Updated on 2025/03/25

写真a

 
IKEDA Masashi
 
Organization
Graduate School of Medicine Program in Integrated Medicine Clinical Neurosciences Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor
 

Papers 34

  1. Anxiety, Depression and Cancer-Related Post-Traumatic Stress in Patients Undergoing Total Laryngectomy

    Yokoi, M; Nishio, N; Kimura, H; Tokura, T; Kishi, S; Tsuzuki, H; Mukoyama, N; Yokoi, S; Wada, A; Shigeyama, M; Fujimoto, Y; Ikeda, M; Sone, M

    LARYNGOSCOPE INVESTIGATIVE OTOLARYNGOLOGY   Vol. 10 ( 2 ) page: e70109   2025.4

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    Language:English   Publisher:Laryngoscope Investigative Otolaryngology  

    Purpose: This study aims to elucidate the incidence of cancer-related post-traumatic stress (PTS) and the fluctuations in anxiety and depression levels before and one year after laryngectomy. Methods: A prospective longitudinal study was conducted on 97 consecutive patients scheduled to undergo laryngectomy (total laryngectomy or pharyngolaryngectomy) at a single university hospital between 2007 and 2022. To assess cancer-related PTS, anxiety, and depression, participants completed two brief self-reported questionnaires: the Impact of Event Scale-Revised (IES-R) and the Hospital Anxiety and Depression Scale (HADS). Results: Prior to laryngectomy, 32 patients planning for the procedure were considered as cancer-related PTS based on IES-R. The prevalence of anxiety and depression before surgery was 56% and 76% in the 32 patients with PTS, respectively, compared to 8% and 20% in the 65 patients without PTS. Patients with PTS exhibited significantly worse HADS-anxiety and HADS-depression scores compared to those without PTS at baseline (p < 0.001 for both). Although no significant difference was found in the HADS-anxiety score between the two groups (p = 0.15), patients with PTS exhibited a significantly worse HADS-depression score than those without PTS one year after surgery (p = 0.03). Conclusion: Early identification of possible depressive disorders and active psychiatric interventions are crucial for patients undergoing laryngectomy during the follow-up period. Preoperative assessment of cancer-related PTS may offer an opportunity to implement appropriate psychological interventions. Level of Evidence: 4.

    DOI: 10.1002/lio2.70109

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  2. Association of sleep-wake state discrepancy and depressive symptoms with restorative sleep in patients with depression Open Access

    Kawai, K; Iwamoto, K; Miyata, S; Okada, I; Ando, M; Fujishiro, H; Noda, A; Ozaki, N; Ikeda, M

    SLEEP MEDICINE   Vol. 127   page: 166 - 169   2025.3

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    Objective: One of the common symptoms of mood disorders is insomnia, and the recovery processes can be negatively impacted by a lack of restorative sleep. Although factors related to restorative sleep in healthy subjects have been investigated, evaluations of these factors in patients with depression have been rarely done. Patients with depression are known to have sleep-wake state discrepancy, which can further influence their restorative sleep beyond that associated with depressive symptoms. Thus, we investigated restorative sleep in depressed patients in our current study, and attempted to identify associated factors, with a particular focus on sleep-wake state discrepancy. Methods: In the 91 participants evaluated in this cross-sectional study, all subjects filled out questionnaires on their symptoms prior to undergoing polysomnography (PSG). Sleep duration and restorative sleep were evaluated on the morning after the PSG. The association between restorative sleep and various factors was then examined using multiple regression analysis. Results: A negative association with restorative sleep was found through multiple regression analysis for depressive symptoms (β = −0.055, p = 0.007), daytime sleepiness (β = −0.106, p = 0.020), and overestimation of wake after sleep onset (β = −0.006, p = 0.030). Conclusions: By subjectively and objectively assessing sleep, addressing depressive symptoms, and implementing appropriate sleep hygiene, clinicians could be able to improve restorative sleep in depressed patients.

    DOI: 10.1016/j.sleep.2025.01.021

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  3. Whole-genome sequencing analysis of Japanese autism spectrum disorder trios

    Furukawa, S; Kushima, I; Kato, H; Kimura, H; Nawa, Y; Aleksic, B; Banno, M; Yamamoto, M; Uematsu, M; Nagasaki, Y; Ogi, T; Ozaki, N; Ikeda, M

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   Vol. 79 ( 3 ) page: 87 - 97   2025.3

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    Language:English   Publisher:Psychiatry and Clinical Neurosciences  

    Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

    DOI: 10.1111/pcn.13767

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  4. Second-generation antipsychotic-induced dystonia: Analysis using the Japanese Adverse Drug Event Report (JADER) database Open Access

    Ebina, T; Iwamoto, K; Ando, M; Ikeda, M

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   Vol. 79 ( 3 ) page: 117 - 124   2025.3

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    Aim: This study aimed to explore the comparative risks for dystonia among different second-generation antipsychotics (SGAs), the influence of sex, and the relationship between the time-to-onset of dystonia and its outcomes. Methods: We analyzed data from the Japanese Adverse Drug Event Report database from April 2004 to November 2023. Cases involving oral SGAs, excluding clozapine, were extracted. We used the odds ratios to assess the reporting proportions among SGAs and sex, analyzed the median time-to-onset and interquartile ranges (IQRs), and conducted a receiver operating characteristic (ROC) curve analysis to investigate the time-to-onset of dystonia and its relationship to outcomes. Results: We extracted 9837 cases involving oral SGAs. Lurasidone was associated with a significantly higher proportion of dystonia reports than risperidone, aripiprazole, quetiapine, and olanzapine. The reporting proportion of dystonia associated with aripiprazole was lower than that of paliperidone and risperidone, but higher than that of quetiapine and olanzapine. Female sex was significantly associated with a higher reporting proportion of dystonia compared with males. Among the 148 cases of oral SGA-induced dystonia, the median time-to-onset was 125 days (IQR, 19.75–453.25 days). Divided into the three outcome groups (recovered, improved, and unrecovered/residual), those with better outcomes had a shorter time-to-onset than those with poorer outcomes. ROC curve analysis suggested a threshold of 91.5 days for discriminating outcomes, with a sensitivity of 71.7% and specificity of 69.9%. Conclusions: The risks of dystonia may vary among SGAs and between sexes. SGA-induced dystonia often manifests in the tardive form.

    DOI: 10.1111/pcn.13785

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  5. Proposal for a Novel Classification of Patients With Enlarged Ventricles and Cognitive Impairment Based on Data-Driven Analysis of Neuroimaging Results in Patients With Psychiatric Disorders Open Access

    Yasuda, Y; Ito, S; Matsumoto, J; Okada, N; Onitsuka, T; Ikeda, M; Kushima, I; Sumiyoshi, C; Fukunaga, M; Nemoto, K; Miura, K; Hashimoto, N; Ohi, K; Takahashi, T; Sasabayashi, D; Koeda, M; Yamamori, H; Fujimoto, M; Takano, H; Hasegawa, N; Narita, H; Yamamoto, M; Tha, KK; Kikuchi, M; Kamishikiryo, T; Itai, E; Okubo, Y; Tateno, A; Nakamura, M; Kubota, M; Igarashi, H; Hirano, Y; Okada, G; Miyata, J; Numata, S; Abe, O; Yoshimura, R; Nakagawa, S; Yamasue, H; Ozaki, N; Kasai, K; Hashimoto, R

    NEUROPSYCHOPHARMACOLOGY REPORTS   Vol. 45 ( 1 ) page: e70010   2025.3

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    Language:English   Publisher:Neuropsychopharmacology Reports  

    One of the challenges in diagnosing psychiatric disorders is that the results of biological and neuroscience research are not reflected in the diagnostic criteria. Thus, data-driven analyses incorporating biological and cross-disease perspectives, regardless of the diagnostic category, have recently been proposed. A data-driven clustering study based on subcortical volumes in 5604 subjects classified into four brain biotypes associated with cognitive/social functioning. Among the four brain biotypes identified in controls and patients with schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and other psychiatric disorders, we further analyzed the brain biotype 1 subjects, those with an extremely small limbic region, for clinical utility. We found that the representative feature of brain biotype 1 is enlarged lateral ventricles. An enlarged ventricle, defined by an average z-score of left and right lateral ventricle volumes > 3, had a sensitivity of 99.1% and a specificity of 98.1% for discriminating brain biotype 1. However, the presence of an enlarged ventricle was not sufficient to classify patient subgroups, as 1% of the controls also had enlarged ventricles. Reclassification of patients with enlarged ventricles according to cognitive impairment resulted in a stratified subgroup that included patients with a high proportion of schizophrenia diagnoses, electroencephalography abnormalities, and rare pathological genetic copy number variations. Data-driven clustering analysis of neuroimaging data revealed subgroups with enlarged ventricles and cognitive impairment. This subgroup could be a new diagnostic candidate for psychiatric disorders. This concept and strategy may be useful for identifying biologically defined psychiatric disorders in the future.

    DOI: 10.1002/npr2.70010

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  6. Distinguishing clinical and genetic risk factors for suicidal ideation and behavior in a diverse hospital population Open Access

    Colbert, SMC; Lepow, L; Fennessy, B; Iwata, N; Ikeda, M; Saito, T; Terao, C; Preuss, M; Pathak, J; Mann, JJ; Coon, H; Mullins, N

    TRANSLATIONAL PSYCHIATRY   Vol. 15 ( 1 ) page: 63   2025.2

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    Suicidal ideation (SI) and behavior (SB) are major public health concerns, but risk factors for their development and progression are poorly understood. We used ICD codes and a natural language processing algorithm to identify individuals in a hospital biobank with SI-only, SB, and controls without either. We compared the profiles of SB and SI-only patients to controls, and each other, using phenome-wide association studies (PheWAS) and polygenic risk scores (PRS). PheWAS identified many risk factors for SB and SI-only, plus specific psychiatric disorders which may be involved in progression from SI-only to SB. PRS for suicide attempt were only associated with SB, and even after accounting for psychiatric disorder PRS. SI PRS were only associated with SI-only, although not after accounting for psychiatric disorder PRS. These findings advance understanding of distinct genetic and clinical risk factors for SB and SI-only, which will aid in early detection and intervention efforts.

    DOI: 10.1038/s41398-025-03287-6

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  7. IMPACT OF ANTIPSYCHOTICS ON PROLACTIN LEVELS IN PEDIATRIC AND ADOLESCENT PATIENTS WITH PSYCHIATRIC DISORDERS IN REAL-WORLD PSYCHIATRIC CLINICAL PRACTICE

    Wada, S; Iwamoto, K; Ikeda, M

    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   Vol. 28   page: i343 - i344   2025.2

  8. WHOLE GENOME SEQUENCING ANALYSIS OF JAPANESE ASD TRIOS: UNRAVELING PATHOGENIC VARIANTS

    Furukawa, S; Kushima, I; Kimura, H; Kato, H; Nawa, Y; Aleksic, B; Ogi, T; Ozaki, N; Ikeda, M

    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   Vol. 28   page: i59 - i59   2025.2

  9. INVESTIGATION OF THE LONG-TERM EFFECTS OF LEMBOREXANT ON OBJECTIVE SLEEP MEASURES USING A MINIATURE ELECTROENCEPHALOGRAM

    Miyata, S; Okada, I; Iwamoto, K; Fujimoto, A; Kogo, Y; Amano, M; Matsuyama, N; Ozaki, N; Ikeda, M

    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   Vol. 28   page: i241 - i242   2025.2

  10. Copy number variations in <i>RNF216</i> and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population Open Access

    Nakatochi, M; Kushima, I; Aleksic, B; Kimura, H; Kato, H; Inada, T; Torii, Y; Takahashi, N; Yamamoto, M; Iwamoto, K; Nawa, Y; Iritani, S; Iwata, N; Saito, T; Ninomiya, K; Okochi, T; Hashimoto, R; Yamamori, H; Yasuda, Y; Fujimoto, M; Miura, K; Ohi, K; Shioiri, T; Kitaichi, K; Itokawa, M; Arai, M; Miyashita, M; Toriumi, K; Takahashi, T; Suzuki, M; Kato, TA; Kanba, S; Horikawa, H; Kasai, K; Ikegame, T; Jinde, S; Kato, T; Kakiuchi, C; Yamagata, B; Nio, S; Kunii, Y; Yabe, H; Okamura, Y; Tadaka, S; Fumihiko, U; Obara, T; Yamamoto, Y; Arioka, Y; Mori, D; Ikeda, M; Ozaki, N

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   Vol. 79 ( 1 ) page: 12 - 20   2025.1

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    Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66–14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane–related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

    DOI: 10.1111/pcn.13752

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  11. Premorbid autistic traits in phenocopy syndrome of behavioral variant frontotemporal dementia: An autopsy revealing primary age-related tauopathy

    Arafuka, S; Torii, Y; Fujishiro, H; Sekiguchi, H; Miwa, A; Habuchi, C; Sasada, K; Yoshida, M; Iritani, S; Iwasaki, Y; Ikeda, M

    ASIAN JOURNAL OF PSYCHIATRY   Vol. 103   page: 104314   2025.1

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    Language:English   Publisher:Asian Journal of Psychiatry  

    DOI: 10.1016/j.ajp.2024.104314

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  12. Genomics yields biological and phenotypic insights into bipolar disorder Open Access

    O’Connell K.S., Koromina M., van der Veen T., Boltz T., David F.S., Yang J.M.K., Lin K.H., Wang X., Coleman J.R.I., Mitchell B.L., McGrouther C.C., Rangan A.V., Lind P.A., Koch E., Harder A., Parker N., Bendl J., Adorjan K., Agerbo E., Albani D., Alemany S., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Antoniou A., Ask H., Bass N., Bauer M., Beins E.C., Bigdeli T.B., Pedersen C.B., Boks M.P., Børte S., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cabana-Domínguez J., Cairns M.J., Carpiniello B., Casas M., Cervantes P., Chatzinakos C., Chen H.C., Clarence T., Clarke T.K., Claus I., Coombes B., Corfield E.C., Cruceanu C., Cuellar-Barboza A., Czerski P.M., Dafnas K., Dale A.M., Dalkner N., Degenhardt F., DePaulo J.R., Djurovic S., Drange O.K., Escott-Price V., Fanous A.H., Fellendorf F.T., Ferrier I.N., Forty L., Frank J., Frei O., Freimer N.B., Fullard J.F., Garnham J., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha T.H., Hahn T., Haraldsson M., Hautzinger M., Havdahl A., Heilbronner U., Hellgren D., Herms S., Hickie I.B., Hoffmann P., Holmans P.A., Huang M.C., Ikeda M., Jamain S., Johnson J.S., Jonsson L., Kalman J.L., Kamatani Y., Kennedy J.L., Kim E., Kim J., Kittel-Schneider S.

    Nature     2025

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    Language:English   Publisher:Nature  

    Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

    DOI: 10.1038/s41586-024-08468-9

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  13. Treatment-resistant schizophrenia with 22q11.2 deletion and additional genetic defects Open Access

    Furukawa, S; Arafuka, S; Kato, H; Ogi, T; Ozaki, N; Ikeda, M; Kushima, I

    NEUROPSYCHOPHARMACOLOGY REPORTS   Vol. 44 ( 4 ) page: 847 - 851   2024.12

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    We report a case of a 61-year-old female with 22q11.2 deletion syndrome (22q11.2DS) and a novel heterozygous nonsense variant in MAP1A, identified through whole-genome sequencing (WGS). The patient presented with intellectual developmental disorder, treatment-resistant schizophrenia (SCZ), and multiple congenital anomalies. Despite aggressive pharmacotherapy, she experienced persistent auditory hallucinations and negative symptoms. WGS revealed a 3 Mb deletion at 22q11.2 and a nonsense variant in MAP1A (c.4652T>G, p.Leu1551*). MAP1A, encoding microtubule-associated protein 1A, is crucial for axon and dendrite development and has been implicated in autism spectrum disorder and SCZ. The MAP1A variant may contribute to the severe psychiatric phenotype, as it is thought to influence synaptic plasticity, a process also affected by 22q11.2 deletion. This case highlights the importance of WGS in identifying additional pathogenic variants that may explain phenotypic variability in 22q11.2DS. Thus, WGS can lead to a better understanding of the genetic architecture of 22q11.2DS. However, further studies are needed to elucidate the role of secondary genetic contributors in the diverse clinical presentations of 22q11.2DS.

    DOI: 10.1002/npr2.12477

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  14. Association of plasma arachidonic acid levels with a bipolar disorder and the effects of a FADS gene variant Open Access

    Ashizawa, T; Saito, T; Okochi, T; Ninomiya, K; Ito, K; Aoki, R; Ikeda, M; Iwata, N

    TRANSLATIONAL PSYCHIATRY   Vol. 14 ( 1 ) page: 435   2024.10

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    Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (β = −0.36, p = 0.023) and arachidonic acid (AA) (β = −0.18, p = 0.013) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADS and BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conducting lipidomics of BD we believe that the allele frequency of FADS must be analyzed.

    DOI: 10.1038/s41398-024-03141-1

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  15. THE INFLUENCE OF DAILY REST AND ACTIVITY ON MENTAL HEALTH AMONG JAPANESE ADULTS DURING THE COVID-19 PANDEMIC

    Miyata, S; Iwamoto, K; Kawai, K; Fujishiro, H; Ozaki, N; Ikeda, M

    SLEEP   Vol. 47   2024.5

  16. Brexpiprazole-related tardive dystonia in a young patient with schizophrenia: A case report

    Ebina, T; Iwamoto, K; Ikeda, M

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   Vol. 78 ( 5 ) page: 334 - 335   2024.5

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    DOI: 10.1111/pcn.13653

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  17. COMPARISON OF VARIOUS SLEEP MEASUREMENT DEVICES IN PSYCHIATRIC PATIENTS

    Kawai, K; Iwamoto, K; Miyata, S; Okada, I; Fujishiro, H; Ando, M; Noda, A; Ozaki, N; Ikeda, M

    SLEEP   Vol. 47   page: A423 - A423   2024.5

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  18. Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets

    Wakuda, T; Benner, S; Uemura, Y; Nishimura, T; Kojima, M; Kuroda, M; Matsumoto, K; Kanai, C; Inada, N; Harada, T; Kameno, Y; Munesue, T; Inoue, J; Umemura, K; Yamauchi, A; Ogawa, N; Kushima, I; Suyama, S; Saito, T; Hamada, J; Kano, Y; Honda, N; Kikuchi, S; Seto, M; Tomita, H; Miyoshi, N; Matsumoto, M; Kawaguchi, Y; Kanai, K; Ikeda, M; Nakamura, I; Isomura, S; Hirano, Y; Onitsuka, T; Ozaki, N; Kosaka, H; Okada, T; Kuwabara, H; Yamasue, H

    BRAIN BEHAVIOR AND IMMUNITY   Vol. 118   page: 398 - 407   2024.5

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    Language:English   Publisher:Brain, Behavior, and Immunity  

    Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose–response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = −0.05, −0.10 to 0.003, P = 0.067; IL-9: −0.01, −0.02 to −0.003, P = 0.005; MIP-1b: −0.02, −0.04 to −0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

    DOI: 10.1016/j.bbi.2024.03.013

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  19. 特集 よくわかる! 精神疾患対応 これ1冊-内科医と精神科医の連携のために 第8部 知っておきたい最近の精神疾患関連トピックス 3 精神科のゲノム医療

    宮田 雅美, 齋藤 竹生, 池田 匡志

    診断と治療   Vol. 112 ( 13 ) page: 311 - 315   2024.3

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    DOI: 10.34433/dt.0000000704

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  20. Machine learning algorithm-based estimation model for the severity of depression assessed using Montgomery-Asberg depression rating scale Open Access

    Shimamoto, M; Ishizuka, K; Ohtani, K; Inada, T; Yamamoto, M; Tachibana, M; Kimura, H; Sakai, Y; Kobayashi, K; Ozaki, N; Ikeda, M

    NEUROPSYCHOPHARMACOLOGY REPORTS   Vol. 44 ( 1 ) page: 115 - 120   2024.3

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    Aim: Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the “rater & estimation-system” reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI-MADRS (Montgomery-Asberg Depression Rating Scale) estimation system, a machine learning algorithm-based model developed to assess the severity of depression. Methods: During interviews with trained psychiatrists and the AI-MADRS estimation system, patients responded orally to machine-generated voice prompts from the AI-MADRS structured interview questions. The severity scores estimated from two models of the AI-MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists. Results: A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62–0.86) for the max estimation model, and 0.86 (0.76–0.92) for the average estimation model. The ANOVA ICC rater & estimation-system reliability with the evaluation scores by trained psychiatrists was 0.51 (−0.09 to 0.79) for the max estimation model, and 0.75 (0.55–0.86) for the average estimation model. Conclusion: The average estimation model of AI-MADRS demonstrated substantially acceptable rater & estimation-system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI-MADRS interviews are expected to improve the performance of AI-MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments.

    DOI: 10.1002/npr2.12404

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  21. Association between copy number variations in parkin (<i>PRKN</i>) and schizophrenia and autism spectrum disorder: A case-control study Open Access

    Lo, TY; Kushima, I; Kimura, H; Aleksic, B; Okada, T; Kato, H; Inada, T; Nawa, Y; Torii, Y; Yamamoto, M; Kimura, R; Funabiki, Y; Kosaka, H; Numata, S; Kasai, K; Sasaki, T; Yokoyama, S; Munesue, T; Hashimoto, R; Yasuda, Y; Fujimoto, M; Usami, M; Itokawa, M; Arai, M; Ohi, K; Someya, T; Watanabe, Y; Egawa, J; Takahashi, T; Suzuki, M; Yamasue, H; Iwata, N; Ikeda, M; Ozaki, N

    NEUROPSYCHOPHARMACOLOGY REPORTS   Vol. 44 ( 1 ) page: 42 - 50   2024.3

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    Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case–control sample. Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

    DOI: 10.1002/npr2.12370

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  22. 特集 精神疾患における環境要因と遺伝-環境相互作用 自閉スペクトラム症の遺伝-環境相互作用および環境要因

    古川 佐和子, 木村 大樹, 池田 匡志

    医学のあゆみ   Vol. 288 ( 7 ) page: 568 - 572   2024.2

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    DOI: 10.32118/ayu28807568

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  23. 特集 精神疾患における環境要因と遺伝-環境相互作用 はじめに

    池田 匡志

    医学のあゆみ   Vol. 288 ( 7 ) page: 549 - 549   2024.2

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    DOI: 10.32118/ayu28807549

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  24. 特集 精神疾患における環境要因と遺伝-環境相互作用 環境要因としてとらえた精神療法の治療反応性予測

    木村 大樹, 池田 匡志

    医学のあゆみ   Vol. 288 ( 7 ) page: 590 - 593   2024.2

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    DOI: 10.32118/ayu28807590

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  25. 特集 精神疾患における環境要因と遺伝-環境相互作用 統合失調症の環境要因と遺伝-環境相互作用

    長崎 由佳子, 木村 大樹, 池田 匡志

    医学のあゆみ   Vol. 288 ( 7 ) page: 563 - 567   2024.2

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    DOI: 10.32118/ayu28807563

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  26. Effect of single-administration of d-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial Open Access

    Wada, S; Iwamoto, K; Okumura, H; Hida, H; Hiraoka, S; Kamei, A; Mori, D; Yamada, K; Ando, M; Ozaki, N; Ikeda, M

    BMC PSYCHIATRY   Vol. 24 ( 1 ) page: 81   2024.1

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    Background: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of d-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. Methods: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of d-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). Results: d-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. Conclusion: Our findings indicate that single-administration of d-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. Trial registration: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

    DOI: 10.1186/s12888-024-05549-x

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  27. Neuropathological substrate of incident dementia in older patients with schizophrenia: A clinicopathological study

    Arafuka, S; Fujishiro, H; Torii, Y; Sekiguchi, H; Habuchi, C; Miwa, A; Yoshida, M; Iritani, S; Iwasaki, Y; Ikeda, M; Ozaki, N

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   Vol. 78 ( 1 ) page: 29 - 40   2024.1

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    Aim: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia. Methods: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences. Results: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia. Conclusion: Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies.

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  28. Differential genetic correlations across major psychiatric disorders between Eastern and Western countries Open Access

    Saito T., Ikeda M., Terao C., Ashizawa T., Miyata M., Tanaka S., Kanazawa T., Kato T., Kishi T., Iwata N.

    Psychiatry and Clinical Neurosciences   Vol. 77 ( 2 ) page: 118 - 119   2023.2

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    DOI: 10.1111/pcn.13498

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  29. 生体肝移植ドナーの併存精神疾患と精神科連携

    木村 宏之, 杉田 尚子, 大橋 綾子, 成田 尚, 藤澤 大介, 岡田 剛史, 松本 洋輔, 岸 辰一, 川崎 弘詔, 西村 勝治, 小倉 靖弘, 池田 匡志

    移植   Vol. 58 ( Supplement ) page: s116_2 - s116_2   2023

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    <p>"【目的】</p><p>世界の中でアジア地区は生体肝移植ドナーの併存精神疾患が多いとされる。今回、生体肝移植ドナーの併存精神疾患の多施設調査について報告する。</p><p>【方法】</p><p>肝臓移植8施設において、生体移植ドナーの併存精神疾患を後方視的に抽出し、1)ドナー評価時に精神疾患併存の生体肝移植ドナーが移植したレシピエントの予後、2)ドナー評価時/移植後に精神疾患併存の生体肝移植ドナーとその移植レシピエントの特性、を検討した。</p><p>【結果】</p><p>精神疾患併存は、546例のうち46例(ドナー評価時の併存16例を含む8.4%)だった。1)ドナー評価時に精神疾患が併存したドナー16例から移植されたレシピエントの生存率は、併存しないドナーと比して有意差はなかった(Log-rank test: p=0.738, HR: 0.788[95%CI: 0.194-3.198], 最終生存率(%): 62.5 vs 73.8)。2)ドナーに精神疾患(ドナー評価時の併存精神疾患を含)が併存した場合、移植レシピエントにも精神疾患が併存しやすかった(χ2=11.28,自由度=1,p<.001)。</p><p>【結論】</p><p>今回の結果では、生体肝移植ドナーに精神疾患が併存すると肝移植レシピエントにも精神疾患が併存しやすく、精神科的問題が重なる可能性がある。生体肝移植ドナーの精神科サポートは肝移植レシピエントと比べて整備されておらず、円滑な連携の標準化が求められる。当日は具体的な併存精神疾患や連携医療を明示する。</p>

    DOI: 10.11386/jst.58.supplement_s116_2

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  30. X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization Open Access

    Kushima, I; Aleksic, B; Kimura, H; Nakatochi, M; Lo, T; Ikeda, M; Arai, M; Hashimoto, R; Numata, S; Okamura, Y; Obara, T; Inada, T; Ozaki, N

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   Vol. 76 ( 12 ) page: 667 - 673   2022.12

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    Aim: The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case–control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies. Methods: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies. Results: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations. Conclusion: These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.

    DOI: 10.1111/pcn.13474

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  31. Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder Open Access

    Kushima, I; Nakatochi, M; Aleksic, B; Okada, T; Kimura, H; Kato, H; Morikawa, M; Inada, T; Ishizuka, K; Torii, Y; Nakamura, Y; Tanaka, S; Imaeda, M; Takahashi, N; Yamamoto, M; Iwamoto, K; Nawa, Y; Ogawa, N; Iritani, S; Hayashi, Y; Lo, TY; Otgonbayar, G; Furuta, S; Iwata, N; Ikeda, M; Saito, T; Ninomiya, K; Okochi, T; Hashimoto, R; Yamamori, H; Yasuda, Y; Fujimoto, M; Miura, K; Itokawa, M; Arai, M; Miyashita, M; Toriumi, K; Ohi, K; Shioiri, T; Kitaichi, K; Someya, T; Watanabe, Y; Egawa, J; Takahashi, T; Suzuki, M; Sasaki, T; Tochigi, M; Nishimura, F; Yamasue, H; Kuwabara, H; Wakuda, T; Kato, TA; Kanba, S; Horikawa, H; Usami, M; Kodaira, M; Watanabe, K; Yoshikawa, T; Toyota, T; Yokoyama, S; Munesue, T; Kimura, R; Funabiki, Y; Kosaka, H; Jung, MY; Kasai, K; Ikegame, T; Jinde, S; Numata, S; Kinoshita, M; Kato, T; Kakiuchi, C; Yamakawa, K; Suzuki, T; Hashimoto, N; Ishikawa, S; Yamagata, B; Nio, S; Murai, T; Son, S; Kunii, Y; Yabe, H; Inagaki, M; Goto, Y; Okumura, Y; Ito, T; Arioka, Y; Mori, D; Ozaki, N

    BIOLOGICAL PSYCHIATRY   Vol. 92 ( 5 ) page: 362 - 374   2022.9

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    Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

    DOI: 10.1016/j.biopsych.2022.04.003

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  32. Special Section on Low-Power and High-Speed Chips FOREWORD

    Arakawa, F; Ikeda, M

    IEICE TRANSACTIONS ON ELECTRONICS   Vol. E105C ( 6 ) page: 207 - 208   2022.6

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  33. Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial Open Access

    Yamasue, H; Kojima, M; Kuwabara, H; Kuroda, M; Matsumoto, K; Kanai, C; Inada, N; Owada, K; Ochi, K; Ono, N; Benner, S; Wakuda, T; Kameno, Y; Inoue, J; Harada, T; Tsuchiya, K; Umemura, K; Yamauchi, A; Ogawa, N; Kushima, I; Ozaki, N; Suyama, S; Saito, T; Uemura, Y; Hamada, J; Kano, Y; Honda, N; Kikuchi, S; Seto, M; Tomita, H; Miyoshi, N; Matsumoto, M; Kawaguchi, Y; Kanai, K; Ikeda, M; Nakamura, I; Isomura, S; Hirano, Y; Onitsuka, T; Kosaka, H; Okada, T

    BRAIN   Vol. 145 ( 2 ) page: 490 - 499   2022.4

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    Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

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  34. Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder Open Access

    Wang, CY; Horigane, S; Wakamori, M; Ueda, S; Kawabata, T; Fujii, H; Kushima, I; Kimura, H; Ishizuka, K; Nakamura, Y; Iwayama, Y; Ikeda, M; Iwata, N; Okada, T; Aleksic, B; Mori, D; Yoshida, T; Bito, H; Yoshikawa, T; Takemoto-Kimura, S; Ozaki, N

    TRANSLATIONAL PSYCHIATRY   Vol. 12 ( 1 ) page: 84   2022.2

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    Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D), and T-type VGCC subunit Cav3.3 (CACNA1I) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different in silico analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in CACNA1D), one de novo SNV (p.A36V in CACNA1C), one rare short deletion (p.E1675del in CACNA1D), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five in silico analyses). Neither p.A36V in CACNA1C nor p.C1451* in CACNA1D were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Cav1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca2+-dependent inhibition, resulting in excessive Ca2+ entry through the mutant channel. These results suggested that this de novo SNV in CACNA1C might predispose to SCZ by affecting Ca2+ homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.

    DOI: 10.1038/s41398-022-01851-y

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KAKENHI (Grants-in-Aid for Scientific Research) 3

  1. Development of a diagnostic and symptom classification method for mental disorders using polygenic scores

    Grant number:24K02381  2024.4 - 2027.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator 

    Grant amount:\18590000 ( Direct Cost: \14300000 、 Indirect Cost:\4290000 )

  2. Comprehensive association study between Complement C4 and schizophrenia

    Grant number:21H02854  2021.4 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Ikeda Masashi

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    Genome-Wide Association Studies (GWAS) of schizophrenia have highlighted the Major Histocompatibility Complex (MHC) region as candidate region, with complement component 4 (C4) being identified as a potential susceptibility gene. In this study, we utilized Japanese schizophrenia GWAS data to perform C4 imputation and examined the associations. Our findings revealed that, in contrast to previously reported data from Caucasian populations, a different haplotype was associated with schizophrenia. These results suggest the possibility of ethnic differences and indicate that further research could lead to a more precise identification of susceptibility genes

  3. Pharmacogenomic study for optimizing dosage of antipsychotic drugs based on individual genetic polymorphism

    Grant number:21K07490  2021.4 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Saito Takeo

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    Authorship:Coinvestigator(s) 

    The aim of this study was to examine the relationship between blood concentrations of antipsychotics and drug metabolizing enzyme genotypes, and to establish a basis for predicting individual optimal doses of antipsychotics. We measured the blood concentrations of clozapine and norclozapine in patients with schizophrenia and conducted association analyses between these concentrations and drug metabolizing enzyme genotypes and single nucleotide polymorphisms (SNPs). The results showed no significant associations between drug metabolizing enzyme genotypes or SNPs and clozapine blood concentrations, norclozapine blood concentrations, or the clozapine/norclozapine concentration ratio. However, it cannot be ruled out that this result may be due to low detection power caused by insufficient sample size. Therefore, further analyses with an expanded sample size are necessary.