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

Abstract

So far, genetic studies of treatment response in schizophrenia, bipolar disorder, and major depression have returned results with limited clinical utility. A gene × environment interplay has been proposed as a factor influencing not only pathophysiology but also the treatment response. Therefore, epigenetics has emerged as a major field of research to study the treatment of these three disorders. Among the epigenetic marks that can modify gene expression, DNA methylation is the best studied. We performed a systematic search (PubMed) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines for preclinical and clinical studies focused on genome-wide and gene-specific DNA methylation in the context of schizophrenia, bipolar disorders, and major depressive disorder. Out of the 112 studies initially identified, we selected 31 studies among them, with an emphasis on responses to the gold standard treatments in each disorder. Modulations of DNA methylation levels at specific CpG sites have been documented for all classes of treatments (antipsychotics, mood stabilizers, and antidepressants). The heterogeneity of the models and methodologies used complicate the interpretation of results. Although few studies in each disorder have assessed the potential of DNA methylation as biomarkers of treatment response, data support this hypothesis for antipsychotics, mood stabilizers and antidepressants.

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Studies on the epigenetic impact on candidate genes of mood stabilizers, especially Li and VPA, have consistently increased in the past decade but attempts to summarize the findings have been scarce (Alladi et al, 2018;Pisanu et al, 2018). This systematic review provides a qualitative summary of the current state of knowledge of the epigenetic effects of nonantipsychotic mood stabilizers in MDD, BD, and SCZ in an attempt to define the specific mechanisms through which these agents act at the epigenomic level.…”

“…Epimutations secondary to gene-environment interactions have been described to have a key role in the pathophysiology of major psychiatric disorders (Abdolmaleky et al, 2019) where aberrant DNA methylation and histone modification patterns have been identified. Histone acetylation levels are significantly altered in individuals with BD and, to a lesser extent, in individuals with SCZ (Gavin and Sharma, 2010;Machado-Vieira et al, 2011).There is also a reduction in global and specific DNA methylation levels in individuals with BD, MDD, and SCZ (Alladi et al, 2018). In vitro and in vivo studies have suggested the potential of mood stabilizers to reverse epimutations in major psychiatric disorders (Pisanu et al, 2018) making them a target for further research.…”

Molecular Psychiatry: Trends and Study Examples

“…Recent findings in the field of Psychiatry have suggested a potentially key role for epigenetic mechanisms in determining not only risk and resilience in patients and vulnerable subjects but also in modulating one's response to a given treatment. The paper by Goud Alladi and colleagues explored through a systematic review the evidence of DNA methylation mechanisms involved in the clinical treatment response in serious mental illness, specifically bipolar disorder, schizophrenia, and major depressive disorder [9]. The authors of this interesting study emphasize the potential clinical use of such markers in predicting whether a patient will respond or not to a medication, which is a highly anticipated approach in the emerging field of personalized medicine.…”

Patterns of Membrane Protein Clustering in Peripheral Lymphocytes as Predictors of Therapeutic Outcomes in Major Depressive Disorder

“…Current approaches to the discovery of novel biomarkers of diagnosis and/or therapeutic efficacy for MDD are mostly based on technological advances in neuroimaging or on the use of “Omics” technologies (i.e., genomics or other “Omics” approaches primarily used to define peripheral biomarkers of MDD) (see Gururajan et al., 2016 ; Voegeli et al., 2017 ; Busch and Menke, 2018 ). Recently, a series of systematic reviews have evaluated the effectiveness of multiple biomarkers of depression using genomics ( Menezes et al., 2019 ), epigenomics ( Goud Alladi et al., 2018 ), metabolomics ( MacDonald et al., 2018 ), antidepressant pharmacologic treatment response ( Voegeli et al., 2017 ), inflammatory biomarkers ( Smith et al., 2018 ; Yang et al., 2018 ), and neuroimaging biomarkers ( Drago et al., 2018 ; Levy et al., 2019 ; Suh et al., 2019 ).…”