Abstract
Background:Metabolic syndrome may be related to folate’s pharmacogenetically regulated metabolism and atypical antipsychotic (AAP) exposure.Aims:We examined folate supplementation on metabolic measures, endothelial functioning (Reactive Hyperemia Index (RHI)), and global methylation in AAP-treated schizophrenia subjects meeting NCEP-ATP-III-a metabolic syndrome criteria.Methods:Subjects were given 5 mg/day open label folate for 3 months. Baseline and end point measurements included RHI, body mass index, fasting metabolic laboratory measures, C-reactive protein, homocysteine, IL-6, and leptin. Subjects were genotyped for methylenetetrahydrofolate reductase (MTHFR) 677C/T and catechol-O-methyltransferase (COMT) 158 Val/Met, as well as global DNA methylation using the LUminometric Methylation Assay (LUMA).Results:Thirty-five subjects (mean age 50±9 years and 70% Caucasian) were included. At end point, RHI improved by 20% (P=0.02), homocysteine decreased 14% (P=0.006), and IL-6 decreased 13% (P=0.09). At baseline, 61% met endothelial dysfunction criteria (RHI<1.67), which decreased to 27% (P=0.0006) at end point. The MTHFR 677C/C+COMT 158Met/Met group also showed significant reduction in those meeting endothelial dysfunction (83% baseline and 16% end point (P=0.001)). Global methylation levels increased after supplementation (4.3%, P<0.0001), with subjects receiving olanzapine or clozapine experiencing greater methylation changes after folate supplementation. Folate may reduce AAP-associated metabolic risks.Conclusions:We report significant reductions in the number of subjects meeting endothelial dysfunction. Given that all subjects met metabolic syndrome criteria, this may prove as a useful avenue to reducing cardiovascular disease risk. MTHFR and COMT genotypes may affect response and underlying changes in DNA methylation may help to explain the mechanistic underpinnings of these findings.
Highlights
Within the general population the incidence of cardiovascular disease is on the rise.[1]
For individuals diagnosed with schizophrenia and treated with an antipsychotic, work previously done by our group and others suggest a relationship between the methylenetetrahydrofolate reductase (MTHFR) 677C/T variant as well as the catechol-O-methyl transferase (COMT) 158 Val/Met variant and metabolic syndrome risk.[6,7]
Our group has found associations between folate, one carbon metabolism, DNA methylation and atypical antipsychotic (AAP) metabolic side-effect risk.[8,9]. As part of these investigations we found a significant relationship between a surrogate maker of global methylation (Long Interspersed Nucleotide Element 1 methylation), and an interaction between MTHFR and gender, after controlling for serum folate (P = 0.008)
Summary
Within the general population the incidence of cardiovascular disease is on the rise.[1]. Our group reported genespecific methylation differences related to COMT that suggest that COMT promoter region methylation is largely influenced by COMT genotype and that physical activity has a significant role in epigenetic modulation of COMT in the schizophrenia population. These two analyses are the basis for gaining a better understanding of the role of folate in the attenuation of metabolic complications seen with AAP use. AIMS: We examined folate supplementation on metabolic measures, endothelial functioning (Reactive Hyperemia Index (RHI)), and global methylation in AAP-treated schizophrenia subjects meeting NCEP-ATP-III-a metabolic syndrome criteria. MTHFR and COMT genotypes may affect response and underlying changes in DNA methylation may help to explain the mechanistic underpinnings of these findings
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