Mood Stabilizers and the Influence on Global Leukocyte DNA Methylation in Bipolar Disorder

Abstract

Little is known about the relationship between treatments for bipolar disorder (BD), their therapeutic responses and the DNA methylation status. We investigated whether global DNA methylation levels differ between healthy controls and bipolar patients under different treatments. Global DNA methylation was measured in leukocyte DNA from bipolar patients under lithium monotherapy (n = 29) or combination therapy (n = 32) and from healthy controls (n = 26). Lithium response was assessed using the Alda scale. Lithium in monotherapy was associated with hypomethylation (F = 4.63, p = 0.036). Lithium + valproate showed a hypermethylated pattern compared to lithium alone (F = 7.27, p = 0.011). Lithium response was not associated with DNA methylation levels. These data suggest that the choice of treatment in BD may lead to different levels of global DNA methylation. However, further research is needed to understand its clinical significance.

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

“…Although the evidence is still very limited, it has been suggested that different mood stabilizers may exert specific effects on the epigenome. Lithium monotherapy has been shown to induce global DNA hypomethylation in leuokocytes, whereas a combination therapy including VPA has been associated with hypermethylation [49]. Very few studies have investigated the extent to which methylation and histone modifications might affect the interindividual response to mood stabilizers.…”

“…Very few studies have investigated the extent to which methylation and histone modifications might affect the interindividual response to mood stabilizers. The only study comparing differences in global DNA methylations levels in responders and non-responders to lithium treatment suggested that the observed epigenetic effects could be independent from the clinical response to the drug [49]. Although intriguing, the hypothesis that response to mood stabilizers may be associated with specific epigenetic signatures still needs to be explored by studies performed on large samples of patients and taking potential confounders into account.…”

“…In vitro lithium treatment increased global methylation levels in relatives but not in BD probands [39]. In another study, global hypomethylation was observed in BD patients in lithium monotherapy, while combination therapy of lithium + VPA was associated with hypermethylation [49]. VPA Histone acetylation and replication-independent DNA demethylation Embryonal kidney 293 cells [52] VPA Alteration of the expression of genes usually suppressed by DNA methylation HEK 293 cells [53] VPA Reduction of the methylation profile of the reelin promoter, increase of the acetylation status of histones H3 and H4…”

“…Another study from Backlund and coworkers [49] measured global DNA methylation in leukocytes from 61 BD patients treated with lithium monotherapy (group I), lithium + VPA (group II) or lithium + antipsychotics (group III) and 26 healthy controls (group IV). All patients were recruited during euthymic state and were non-smokers.…”

DNA Methylation as a Biomarker of Treatment Response Variability in Serious Mental Illnesses: A Systematic Review Focused on Bipolar Disorder, Schizophrenia, and Major Depressive Disorder

“…In a study of global DNA methylation in the leukocytes of BD patients, no differences were found compared to the healthy control. However a significantly lower DNA methylation level was observed in patients on lithium monotherapy, compared to controls or BD patients treated with a combination of lithium + VPA [ 82 ]. In this study, the DNA methylation level could not be correlated with the lithium response as assessed with the Alda scale.…”