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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 (<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content><\/jats:italic> isoform\u2013specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Cross\u2010sectional observational study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Clinical research services center at an academic center.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>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\u2010g oral glucose tolerance test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements and Main Results<\/jats:title><jats:p>Skeletal muscle <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation near the promoter region for three genes, <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>2<\/jats:italic>, and <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>3,<\/jats:italic> was measured by methylation\u2010sensitive high\u2010resolution 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, <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>1<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>2<\/jats:italic> 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 <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>2<\/jats:italic> hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>2<\/jats:italic> methylation with increasing insulin resistance was observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Overall, our findings suggest that the <jats:italic><jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content><\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.2097","type":"journal-article","created":{"date-parts":[[2018,2,27]],"date-time":"2018-02-27T02:53:39Z","timestamp":1519700019000},"page":"428-435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Association of Protein Kinase B (<scp>AKT<\/scp>) <scp>DNA<\/scp> Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-5149","authenticated-orcid":false,"given":"Kyle J.","family":"Burghardt","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit 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