Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia

Makoto Kinoshita; Shusuke Numata; Atsushi Tajima; Hidenaga Yamamori; Yuka Yasuda; Michiko Fujimoto; Shinya Watanabe; Hidehiro Umehara; Shinji Shimodera; Takanobu Nakazawa; Masataka Kikuchi; Akihiro Nakaya; Hitoshi Hashimoto; Issei Imoto; Ryota Hashimoto; Tetsuro Ohmori

doi:10.3390/ijms18030632

International Journal of Molecular Sciences (Mar 2017)

Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia

Makoto Kinoshita,
Shusuke Numata,
Atsushi Tajima,
Hidenaga Yamamori,
Yuka Yasuda,
Michiko Fujimoto,
Shinya Watanabe,
Hidehiro Umehara,
Shinji Shimodera,
Takanobu Nakazawa,
Masataka Kikuchi,
Akihiro Nakaya,
Hitoshi Hashimoto,
Issei Imoto,
Ryota Hashimoto,
Tetsuro Ohmori

Affiliations

Makoto Kinoshita: Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan
Shusuke Numata: Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan
Atsushi Tajima: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
Hidenaga Yamamori: Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan
Yuka Yasuda: Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan
Michiko Fujimoto: Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan
Shinya Watanabe: Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan
Hidehiro Umehara: Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan
Shinji Shimodera: Department of Neuropsychiatry, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan
Takanobu Nakazawa: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8, Yamada-Oka, Suita, Osaka 565-0871, Japan, [email protected]
Masataka Kikuchi: Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan
Akihiro Nakaya: Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan
Hitoshi Hashimoto: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan
Issei Imoto: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
Ryota Hashimoto: Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan
Tetsuro Ohmori: Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan

DOI: https://doi.org/10.3390/ijms18030632
Journal volume & issue: Vol. 18, no. 3
p. 632

Abstract

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Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for “cell substrate adhesion” and “cell matrix adhesion” gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ.

Published in International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General); Science: Chemistry
Website: http://www.mdpi.com/journal/ijms

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