Association of Protein Kinase B (<scp>AKT</scp>) <scp>DNA</scp> Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder

Burghardt, Kyle J.; Seyoum, Berhane; Dass, Sabrina E; Sanders, Elani; Mallisho, Abdullah; Yi, Zhengping

doi:10.1002/phar.2097

Cited by 18 publications

(11 citation statements)

References 52 publications

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“…Given the strong influence of these medications on AKT expression levels, gene-specific methylation patterns in the promoters of AKT1 , 2 and 3 were analyzed in fasting skeletal muscle biopsies from 16 patients with bipolar disorders treated with an SGA (quetiapine, risperidone, olanzapine, asenapine or aripiprazole) and compared with 14 patients treated with mood stabilizers for at least 3 months. Methylation of AKT1 and AKT2 was higher in SGA-treated patients than in patients treated with mood stabilizers, whereas no differences were found in AKT3 methylation [153]. Accordingly, increased AKT promoter methylation might explain the decreased insulin sensitivity in skeletal muscle associated with treatment, as increased methylation in the gene promoters is generally linked to decreased gene expression and functionality.…”

Section: New Insights Into the Molecular Mechanisms By Which Sgas mentioning

confidence: 99%

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Grajales

Ferreira

Valverde

2019

Cells

109

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Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.

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Section: New Insights Into the Molecular Mechanisms By Which Sgas mentioning

confidence: 99%

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Grajales

Ferreira

Valverde

2019

Cells

109

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“…Our systematic review yielded 29 studies (Table 1). Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of patients with schizophrenia and bipolar disorder. The majority (n=22) of studies included observational sampling, such as cross‐sectional or case‐control studies, and the remaining analyzed changes in a prospective manner.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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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.

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“…As the skeletal muscle is the primary tissue involved in insulin-stimulated glucose uptake, the potential effects on these various glucose metabolism pathways could aid in describing the direct effects of AAPs on insulin sensitivity [ 10 ]. As previously described, work in L6 muscle models has demonstrated that olanzapine may cause dysregulation in the PI3K/AKT and glycogen synthesis pathways, and our group has identified epigenetic dysregulation of the AKT pathway in the skeletal muscle [ 27 , 28 , 49 ]. The pathway analysis results from this study are the first to suggest that there may be protein dysregulation occurring within these related pathways of the skeletal muscle in-vivo.…”

Section: Discussionmentioning

confidence: 99%

Profiling the Skeletal Muscle Proteome in Patients on Atypical Antipsychotics and Mood Stabilizers

et al. 2022

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Atypical antipsychotics (AAP) are used in the treatment of severe mental illness. They are associated with several metabolic side effects including insulin resistance. The skeletal muscle is the primary tissue responsible for insulin-stimulated glucose uptake. Dysfunction of protein regulation within the skeletal muscle following treatment with AAPs may play a role in the associated metabolic side effects. The objective of this study was to measure protein abundance in the skeletal muscle of patients on long-term AAP or mood stabilizer treatment. Cross-sectional muscle biopsies were obtained from patients with bipolar disorder and global protein abundance was measured using stable isotope labeling by amino acid (SILAC) combined with high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Sixteen patients completed muscle biopsies and were included in the proteomic analyses. A total of 40 proteins were significantly different between the AAP group and the mood stabilizer group. In-silico pathway analysis identified significant enrichment in several pathways including glucose metabolism, cell cycle, apoptosis, and folate metabolism. Proteome abundance changes also differed based on protein biological processes and function. In summary, significant differences in proteomic profiles were identified in the skeletal muscle between patients on AAPs and mood stabilizers. Future work is needed to validate these findings in prospectively sampled populations.

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Association of Protein Kinase B (AKT) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder

Cited by 18 publications

References 52 publications

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

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

Profiling the Skeletal Muscle Proteome in Patients on Atypical Antipsychotics and Mood Stabilizers

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