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

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.

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

“…A previous study of PTSD in veterans found that pretreatment GR methylation patterns predicted treatment outcome while FKBP5 methylation decreased across the course of therapy in treatment responders, but increased in nonresponders 33. Another study examining response to intensive dialectical behavior therapy in adults with borderline personality disorder demonstrated differential patterns of BDNF methylation change associated with scores of depression, hopelessness, and impulsivity following treatment 29. Finally, we previously showed that one CpG site upstream of the SERT promoter increased in DNA methylation during the course of therapy in treatment responders, but decreased in nonresponders 27.…”

DNA methylation of BDNF as a biomarker of early-life adversity

“…Similarly, BDNF DNA methylation changes have been found in the peripheral blood of patients suffering from depression (13), bipolar disorder (12), schizophrenia (14), and eating disorders (51), and a change in BDNF DNA methylation status correlated with a positive response to psychotherapy in borderline personality disorder (52). In addition, within a psychiatric population, high BDNF DNA methylation was strongly associated with the history of child maltreatment (51,52). It seems likely that BDNF DNA methylation status may represent a more stable and reliable marker of psychiatric vulnerability compared with the levels of BDNF protein.…”

“…Recent studies suggested that concentrations of BDNF protein in the blood (serum or plasma) may represent peripheral manifestation of depression (48) and schizophrenia (49) and could be used as a biomarker for therapeutic efficacy (50). Similarly, BDNF DNA methylation changes have been found in the peripheral blood of patients suffering from depression (13), bipolar disorder (12), schizophrenia (14), and eating disorders (51), and a change in BDNF DNA methylation status correlated with a positive response to psychotherapy in borderline personality disorder (52). In addition, within a psychiatric population, high BDNF DNA methylation was strongly associated with the history of child maltreatment (51,52).…”

BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues

“…At an epigenetic level, environmental factors have been shown to affect the methylation status of various BDNF promoters among which promoter IV was the most investigated. In rodents and humans, early-life adversity has been associated with changes in the methylation status of BDNF (Berton et al, 2006;Ivy et al, 2008;Roth et al, 2009;Perroud et al, 2013). In rodent models of early-life stress, increased methylation of BDNF promoter IV was found to be associated with decreased mRNA expression of BDNF in the prefrontal cortex (Ivy et al, 2008;Roth et al, 2009).…”

“…A recent study comparing BDNF promoter I and IV methylation levels between 100 controls and 100 schizophrenic patients reported a gender-dependant DNA methylation status in peripheral blood (Ikegame et al, 2013). A major limitation to these human studies relates to the fact that BDNF methylation levels are generally measured in DNA extracted from blood cells (Ikegame et al, 2013;Perroud et al, 2013) and muscle and brain regions extracted from patients who died from different causes. We also aimed at determining whether sexdifferences in BDNF methylation status could be observed across tissues.…”