Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD

Abstract

Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of “environmental regulation” that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

“…Evidence suggests that the role of FKBP5 in the mammalian stress response includes epigenetic mechanisms such as DNA methylation status. Previous reports from the clinical literature have shown that methylation of the Fkbp5 gene (at the promoter region of exon 1) did not predict treatment response, but decreased in association with recovery (Yehuda et al, 2013). A study using a chronic corticosterone administration paradigm, that had been previously shown to result in a phenotype similar to chronic stress exposure (Gourley et al, 2009), induced an increase in Fkbp5 mRNA expression in the hippocampus, hypothalamus, and blood of mice with a correspondent decrease in DNA methylation at Fkbp5 intron 5 (Lee et al, 2010).…”

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“…The authors found that these changes in DNA methylation correlated with changes in cognitive functions. Yehuda et al (2013), in a pilot study, found that DNA methylation of the FKBP5 gene decreased during the course of psychotherapy of war veterans with PTSD. Roberts et al (2014) found in children with anxiety disorders that methylation of the promoter of the gene encoding the serotonin transporter (5HTT) increased in responders as compared to non-responders after the start of cognitive behaviour therapy.…”