Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene

N Perroud,M-E Hoeppli,S Ardu,P Prada,S Furrer,F Karege,A Salzmann,R Nicastro,I Krejci,A Malafosse

doi:10.1038/tp.2012.140

Abstract

Downregulation of brain-derived neurotrophic factor (BDNF) gene expression with corresponding increased methylation at specific promoters has been associated with stressful experiences in early life and may explain later adulthood psychopathology. We measured the percentage of methylation at BDNF CpG exons I and IV as well as plasma BDNF protein levels in 115 subjects with borderline personality disorder (BPD) and 52 controls. BPD subjects then underwent a 4-week course of intensive dialectical behavior therapy (I-DBT). BDNF methylation status and protein levels were re-assessed at the end of treatment. BPD subjects had significantly higher methylation status in both CpG regions than controls. In addition, the higher the number of childhood trauma, the higher was the methylation status. In BPD subjects, BDNF methylation significantly increased after I-DBT. Nonresponders accounted for the majority of this increase, whereas responders showed a decrease in methylation status over time. Accordingly, the changes in methylation status over time were significantly associated with changes in depression scores, hopelessness scores and impulsivity. No association was found between protein levels and BDNF methylation status. We here found a relationship between child maltreatment and higher DNA methylation of BDNF. These results moreover support the idea that these epigenetic marks may be changed through psychotherapeutic approaches and that these changes underline changes in cognitive functions.

Highlights

Borderline personality disorder (BPD) is a disorder characterized by marked impulsivity, lack of emotional control, disturbed interpersonal relationships and frequent self-injurious and suicidal behaviors
This study aims to answer the following questions: is the DNA methylation status of brain-derived neurotrophic factor (BDNF) exons I and IV higher in BPD compared with control subjects? Is this higher DNA BDNF methylation in BPD subjects linked to child maltreatment? And can these epigenetic processes be changed through a specific psychotherapeutic approach to subjects with BPD and are they linked to response to treatment?
We identified by UCSC (University of California, Santa Cruz) genome browser a CpG island region located at chr11:27743473–27744564 (CpG count: 81, % GC 1⁄4 60.5 and Obs/Exp 1⁄4 0.83) in the BDNF promoter region, upstream of the ATG start in exon I

Summary

Introduction

Borderline personality disorder (BPD) is a disorder characterized by marked impulsivity, lack of emotional control, disturbed interpersonal relationships and frequent self-injurious and suicidal behaviors. Not surprisingly, it is associated with high socioeconomic burden and high morbidity and mortality. Posttranslational modifications of histones have been shown to be an important correlate of environmental epigenetic modifications, DNA methylation status at CpG sites within the promoter/exon IV has been extensively studied and found to be an important correlate of the impact of early developmental stress.[9,10,11] Roth et al.[9,11] found that psychosocial stress in rats increased BDNF DNA methylation at promoter/exon IV, suggesting that there may be a mechanism underlying cognitive deficits found in adult subjects maltreated in their childhood. Epigenetic modifications of the BDNF gene have never been explored in BPD, increased DNA methylation at specific CpG sites in the BDNF promoter/exon IV and lower BDNF mRNA levels in the Wernike area have been found in suicide victims, a phenotype closely related to BPD.[12]

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