Affiliation Department etc.

Health Support Center



Academic Society Affiliations






    The Japanese Society for Child and Adolescent Psychiatry



  • Autistic traits as predictors of persistent depression.

    Kanako Ishizuka, Tomomi Ishiguro, Norio Nomura, Toshiya Inada

    European archives of psychiatry and clinical neuroscience     2021.07

    Research paper (scientific journal)   Multiple Authorship

    Persistent depression has been suggested to be associated with autistic traits in people of working age. This study aimed to clarify which autistic characteristics at the initial visit were associated with persistent depression at the 12 week follow-up in a primary care setting. Newly depressed outpatients aged 24-59 years with no history of autism were asked to complete the 50-item autism spectrum quotient (AQ) and the Beck depression inventory (BDI) at baseline and 12 week follow-up (N = 123, males: 48%, age: 37.7 ± 9.15 years). Nearly 40% of participants had an AQ score ≥ 26. Significant differences were observed between the group with remitted depression (N = 43) and those with persistent depression (N = 80) in educational years and AQ "attention switching" and "attention to detail" subscale scores. In addition, a statistically significant decrease in the total AQ and the "communication" and "imagination" scores were observed in the remitted group, while no such change was observed in the group with persistent depression. It remains unclear whether the self-perceived severity of communication and imagination traits in persistent depression was due to the state of persistent depression or a kind of premorbid autistic trait. The results suggest that high levels of autistic traits are frequently present in adults with depression. High "attention switching" and "attention to detail" scores in AQ screening at the first visit might predict the persistence of depressive symptoms after 12 weeks in adults with depression, while total AQ scores, especially for "communication" and "imagination" items, might be state-dependent.

  • Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital.

    Yoshihiro Nishida, Kunihiro Ikuta, Atsushi Natsume, Naoko Ishihara, Maki Morikawa, Hiroyuki Kidokoro, Yukako Muramatsu, Norie Nonobe, Kanako Ishizuka, Takuya Takeichi, Miki Kanbe, Seiji Mizuno, Shiro Imagama, Norio Ozaki

    Scientific reports   11 ( 1 ) 11933 - 11933   2021.06

    Research paper (scientific journal)   Multiple Authorship

    Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.

  • Depressive mood changes are associated with self-perceptions of ADHD characteristics in adults.

    Kanako Ishizuka, Tomomi Ishiguro, Norio Nomura, Toshiya Inada

    Psychiatry research   300   113893 - 113893   2021.03  [Refereed]

    Research paper (scientific journal)   Multiple Authorship

    Subjective attention deficit/hyperactivity disorder (ADHD) symptoms seen in adult depressive patients have often become a pathophysiological topic in recent years. Screening questionnaires are widely used for detecting ADHD; however, the risk of misdiagnosis exists. The present study examined whether self-perceptions of ADHD-related characteristics were consistent regardless of changes in the severity of depressive symptoms. Between April to October 2018, newly diagnosed depressed outpatients aged 24-59 years with good social functioning and without a history of ADHD were asked to fill out the Adult ADHD Self-Report Scale version 1.1 (ASRS) and the Beck Depression Inventory (BDI) at baseline (n = 726) and 12-week follow-up (n = 202). A statistically significant correlation was found between a change in BDI and ASRS scores (score at baseline minus score at the endpoint; r = .57). In addition, the higher the rate of improvement in BDI, the lower the frequency of positive screening for ADHD by ASRS. This study showed that subjective ADHD symptoms were correlated with depressive states. Diagnostic evaluation of comorbid ADHD using self-report scales in a primary care setting should be made with caution.

  • Peripheral biomarkers of attention-deficit hyperactivity disorder: Current status and future perspective.

    Nagahide Takahashi, Kanako Ishizuka, Toshiya Inada

    Journal of psychiatric research   137   465 - 470   2021.03

    Research paper (scientific journal)   Multiple Authorship

    Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. Since the diagnosis of ADHD is defined by operational diagnostic criteria consisting of several clinical symptoms, a number of heterogeneous mechanisms have been considered to be implicated in its pathophysiology. Although no clinically reliable biomarkers are available for the diagnosis of ADHD, several plausible candidate biomarkers have been proposed based on recent advances in biochemistry and molecular biology. This review article summarizes potential peripheral biomarkers associated with ADHD, mainly from recently published case-control studies. These include 1) biochemical markers: neurotransmitters and their receptors, neurotrophic factors, serum electrolytes, and inflammation markers; 2) genetic and epigenetic markers: microRNA, mRNA expression, and peripheral DNA methylation; 3) physiological markers: eye movement and electroencephalography. It also discusses the limitations and future directions of these potential biomarkers for application in clinical practice.

  • Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder.

    Hidekazu Kato, Itaru Kushima, Daisuke Mori, Akira Yoshimi, Branko Aleksic, Yoshihiro Nawa, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Hiroki Kimura, Yuko Arioka, Keita Tsujimura, Mako Morikawa, Takashi Okada, Toshiya Inada, Masahiro Nakatochi, Keiko Shinjo, Yutaka Kondo, Kozo Kaibuchi, Yasuko Funabiki, Ryo Kimura, Toshimitsu Suzuki, Kazuhiro Yamakawa, Masashi Ikeda, Nakao Iwata, Tsutomu Takahashi, Michio Suzuki, Yuko Okahisa, Manabu Takaki, Jun Egawa, Toshiyuki Someya, Norio Ozaki

    Translational psychiatry   10 ( 1 ) 421 - 421   2020.12

    Research paper (scientific journal)   Multiple Authorship

    Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

  • Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility.

    Yoshihiro Nawa, Hiroki Kimura, Daisuke Mori, Hidekazu Kato, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Itaru Kushima, Branko Aleksic, Yuko Arioka, Mako Morikawa, Takashi Okada, Toshiya Inada, Kozo Kaibuchi, Masashi Ikeda, Nakao Iwata, Michio Suzuki, Yuko Okahisa, Jun Egawa, Toshiyuki Someya, Fumichika Nishimura, Tsukasa Sasaki, Norio Ozaki

    Human genome variation   7 ( 1 ) 37 - 37   2020.11

    Research paper (scientific journal)   Multiple Authorship

    Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

  • Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia.

    Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki

    Psychiatry and clinical neurosciences   74 ( 5 ) 318 - 327   2020.05  [Refereed]

    Research paper (scientific journal)   Multiple Authorship

    AIM: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia. METHODS: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed. RESULTS: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice. CONCLUSION: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia.

  • Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia.

    Kanako Ishizuka, Hiroki Kimura, Itaru Kushima, Toshiya Inada, Yuko Okahisa, Masashi Ikeda, Nakao Iwata, Daisuke Mori, Branko Aleksic, Norio Ozaki

    Psychiatric genetics   28 ( 5 ) 90 - 93   2018.10

    Research paper (scientific journal)   Multiple Authorship

    Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

  • Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights.

    Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki

    Cell reports   24 ( 11 ) 2838 - 2856   2018.09  [Refereed]

    Research paper (scientific journal)   Multiple Authorship

    Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

  • Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant.

    Yuko Arioka, Emiko Shishido, Hisako Kubo, Itaru Kushima, Akira Yoshimi, Hiroki Kimura, Kanako Ishizuka, Branko Aleksic, Takuji Maeda, Mitsuru Ishikawa, Naoko Kuzumaki, Hideyuki Okano, Daisuke Mori, Norio Ozaki

    Translational psychiatry   8 ( 1 ) 129 - 129   2018.07

    Research paper (scientific journal)   Multiple Authorship

    Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.

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Academic Activity

  • 2020.10

    The Japanese Society for Child and Adolescent Psychiatry