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Both severe mental illness and atypical antipsychotics have been independently associated with insulin resistance and weight gain. Altered regulation of skeletal muscle DNA methylation may play a role. We aimed to evaluate DNA methylation modifications in human skeletal muscle samples to further understand its potential role in the metabolic burden observed in psychiatric patients and psychopharmacologic treatment. Subjects were included in our study if they had a bipolar diagnosis and were currently treated with a mood stabilizer or atypical antipsychotic. A healthy control group free of psychiatric or physical disease was also included for comparisons. Anthropometric, BMI and hemoglobin A1C (HbA1C%) were measured. Fasting skeletal muscle biopsies were obtained and methylation levels of 5-methycytosine (5-mC), 5-hydroxymethylcytosine (5-hmC) and 5-formylcytosine (5-fC) were measured. Skeletal muscle global methylation of 5-mC and 5-fC were significantly higher in bipolar subjects compared to healthy controls. 5-mC was significantly higher in the AAP group compared to the mood stabilizer group. Significant correlations were observed between 5-fC methylation and HbA1C%. Our findings suggest that psychiatric disease and treatment may influence some methylation measures in the skeletal muscle of patients with bipolar disorder, which may be further influenced by medication treatment., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Study Objective: Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure AKT isoform-specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy., Design: Cross-sectional observational study., Setting: Clinical research services center at an academic center., Patients: Thirty patients with a confirmed diagnosis of bipolar disorder who were treated with either an atypical antipsychotic (16 patients) or mood stabilizer (14 patients) at a consistent dose for at least 3 months., Interventions: A fasting skeletal muscle biopsy was performed in the vastus lateralis in each patient. Patients also underwent fasting blood sample collection and a standard 75-g oral glucose tolerance test., Measurements and Main Results: Skeletal muscle DNA methylation near the promoter region for three genes, AKT1, AKT2, and AKT3, was measured by methylation-sensitive high-resolution melting. Gene methylation was analyzed based on atypical antipsychotic versus mood stabilizer maintenance therapy. Associations between gene methylation, insulin resistance, and glucose tolerance were also analyzed. In patients treated with atypical antipsychotics, AKT1 and AKT2 methylation was increased compared with patients treated with mood stabilizers (p=0.03 and p=0.02, respectively). In addition, for patients receiving atypical antipsychotics, a positive trend for AKT2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT2 methylation with increasing insulin resistance was observed., Conclusion: Overall, our findings suggest that the AKT gene is differentially methylated in the skeletal muscle of patients taking atypical antipsychotics or mood stabilizer maintenance therapy. These results may direct future approaches to reduce the harmful adverse effects of atypical antipsychotic treatment., (© 2018 Pharmacotherapy Publications, Inc.)

Antipsychotics are associated with severe metabolic side effects including insulin resistance; however, the mechanisms underlying this side effect are not fully understood. The skeletal muscle plays a critical role in insulin-stimulated glucose uptake, and changes in skeletal muscle DNA methylation by antipsychotics may play a role in the development of insulin resistance. A double-blind, placebo-controlled trial of olanzapine was performed in healthy volunteers. Twelve healthy volunteers were randomized to receive 10 mg/day of olanzapine for 7 days. Participants underwent skeletal muscle biopsies to analyze DNA methylation changes using a candidate gene approach for the insulin signaling pathway. Ninety-seven methylation sites were statistically significant (false discovery rate < 0.05 and beta difference between the groups of ≥10%). Fifty-five sites had increased methylation in the skeletal muscle of olanzapine-treated participants while 42 were decreased. The largest methylation change occurred at a site in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PPARGC1A) gene, which had 52% lower methylation in the olanzapine group. Antipsychotic treatment in healthy volunteers causes significant changes in skeletal muscle DNA methylation in the insulin signaling pathway. Future work will need to expand on these findings with expression analyses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]