DNA Methylation Signatures of Mood Stabilizers and Antipsychotics in Bipolar Disorder

Abstract

Psychiatric drugs influence DNA methylation patterns over and above cell type composition in bipolar disorder. Drug-related changes in DNA methylation are therefore not only an important confounder in psychiatric epigenetics but may also inform on the biological mechanisms underlying drug efficacy.

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

“…Genome-wide methylation differences have also been analyzed in blood (Dempster et al, 2011; Houtepen et al, 2016; Li et al, 2015; Sabunciyan et al, 2015; Walker et al, 2016) and in different post-mortem brain regions, such as the BA9 (Zhao et al, 2015), frontal cortex (Mill et al, 2008; Xiao et al, 2014), anterior cingulate (Xiao et al, 2014), and cerebellum (Chen et al, 2014) from BD patients and controls.…”

“…Specifically, the inconsistencies are coming not only from the different tissues analyzed (blood, prefrontal cortex, anterior cingulate, cerebellum, and sperm), but also due to methodological variations in the studies: three studies have used methylated DNA immunoprecipitation (MeDIP-seq) followed by next generation sequencing (Li et al, 2015; Xiao et al, 2014; Zhao et al, 2015), two studies have used the Illumina Infinium HumanMethylation27 beadchip (Chen et al, 2014; Dempster et al, 2011), three studies have used the Illumina Infinium HumanMethylation450 beadchip (Houtepen et al, 2016; Sabunciyan et al, 2015; Walker et al, 2016), and one used CpG-island microarrays (Mill et al, 2008) for the assessment of methylation changes. Of note, even though MeDIP-seq and microarray-based analyses have been shown to present a good positive correlation, MeDIP-seq allows a wider interrogation of methylation regions of the genome, including thousands of non-RefSeq genes and repetitive elements that are not assessed in microarrays (Clark et al, 2012).…”

“…In line, Milutinovic et al found that valproate induced histone acetylation and activated DNA demethylation in the same gene systems in HEK293 cells, suggesting that valproate might trigger demethylation of genes through histone acetylation (Milutinovic et al, 2007). Indeed, in human PBMCs, treatment with valproate led to a significant reduction of ~24% in BDNF promoter methylation (D’Addario et al, 2012; Dell’Osso et al, 2014), whereas it was also shown to decrease the methylation of p21 (Aizawa and Yamamuro, 2015), RELN (Dong et al, 2008), and glutamate type I transporter ( GLT-1 ) genes (Perisic et al, 2010), as well as induce a significantly altered methylation signature in BD patients (Houtepen et al, 2016). …”

Understanding the molecular mechanisms underlying mood stabilizer treatments in bipolar disorder: Potential involvement of epigenetics

“…Recently, Houtepen and colleagues [37] investigated DNA methylation signatures of psychotropic medications in 172 BD patients under treatment with mood stabilizers (lithium, VPA, carbamazepine or lamotrigine) or antipsychotics (olanzapine and quetiapine). The authors explored the influence of these drugs on blood-based DNA methylation levels.…”

Awakening the sleeping giant: methods for reactivating the inactive X chromosome as clinical treatment for X-linked disorders

“…Epimutations on the X chromosome have also been associated with a number of mental health conditions (e.g. depression, bipolar disorder and schizophrenia) [3][4][5][6] . Thanks to X chromosome inactivation (XCI), a mechanism which reversibly silences one of the two X chromosomes in females, female mammals are a somatic mosaic of two populations of cells, expressing either the paternal or the maternal X chromosome, usually in a 50-50 ratio [7][8][9] .…”