DNA methylation as predictor of clozapine response in treatment-resistant schizophrenia

Abstract

Schizophrenia is a complex neuropsychiatric disorder with a worldwide prevalence of up to 1.5%. Around 30% of schizophrenia patients can be classified as treatment-resistant, meaning they do not respond to at least two different antipsychotics. Clozapine is the only antipsychotic that has been proved to effectively treat psychotic symptoms in treatment-resistant schizophrenia. Despite this, it is largely underutilised due to issues including serious side effects and lack of adherence. In addition, clozapine has a prolonged response period compared to other antipsychotics. For these reasons, it would be highly beneficial to be able to predict individuals’ response to clozapine. A growing body of research points towards the notion that antipsychotics affect DNA methylation and in some studies, such changes in DNA methylation have been related to clinical response. Based on this, we hypothesize that specific DNA methylation patterns are be able to predict individuals’ response to antipsychotics. The purpose of the proposed study is to identify DNA methylation sites at baseline of clozapine treatment that predict clinical response. To this aim, a longitudinal study will be conducted in which an epigenome-wide association study will be performed. Differentially methylated positions distinguishing clozapine responders from clozapine non-responders could provide a basis for future research on a baseline biomarker to predict clozapine response in treatment-resistant schizophrenia.