Kyle J. Burghardt

Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population

Since a poor diet is often cited as a contributor to metabolic syndrome for subjects diagnosed with bipolar disorder and schizophrenia, we sought to examine dietary intake, cigarette smoking, and physical activity in these populations and compare them with those for the general population.

The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia

The catechol-O-methyl transferase (COMT) 158Val/Met variant has been suggested to play a role in COMT function. Epigenetic regulation of COMT may further influence the prevalence of metabolic syndrome in these patient populations. This study examined the correlation between COMT promoter methylation and metabolic syndrome in schizophrenia patients receiving atypical antipsychotic (AAP) therapy. DNA was extracted from peripheral blood samples of schizophrenia subjects screened for metabolic syndrome. Pyrosequencing was used to analyze two methylation sites of the soluble COMT (COMT-s) promoter region. Associations between AAP use, lifestyle variables, metabolic syndrome and COMT genotype with peak methylation values were analyzed. Data are reported in 85 subjects. Methylation on CpG site 1 had a mean of 79.08% (±4.71) and it was 12.43% (±1.19) on site 2. COMT genotype proved to be an indicator of COMT methylation status on site 1 (F(2, 84)=5.78, P=0.0044) and site 2 (F(2, 84),=3.79, P=0.027). A significant negative correlation between physical activity and COMT promoter region methylation was found in Val/Val homozygous patients (site 1: P=0.013 and site 2: P=0.019). Those homozygous for Met/Met showed a positive correlation between promoter site methylation and physical activity (site 1: P=0.027, site 2: P=0.005), and between CpG site methylation and metabolic syndrome (site 1: P=0.002; site 2: P=0.001). The results of this study suggest that COMT promoter region methylation is largely influenced by COMT genotype and that physical activity plays a significant role in epigenetic modulation of COMT.

DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences

AIM In schizophrenia, metabolic syndrome incidence is double that of the general population, with women having a higher incidence. Pharmacogenetically regulated folic acid may be related to this risk. DNA methylation and metabolic syndrome within this group has not been previously studied. METHODS Metabolic syndrome was evaluated with fasting laboratory measurements, and dietary and lifestyle assessments. Methylation analysis used a peripheral sample for the LINE-1 assay. DNA was also genotyped for MTHFR 677C/T. RESULTS This analysis included 133 subjects. We found a significant relationship between LINE-1 methylation, and an interaction between MTHFR and gender, controlling for serum folate (p = 0.008). Females with the 677TT genotype had the lowest methylation (56%) compared with the other groups (75%). CONCLUSION TT genotype females had the lowest methylation, which may explain metabolic syndrome gender differences in schizophrenia. Folate supplementation may be a suggested intervention within schizophrenia; however, additional work is required.

Endothelial nitric oxide synthetase genetic variants, metabolic syndrome and endothelial function in schizophrenia

Objective: The increasing rates of metabolic syndrome and cardiovascular disease in schizophrenia led to investigation into their causes, including atypical antipsychotics and pharmacogenetic variants. This study focused on the peripheral vasculature as a cardiovascular phenotype and the influence of atypical antipsychotics, the aberrant metabolism of nitric oxide caused by endothelial nitric oxide synthetase (eNOS) genetic variants and metabolic syndrome in a cross-sectional sample of schizophrenia subjects. Methods: Associations between eNOS genetic variants and endothelial function was assessed in a cohort of schizophrenia patients taking antipsychotic drugs, whom were undergoing a clinical assessment for endothelial function via the method of peripheral artery tonometry (RH-PAT), as well as metabolic syndrome criteria screening. Analyses were conducted on the entire cohort, then again after stratifying by metabolic syndrome, to investigate the effect of the eNOS variants and metabolic syndrome on endothelial functionality. Results: We included 203 subjects with a mean age of 46 years. The cohort was 36% female, 36% had metabolic syndrome and 85% were currently using atypical antipsychotics. We found associations between the eNOS T-786C and worse endothelial functioning (lower RH-PAT values) only in schizophrenia patients without metabolic syndrome. Conclusions: Our results suggested that when schizophrenia patients progress to meet metabolic syndrome criteria, the genetic protection of the eNOS T-786C variant on endothelial function is no longer seen: Other factors of this pro-inflammatory state may be overriding this effect. The results of this study need replication and the factors driving endothelial dysfunction in patients with metabolic syndrome warrant further investigation.

Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy: Is there a role for folate?

In general, the presence of metabolic syndrome is associated with significant cardiovascular mortality and represents a growing public health concern in the USA. Patients with schizophrenia have a three times greater risk of death than the general population, with cardiovascular disease being the most common cause of this mortality. Use of atypical antipsychotics (AAPs) to treat schizophrenia contributes significantly to this cardiovascular risk. While several different clinical guidelines currently exist to monitor the metabolic consequences of AAP use, implementation is lacking. Because of under-monitoring of side effects and the lack of alternative treatment choices in schizophrenia, research has focused on identification of various biomarkers and pharmacogenomic targets to focus on the patients at greatest risk of metabolic syndrome, thus aiming to increase the efficacy and minimize the side effects of AAPs. This has led to several different lines of research. This review focuses on summarizing the differing metabolic syndrome criteria, monitoring guidelines for use of AAPs, and the role of folic acid as it relates to metabolic syndrome within the schizophrenia population. It concentrates not only on the pharmacogenomics of folic acid metabolism but also on its epigenetic interaction with the environment. From this work, genetic variation within both the methylenetetrahydrofolate reductase (MTHFR) gene and the catechol-O-methyltransferase (COMT) gene has been associated with an increased risk of metabolic syndrome in schizophrenia patients treated with AAPs. Furthermore, work on the combination of folate pharmacogenetics and epigenetics has uncovered relationships between methylation, schizophrenia disease, treatment type, and metabolic syndrome. Despite several areas of biomarker research into schizophrenia-related metabolic syndrome, translation into the clinical setting is still lacking, and further studies are needed to bridge this gap. In the future, folate supplementation may prove to be an easy and effective clinical tool for prevention and/or treatment of metabolic syndrome associated with AAP treatment, but clearly more research needs to be done in this area.

Risk-assessment and Coping Strategies Segregate with Divergent Intrinsic Aerobic Capacity in Rats

Metabolic function is integrally related to an individuals susceptibility to, and progression of, disease. Selective breeding for intrinsic treadmill running in rats has produced distinct lines of high- or low-capacity runners (HCR and LCR, respectively) that exhibit numerous physiological differences. To date, the role of intrinsic aerobic capacity on behavior and stress response in these rats has not been addressed and was the focus of these studies. HCR and LCR rats did not differ in their locomotor response to novelty or behavior in the light/dark box. In contrast, immobility in the forced swim test was higher in LCR rats compared with HCR rats, regardless of desipramine treatment. Although both HCR and LCR rats responded to cat odor with decreased exploration and increased risk assessment, HCR rats showed greater contextual conditioning to cat odor. HCR rats exhibited higher expression of corticotropin-releasing hormone in the central nucleus of the amygdala, as well as heavier adrenal and thymus weight. Corticosterone was comparable among HCR and LCR rats at light/dark transitions, and in response to unavoidable cat odor. HCR rats, however, exhibited a greater corticosterone response following the light/dark box. These experiments show that the LCR phenotype associates with decreased risk assessment in response to salient danger signals and passive coping. In contrast, HCR rats show a more naturalistic strategy in that they employ active coping and a more vigilant and cautious response to environmental novelty and salient danger signals. Within this context, we propose that intrinsic aerobic capacity is a central feature mechanistically linking complex metabolic disease and behavior.

Fatty Acid Desaturase Gene Polymorphisms and Metabolic Measures in Schizophrenia and Bipolar Patients Taking Antipsychotics

Atypical antipsychotics have become a common therapeutic option in both schizophrenia and bipolar disorder. However, these medications come with a high risk of metabolic side effects, particularly dyslipidemia and insulin resistance. Therefore, identification of patients who are at increased risk for metabolic side effects is of great importance. The genetics of fatty acid metabolism is one area of research that may help identify such patients. Therefore, in this present study, we aimed to determine the effect of one commonly studied genetic polymorphism from both fatty acid desaturase 1 (FADS1) and FADS2 gene on a surrogate measure of insulin resistance and lipid levels in a metabolically high-risk population of patients largely exposed to atypical antipsychotics. This study used a cross-sectional design, fasting blood draws, and genetic analysis to investigate associations between polymorphisms, haplotypes, and metabolic measures. A total of 320 subjects with schizophrenia (n = 226) or bipolar disorder (n = 94) were included in this study. The mean age of the population was 42.5 years and 45% were male. A significant association between FADS1 and FADS2 haplotypes was found with insulin resistance while controlling for confounders. Further investigation is required to replicate this finding.

An Untargeted Metabolomics Analysis of Antipsychotic Use in Bipolar Disorder

Second generation antipsychotic (SGA) use in bipolar disorder is common and has proven effective in short‐term trials. There continues to be a lack of understanding of the mechanisms underlying many of their positive and negative effects in bipolar disorder. This study aimed to describe the metabolite profiles of bipolar subjects treated with SGAs by comparing to metabolite profiles of bipolar subjects treated with lithium, and schizophrenia subjects treated with SGAs.

DNA methylation, insulin resistance and second-generation antipsychotics in bipolar disorder

AIMS This study aimed to assess the effect of second-generation antipsychotic (SGA) use and insulin resistance on a global measure of DNA methylation in patients diagnosed with bipolar disorder. MATERIALS & METHODS Subjects stable on medication (either mood stabilizer monotherapy or adjuvant SGAs) were assessed for insulin resistance. Global methylation levels were assessed in leukocyte DNA from whole blood using the Luminometric Methylation Assay. Multivariable linear regression was used to investigate the effect of insulin resistance and SGA use on DNA methylation. RESULTS A total of 115 bipolar I subjects were included in this study. The average age was 43.1 ±12.2 years and 73% were on SGAs. Average% global methylation was 77.0 ± 3.26 and was significantly influenced by insulin resistance, SGA use and smoking. CONCLUSION This is the first study to show a relationship between SGA use, insulin resistance and global DNA methylation. Further work will be needed to identify tissue- and gene-specific methylation changes.

Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics

OBJECTIVE Patients with schizophrenia treated with antipsychotics often develop metabolic side effects including dyslipidemia. Antipsychotics potentially upregulate gene expression of a lipid metabolism pathway protein called SREBP via SREB transcription factors (SREBFs). Genetic variation within SREBF may contribute to dyslipidemias and lipid medication efficacy within schizophrenia. RESULTS A cross-sectional study of 157 patients were genotyped for SREBF1 (rs11868035) and SREBF2 (rs1057217) variants, and assessed for fasting lipids. The cohorts mean age was 46.6 years, was 64% male and 86% were using atypical antipsychotics. When stratified by statin use, those receiving a statin and carrying the SREBF1 T allele exhibited higher total cholesterol levels (p = 0.01), triglyceride levels (p = 0.04) and low-density lipoprotein levels (p = 0.03). A regression analysis controlling for gender differences in lipids showed that the SREBF1 T allele and statin interaction remained only for total cholesterol levels (F[4,149] = 5.8; p < 0.0001). CONCLUSION For schizophrenia individuals with the SREBF1 rs11868035 T allele, incomplete response to statin medications may be seen. Future investigations may allow for personalizing dyslipidemia treatment based on pharmacogenetics within schizophrenia.