Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants

https://doi.org/10.1016/j.schres.2007.09.030Get rights and content

Abstract

Introduction

The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two-to-four-fold higher than the general population.

Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications.

Purpose

To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for ≥ 12 months.

Methods

Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298A/C genotype.

Results

Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR = 3.7, (95% CI = 1.24–12.66, p = 0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F = 8.35, df = 5, 51, p < 0.0001), with these two terms interacting (F = 8.6, df = 2, p = 0.0006) suggesting that TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis.

Conclusion

Results should be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications.

Introduction

The metabolic syndrome has been associated with significant cardiovascular mortality (Maggi et al., 2006, Onat et al., 2006), and the growing association between atypical antipsychotic (AAPs) use and this syndrome represents a particular problem for psychiatric populations treated with these medications. Although several definitions for the metabolic syndrome have been cited, the National Cholesterol Education Program Adult Treatment Protocol (NCEP ATP III) is most often used and requires at least three of the following: abdominal obesity, elevated triglycerides, low HDL, elevated blood pressure, or elevated fasting glucose (Lee et al., 2001). AAPs, primarily used for the treatment of schizophrenia, have been associated with significant metabolic complications, including hyperlipidemia (Gaulin et al., 1999, Osser et al., 1999, Spivak et al., 1999, Henderson et al., 2000, Huang and Chen, 2005), insulin resistance and diabetes mellitus (Henderson et al., 2000, Gianfrancesco et al., 2003, Ollendorf et al., 2004, Carlson et al., 2006, Henderson et al., 2005, Lambert et al., 2005, Sernyak et al., 2005, Guo et al., 2006), obesity (Henderson et al., 2000, Volavka et al., 2002, Simpson, 2005, Zipursky et al., 2005), and hyperhomocysteinemia (Levine et al., 2002, Applebaum et al., 2004, Muntjewerff and Blom, 2005, Muntjewerff et al., 2005). These metabolic complications result in a two-to-four-fold increase in the rate of metabolic syndrome in patients with schizophrenia (Kato et al., 2004, McEvoy et al., 2005, Nasrallah, 2006). The presence of the metabolic syndrome itself is associated with an increased risk for coronary heart disease, CVD, and diabetes mellitus (Wilson et al., 2005a, Wilson et al., 2005b), and patients with schizophrenia treated with AAPs are at greater risk for vascular disease and have a three fold increase in sudden cardiac death compared to the general population (Saari et al., 2005).

Because APPs such as clozapine and olanzapine may provide superior clinical benefits (Lieberman et al., 2005, McEvoy et al., 2006) there is a pressing need to identify patients at risk for the metabolic syndrome and the associated complications. Among the risk factors associated with the development of CVD, insulin resistance, and diabetes mellitus in the general population are the 677C/T and 1298A/C genetic variants of methylenetetrahydrofolate reductase (MTHFR) which are involved in folate and homocysteine metabolism (Klerk et al., 2002, Lewis et al., 2005). These polymorphisms have been associated with up to a 70% reduction in folate acid metabolism, hyperhomocysteinemia, and a greater risk for CVD (Klerk et al., 2002, Matthews, 2002, Gueant-Rodriguez et al., 2005). The relationship between these variants and risk for the metabolic syndrome or insulin resistance in the schizophrenia population receiving AAPs has not been previously investigated, as to our knowledge; our research group is the first to report an association.

Section snippets

Subjects

Subjects were recruited through the University of Iowa Department of Psychiatry. All met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder, were between the ages of 18–90, and had been receiving treatment with an antipsychotic for at least 12 months. Subjects were excluded if they had a history of thyroid problems or other medical condition that may affect body weight (i.e. cancer), were unable to provide informed consent, or unwilling to participate.

Results

A total of fifty-nine subjects were recruited for this study, with one opting to not provide a DNA sample which resulted in a final sample size of fifty-eight (males = 38 (66%), females = 20 (34%)). There were no differences in age, gender, race, smoking, or psychopathology between the genotype groups. Table 2 provides details regarding the baseline characteristics of this population by 677 genotype group.

At the time of screening, subjects were receiving a variety of antipsychotic medications with

Discussion

This investigation is the first to examine the relationship between the MTHFR 677C/T and 1298A/C variants and metabolic syndrome and insulin resistance risk in a schizophrenia population receiving atypical antipsychotics. Recent research has highlighted the importance of genes as well as environmental/nutritional factors in the body's ability to regulate genome machinery (Ames, 2001). This has lead to the field of epigenetics, whose focus is on how diet and nutrition affect DNA functioning or

Study limitations

Due to the small number of subjects included in this analysis and the cross-sectional nature of this study, our data has several limitations. First, in looking at our current analysis, it appears that the majority of the relationships found with metabolic syndrome and insulin resistance is being driven by the small number of subjects with the 677TT genotype. Thus, future investigations need to expand the number of subjects included. Additionally, for many of these subjects this was the first

Role of funding source

This project was supported by a grant from the National Institute of Mental Health (K08 MH64158) and the National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health (M01-RR-59). Both the NIMH and the NCRR had no further role in the 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

Dr. Ellingrod designed the study, wrote the protocol, managed the literature searches and data analyses, and wrote the first draft of the manuscript. Dr. Miller oversaw the clinical care of the subjects, and aided in the interpretation of the results, and preparation of the manuscript. Dr. Taylor aided in the interpretation of the results and the manuscript preparation. Ms. Moline aided in the genotype analysis, and the management of the literature searches and manuscript writing. Mr. Holman

Conflict of interest

The authors have no conflicts of interest to disclose in relation to this manuscript.

Disclosure statement for Vicki L. Ellingrod, Pharm.D., BCPP

June 25, 2007 — for the last 3 years

Dr. Ellingrod is a paid author for LexiComp Inc., and has no other direct financial relationships with any pharmaceutical company, including consulting arrangements, speakers' bureau, or board memberships.

List of entities from whom compensation for professional services was received:

National Institutes of Health

Acknowledgements

None.

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