T50 - Longitudinal Epigenetic Analysis Of Clozapine Use In Treatment-Resistant Schizophrenia: Data From The Crestar Consortium

Abstract

Background Approximately one-third of patients with schizophrenia are considered treatment-resistant. For these patients, the atypical antipsychotic drug clozapine is recommended as the only evidence based treatment available. However, there is still significant variability in treatment-response. Animal studies have demonstrated that clozapine influences histone modification and DNA methylation, and a recent EWAS study in humans identified multiple differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in clozapine-exposed samples. We used a longitudinal, within-participant design to conduct genome-wide analysis of DNA methylation changes in treatment resistant patients over 6 months of clozapine use. Methods We recruited 20 participants with a diagnosis of treatment-resistant schizophrenia, before they were prescribed clozapine. We then collected whole-blood samples at baseline and follow-up (6 weeks, 12 weeks and 6 months after clozapine start date), alongside clinical assessments. We quantified DNA methylation at ~ 480,000 sites across the genome using the Illumina 450 K HumanMethylation array and following pre-processing, normalization and quality control, an epigenome-wide association study was performed comparing DNA methylation at each time point. Results Preliminary data demonstrates an overall reduction in DNA methylation in the 6 months of clozapine use, with multiple individual CpG sites showing changes in DNA methylation that were found to be significantly associated with length of time exposed to clozapine. During analysis of the first 10 patients, the most significant CpG site was located in the gene body of CRB1; CRB1 is expressed exclusively in the eye, and the central nervous system, and has been previously associated with Lever’s congenital amaurosis and retinitis pigmentosa. The findings and analysis for all 20 participants will be presented at the meeting. Discussion This is the first study to identify longitudinal epigenetic changes following clozapine exposure in human subjects, replicating findings in animal studies of decreased methylation. Recruitment is ongoing and further analysis will look at whether epigenetic changes are associated with treatment-response/adverse reactions. Ultimately, these data will help us understand the mechanisms involved in clozapine, potentially providing biomarkers to predict clozapine response.