Antipsychotic Medications and DNA Methylation in Schizophrenia and Bipolar Disorder: A Systematic Review

Abstract

The pharmacoepigenetics of antipsychotic treatment in severe mental illness is a growing area of research that aims to understand the interface between antipsychotic treatment and genetic regulation. Pharmacoepigenetics may some day assist in identifying treatment response mechanisms or become one of the components in the implementation of precision medicine. To understand the current evidence regarding the effects of antipsychotics on DNA methylation a systematic review with qualitative synthesis was performed through Pubmed, Embase and Psychinfo from earliest data to June 2019. Studies were included if they analyzed DNA methylation in an antipsychotic‐treated population of patients with schizophrenia or bipolar disorder. Data extraction occurred via a standardized format and study quality was assessed. Twenty‐nine studies were identified for inclusion. Study design, antipsychotic type, sample source, and methods of DNA methylation measurement varied across all studies. Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of schizophrenia and bipolar disorder. Twenty‐two studies used observational samples whereas the remainder used prospectively treated samples. Six studies assessed global methylation, five assessed epigenome‐wide, and 15 performed a candidate epigenetic study. Two studies analyzed both global and gene‐specific methylation, whereas one study performed a simultaneous epigenome‐wide and gene‐specific study. Only three genes were analyzed in more than one gene‐specific study and the findings were discordant. The state of the pharmacoepigenetic literature on antipsychotic use is still in its early stages and uniform reporting of methylation site information is needed. Future work should concentrate on using prospective sampling with appropriate control groups and begin to replicate many of the novel associations that have been reported.

ANK3 Gene Polymorphism Rs10994336 Influences Executive Functions by Modulating Methylation in Patients With Bipolar Disorder

“…Path AB is the mediation (indirect) effect and is significant at P < 0.05 based on confidence intervals from bias-corrected bootstrapping of 5,000 samples. use were believed to influence DNA methylation (Burghardt et al, 2020;Gardea-Resendez et al, 2020;Webb et al, 2020), we add these confounding factors in our linear regression model as covariates to explore the allele-associated methylation. After adjusting these confounders, the effect of rs10994336 polymorphism on methylation of the CpG site cg02172182 within the gene body of ANK3 was observed in HC and replicated in patients with BD in the same direction where the risk T-allele carriers presented a reduced methylation relative to homozygous CC participants, suggesting that the effect of genotype on methylation is not driven by the disease and rs10994336 could be referred to as a reliable meQTL.…”

Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics?

“…Consequently, neurological signaling was affected via induced transcriptional and proteomic abnormalities [ 76 ]. Additionally, the effect of antipsychotic drugs on DNA methylation in bipolar disorder and schizophrenia patients has also been reported [ 77 ].…”

Drug Response-Related DNA Methylation Changes in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

“…Global DNAm reflects the DNAm status of total genomic content within a sample. Several methods exist to assess global DNAm status, including enzyme-linked immunosorbent assays (ELISA), the use of a previously validated protocol of Linear Interspersed Nuclear Element 1 (LINE- 1) and the use of restriction enzymes ( Burghardt et al, 2020 ). However, this approach only assesses DNAm changes at the genome level, and thus does not further provide data on region-specific DNAm changes to characterize critical regulatory regions (e.g., CpG islands and promoter regions).…”