Methylomic Biomarkers of Lithium Response in Bipolar Disorder: A Proof of Transferability Study.

Cynthia Marie-Claire,Frank Bellivier,Cindie Courtin,Jan Scott,Bruno Etain

doi:10.3390/ph15020133

Abstract

Response to lithium (Li) is highly variable in bipolar disorders (BD) and no clinical or biological predictors of long-term response have been validated to date. Using a genome-wide methylomic approach (SeqCapEpi), we previously identified seven differentially methylated regions (DMRs) that discriminated good from non-responders (prophylactic response phenotype defined using the “Alda” scale). This study is a proof of transferability from bench to bedside of this epigenetic signature. For this purpose, we used Methylation Specific High-Resolution Melting (MS-HRM), a PCR based method that can be implemented in any medical laboratory at low cost and with minimal equipment. In 23 individuals with BD, MS-HRM measures of three out of seven DMRs were technically feasible and consistencies between SeqCapEpi and MS-HRM-measures were moderate to high. In an extended sample of individuals with BD (n = 70), the three MS-HRM-measured DMRs mainly predicted nonresponse, with AUC between 0.70–0.80 according to different definitions of the phenotype (Alda- or machine-learning-based definitions). Classification tree analyses further suggested that the MS-HRM-measured DMRs correctly classified up to 84% of individuals as good or non-responders. This study suggested that epigenetic biomarkers, identified in a retrospective sample, accurately discriminate non-responders from responders to Li and may be transferrable to routine practice.

Highlights

Bipolar disorder (BD) is one of the leading causes of disability in young people [1,2].BD is characterized by the recurrence of major depressive andmanic episodes interspersed by periods of remission or residual mood symptoms
In individuals with BD who received Li, three subpopulations (full or good responders (GR), partial responders (PaR) and non-responders (NR)) have been repeatedly identified, with around one third of the patients belonging to each group [5,6]
By comparing good responders (GRs) to non-responders (NRs), we identified an epigenetic signature of response to Li that combines seven differentially methylated regions (DMRs)

Summary

Introduction

BD is characterized by the recurrence of major depressive and (hypo)manic episodes interspersed by periods of remission or residual mood symptoms. Lithium (Li) is the first-line prophylactic treatment for BD and has proven efficacy for treating acute manic episodes, preventing mood relapses, and for decreasing suicidal risk [3,4]. After at least two consecutive years of treatment, only a fraction of patients receiving Li will display significant improvement in the frequency and/or severity of mood recurrences. In individuals with BD who received Li, three subpopulations (full or good responders (GR), partial responders (PaR) and non-responders (NR)) have been repeatedly identified, with around one third of the patients belonging to each group [5,6]

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