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

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

Int J Mol Sci. 2017 Mar 14;18(3):632. doi: 10.3390/ijms18030632.

Authors

Makoto Kinoshita¹, Shusuke Numata², Atsushi Tajima^{3

4}, Hidenaga Yamamori⁵, Yuka Yasuda⁶, Michiko Fujimoto⁷, Shinya Watanabe⁸, Hidehiro Umehara⁹, Shinji Shimodera¹⁰, Takanobu Nakazawa^{11

12}, Masataka Kikuchi¹³, Akihiro Nakaya¹⁴, Hitoshi Hashimoto^{15

16

17

18}, Issei Imoto¹⁹, Ryota Hashimoto^{20

21}, Tetsuro Ohmori²²

Affiliations

¹ Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. knst5511mkt@sunny.ocn.ne.jp.
² Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. shu-numata@umin.ac.jp.
³ Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. atajima@med.kanazawa-u.ac.jp.
⁴ Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8640, Japan. atajima@med.kanazawa-u.ac.jp.
⁵ Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. yamamori@psy.med.osaka-u.ac.jp.
⁶ Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. yasuda@psy.med.osaka-u.ac.jp.
⁷ Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. mfujimoto@psy.med.osaka-u.ac.jp.
⁸ Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. wata-shin@tokushima-u.ac.jp.
⁹ Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. umeharatokushima@yahoo.co.jp.
¹⁰ Department of Neuropsychiatry, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. shimodes@kochi-u.ac.jp.
¹¹ Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8, Yamada-Oka, Suita, Osaka 565-0871, Japan, nakazawa@phs.osaka-u.ac.jp. nakazawa@phs.osaka-u.ac.jp.
¹² 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. nakazawa@phs.osaka-u.ac.jp.
¹³ Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. kikuchi@gi.med.osaka-u.ac.jp.
¹⁴ Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. nakaya@gi.med.osaka-u.ac.jp.
¹⁵ 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. hasimoto@phs.osaka-u.ac.jp.
¹⁶ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. hasimoto@phs.osaka-u.ac.jp.
¹⁷ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan. hasimoto@phs.osaka-u.ac.jp.
¹⁸ Division of Bioscience, Institute for Datability Science, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan. hasimoto@phs.osaka-u.ac.jp.
¹⁹ Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. issehgen@tokushima-u.ac.jp.
²⁰ Department of Psychiatry, Graduate School of Medicine, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. hashimor@psy.med.osaka-u.ac.jp.
²¹ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. hashimor@psy.med.osaka-u.ac.jp.
²² Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. ohmori@tokushima-u.ac.jp.

Abstract

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.

Keywords: DNA methylation; clozapine; schizophrenia.

MeSH terms

Adult
Antipsychotic Agents / pharmacology*
Antipsychotic Agents / therapeutic use
CREB-Binding Protein / genetics
Clozapine / pharmacology*
Clozapine / therapeutic use
CpG Islands
DNA Methylation / drug effects*
Drug Resistance
Female
Humans
Leukocytes / metabolism
Male
Middle Aged
Schizophrenia / drug therapy
Schizophrenia / genetics*

Substances

Antipsychotic Agents
CREB-Binding Protein
CREBBP protein, human
Clozapine