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.
Highlights
Schizophrenia (SCZ) is a mental disorder characterized by symptoms that include delusions, hallucinations, and disorganized speech [1]
Decreases in DNA methylation following clozapine treatment were more likely to occur in promoter regions than in other regions (60.5% in promoter regions vs. 51.6% in other regions; Fisher’s exact test p = 7.00 × 10−16; Figure 1)
Sites of decreased DNA methylation following clozapine treatment were more likely to occur in CGI regions than in other regions (66.9% in CGI regions versus 51.0% in other regions; Fisher’s exact test p = 3.83 × 10−36; Figure 1)
Summary
Schizophrenia (SCZ) is a mental disorder characterized by symptoms that include delusions, hallucinations, and disorganized speech [1]. We have demonstrated that cell adhesion molecules, which play an important role in brain development including in axonal/dendrite growth, synapse formation and plasticity [5], were potential candidates for the molecular basis of clozapine response by conducting gene expression profiling using induced pluripotent stem (iPS) cell-based technology [6]. A number of studies have demonstrated aberrant DNA methylation in SCZ [10,11,12,13,14,15,16,17,18]. Growing evidence suggests that DNA methylation may be involved in the therapeutic efficacy of atypical antipsychotic drugs [19,20,21,22,23,24]. To our knowledge, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported
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