ketamine (0.5 mg/kg) or placebo, administered over 40 min, twice a week, for 2 weeks. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to post-treatment. Secondary outcomes included changes in other depressive symptomatology scores and remission, response, and partial response rates. We also examined the association between baseline clinical demographic characteristics and changes in the MADRS total score. Results: Intention-to-treat analysis indicated no significant difference in the decrease in MADRS total score between the groups (−8.1 ± 10.0 vs −2.5 ± 5.2, t[32] = 2.02, P = 0.052), whereas per-protocol analysis showed a significant reduction in the ketamine group compared to the placebo group (−9.1 ± 10.2 vs −2.7 ± 5.3, t[29] = 2.22, P = 0.034). No significant group differences were observed in other outcomes. Adverse events were more frequent in the ketamine group than in the placebo group, and no serious adverse events were reported. A higher baseline MADRS total score and body mass index were associated with a greater reduction in the MADRS total score. Conclusion: Intravenous ketamine outperformed placebo in Japanese patients with TRD who completed the study, suggesting that ketamine could alleviate depressive symptoms of TRD across diverse ethnic populations.

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Influence of dementia-specialized care team on clinical outcomes in a general hospital

Shimomura Y., Nishimura W., Murayama M., Yoshimura K., Mimura M., Uchida H., Takeuchi H., Shishida K.

Asian Journal of Psychiatry 102 104256 2024.12

ISSN 18762018

Background: Because of the increasing prevalence of dementia in Japan, the government introduced financial incentives for specialized care for dementia at acute care hospitals in 2016. Our hospital then introduced a multidisciplinary collaborative specialized team, referred to as dementia-specialized care team. The aim of this study is to examine the influence of dementia-specialized care team on clinical outcomes for elderly inpatients. Methods: In this retrospective observational study at a general hospital with 650 beds in Japan, we compared clinical outcomes such as incidence of falls, prescription of hypnotics, length of hospital stay, in-hospital mortality, and discharge destinations in inpatients aged 65 years and older between a two-year pre-intervention period (2014–2015) and a two-year post-intervention period (2017–2018). Results: During the observation period, a total of 34,097 patients were admitted, with 16,237 patients in the pre-intervention period and 17,860 patients in the post-intervention period. The proportion of patients receiving any hypnotics decreased from 21.2 % to 19.2 %, notably with benzodiazepine from 19.8 % to 13.2 %. The incidence of falls from a seated or lying position, particularly at night, was significantly lower (from 0.5 % to 0.2 %) as was the length of hospital stay (from 13.7 days to 13.2 days) during the post-intervention period. Conclusion: After the implementation of dementia-specialized care team, favorable outcomes such as a reduction in the use of hypnotics, the incidence of falls, and the length of hospitalization were observed. Introduction of the team and associated incentives may be effective in improving clinical outcomes in elderly inpatients.

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Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer's disease patients revealed by positron emission tomography

Suzuki H., Tagai K., Ono M., Shimizu H., Endo H., Matsumoto H., Kubota M., Kataoka Y., Moriguchi S., Kurose S., Ichihashi M., Shinotoh H., Matsuoka K., Kokubo N., Tatebe H., Matsuura S., Yamamoto Y., Momota Y., Kawamura K., Zhang M.R., Takado Y., Shimada H., Tokuda T., Onaya M., Mimura M., Kakita A., Sahara N., Uchida H., Higuchi M., Takahata K.

Journal of Alzheimer S Disease 102 ( 4 ) 1271 - 1285 2024.12

ISSN 13872877

Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

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Development of the Japanese version of the Challenging Experience Questionnaire

Tani H., Yonezawa K., Kusudo K., Barrett F.S., Nakajima S., Uchida H.

Neuropsychopharmacology Reports 44 ( 3 ) 534 - 539 2024.09

Introduction: The therapeutic potential of psychedelics for various mental disorders has gained significant interest. Previous studies have highlighted that psychedelics induce psychoactive effects, including challenging aspects of experiences. These experiences are assessed using the Challenging Experience Questionnaire (CEQ), yet its Japanese version has been unavailable. This study aimed to create a Japanese version of the CEQ. Methods: We followed the “Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation.” Initially, two Japanese psychiatrists independently conducted the forward translations. These were then reconciled into a single version, which was back-translated into English. The original authors reviewed this back-translation for accuracy, leading to revisions through continuous dialogue until the original authors approved the final version. Results: The final, approved back-translated version of the CEQ is presented in the figure. Conclusions: This study developed a Japanese version of the CEQ, enabling the assessment of challenging experiences during psychedelic-assisted therapy for Japanese speakers. Further studies are needed to assess the reliability and validity of this newly translated version.

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A case of painful legs and moving toes syndrome mimicking somatic symptom disorder

Mimura Y., Komatsu K., Yasushi Y., Seki M., Nakajima S., Uchida H., Mimura M.

Psychogeriatrics (Psychogeriatrics) 24 ( 4 ) 1023 - 1029 2024.07

ISSN 13463500

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Aberrant heartbeat-evoked potential in schizophrenia

Koreki A., Ogyu K., Miyazaki T., Takenouchi K., Matsushita K., Honda S., Koizumi T., Onaya M., Uchida H., Mimura M., Nakajima S., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 132 110969 2024.06

ISSN 02785846

Self-disturbance is considered a core feature underlying the psychopathology of schizophrenia. Interoception has an important role in the development of a sense of self, leading to increased interest in the potential contribution of abnormal interoception to self-disturbances in schizophrenia. Several neuropsychological studies have demonstrated aberrant interoception in schizophrenia. However, cortical interoceptive processing has not yet been thoroughly investigated. Thus, we sought to examine resting-state heartbeat-evoked potential (HEP) in this population. We hypothesized that patients with schizophrenia would exhibit significant alterations in HEP compared to healthy controls (HCs). In this cross-sectional electroencephalogram (EEG) study, we compared the HEPs between age- and sex-matched groups of patients with schizophrenia and HCs. A 10-min resting-state EEG with eyes closed and an electrocardiogram (ECG) were recorded and analyzed for the time window of 450 ms to 500 ms after an ECG R peak. A positive HEP shift was observed in the frontal-central regions (F [1, 82] = 7.402, p = 0.008, partial η2 = 0.009) in patients with schizophrenia (n = 61) when compared with HCs (n = 31) after adjusting for confounders such as age, sex, and heart rate. A cluster-based correction analysis revealed that the HEP around the right frontal area (Fp2, F4, and F8) showed the most significant group differences (F [1, 82] = 10.079, p = 0.002, partial η2 = 0.021), with a peak at the F4 electrode site (F [1, 82] = 12.646, p < 0.001, partial η2 = 0.069). We observed no correlation between HEP and symptoms in patients with schizophrenia. A positive shift of HEP during the late component could reflect a trait abnormality in schizophrenia. Further research is required to determine the association between the altered cortical interoceptive processing indexed with HEP and self-disturbances in schizophrenia.

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Decreased short-latency afferent inhibition in individuals with mild cognitive impairment: A TMS-EEG study

Mimura Y., Tobari Y., Nakajima S., Takano M., Wada M., Honda S., Bun S., Tabuchi H., Ito D., Matsui M., Uchida H., Mimura M., Noda Y.

Progress in Neuro-Psychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry) 132 110967 2024.06

ISSN 02785846

TMS combined with EEG (TMS-EEG) is a tool to characterize the neurophysiological dynamics of the cortex. Among the TMS paradigms, short-latency afferent inhibition (SAI) allows the investigation of inhibitory effects mediated by the cholinergic system. The aim of this study was to compare cholinergic function in the DLPFC between individuals with mild cognitive impairment (MCI) and healthy controls (HC) using TMS-EEG with the SAI paradigm. In this study, 30 MCI and 30 HC subjects were included. The SAI paradigm consisted of 80 single pulse TMS and 80 SAI stimulations applied to the left DLPFC. N100 components, global mean field power (GMFP) and total power were calculated. As a result, individuals with MCI showed reduced inhibitory effects on N100 components and GMFP at approximately 100 ms post-stimulation and on β-band activity at 200 ms post-stimulation compared to HC. Individuals with MCI showed reduced SAI, suggesting impaired cholinergic function in the DLPFC compared to the HC group. We conclude that these findings underscore the clinical applicability of the TMS-EEG method as a powerful tool for assessing cholinergic function in individuals with MCI.

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Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants

Hart X.M., Spangemacher M., Defert J., Uchida H., Grnder G.

Therapeutic Drug Monitoring (Therapeutic Drug Monitoring) 46 ( 2 ) 155 - 169 2024.04

ISSN 01634356

Background:Compared with antipsychotics, the relationship between antidepressant blood (plasma or serum) concentrations and target engagement is less well-established.Methods:We have discussed the literature on the relationship between plasma concentrations of antidepressant drugs and their target occupancy. Antidepressants reviewed in this work are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, milnacipran, tricyclic antidepressants (amitriptyline, nortriptyline, and clomipramine), bupropion, tranylcypromine, moclobemide, and vortioxetine. Four electronic databases were systematically searched.Results:We included 32 articles published 1996-2022. A strong relationship between serotonin transporter (SERT) occupancy and drug concentration is well established for selective serotonin reuptake inhibitors. Lower limits of recommended therapeutic reference ranges largely corroborate with the findings from positron emission tomography studies (80% SERT occupancy). Only a few novel studies have investigated alternative targets, that is, norepinephrine transporters (NETs), dopamine transporters (DATs), or monoamine oxidase A (MAO-A). For certain classes of drugs, positron emission tomography study data are inconclusive. Low DAT occupancy after bupropion treatment speculates its discussed mechanism of action. For MAO inhibitors, a correlation between drug concentration and MAO-A occupancy could not be established.Conclusions:Neuroimaging studies are critical in TDM-guided therapy for certain antidepressants, whereas for bupropion and MAO inhibitors, the available evidence offers no further insight. Evidence for selective serotonin reuptake inhibitors is strong and justifies a titration toward suggested ranges. For SNRIs, duloxetine, and venlafaxine, NETs are sufficiently occupied, well above the SERT efficacy threshold. For these drugs, a titration toward higher concentrations (within the recommended range) should be considered in case of no response at lower concentrations.

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Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance

Sone D., Young A., Shinagawa S., Tsugawa S., Iwata Y., Tarumi R., Ogyu K., Honda S., Ochi R., Matsushita K., Ueno F., Hondo N., Koreki A., Torres-Carmona E., Mar W., Chan N., Koizumi T., Kato H., Kusudo K., de Luca V., Gerretsen P., Remington G., Onaya M., Noda Y., Uchida H., Mimura M., Shigeta M., Graff-Guerrero A., Nakajima S.

Schizophrenia Bulletin (Schizophrenia Bulletin) 50 ( 2 ) 393 - 402 2024.03

ISSN 05867614

Background and Hypothesis: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. Study Design: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machinelearning analysis. Study Results: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). Conclusions: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

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Associations Between Structural Covariance Network and Antipsychotic Treatment Response in Schizophrenia

Tsugawa S., Honda S., Noda Y., Wannan C., Zalesky A., Tarumi R., Iwata Y., Ogyu K., Plitman E., Ueno F., Mimura M., Uchida H., Chakravarty M., Graff-Guerrero A., Nakajima S.

Schizophrenia Bulletin 50 ( 2 ) 382 - 392 2024.03

ISSN 05867614

Background and Hypothesis: Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia. Study Design: We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinicodemographics was also explored. Study Results: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and frontooccipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group. Conclusions: These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease.

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Development of the Japanese version of the 30-item Mystical Experience Questionnaire

Yonezawa K., Tani H., Nakajima S., Uchida H.

Neuropsychopharmacology Reports (Neuropsychopharmacology Reports) 44 ( 1 ) 280 - 284 2024.03

Introduction: Psychedelics have garnered increased attention as potential therapeutic options for various mental illnesses. Previous studies reported that psychedelics cause psychoactive effects through mystical experiences induced by these substances, including an altered state of consciousness. While this phenomenon is commonly assessed by the Mystical Experiences Questionnaire (MEQ30), a Japanese version of the MEQ30 has not been available. The aim of this study was to develop the Japanese version of the MEQ30. Methods: We adhered to the “Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation” in our translation process. Two Japanese psychiatrists independently performed forward translations, from which a unified version was derived through reconciliation. This version was subsequently back-translated into English and reviewed by the original authors for equivalency. The iterative revision process was carried out through ongoing discussions with the original authors until they approved the final back-translated version. Results: The final, approved back-translated version of the MEQ30 is presented in the accompanying figure. Additionally, the authorized Japanese version of the MEQ30 is included in the Appendix A. Conclusions: In this study, we successfully developed a Japanese version of the MEQ30. This scale will facilitate the assessment of mystical experiences associated with psychedelic-assisted therapy among Japanese speakers. Further research is warranted to evaluate the reliability and validity of this newly translated scale.

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Development of the Japanese version of the Ego-Dissolution Inventory (EDI)

Kusudo K., Tani H., Yonezawa K., Nakajima S., Nour M.M., Carhart-Harris R., Uchida H.

Neuropsychopharmacology Reports (Neuropsychopharmacology Reports) 44 ( 1 ) 292 - 297 2024.03

Aim: Psychedelics have recently gained attention as potential therapeutic agents for various psychiatric disorders. Previous research has highlighted that a diminished sense of self, commonly termed “ego-dissolution” is a pivotal feature of the psychedelic-induced state. While the Ego-Dissolution Inventory (EDI) is a widely acknowledged instrument for measuring this phenomenon, no Japanese version has been available. This study aimed to develop a Japanese version of the EDI. Methods: We adhered to the “Guidelines for Best Practices in the Translation and Cultural Modification Process for Patient-Reported Outcomes Instruments: Document from the ISPOR Committee on Translation and Cultural Modification” during our translation approach. Two Japanese psychiatrists independently conducted initial translations, and a consolidated version was achieved via mutual agreement. This version was then back-translated to English and assessed by the original authors for consistency. The repetitive modification process was conducted in continuous dialogues with the original authors until they accepted the concluding back-translated version. Results: The finalized, approved back-translated version of the EDI is presented in the accompanying figure. In addition, the authorized Japanese version of the EDI is included in the Appendix. Conclusions: In this study, we successfully developed the Japanese version of the EDI. This instrument will assist in assessing ego-dissolution experiences associated with psychedelic-assisted therapy among Japanese speakers. Additional studies are necessary to evaluate the reliability and validity of this newly translated instrument.

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治療抵抗性うつ病の回復過程に関わる病態基盤の解明

内田裕之

先進医薬研究振興財団研究成果報告集 ((公財)先進医薬研究振興財団) 2023年度 284 - 286 2024.03

ISSN 2189-1303

治療抵抗性うつ病患者にケタミンを投与し、その治療前後でAMPA-PETを用いてAMPA受容体の密度と分布の変化を検証し、ケタミンの作用発現過程およびうつ病の回復過程をAMPA受容体の観点から検討した。本研究はプラセボ対照二重盲検無作為化比較試験であり、現在のうつエピソードに対して抗うつ薬を2種類以上使用しても反応しなかった34名を対象とした。主要評価尺度であるモンゴメリ・アスベルグうつ病評価尺度(MADRS)を用いて評価した気分症状の重症度の変化は、intention-to-treat解析においてケタミン群とプラセボ群の間でのMADRS総点の低下に有意差は認めず、per-protocol解析ではケタミン群のMADRS総点の有意な低下が認められた。ケタミン部分反応者において、ケタミン治療介入により有意にstandardized uptake value ratioが有意に上昇している領域として、下前頭回、中眼窩回などの前頭葉、中心後回、下頭頂葉、縁上回が抽出された。腹側被蓋野～内側視床にかけての領域、海馬、被殼におけるケタミン治療介入前のstandardized uptake value ratioが低いことと治療介入前後のMADRS総点の減少が有意に相関していた。

Relationship between Loneliness and Mild Behavioral Impairment: Validation of the Japanese Version of the MBI Checklist and a Cross-Sectional Study

Matsuoka T., Ismail Z., Imai A., Shibata K., Nakamura K., Nishimura Y., Rubinstein E., Uchida H., Mimura M., Narumoto J.

Journal of Alzheimer's Disease 97 ( 4 ) 1951 - 1960 2024.02

ISSN 13872877

Background: Mild behavioral impairment (MBI) and loneliness are associated with cognitive decline and an increased risk of dementia. Objective: Our aim was to examine the validity of the Japanese version of the MBI checklist (MBI-C) and investigate the relationship between loneliness and MBI. Methods: The participants in this cross-sectional study included 5 cognitively normal persons and 75 persons with mild cognitive impairment. MBI-C and the revised University of California at Los Angeles loneliness scale (LS) were used to assess MBI and loneliness, respectively. Diagnostic performance of MBI-C was examined using receiver operating characteristic analysis. The relationship between MBI-C and LS was examined using multiple linear regression in 67 subjects who were assessed with both scales, with MBI-C total or domain score as the dependent variable and LS as the independent variable, adjusted for age, gender, living situation, presence of visual and hearing impairment, and Mini-Mental State Examination score. Results: Per the Youden index, in this mostly MCI sample, the optimal MBI-C cut-off score was 5.5 with sensitivity 0.917 and specificity 0.949. In multiple linear regression analysis, LS score was detected as a significant predictor of MBI-C total scores, and MBI-C decreased motivation, affective dysregulation, and abnormal thought and perception scores. Conclusions: The caregiver-rated Japanese MBI-C has excellent diagnostic performance. Loneliness is associated with a greater MBI burden, especially in the decreased motivation, affective dysregulation, and abnormal thought and perception domains. Interventions for loneliness in older people may have the potential to improve MBI.

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Update Lessons from Positron Emission Tomography Imaging Part I: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antipsychotics

Hart X.M., Spangemacher M., Uchida H., Gründer G.

Therapeutic Drug Monitoring (Therapeutic Drug Monitoring) 46 ( 1 ) 16 - 32 2024.02

ISSN 01634356

Background:Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring-guided antipsychotic drug therapy. The optimal therapeutic windows for D2antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search.Methods:This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D2-like and 5-HT2Areceptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion.Results:The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect.Conclusions:Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring.

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