Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia.
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.
Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. knst5511mkt@sunny.ocn.ne.jp.
Makoto
M
Kinoshita
Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. shu-numata@umin.ac.jp.
Shusuke
S
Numata
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.|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.
Atsushi
A
Tajima
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.
Hidenaga
H
Yamamori
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.
Yuka
Y
Yasuda
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.
Michiko
M
Fujimoto
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.
Shinya
S
Watanabe
Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. umeharatokushima@yahoo.co.jp.
Hidehiro
H
Umehara
Department of Neuropsychiatry, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. shimodes@kochi-u.ac.jp.
Shinji
S
Shimodera
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.|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.
Takanobu
T
Nakazawa
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.
Masataka
M
Kikuchi
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.
Akihiro
A
Nakaya
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.|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.|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.|Division of Bioscience, Institute for Datability Science, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan. hasimoto@phs.osaka-u.ac.jp.
Hitoshi
H
Hashimoto
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.
Issei
I
Imoto
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.|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.
Ryota
R
Hashimoto
Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University, 3-8-15, Kuramoto-cho, Tokushima 770-8503, Japan. ohmori@tokushima-u.ac.jp.
Tetsuro
T
Ohmori
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050882:CREB-Binding Protein / Q000235:genetics; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*
D014150:Antipsychotic Agents; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D003024:Clozapine
DNA methylation; clozapine; schizophrenia