Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs)

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Abstract

Purpose

Within schizophrenia cardiovascular disease (CVD) is highly prevalent secondary to atypical antipsychotic (AAP) use. Thorough assessments of diet, lifestyle, and endothelial functioning have not been done in this population. Omega 3 Fatty Acids (N-3 FAs) have garnered attention in relation to psychopathology as well as cardioprotection. This study examined the status of endothelial function within the schizophrenia population and determined pharmacogenetic, medication, dietary, and lifestyle factors associated with this functioning.

Methods

Schizophrenia subjects were screened for the metabolic syndrome along with physical activity, smoking, and variants related to folate pharmacogenetics in this cross-sectional analysis. Arteriole endothelial-dependent vasodilatation was measured using non-invasive peripheral arterial tonometry (RH-PAT, EndoPAT2000). A 24 h dietary food recall was used to construct intake profiles using the Nutrition Data Systems for Research software (NDSR). We examined associations between AAP use and RH-PAT values, and the influence of N-3 FA dietary intake on this measure. Preliminary data are reported in 83 subjects with a mean age (± s.d.) of 45.89 (± 11.49), 64% were Caucasian (n = 53), 64% were male (n = 53), and 77% were receiving AAP treatment (n = 63).

Results

A significant positive relationship was found between RH-PAT values and N-3 FA intake (F = 17.7(1,16), p = 0.0007) in subjects not receiving AAPs. This relationship was lost in those treated with AAPs (F = 0.25(1,43), p > 0.6). Regression analysis confirmed the interaction effect of AAP treatment on the relationship between RH-PAT and N-3 FAs (p = 0.0105). Endothelial dysfunction was also related to folate pharmacogenetic variants.

Conclusions

AAPs may counteract some vascular health benefits of a diet high in N-3 FAs. AAP use may necessitate a higher N-3 FA dose to regain these effects, but additional research is necessary to strengthen the preliminary findings. Pharmacogenetic variants related to folate and homocysteine metabolism may also increase endothelial dysfunction risk.

Introduction

The metabolic syndrome affects persons with schizophrenia significantly more than the general population, a fact related to the use of atypical antipsychotics (AAPs) (McEvoy et al., 2005). The metabolic syndrome comprises a cluster of risk factors including abdominal obesity; abnormalities in glucose metabolism, dyslipidemia, and elevated blood pressure, and was associated with an increased risk of cardiovascular disease (CVD) and diabetes (DM) (Davidson, 2002). Our group, and others, have reported that occurrence of metabolic syndrome within schizophrenia is associated with pharmacogenetically regulated folate and homocysteine metabolism as well as folate exposure though dietary intake (Ellingrod et al., 2008, Garcia-Miss Mdel et al., 2010, van Winkel et al., 2010a, van Winkel et al., 2010b, Ellingrod et al., 2010). Presence of at least one variant allele for either of the key enzymes methylenetetrafolate reductase (MTHFR) 677 C/T (rs1801133), 1298A/C (rs1801131) or catechol-o-methylatransferase (COMT) 158 Val/Met (rs4680) may increase the risk of metabolic syndrome within this population due to their roles in folate and homocysteine metabolism (Ellingrod et al., 2008, Tunbridge et al., 2008). While the literature related to metabolic syndrome risk within schizophrenia is rapidly expanding and lifestyle factors such as poor diet and a high incidence of cigarette smoking have also been identified as risk factors for increased CVD within this group (Vancampfort et al., 2010, DE Hert et al., 2009, Bobes et al., 2010), much remains unknown about the pathophysiology of CVD within schizophrenia. It is known that the vascular endothelium is adversely affected by the metabolic syndrome, (Benjamin et al., 2004, McVeigh et al., 1992, Brook et al., 2001, Lupattelli et al., 2000, Kuvin et al., 2003a, Tziomalos et al., 2010), increasing the cardiovascular disease (CVD) risk.

The endothelium is a vital organ that has garnered important attention due to its relationship to CVD (Ross, 1999, Haynes, 2003, Rubinshtein et al., 2010). Physiologically the endothelium is comprised of a single layer of cells that line all blood vessels, and represents an important organ though its effects on regulating vasomotor tone, thrombosis, inflammation, platelet and leukocyte adhesion and vascular permeability (Lane et al., 2006). The presence of endothelial dysfunction increases the risk of CVD not only in individuals with established vascular disease, but also in those without (Kullo and Malik, 2007). Thus measuring endothelial functioning may help to identify those at greatest risk for CVD. Unfortunately this measure has primarily been a research tool due to the invasive nature of this assessment as well as issues related to operator dependency (Bonetti et al., 2004). However, recently, measurement of fingertip pulse amplitude tonometry (RH-PAT) has introduced a non-invasive method for measuring small vessel (arteriole) endothelial-dependent vasodilatation and determining vascular health within the ambulatory clinic setting (Bonetti et al., 2004, Kuvin et al., 2003b, Kuvin et al., 2007). Pulse amplitude hyperemic response impairment has been associated with endothelial dysfunction and abnormal RH-PAT results have been correlated with the traditional invasive assessments of arteriole endothelial-dependent vasodilatation (Bonetti et al., 2004).

The aim of this investigation was to measure arteriole endothelial-dependent vasodilatation and the extent of endothelium dysfunction within the schizophrenia population using a non-invasive method, to determine the associated pharmacogenetic, medication, dietary, and lifestyle factors. We hypothesized that the prevalence of endothelial dysfunction would be similar to the prevalence of metabolic syndrome. Additionally we also proposed that presence of poorer arteriole endothelial-dependent vasodilatation and endothelial dysfunction would be related to AAP use, dietary and lifestyle measures, and the MTHFR and COMT genetic variants that regulate folate and homocysteine metabolism.

Section snippets

Subjects

Subjects were included in this cross-sectional analysis if they meet the following inclusion criteria: 1) Presence of a DSM-IV diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder, 2) between the ages of 18–90 years of age, and 3) their physician determined that they should be treated with an antipsychotic which they had been receiving for at least 6 months. Subjects were excluded if they 1) were unwilling to participate, 2) lacked the ability to give informed

Statistical analysis

Subjects currently receiving olanzapine, clozapine, quetiapine, risperidone, or paliperidone were classified as receiving an atypical antipsychotic (AAP). Ziprasidone and aripiprazole were not included in this primary classification due to their lack of weight gain liability (Komossa et al., 2009a, Komossa et al., 2009b). The criteria used for endothelial dysfunction was an RH-PAT value of < 1.67 as previously discussed. Both the MTHFR and COMT variants have shown a relationship between CVD risk

Results

We analyzed a total of 83 subjects with a schizophrenia spectrum diagnosis. The mean age (± s.d.) of subjects in years was 45.89 ± 111.49 (range = 22–70 years old). The majority of subjects (64%, n = 53) were Caucasian, with 27% (n = 22) reporting to be African American. Similar to the overall demographics of schizophrenia, 64% (n = 53) of our study group was male. The mean body mass index (BMI) of subjects was 33.2 ± 7.97 and 44% (n = 36) met metabolic syndrome criterion which is in line with the previous

Discussion

Overall this investigation found that 50% of schizophrenia subjects meet criteria for endothelial dysfunction (RH-PAT < 1.67) (Bonetti et al., 2004), which is to our knowledge the first time this has been reported. Given that at least 40% of schizophrenia subjects meet metabolic syndrome criteria, and that this population is at high risk for AAP associated metabolic complications, we hypothesized that at least 40% of our group would have an RH-PAT < 1.67, similar to the incidence of metabolic

Limitations

Despite our best research efforts this investigation has some limitations. Most notably this is a cross-sectional study that only had one assessment for the arteriole endothelial-dependent vasodilatation. Additionally lack of a specific control may limit our results and the use of the 24 h food recount for quantifying an average daily intake is not optimal, despite our use of this assessment in triplicate in an effort to obtain a good approximation of each subject's usual diet. Lack of blood

Summary

In summary, as part of this investigation we found that 50% of individuals with schizophrenia met the criteria for endothelial dysfunction when measured using the non-invasive EndoPAT2000. This percentage is similar to the 40% incidence of metabolic syndrome seen in this population. This investigation is the first, to our knowledge, to report on the prevalance of endothelial dysfunction (RH-PAT < 1.67) within the schizophrenia population. Additionally we found an interaction between total dietary

Funding sources and roles

This project was supported by the NIMH (R01 MH082784-01) and the NIH-NCCR, GCRC Program (M01-RR-59 and UL1RR024986), the Chemistry Core of the Michigan Diabetes Research and Training Center (NIH5P60 DK 20572), and the Washtenaw Community Health Organization (WCHO). None of these funding and support agencies had any further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Authors Ellingrod, Taylor, Zoellner, Brook, Dalack and Pop-Busui designed the study and wrote the protocol. Authors Ellingrod, Evans, Grove, and Bly managed the literature searches and analyses. Authors Ellingrod and Zöllner undertook the statistical analysis, and author Ellingrod wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors have no conflicts of interest to disclose.

Acknowledgments

We wish to thank all of the study participants.

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