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Association of Protein Kinase B ( AKT ) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder
Author(s) -
Burghardt Kyle J.,
Seyoum Berhane,
Dass Sabrina E.,
Sanders Elani,
Mallisho Abdullah,
Yi Zhengping
Publication year - 2018
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.2097
Subject(s) - insulin resistance , protein kinase b , atypical antipsychotic , medicine , skeletal muscle , mood stabilizer , endocrinology , antipsychotic , dna methylation , diabetes mellitus , bipolar disorder , biology , psychiatry , schizophrenia (object oriented programming) , signal transduction , genetics , gene , gene expression , lithium (medication)
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, AKT 1, AKT 2 , and AKT 3, 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, AKT 1 and AKT 2 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 AKT 2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT 2 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.

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