Jurnal DR 56

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Mol Diagn Ther. Author manuscript; available in PMC 2014 July 01.
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Mol Diagn Ther. 2013 February ; 17(1): 21–30. doi:10.1007/s40291-013-0017-8.
Detection of the Metabolic Syndrome in Schizophrenia and

Implications for Antipsychotic Therapy: Is There a Role for
Folate?
Kyle J Burghardt, Pharm.D1 and Vicki L Ellingrod, Pharm.D., FCCP1,2
1Department of Clinical Social and Administrative Sciences, College of Pharmacy. University of
Michigan, 428 Church St., Ann Arbor, MI, 48109
2Department of Psychiatry, School of Medicine, University of Michigan, 4250 Plymouth Rd., Ann
Arbor, MI, 48109
Abstract
In general, presence of the metabolic syndrome is associated with significant cardiovascular

mortality and represents a growing public health concern in the United States. Patients with a
schizophrenia have a three times greater risk of death compared to the general population, with
cardiovascular disease being the most common cause of this mortality. Use of the atypical
antipsychotics (AAPs) to treat schizophrenia contributes significantly to this cardiovascular
disease risk. While currently several different clinical guidelines exist to monitor for the metabolic
consequences of AAP use, implementation is lacking. Due to the under monitoring of side effects
and the lack of alternative treatment choices in schizophrenia, research has focused on the
identification of various biomarkers and pharmacogenomic targets to focus on those at greatest
risk for metabolic syndrome, thus aiming to increase the efficacy and minimize the side effects of
the AAPs. This has led to several different lines of research. This manuscript focuses on
summarizing the differing metabolic syndrome criteria, monitoring guidelines for AAPs and the
role of folic acid as it relates to metabolic syndrome within the schizophrenia population. It will
concentrate not only on the pharmacogenomics of folic acid metabolism, but also its epigenetic
interaction with the environment. From this work, genetic variation within both the
methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT) genes

has been associated with increased metabolic syndrome risk in schizophrenia patients treated with
AAPs. Furthermore, the combination of folate pharmacogenetics and epigenetics has uncovered
relationships between methylation, schizophrenia disease, treatment type and metabolic syndrome.
Despite the several areas of biomarker research for schizophrenia related metabolic syndrome,
translation to the clinical setting is still lacking and further studies are needed to bridge this gap.
Future folate supplementation research may prove to be an easy and effective clinical tool for the
prevention and/or treatment of metabolic syndrome associated with AAP treatment, but clearly
more work needs to be done in this area.
Corresponding Author: Vicki L. Ellingrod, PharmD, FCCP, vellingr@umich.edu.

Present Address: 428 Church Street Ann Arbor, Michigan 48109, Telephone #: 734-615-4728
Burghardt and Ellingrod Page 2
Keywords
Schizophrenia; Metabolic Syndrome; Folic Acid; Homocysteine; MTHFR; Epigenetics
1. Introduction
In the general population, the presence of the metabolic syndrome is associated with
significant cardiovascular mortality and represents a growing public health concern in the
United States (1,2). While the term, metabolic syndrome, has been coined within the past 20
years (previously called Syndrome X), the constellation of symptoms that make up
metabolic syndrome (such as central adiposity and elevations in cholesterol, blood glucose,
and blood pressure) have historically been recognized as risk factors for cardiovascular
disease (3–5). Metabolic syndrome is seen in about 25% of men and women (6). For those
meeting metabolic syndrome criteria, the population-attributable risk estimates for
cardiovascular disease, coronary heart disease, and diabetes mellitus are 34%, 29%, and
62% for men and 16%, 8% and 47% for women (7). Thus, presence of the metabolic
syndrome criteria is associated with increased risk for significant cardiovascular morbidity
and mortality and has undoubtedly become a national health crisis as the rates of this illness
continue to rise. Unfortunately the risks for metabolic syndrome in those with a serious
mental illness such as schizophrenia or bipolar disorders are more than double that seen in
the general population which has also resulted in a significant proportion of the morbidity
and mortality seen within these populations (8–10). Although the exact cause for this
increased risk for the metabolic syndrome in serious mental illness is unknown, the high
prevalence of atypical antipsychotic use has been suggested as being a major contributor
(8,11). Much work has been done examining the pharmacogenomics of atypical
antipsychotic metabolic consequences; however consensus regarding these risks currently
does not remain. One promising line of work has focused on folic acid and its
pharmacogenetically regulated metabolism through the methylenetetrahydrofolate reductase
(MTHFR) enzyme. Thus the purpose of this review is to focus on the increased risk for
metabolic syndrome within the schizophrenia population. It will give a brief background
examining the different criteria used for a diagnosis of metabolic syndrome followed by a
summary regarding monitoring for metabolic syndrome within the schizophrenia population.
Lastly the role of biomarkers for the detection of metabolic syndrome within schizophrenia
will be touched on with a summarization of the available literature regarding folate

pharmacogenomics and epigenomics in antipsychotic-associated metabolic syndrome within
this population.
2. Criteria for Diagnosis of Metabolic Syndrome

Before discussing the increased incidence of the metabolic syndrome within the
schizophrenia population, a thorough understanding of the different criteria currently
available is necessary. Although there is significant overlap between these differing criteria,
there is no one set of criteria that are consistency used by all, and as such this lack of
consistency makes comparing the rates of metabolic syndrome across populations difficult.
Additionally differing patient populations (i.e. treatment naïve and non-treatment naïve) are
often included when examining the true incidence of metabolic syndrome due to atypical
antipsychotic use. Thus, current estimates range from 13.4%, as seen within the Comparison
of Atypicals for First Episode (CAFE) trial (12) which included younger drug naive
subjects, to 40%–52% as reported in the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) trial, as well as other recent larger database studies which did not
include treatment naïve subjects (9,11,13).
In looking at the different criteria available for the diagnosis of metabolic syndrome, those
defined by the National Cholesterol Education Program (NCEP) in 2001, and the
International Diabetes Federation (IDF) in 2006 (14,15) appear to be the most commonly
cited and referenced when examining the overall risk in schizophrenia. In examining the
NCEP criteria it can be seen that a diagnosis of metabolic syndrome can be given when
patients meet at least 3 of the following criteria: abdominal obesity (waist circumference ≥
40 inches in males or 35 inches in females), elevated triglycerides (≥ 150 mg/dL), low HDL
(< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (≥ 130 / 85 or on
antihypertensive medication), or elevated fasting glucose (≥ 100 mg/dL or on medication for
diabetes) (16). This popular NCEP definition, which was subsequently updated with a lower
impaired fasting glucose threshold by the American Heart Association in 2005, was
published in the third Adult Treatment Protocol (ATP III-A). Since 2001, various definitions
have typically been updates to the original ATP III definition (17) and so these competing
definitions have significant overlap with key components such as glucose dysregulation, and
central adiposity. It is only the NCEP ATP III-A guideline that do not require any core
elements be present for a diagnosis of metabolic syndrome. In contrast to this, both the
International Diabetes Foundation and the European Group for the Study of Insulin
Resistance require either a BMI >30 kg/m2 or elevated insulin levels, respectively as part of
their core definition. Thus for all of these guidelines, at the heart each are the same core risk
factors, it is just how they are used in defining a diagnosis of metabolic syndrome that
potentially allows for some of the variation seen in the incidence of metabolic syndrome
within the seriously mentally ill populations. To overcome this, some groups have worked
together to create a more symbiotic approach to developing metabolic syndrome criteria
(with added ethic and race specificity) such as the consensus definition suggested by Alberti
and colleagues (18). Thus while it is easy to understand that presence of the metabolic
syndrome confers with it an increased risk for cardiovascular disease, understanding the
specific criteria that need to be met in order to obtain this diagnosis is often not so simple
which may contribute to the confusion often associated with metabolic syndrome and its
diagnosis (19). The anticipated release of the ATP-IV guidelines however, could result in
another update to the definition and criteria of the metabolic syndrome and possibly include
ethnic and race specificity which may further complicate this issue.
3. Metabolic syndrome Within Schizophrenia

Presence of a mental illness has long been associated with increased overall mortality (20–
22). Cardiovascular disease undoubtedly also contributes to excess morbidity and mortality
in individuals with a serious mental illness. In patients with schizophrenia, it is estimated
that approximately 34% of deaths among male patients and 31% of deaths among female
patients are attributed to cardiovascular disease which is only surpassed by suicide (21,23).
In general, schizophrenia is an often debilitating mental illness that affects approximately
1% of the population (24) usually manifesting not only through positive and negative
symptoms, but significant cognitive dysfunction as well (25). The overall goal of treatment
for schizophrenia is remission of symptoms, and for most individuals with schizophrenia,
antipsychotic medications play an important role in this process. While our

pharmacotherapeutic treatment choices for schizophrenia have expanded over the last few
decades, pharmacologically these medications traditionally achieve their effect through
blockade of the dopamine 2 receptor (26). More recently, the atypical antipsychotics (AAPs)
(olanzapine, clozapine, risperidone, paliperidone, iloperidone, quetiapine, asenapine,
lurasidone, aripirazole, and ziprasidone) have become the first line treatment for
schizophrenia due to their differing serotonin antagonism, primarily at 5HT2A and 5HT2C,
their possible association with negative symptom improvement, as well as attenuation of
extrapyramidal side effects (27).
Although AAPs are effective for the treatment of schizophrenia, their use has now become
common place in other mental illnesses and younger age groups as well. Most AAPs carry
significant risks such as diabetes, weight gain and dyslipidemia which, as previously
discussed, make up the constellation of cardiovascular risk factors outlined in the metabolic
syndrome criteria (28–31). Patients taking AAPs frequently manifest early symptoms of
metabolic syndrome followed by the actual development of more serious cardiac

complications. The end result is up to 30 years of life lost (23,32) for those with
schizophrenia. Furthermore, recent studies have suggested the standardized mortality ratio
(SMR) for cardiac disease may be increasing in schizophrenia patients relative to the general
population following the introduction of AAPs (33,34). These findings are particularly
concerning given the known association between these medications and CVD risk factors,
adding biological plausibility to the epidemiological findings. A comparison of the Clinical
Antipsychotic Trial of Intervention Effectiveness (CATIE) participants with schizophrenia
to matched controls from the National Health and Nutrition Examination Survey (NHANES
III) on ten-year risk of coronary heart disease based on the Framingham Heart Study
formula demonstrated an elevation in risk for coronary heart disease of 34% in males and
50% in females with schizophrenia (35). Similar elevations in cardiac risk with
schizophrenia have been demonstrated in other studies (36,37) and are much higher than that
reported in the Framingham Heart Study Offspring Study.
Until recently, significant weight gain with AAP use was the primary research focus
involving AAP metabolic complications, and in fact, CATIE showed that over 30% of
subjects gained greater than 7% of their baseline body weight with at least 18 months of
AAP treatment (38). This trial also confirmed that overall men and women with
schizophrenia were 85% and 137% more likely to develop metabolic syndrome,
respectfully, than NHANES matched controls (9) and that “Clinical attention must be given
to monitoring for this syndrome and minimizing the risks associated with antipsychotic
treatment”. This work has been replicated by other groups showing that schizophrenia
patients treated with AAPs have a two to four fold greater risk for metabolic syndrome
compared to the general population (39). The precise explanation for this increased risk
linked to AAPs remains unknown; however the body of literature regarding the risks seen
with AAP use has grown substantially throughout the last decade (40). In addition, recent
guidelines based on this work have been developed in an effort to help mitigate the
cardiovascular risks seen with AAP use in persons with a serious mental illness.
4. Monitoring Recommendations for AAP use in Schizophrenia

Although much of this literature contributes the risk for metabolic syndrome in the seriously
mentally ill population to atypical antipsychotic use, not all clinicians agree that this is
simply a medication associated side effect. Regardless of the etiology, there is consensus
regarding the importance of routine monitoring for metabolic syndrome within the mental
health population and several specific guidelines have been published for those receiving an
atypical antipsychotic. The first of these guidelines was authored within the United States
and was published on behalf of the American Diabetes Association (ADA) and the
American Psychiatric Association (APA) in 2004 (41). Key to these guidelines is the routine
monitoring of weight, waist circumference, blood pressure, fasting plasma glucose level, and
fasting lipid profile. Table 1 is a summary of the APA/ADA monitoring guideline
recommendations. In addition to these practice guidelines, several others have been
published such as those supported by the United Kingdom’s National Institute for Health
and Clinical Excellence (NICE) and the Quality and Outcomes Framework (QOF) (42,43) as
well as publications published in the Canadian Journal of Psychiatry (44,45). Finally, much
work has looked at the quality of proposed guidelines for monitoring metabolic syndrome
within schizophrenia which is beyond the scope of this review however several reviews are
available (46,47). While there might be slight differences in the exact monitoring these
various guidelines recommend; they all highlight the importance of continued monitoring
and preventative care for those with a serious mental illness especially in those populations
receiving AAPs.
Unfortunately the reality is that, despite clear recommendations, these guidelines are not
being followed (48–51). Adherence to these guidelines has recently become a priority
research area for many in an effort to document some of the health disparities related to
those with a serious mental illness. In a recent meta-analysis on this topic, Mitchell and
colleagues found 48 studies on the topic of metabolic monitoring in mental health (47). As
part of their meta-analysis they found that across these studies, routine baseline monitoring
was very low and that only blood pressure and triglyceride monitoring were occurring in
more than half of patients receiving an atypical antipsychotic. More specifically weight was
only monitored in 48% of patients, followed by glucose in 44%, cholesterol in 42% and
lipids and glycosylated hemoglobin (HbA1c) in less than 25% of patients. Thus, while we
have many different monitoring guidelines to choose from which can be used to guide the
treatment of those with a serious mental illness, these recommendations are not being
consistently followed. Additionally these authors examined the literature regarding
monitoring changes after specific educational interventions were made for clinicians
regarding these guidelines. They found that monitoring in areas like blood pressure, weight
gain, glucose and lipids did increase, but that overall the rates of monitoring were still low
related to glucose (56%) and lipids (29%)(47). The low use of these guidelines in clinical
practice is of concern and indicates that this patient group does not receive adequate testing
or monitoring for metabolic complications. Furthermore, clinicians must use this monitoring
to guide treatment of identified metabolic abnormalities with appropriate medications in

order to prevent future cardiovascular consequences from the metabolic syndrome.
While monitoring for metabolic complications of AAP use continues to be an emphasized

issue, the research community has continued to work towards understanding the
mechanisms behind these medication side effects resulting in the identification of different
biomarkers which have been proposed for their potential use in the clinic (52–56).
Potentially having a biomarker for the metabolic side effects seen with AAP use would be
highly desirable, as it would allow the clinician to easily measure a patients risk for
metabolic syndrome before any medication is administered. This would aid in the effort to
personalize mental illness pharmacotherapy and optimize treatment. While the research on
various biomarkers related to the risk for weight gain and metabolic syndrome seen with
AAPs is fairly expansive (56–58), no definitive recommendations have currently been
translated into clinical practice and thus work within this area must continue.
5. Folic Acid Pharmacogenetics and Epigenetics

Our continued understanding of the pharmacogenomics of antipsychotic-associated
metabolic syndrome has highlighted the importance of environment and nutrition in the
body’s ability to regulate the genome (59) though dietary folic acid intake and its
pharmacogenetically regulated metabolism. Briefly, folate is a water soluble B-vitamin
involved in the synthesis, repair, and methylation of DNA (60) whose effective utilization is
dependent on adequate daily intake as well as genetically altered metabolism (60). Within
the AldoMet cycle, the methylenetetrahydrofolate reductase (MTHFR) enzyme metabolizes
folate to methyltetrahydrofolate (5-methyl THF) which then converts homocysteine to
methionine and adenosyl methionine by methionine synthetase (MTR) (Figure 1). Reduced
MTHFR activity results in hyperhomocysteinemia, which is associated with cardiovascular
disease. The AldoMet cycle’s final product is the universal methyl donor for several
biological methylation reactions. It is these methyl groups which form the basis for
epigenetic modulation of DNA processes, which is beyond the scope of this review (61).
MTHFR relies on dietary folate as well as genetic variants in determining its efficiency (62).
When inadequate amounts of 5-methyl THF are available for MTR, homocysteine increases
and s-adenosyl methionine formation is reduced, resulting in DNA hypomethylation (63,64).
Thus, folic acid plays an important role in maintaining genomic stability as well as
homocysteine levels (65). Genetic variation within this enzyme has also been shown to
affect its efficiency. For MTHFR, the 677C/T variant, resulting in an alanine to valine
substitution is the most prominent and produces a thermo-labile variant with reduced
activity (66). The T allele is relatively common, with homozygosity occurring in up to 20%
of North American and European populations (60). Individuals with a TT genotype have a
70% reduction in MTHFR activity, compared to the CC genotype group, while
heterozygotes have a 35% reduction (67). Of the AldoMet cycle enzymes, the MTHFR
677TT variant is the best characterized and is most consistently associated with
hyperhomocysteinemia, cardiovascular disease, metabolic syndrome and methylation status.
This relationship is exaggerated by low dietary intake and reduced total body stores of folic
acid (68). Research currently points to MTHFR in the development of metabolic syndrome
in mental health patients taking AAPs as summarized and discussed below (28,31).
Pertinent to the metabolism of homocysteine is the enzyme catechol-O-methyl transferase

(COMT). Despite the lack of clarity concerning COMT’s role in the pathogenesis of
schizophrenia, it has been shown that the 158Met variant produces a more thermolabile
protein resulting in reduced activity compared to the 158Val variant. Those with the Val/Val
genotype have 30–50% greater activity than those with the Met/Met genotype (69). Thus, in
relation to homocysteine metabolism, individuals with the COMT 158Val allele would have
higher COMT activity leading to increased homocysteine concentrations, which may be
exaggerated in individuals who also have MTHFR variants associated with
hyperhomocysteinemia (70). The risks seen with the AldoMet variants are often exaggerated
in situations of low folate exposure (71) and therefore dietary assessments as well as genetic
measurements are dually important to understanding homocysteine, cardiovascular disease
and the risk of metabolic syndrome within those receiving AAPs.
6. Role of Folic Acid in Atypical Antipsychotic Metabolic Syndrome

Multiple studies have demonstrated relationships between MTHFR gene variants and
schizophrenia pathogenesis, but more recently this work has begun to focus on the role of
aberrant folate metabolism as it relates to metabolic syndrome risk in the schizophrenia
population using AAPs. To identify available literature associated with this topic, a pubmed
search was conducted using combinations of the following words: schizophrenia, folate,
metabolic syndrome, antipsychotic, pharmacogenetic, epigenetic, MTHFR, COMT and
MTR. A total of 22 studies were found, 15 were excluded either because they were not
conducted in humans, were conducted without reference to antipsychotic use, were reviews
or did not relate to metabolic syndrome. Furthermore, references of included articles were
searched for further literature sources. Table 2 is a summary of those studies on this topic
that are discussed below.
The first report of this relationship included 58 subjects with schizophrenia who were
receiving AAPs. It was reported that patients with schizophrenia who carried a MTHFR
677T allele had a 3.6 times greater risk for meeting metabolic syndrome criteria while taking
an AAP (p = 0.02) (28). Additionally, the data showed that after controlling for waist
circumference, those with the MTHFR 677T allele were also at increased risk for developing
higher levels of insulin resistance (28). At this time, this report was the first to examine the
relationship between MTHFR variants and metabolic syndrome risk within this population.
This study was then followed up by Van Winkel and colleagues (72). While this group also
found a relationship between MTHFR and metabolic syndrome within schizophrenia, the
authors reported that the MTHFR 1298A>C allele instead of the 677C>T allele was related
to a significant increase in risk of metabolic syndrome (p = 0.02). Overall these authors
found that patients with the 1298C/C genotype had a 2.4 times increase risk of metabolic
syndrome (p = 0.009) which was similar to our previously reported odds ratio of 2.54 for the
677 T variant (28,72). Van Winkel and colleagues also conducted a prospective, naturalistic
3 month follow-up study to evaluate the association between MTHFR 677C>T and
1298A>C variants and metabolic parameters after initiation of an AAP. In this study they
found genotype × time associations between the 1298A>C variant and measures of glucose,
weight and waist circumference. Although this study did not measure the occurrence of
metabolic syndrome over time, it supports their earlier results where schizophrenia patients
with the 1298 C allele have genetic loading for metabolic side effects from AAPs (73).
More recently, our group has gone on to confirm our initial findings in a separate group of
237 subjects with bipolar disorder or schizophrenia who were screened for metabolic
syndrome and genotyped for both MTHFR and COMT variants. In addition, subjects
underwent a fairly comprehensive assessment for dietary and lifestyle factors (i.e. physical
exercise, medication use, 24 hour food recount, and smoking assessment) as well as folate
exposure. Overall, 41% of our subjects met metabolic syndrome criteria (n=98). There were
no significant differences in age, gender, AAP exposure, or BMI between genotype groups.
We found that occurrence of the metabolic syndrome was related to age, smoking and
MTHFR 677T and COMT 158Val alleles (p<0.0001). Those with these two risk alleles
(MTHFR 677T and COMT 158 Val alleles) met metabolic syndrome criteria at a much
earlier age than those without these alleles (46 vs. 52 years) (31).
Additionally, studies have looked at the epigenetics of AAP-associated metabolic syndrome

due to the link between folate pharmacogenetics and methylation as described above.
Epigenetics is a rapidly growing field in psychiatry due to the known influence of
environment on mental illness and yet, it requires cautious interpretation due to the
complexities of epigenetic mechanisms and as study designs within schizophrenia continue
to be defined (74). One such study investigated the role of the soluble COMT (COMT-s)
methylation promoter status and metabolic syndrome in the peripheral blood samples from
schizophrenia patients largely on atypical antipsychotics (75). This study found that COMT
genotype was an indicator of COMT methylation status of the two CpG sites investigated
(p=0.0044 for site 1 and p=0.027 for site 2). Furthermore, those homozygous for the
met/met COMT genotype showed a positive correlation between CpG site methylation and
metabolic syndrome (site 1: p=0.001 and site 2: p=0.001). In addition to this investigation, a
different study using peripheral blood samples found that females carrying the MTHFR
677TT genotype had the lowest measure of global methylation, measured using the long
interspersed nucleotide element-1 (LINE-1), which may help to explain the gender
metabolic syndrome differences seen in schizophrenia (76). Finally, investigators have
reported that global DNA methylation (using the Luminometric assay) differed based on
schizophrenia onset status as well as treatment type (with AAPs users having lower levels of
global of methylation) (77). Although this study did not look at metabolic indices it does
begin to show that methylation status can be affected not only by antipsychotic treatment but
by antipsychotic class.
Therefore, these studies provide evidence of a link between different enzymes related to
folic acid metabolism and an increased risk of metabolic syndrome for patients with
schizophrenia when taking an AAP. The results could possibly provide the evidence for
pharmacogenetic testing of patients before starting an antipsychotic medication in an effort
to reduce this risk or in addition to direct dietary and lifestyle interventions for those at
greatest risk. Given that pharmacogenetic assays for MTHFR and its variants are
commercially available and often done within other medical specialties, the era of
personalized medicine for schizophrenia may not be so far off.
7. Summary and Conclusions

It is now well known that use of the atypical antipsychotics is perhaps the most effective
treatment we currently have for schizophrenia and other serious mental illnesses.
Unfortunately due to their associated risk for metabolic syndrome, use of these medications
may be placing these individuals at greater risk for several comorbidities, resulting in an
accumulation of life years lost due to cardiovascular disease. There currently is a lack of
consensus regarding the specific criteria which should be used when diagnosing metabolic
syndrome within the serious mentally ill population, although some agreement does exist
regarding which criteria are important and potentially place individuals at greater risk for the
development of cardiovascular disease. While monitoring guidelines for the use of atypical
antipsychotics and metabolic syndrome risk have been developed and widely circulated, the
reality is that they are often not followed for many reasons. Although many biomarkers have
been proposed for the possible prevention of metabolic syndrome seen with atypical
antipsychotic use, this research has not been successfully translated into the clinic. The role
of folic acid in the development of these metabolic complications is currently being

investigated and current data suggests that for those with the MTHFR 677T and COMT
158Val allele, metabolic syndrome risk may be elevated or occurring at a younger age.
Furthermore, evidence is beginning to show schizophrenia subjects reside in a global
hypomethylation and possibly less stable genetic state. While the natural next step in this
currently research is folate supplementation, ongoing work in this area is not yet available.
Studies using folate supplementation in schizophrenia patients using AAPs and carrying
these increased risk pharmacogenomics and epigenomic targets are needed in order to begin
to translate this research into practice. Thus, at this time, educating patients and their
caregivers about the importance of a balanced healthy diet with exercise as well as proper
pharmacotherapeutic management of metabolic abnormalities is crucial to combating the
staggering cardiovascular mortality seen within this group. For those whose diets do not
include the minimum recommended daily allowance of folate, a supplement may be
appropriate until such a time when conclusive data can be presented regarding the role of
folic acid in the diagnosis and detection of metabolic syndrome within schizophrenia.
Acknowledgments
The following sources were utilized for this publication: The following funding sources were utilized for this
publication: NIMH (R01 MH082784) and NIMH (K08 MH64158).
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Figure 1.
The Aldo Met cycle converts homocysteine to methionine and is facilitated by folate and
methylenetetrahydrolfate reductase (MTHFR). Catechol-o-methyltransferase (COMT)
converts methionine to S-adenyl methionine (SAM), also producing homocysteine. Genetic
variants within these enzymes affect their efficiency within this cycle.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 1
Summary of American Diabetes Association and American Psychiatric Association Monitoring Guidelines for the implementation of Atypical
Antipsychotics (41)
Monitoring Parameters Baseline 4 weeks 8 weeks 12 weeks Annually Every 5 years
Personal/Family History X X
Weight (BMI) X X X X X (Obtain Quarterly) X

Burghardt and Ellingrod
Waist Circumference X X
Blood Pressure X X X
Fasting Plasma Glucose X X X
Fasting Lipid Profile X X X
Page 15
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 2
Summary of studies for folic acid pharmacogenomics and metabolic syndrome with atypical antipsychotic use in schizophrenia.
Author Year Subjects Genotype Outcomes Results

Ellingrod VL and 2008 58 patients with schizophrenia MTHFR 677C>T Metabolic Syndrome HOMA-IR MTHFR T allele resulted in a 3.6 times more
colleagues taking an antipsychotic for at least MTHFR 1298A>C likelihood of developing AAP associated metabolic
12 months syndrome (p = 0.02). Also, the TT genotype patients
were at greater risk for insulin resistance and
increasing waist circumference (p = 0.0006).
Burghardt and Ellingrod
Van Winkel and 2010 518 patients with schizophrenia MTHFR 677C>T Association between genotype and metabolic MTHFR 1298 C/C genotype had a 2.4 times risk of
colleagues MTHFR 1298A>C syndrome developing metabolic syndrome (p = 0.009)
Van Winkel and 2010 155 patients with schizophrenia or MTHFR 677C>T Genotype × time interactions for metabolic No significant effect for 677C>T variant. Significant
colleagues schizoaffective disorder newly MTHFR 1298A>C variables (weight, waist circumference, genotype × time interaction for 1298A>C and weight
started on a atypical antipsychotic. fasting glucose, 120 minute OGTT level and (p=0.006), waist (p=0.050), fasting glucose (p=0.024)
Patients with diabetes or metabolic lipids and 120 minute OGTT levels (p=0.018), with a dose-
syndrome at baseline were excluded response pattern with increasing C-allele loading.
Ellingrod VL and 2012 237 patients with schizophrenia and MTHFR 677C>T Metabolic Syndrome Metabolic syndrome was related to age, smoking and
colleagues bipolar patients taking an MTHFR 1298A>C the MTHFR 677T and COMT 158Val alleles (χ2=34.4,
antipsychotic for at least 6 months COMT 158Val>Met p<0.0001).
Lott SA and 2012 85 schzophrenia patients taking an COMT 158Val>Met Genotype, promoter methylation and Associations found between COMT 158MetMet
colleagues atypical antipsychotic and COMT-s metabolic syndrome genotype, COMT-S promoter methylation and
promoter methylation metabolic syndrome
Burghardt KJ and 2012 133 patients with schizophrenia MTHFR 677C>T and Genotype and global methylation measure LINE-1 methylation lower in females carrying the
colleagues stable on an antipsychotic LINE-1 methylation MTHFR 677 TT genotype when controlling for serum
folate
Melas PA and 2012 171 schizophrenia patients and 171 LUMA methylation, Disease onset, treatment type and global LUMA methylation related to schizophrenia onset and
colleagues controls COMT-s methylation methylation measure antipsychotic type
Abbreviations: HOMA-IR - Homeostatic Model Assessment Insulin Resistance, MTHFR –Methylenetetrahyrofolate reductase, COMT – Catechol-o-Methyl Transferase, LINE-1 long interspersed
nucleotide element-1, LUMA - Luminometric assay.
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Mol Diagn Ther. 2013 February ; 17(1): 21–30. doi:10.1007/s40291-013-0017-8.

Detection of the Metabolic Syndrome in Schizophrenia and

In general, presence of the metabolic syndrome is associated with significant cardiovascular

methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT) genes

Corresponding Author: Vicki L. Ellingrod, PharmD, FCCP, vellingr@umich.edu.

will be touched on with a summarization of the available literature regarding folate

2. Criteria for Diagnosis of Metabolic Syndrome

3. Metabolic syndrome Within Schizophrenia

antipsychotic medications play an important role in this process. While our

metabolic syndrome followed by the actual development of more serious cardiac

4. Monitoring Recommendations for AAP use in Schizophrenia

to guide treatment of identified metabolic abnormalities with appropriate medications in

While monitoring for metabolic complications of AAP use continues to be an emphasized

5. Folic Acid Pharmacogenetics and Epigenetics

Pertinent to the metabolism of homocysteine is the enzyme catechol-O-methyl transferase

6. Role of Folic Acid in Atypical Antipsychotic Metabolic Syndrome

Additionally, studies have looked at the epigenetics of AAP-associated metabolic syndrome

7. Summary and Conclusions

of folic acid in the development of these metabolic complications is currently being

complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a

1997 Dec 01; 171(6):502–508. [PubMed: 9519087]

methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants. Schizophr Res.

41. American Diabetes Association, American Psychiatric Association, American Association of

Monitoring Parameters Baseline 4 weeks 8 weeks 12 weeks Annually Every 5 years

Weight (BMI) X X X X X (Obtain Quarterly) X

Fasting Plasma Glucose X X X

Fasting Lipid Profile X X X

Author Year Subjects Genotype Outcomes Results

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