Folic acid and its metabolism and utilization has become of increasing importance within the field of schizophrenia. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme responsible for the formation of methyltetrahydrofolate (5-methyl THF) from dietary folate. Multiple studies have demonstrated relationships between MTHFR gene variants and schizophrenia. This review discusses these studies, and their findings regarding the relationship between different variants of the MTHFR gene and risk of antipsychotic-related metabolic syndrome, and the relationship between the pharmacogenetics of folate and the negative/cognitive symptoms of schizophrenia.

Folic acid is a water-soluble B vitamin that is garnering greater interest in schizophrenia research. Its metabolism is pharmacogenetically regulated and thus may be useful in personalizing the treatments for schizophrenia. This article will review folate's role on schizophrenia symptomatology as well as risks associated with atypical antipsychotics.

Schizophrenia is an often debilitating mental illness that affects approximately 1% of the population,1 usually manifesting not only through positive and negative symptoms, but also causing significant cognitive dysfunction.2 Briefly, the positive symptoms seen in schizophrenia are not normally present in a mentally healthy individual. Examples of positive symptoms may include, but are not necessarily limited to, hallucinations and delusions.3 Negative symptoms are disruptions in normal responses for a healthy individual and commonly include the inability to experience pleasure, disturbance of speech, flattened affect, and lack of motivation.4 The overall goal of treatment for schizophrenia is recovery, and for some, antipsychotic medications are a large part of this process. These medications traditionally achieve their effect through blockade of the dopamine 2 receptor.5 More recently, atypical antipsychotics (AAPs) have become the first line treatment for schizophrenia due to their differing pharmacology of serotonin antagonism, primarily 5HT2A and 5HT2C, and possible association with negative symptom improvement, as well as attenuation of extrapyramidal side effects.6 

Although AAPs are effective, their use carries risks such as diabetes, weight gain, dyslipidemia, and metabolic syndrome, which is a constellation of cardiovascular risk factors.7–10 Patients with a serious mental illness have a three times greater risk of death compared to the general population, with cardiovascular disease (CVD) being the most common cause of this mortality.11 Use of the AAPs to treat serious mental illness contributes significantly to this CVD risk, as patients taking AAPs frequently manifest early symptoms of metabolic syndrome, followed by the actual development of more serious CVD complications. The end result is up to 30 years of life lost for those with schizophrenia.11 Understanding the role of folate, and its pharmacogenetically regulated metabolism, may assist us in reducing CV adverse effects in this patient population and potentially decreasing this staggering statistic.

Recently, folic acid and its metabolism and utilization has become of increasing importance within the field of schizophrenia. Folate is a water soluble B-vitamin involved in the synthesis, repair, and methylation of DNA, whose effective utilization is dependent on adequate daily intake, as well as genetically altered metabolism.12 

Methylenetetrahydrofolate reductase (MTHFR) is the enzyme responsible for the formation of methyltetrahydrofolate (5-methyl THF) from dietary folate. 5-methyl THF allows conversion of homocysteine to methionine and adenosyl methionine by methionine synthetase (MTR) as part of the AldoMet cycle.12 Reduced MTHFR activity results in hyperhomocysteinemia, which has been associated with CVD.13 Pertinent to the metabolism of homocysteine is the enzyme catechol-O-methyl transferase (COMT). Despite the lack of clarity concerning COMT's role in 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.14 

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.15 The risks seen with the MTHFR variants are often exaggerated in situations of low folate exposure,13 thus dietary assessments as well as genetic measurements are dually important to understanding homocysteine and risk of metabolic syndrome and other metabolic consequences of AAP use within these groups.

Patients with the MTHFR 677C>T allele have a 35% reduction in MTHFR activity and patients with two copies of the T allele show a 70% reduction. Approximately 12% of the general population has the T/T genotype; however, it is believed that the percentage is higher among patients with schizophrenia.16 Therefore, the aim of this review is to discuss the potential role of folic acid and its pharmacogenetically regulated metabolism in the treatment of schizophrenia.

Multiple studies have demonstrated relationships between MTHFR gene variants and schizophrenia. Table I is a summary of those that will be discussed in this review. Two separate but relevant areas of study have been examined in relation to folate pharmacogenetics in schizophrenia. The first of these fields is the relationship between MTHFR and the occurrence of metabolic syndrome in relation to the use of atypical antipsychotics (Table I). In general, metabolic syndrome is a constellation of cardiovascular risk factors that result in an overall greater risk for CVD than each individual risk factor alone. The occurrence of metabolic syndrome can be defined via NCEP ATP III guidelines of having three or more of the following: blood pressure ≥ 130/85 mmHg; fasting blood glucose ≥ 100 mg/dL; large waist circumference (men ≥ 40”,women ≥ 35”); low HDL cholesterol (men < 40 mg/dL, women < 50 mg/dL), and/or triglycerides ≥ 150 mg/dL.17 The first report of this relationship included 58 subjects with schizophrenia who were receiving AAPs. Ellingrod and colleagues demonstrated 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). Additionally this group 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.7 This study was then followed up by Van Winkel and colleagues.18 

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). Van Winkel and colleagues found patients with the 1298C/C genotype had a 2.4 times increase risk of metabolic syndrome (p = 0.009).18 More recently, Ellingrod and colleagues have confirmed their initial findings in a separate group of 237 subjects with bipolar disorder or schizophrenia who were screened for metabolic syndrome and genotyped.19 Serum folate and homocysteine levels were measured along with lifestyle factors. Overall, 41% met metabolic syndrome criteria (n=98). There were no significant differences in age, gender, AAP exposure, or BMI between genotype groups. Metabolic syndrome was related to age, smoking and MTHFR 677T and COMT 158Val alleles (c2=34.4, p<0.0001). Those with these two risk alleles met metabolic syndrome criteria at a much earlier age than those without these alleles (46 vs. 52 years).10 

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.

Table 1:

Studies Evaluating the MTHFR Gene Variants

Studies Evaluating the MTHFR Gene Variants
Studies Evaluating the MTHFR Gene Variants

Parallel to the work done on MTHFR and metabolic syndrome is the relationship between the pharmacogenetics of folate and the negative/cognitive symptoms of schizophrenia. For those who suffer from this debilitating illness, cognitive function is often a primary concern as it relates to overall functionality as well as quality of life. Spearheading the work done on folate's role in the cognitive dysfunction seen with schizophrenia is a group at Harvard University. Their first study utilized functional Magnetic Resonance Imaging (fMRI) on patients who were performing the Sternberg Item Recognition Program (SIRP) to determine the effect of the different MTHFR 677C/T and COMT Val158 Met alleles on memory load-dependent activation.20 Overall these investigators found the MTHFR 677C>T allele was associated with a reduction in left dorsolateral prefrontal cortex (DLPFC) recruitment which is located within a region essential for effective working memory (p < 0.005). This work may suggest that those with the MTHFR T allele are at increased risk for deficits in working memory which contribute to the overall cognitive dysfunction seen in schizophrenia.

These authors further reported on a possible link between the severity of these negative symptoms within schizophrenia and the folate pathway.4 For this study, the investigators included 200 patients with schizophrenia and evaluated them using the Positive and Negative Symptom Score (PANSS). Overall, this group reported that the MTHFR 677C>T allele was associated with greater negative symptoms (p = 0.041) and that for those patients homozygous for the MTHFR 677T allele a significant correlation was shown between low serum folate levels and negative symptom severity (p= 0.007). Thus, in addition to being associated with cognitive dysfunction, the MTHFR T allele may also be a significant factor in the occurrence of negative symptoms.

Due to the demonstrated inverse relationship between serum folate levels and severity of negative symptoms, Hill and colleagues examined the role of supplemental folate on negative symptom presentation in patients with schizophrenia.16 The study included 32 patients with schizophrenia who were randomized to either receive 2 mg/d of folate or placebo. The primary study assessment was the Scale for the Assessment of Negative Symptoms in Schizophrenia (SANS) and the primary aim was to determine the effect of 12 weeks of folate supplementation on this measure. Overall, this investigation showed that 2 mg/day of folate supplementation was more likely to improve negative symptoms for patients with at least one copy of the T allele (p = 0.01).16 

Similar to the work previously presented in relation to folic acid and metabolic consequences from AAPuse, folate's role in schizophrenia may extend to the reduction of symptomatology that is key to the illness itself. This leads to the question then, “Should everyone with schizophrenia be placed on folic acid?” Intriguing as this may be, there are some limitations to this work which may make this clinical option a bit premature. First, the dose of folic acid used by the Roffman group was 2 mg/day. Current dietary recommendations for daily folate intake reside at 400 mcg/day for the general population and 1 mg/day for pregnant women.21 Therefore, the dose used by the Roffman group was twice what is recommended for pregnant women. Additionally, within the literature there have been some recent reports linking folic acid supplementation and the occurrence of colon cancer, lung cancer, and even autistic disorder.21 Thus, while placing individuals with schizophrenia on folate may seem like a simple intervention with low risk and potential benefits, clearly more work in this area is needed. At this time, educating patients and their caregivers about the importance of a balanced healthy diet 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.

1.
Weiss
A
,
Movahed
R
,
Dym
H.
Schizophrenia: current therapy and review
.
J Oral Maxillofac Surg
.
2011
;
69
(
1
):
192
8
. .
2.
Chan
KK
,
Xu
JQ
,
Liu
KC
,
Hui
CL
,
Wong
GH
,
Chen
EY.
Executive function in first-episode schizophrenia: a three-year prospective study of the Hayling Sentence Completion Test
.
Schizophr Res
.
2012
;
135
(
1–3
):
62
7
. .
3.
Pogue-Geile
MF
,
Harrow
M.
Negative and positive symptoms in schizophrenia and depression: a followup
.
Schizophr Bull
.
1984
;
10
(
3
):
371
87
.
PubMed PMID: 6474100
.
4.
Roffman
JL
,
Brohawn
DG
,
Nitenson
AZ
,
Macklin
EA
,
Smoller
JW
,
Goff
DC.
Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia
.
Schizophr Bull
.
2013
;
39
(
2
):
330
8
.
DOI: 10.1093/schbul/sbr150. PubMed PMID: 22021659
.
5.
Roerig
JL
,
Steffen
KJ
,
Mitchell
JE.
Atypical antipsychotic-induced weight gain: insights into mechanisms of action
.
CNS Drugs
.
2011
;
25
(
12
):
1035
59
. .
6.
Lieberman
JA
,
Stroup
TS
,
McEvoy
JP
,
Swartz
MS
,
Rosenheck
RA
,
Perkins
DO
et al
.
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia
.
N Engl J Med
.
2005
;
353
(
12
):
1209
23
.
DOI: 10.1056/NEJMoa051688. PubMed PMID: 16172203
.
7.
Ellingrod
VL
,
Miller
DD
,
Taylor
SF
,
Moline
J
,
Holman
T
,
Kerr
J.
Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants
.
Schizophr Res
.
2008
;
98
(
1–3
):
47
54
.
DOI: 10.1016/j.schres.2007.09.030. PubMed PMID: 17976958 ; PubMed Central PMCID: PMC2271139
.
8.
Gautam
S
,
Meena
PS.
Drug-emergent metabolic syndrome in patients with schizophrenia receiving atypical (second-generation) antipsychotics
.
Indian J Psychiatry
.
2011
;
53
(
2
):
128
33
. .
9.
Ray
WA
,
Chung
CP
,
Murray
KT
,
Hall
K
,
Stein
CM.
Atypical antipsychotic drugs and the risk of sudden cardiac death
.
N Engl J Med
.
2009
;
360
(
3
):
225
35
.
DOI: 10.1056/NEJMoa0806994. PubMed PMID: 19144938
.
10.
Ellingrod
VL
,
Taylor
SF
,
Dalack
G
,
Grove
TB
,
Bly
MJ
,
Brook
RD
et al
.
Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics
.
J Clin Psychopharmacol
.
2012
;
32
(
2
):
261
5
.
DOI: 10.1097/JCP.0b013e3182485888. PubMed PMID: 22370993 ; PubMed Central PMCID: PMC3622480
.
11.
Colton
CW
,
Manderscheid
RW.
Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states
.
Prev Chronic Dis
.
2006
;
3
(
2
):
A42
.
PubMed PMID: 16539783
.
12.
Friso
S
,
Choi
SW.
Gene-nutrient interactions in one-carbon metabolism
.
Curr Drug Metab
.
2005
;
6
(
1
):
37
46
.
PubMed PMID: 15720206
.
13.
Klerk
M
,
Verhoef
P
,
Clarke
R
,
Blom
HJ
,
Kok
FJ
,
Schouten
EG.
MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis
.
JAMA
.
2002
;
288
(
16
):
2023
31
.
PubMed PMID: 12387655
.
14.
Chen
J
,
Lipska
BK
,
Halim
N
,
Ma
QD
,
Matsumoto
M
,
Melhem
S
et al
.
Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain
.
Am J Hum Genet
.
2004
;
75
(
5
):
807
21
.
DOI: 10.1086/425589. PubMed PMID: 15457404
.
15.
Tunbridge
EM
,
Harrison
PJ
,
Warden
DR
,
Johnston
C
,
Refsum
H
,
Smith
AD.
Polymorphisms in the catechol-O-methyltransferase (COMT) gene influence plasma total homocysteine levels
.
Am J Med Genet B Neuropsychiatr Genet
.
2008
;
147B
(
6
):
996
9
.
DOI: 10.1002/ajmg.b.30700. PubMed PMID: 18189241
.
16.
Hill
M
,
Shannahan
K
,
Jasinski
S
,
Macklin
EA
,
Raeke
L
,
Roffman
JL
et al
.
Folate supplementation in schizophrenia: a possible role for MTHFR genotype
.
Schizophr Res
.
2011
;
127
(
1–3
):
41
5
. .
17.
Grundy
SM
,
Cleeman
JI
,
Daniels
SR
,
Donato
KA
,
Eckel
RH
,
Franklin
BA
et al
.
Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary
.
Crit Pathw Cardiol
.
2005
;
4
(
4
):
198
203
.
PubMed PMID: 18340209
.
18.
van Winkel
R
,
Rutten
BP
,
Peerbooms
O
,
Peuskens
J
,
van Os
J
,
De Hert
M.
MTHFR and risk of metabolic syndrome in patients with schizophrenia
.
Schizophr Res
.
2010
;
121
(
1–3
):
193
8
19.
Ford
ES
,
Giles
WH
,
Dietz
WH.
Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey
.
JAMA
.
2002
;
287
(
3
):
356
9
.
PubMed PMID: 11790215
.
20.
Roffman
JL
,
Weiss
AP
,
Deckersbach
T
,
Freudenreich
O
,
Henderson
DC
,
Purcell
S
et al
.
Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia
.
Schizophr Res
.
2007
;
92
(
1–3
):
181
8
. .
21.
Shelke
N
,
Keith
L.
Folic Acid Supplementation for Women of Childbearing Age versus Supplementation for the General Population: A Review of the Known Advantages and Risks
.
Int J Family Med
.
2011
;
2011
:
173705
.
DOI: 10.1155/2011/173705. PubMed PMID: 22295182
.