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LowerFolate Levels in Schizophrenia: a Meta-Analysis

Article · July 2016


DOI: 10.1016/j.psychres.2016.03.003

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Psychiatry Research 245 (2016) 1–7

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Review article

Lower folate levels in schizophrenia: A meta-analysis


Bing Cao a,1, Dong-Fang Wang a,1, Mei-Yan Xu b, Ya-Qiong Liu a, Lai-Lai Yan a,
Jing-Yu Wang a,n, Qing-Bin Lu a,n
a
School of Public Health, Peking University, Beijing 100191, PR China
b
Department of Nutrition, Aerospace Center Hospital, Beijing 100049, PR China

art ic l e i nf o a b s t r a c t

Article history: This meta-analysis aimed to estimate the association between folate level and schizophrenia in order to pro-
Received 20 August 2015 vide the evidence for the treatment of schizophrenia. Data were extracted from all the studies meeting our
Received in revised form inclusion and exclusion criteria. The association between the folate level and schizophrenia was evaluated by
1 March 2016
the standardized mean difference (SMD) and 95% confidence interval (CI). The 20 published articles of our
Accepted 2 March 2016
Available online 22 July 2016
meta-analysis included 1463 (53.4%) cases and 1276 (46.6%) controls. The folate level was significantly lower in
schizophrenia cases than in healthy controls. Subgroup analysis showed the folate level was lower in cases from
Keywords: Asia subgroup than in healthy controls. Sensitivity analysis showed that the current results were credible and
Folate reliable and the funnel plots indicated no publication bias in our meta-analysis. Our study indicates that
Case-control study
schizophrenia patients may have lower folate levels. More epidemiological and laboratory studies are still
Subgroup analysis
needed to confirm whether it is necessary to supplement folate in schizophrenia patients.
Psychotic disorders
& 2016 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Literature searches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.4. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Basic statistics of the studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Homogeneity analysis and effect estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.3. Subgroup analysis and meta-regression analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.4. Sensitivity analysis and publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Appendix A. Supporting information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1. Introduction

n
Corresponding authors. The psychopathological manifestations of schizophrenia consist of
E-mail addresses: wjy@bjmu.edu.cn ( J.-Y. Wang),
qingbinlu@bjmu.edu.cn (Q.-B. Lu).
separation from reality with delusion formation, disorganized beha-
1
These authors contributed equally to this work. vior, hallucinations, and emotional dysregulation (Millier et al., 2014).

http://dx.doi.org/10.1016/j.psychres.2016.03.003
0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.
2 B. Cao et al. / Psychiatry Research 245 (2016) 1–7

Fig. 1. Flow chart depicting exclusion/inclusion of individual studies for meta-analysis.

It is a debilitating disorder that affects 1% of the population world- and were published in English or Chinese in an electronic data-
wide (Arroll et al., 2014). Schizophrenia evolves in cycles of remis- base. Search terms included “schizophrenia OR psychotic disorders
sions and relapses (Millier et al., 2014) with financial burden and OR psychosis”, “folate OR folic acid OR vitamin 9”. PubMed, EM-
humanistic burden on society (Abouzaid et al., 2010). BASE literature database were used to search the studies published
Folate is one of the B vitamins which is required for cell divi- in English. And China Biology Medical (CBM), China National
sion and cell maintenance and folate is the re-methylation of Knowledge Infrastructure (CNKI), VIP information (VIP) were used
plasma homocysteine to methionine (Mitchell et al., 2014). Studies to search the studies in Chinese. Searches were limited to articles
have been reported that folate is essential for neuronal function about human studies before the end of April 2015.
(Czeizel et al., 2013). Severe folate deficiencies may be linked to
the increased risk of neurodevelopmental disorders, psychiatric 2.2. Inclusion and exclusion criteria
diseases and dementia (Mitchell et al., 2014). The association be-
tween folate level and schizophrenia is still controversial (Ayesa- Inclusion criteria of the studies were met if they (1) used a
Arriola et al., 2012; Bouaziz et al., 2010; Chen, 2014; Eren et al., cohort or case–control design; (2) assessed a group of unaffected
2010; Feng et al., 2009; Garcia-Miss Mdel et al., 2010; Haidemenos controls (control subjects were selected from healthy volunteers
et al., 2007; Hei et al., 2014; Kim and Moon, 2011; Mabrouk et al., who were recruited from students, company employees and so on
2011; Misiak et al., 2014; Muntjewerff et al., 2003; Ozcan et al., documented to be free from psychiatric problems and histories of
2008; Petronijevic et al., 2008; Qian et al., 2009; Saedisomeolia mental illness); (3) diagnosed schizophrenia according to Diag-
et al., 2011; Song et al., 2014; Zhang et al., 2010; Zhang et al., 2007; nostic and Statistical Manual of Mental Disorders (DSM)-IV criteria
Zhu et al., 2010). Several studies revealed a positive relationship by at least 2 psychiatrists on the basis of extensive clinical inter-
between folate deficiency and schizophrenia (Chen, 2014; Kim and views and a review of medical records; (4) had available folate
Moon, 2011; Mabrouk et al., 2011). While other studies did not levels of participants .
find that folate deficiency increased the risk of schizophrenia Exclusion criteria of the studies were met if they (1) did not
(Ayesa-Arriola et al., 2012; Bouaziz et al., 2010; Garcia-Miss Mdel focus on evaluating the folate levels on schizophrenia; (2) did not
et al., 2010; Ozcan et al., 2008). Therefore, the relationship needs report the exact values of folate level; (3) included unhealthy
to be further evaluated. control groups; (4) were repetitive publications from the same
Taking all findings into consideration, we performed this meta- datasets by the same or different authors.
analysis to evaluate the association of them and then to provide
the evidence for the treatment of schizophrenia. 2.3. Data extraction

Data were extracted from all the studies that met our inclusion
2. Methods and exclusion criteria. We designed a data form in Excel to extract
the relevant data for our review. Two investigators abstracted in-
2.1. Literature searches formation independently for each eligible article, and reached a
consensus on all the items through discussion of disagreements.
We performed a systematic literature search to identify eligible Detailed information about the index test was extracted from the
relevant studies that reported the folate status of schizophrenia studies which included first author, publication year, country,
B. Cao et al. / Psychiatry Research 245 (2016) 1–7 3

geographic area, gender ratio and age of patients, specimen nee-


Detection method
ded for test, sample detection method, whether or not first-epi-
sode of patients, sample size and mean folate levels with standard
deviation (SD) of participants. The Newcastle-Ottawa Scale (NOS)

MPEIA

MPEIA
ECLIA
ECLIA
ECLIA

ECLIA
ECLIA

ECLIA
ECLIA
ECLIA
ECLIA

ECLIA
ECLIA
ECLIA
ECLIA
ECLIA
criteria were used to assess the quality of each study.
RIDA

RIDA
RIDA
FPIA
2.4. Statistical analysis
First episode

The association between the folate level and schizophrenia was


evaluated by the standardized mean difference (SMD) and 95%
Yes

Yes

Yes

Yes
Yes
Yes
Yes
Yes
No
No

No
No
No

No
No

No
No
No
No
No
confidence interval (CI). Heterogeneity of effect estimates within
each group of studies was assessed by chi-square statistics and I2

99/135
40/26

75/64
30/26
67/30

72/50
37/20

71/59
39/21
28/14

26/19

28/18
24/18
74/31
statistics. P o0.10 or I2 450% was considered that the hetero-
44/0

66/0

54/7
33/0
27/8

10/8
M/F

geneity had statistically significant differences. If the data were


homogeneous, the fixed effect model would be applied to evaluate
Age (range or mean 7 SD)

the folate status of schizophrenia. Otherwise, the random effect


model would be adopted. Sensitivity analysis was performed to
strengthen the results of the meta-analysis. Publishing bias was
tested using the funnel plot with Begg's test and Egger's test. The
40.4 710.5

32.17 10.8

27.0 7 12.0
31.0 7 10.0

32.4 711.7
38.0 7 9.0

22.5 7 5.8
33.6 7 11

meta-analysis data were analyzed by Stata 12.0 (Stata Corp LP,


39.4 79.0

34.7 78.7

36.6 79.0

22.7 73.9

33.3 7 9.2

22.17 5.0
29.0 77.7
27.0 7 4.8

15.0–55.0

27.2 7 7.3
31.0 7 7.0
21.0–76.0

College Station, TX, USA).

3. Results
Sample type

Plasma
Plasma

Plasma

Plasma

Plasma

Plasma

Plasma
Serum
Serum
Serum
Serum
Serum

Serum
Serum

Serum

Serum

Serum

Serum
Serum
Serum

3.1. Basic statistics of the studies

Our initial search identified 326 potentially relevant studies.


Geographic area

After screening of titles and abstracts, and removing the duplicates


and other unrelated references, 89 articles were remained for
further evaluation. Following detailed assessment, 20 references
America
Europe
Europe

Europe

Europe

Europe
Europe
Africa

Africa

met our inclusion criteria and were recruited into the meta-ana-
Asia
Asia

Asia
Asia

Asia
Asia

Asia
Asia

Asia
Asia
Asia

lysis (Ayesa-Arriola et al., 2012; Bouaziz et al., 2010; Chen, 2014;


Eren et al., 2010; Feng et al., 2009; Garcia-Miss Mdel et al., 2010;
Netherlands

Haidemenos et al., 2007; Hei et al., 2014; Kim and Moon, 2011;
Country

Mabrouk et al., 2011; Misiak et al., 2014; Muntjewerff et al., 2003;


Mexico
Tunisia

Tunisia
Turkey

Turkey
Greece

Poland
Serbia

Korea
China

China
China

China
China

China
China
China
Spain

Ozcan et al., 2008; Petronijevic et al., 2008; Qian et al., 2009;


Iran

Saedisomeolia et al., 2011; Song et al., 2014; Zhang et al., 2010;


Zhang et al., 2007; Zhu et al., 2010). Fig. 1 provided the literature
15.2
1.41
3.8

3.8
6.5
2.7
2.2

3.5

3.2
3.9

review process.
3.1

2.1
1.7

1.7
1.9

1.2

1.9

1.7
SD

The 20 studies included 1463 (53.4%) cases and 1276 (46.6%)


Healthy controls

controls. They were all case-control studies. Most studies were


Mean

10.6

16.9

7.11
11.1
6.2
3.4

8.2
8.8
5.8
5.6
4.8

9.4

8.8
5.7
6.7
8.2
7.7

7.5

7.7

from Asia (11/20, 55.0%). There were 13 studies on serum and


9

seven studies on plasma. Detection methods used in the studies


were electro-chemo-luminescence immunoassay (ECLIA), micro
234
122
104
103
30
20
20

30

28
50
34

60
46
99
53
28
80
30
35
70
n

particle enzyme immunoassay (MPEIA), radio isotope dilution


assay (RIDA), and fluorescence-polarization immunoassay (FPIA).
We evaluated all articles by NOS. All studies indicated good qua-
10.7
1.86
2.8

4.6

3.7

2.8

2.9
2.2
2.9
2.3
3.7
2.2
3.9
2.9

2.6
1.4

1.8

1.7

1.9
SD

lities with a score of more than or equal to 6. Table 1 presented the


4
Characteristics of the included studies in the meta-analysis.

Schizophrenic patients

characteristics of 20 included studies.


Mean

15.5

3.2. Homogeneity analysis and effect estimation


4.6
2.8
8.8
6.9
9.4

5.2
4.2

8.5
4.6

3.8
5.5
4.2

6.3

5.6
5.1

4.1
7.4

7.8

The random-effects model was used due to the high hetero-


geneity (I2 ¼82.8%, P o0.001) (Fig. 2). Our meta-analysis identified
234
122

139

130
44

42

42
66
66

60

56
45

46
35

33
70
97
57

61
18
n

a significant association between folate level and schizophrenia


(SMD¼  0.57; 95% CI:  0.76,  0.37; Po 0.001) (Fig. 3).
2003

2008
2008
2009
2009
2007
2007

2012
2010
2010
2010
2010
2010

2014
2014
2014
2014
2011
2011
2011
Year

3.3. Subgroup analysis and meta-regression analysis


Saedisomeolia

Ayesa-Arriola
Muntjewerff
Haidemenos

Petronijevic

García-Miss

Subgroup analysis was conducted by publish year (before/after


Mabrouk
Bouaziz

2010), age of patients ( o30/ Z30 years), gender ratio (F/M¼0;


Author

Misiak
Zhang

Zhang
Ozcan

Chen

Song
Feng
Qian

Eren
Kim
Zhu

0 oF/M r1; F/M 41), geographic area (Asia/Europe/Africa/Amer-


Hei

ica), sample type (Serum/Plasma), detection method (ECLIA/


Table1

MPEIA/RIDA/FPIA) and whether first-episode of patients (Yes/No).


No.

20
12
10

13
14
15
16

19
18
17
11
1
2
3
4
5
6
7
8
9

All the results of subgroup analysis showed the folate level of each
4 B. Cao et al. / Psychiatry Research 245 (2016) 1–7

Fig. 2. Meta-analysis for the difference of the folate levels between schizophrenia cases and healthy controls by random effect analysis. The forest plot illustrates the SMD
and its 95% CI for each study, and the results of the homogeneity test. SMD, standardized mean difference. The graph was produced using Stata 12.0.

Fig. 3. Sensitivity analysis through deletion of one study at a time to reflect the influence of the individual dataset to the pooled SMDs of the folate levels in schizophrenia
and healthy controls using Stata 12.0.
B. Cao et al. / Psychiatry Research 245 (2016) 1–7 5

Table 2 4. Discussion
Meta-regression analysis on the heterogeneity for the association between folate
level and schizophrenia.
The findings in our meta-analysis have indicated that folate
Factor Coeffient β t P 95% CI level was significantly lower in schizophrenia cases than in healthy
controls. Nevertheless, the exact mechanism that how folate level
Age 0.770 0.538 1.43 0.178  0.40, 1.94 is related to the development and progression of schizophrenia
First-episode  0.604 0.563  1.07 0.305  1.83, 0.62
has been not fully understood at present.
Sample type  0.307 0.302  1.02 0.330  0.96, 0.35
Gender ratio 0.199 0.340 0.59 0.569  0.54, 0.94 There are numerous evidence supporting our results. Mitchell
Geographic area 0.190 0.170 1.12 0.286  0.18, 0.56 et al. have shown that people who had a low folate intake and ge-
Publish year  0.385 0.255  1.51 0.157  0.94, 0.17 netic homocysteine metabolism disorder affected the occurrence of
Detection method  0.101 0.169  0.59 0.564  0.47, 0.27
schizophrenia (Mitchell et al., 2014). A review of Moustafa et al. in-
Constant  0.358 0.908  0.39 0.700  2.34, 1.62
dicated that low folate levels and high homocysteine levels might
SE, standard error. influence cognition, since homocysteine plays a role in working
memory processes, supplementation of folate has been proved to be
subgroup was lower in patients than in healthy controls (all effective in lowering homocysteine levels (Moustafa et al., 2014). A
P o0.05) except for geographic area and detection method. The Korean study reported a high folate level reduced the possibility of
subgroup analysis of geographic area showed the folate level was schizophrenia risk (Kim and Moon, 2011). Mudd et al. also asserted
lower in patients from Asia than in healthy controls (SMD ¼ 0.72; the folate helped to prevent the incidence of schizophrenia (Mudd
95% CI:  0.94,  0.49; P o0.001), while there were no significant and Freeman, 1974). Data from various original articles and meta-
differences in Europe (SMD ¼ 0.27; 95% CI: 0.56, 0.02; analyses suggested that high homocysteine level was associated with
P ¼0.078), Africa (SMD¼  0.84; 95% CI:  2.13,  0.45; P¼ 0.201), schizophrenia (Haidemenos et al., 2007; Levine et al., 2005; Nishi
and America (SMD¼  0.16; 95% CI:  0.49, 0.17; P ¼0.350) sub- et al., 2014). The major cause of schizophrenia was a defect in the 5,
groups. No factors explain the existed heterogeneity in our meta- 10-methyleneterahydrofolate reductase (MTHFR), which re-methy-
analysis. Meta-regression analysis was also used to explore the late homocysteine into methionine. The administration of folate
sources of the heterogeneity. We performed a meta-regression could treat the genetic defect of MTHFR (Levine et al., 2006; Munt-
with the seven factors mentioned above, but still failed to find the jewerff et al., 2011). One possible pathway was that high homo-
sources of heterogeneity (all P 40.05) (Table 2). cysteine concentration affected schizophrenia by virtue of a neuro-
toxic mechanism, and schizophrenia patients with high homo-
cysteine levels benefited from high folate ingestion, because the fo-
3.4. Sensitivity analysis and publication bias late serves as a cofactor for methionine synthesis by transferring
methyl group to homocysteine (Akanji et al., 2007). The increase of
Each study included in this meta-analysis was omitted one by plasma homocysteine in the general population was caused by low
one to determine the effect of an individual dataset to the pooled levels of serum folate, vitamin B12 and betaine (Brown and Roffman,
SMDs. The results showed that the overall statistical significance 2014; Misiak et al., 2014; Roffman et al., 2013) which shared func-
did not change when each single study was omitted (Fig. 4). tions in one-carbon metabolism (Geller et al., 2013). Vitamin B12 and
Therefore, the current meta-analysis results were robustly credible folate deficiency are contributors to this pathway (Fenech, 2012). A
and reliable. The possibility of publication bias in the study was 16 weeks' parallel group trial of 140 schizophrenia patients indicated
evaluated with the Egger's test and Begg's test. The graphical folate plus vitamin B12 supplementation improved negative symp-
funnel plots of those 20 studies indicated no publication bias in toms of schizophrenia, but treatment response was influenced by
our meta-analysis (Fig. 5), and the same results were found in genetic variation in folate absorption (Roffman et al., 2013). Whether
Egger's test (Z¼  0.80, P¼ 0.435) and Begg's test (Z¼  0.65, it is necessary to supplement folate in schizophrenia patients still
P ¼0.516). needs more exploration.

Fig. 4. Begg's Funnel plot of the estimation of publication bias. Each point represents a separate study for the indicated association. The graph was produced using Stata 12.0.
6 B. Cao et al. / Psychiatry Research 245 (2016) 1–7

Fig. 5. Egger's Funnel plot of the estimation of publication bias. Each point represents a separate study for the indicated association. The graph was produced using Stata 12.0.

To investigate the exact relationship between folate level and Funding


schizophrenia, we also carefully carried out subgroup analysis on
the basis of publish year, age of patients, gender ratio, geographic This work was supported by the Youth Talent Support Program by
area, sample type, detection method and whether or not first- School of Public Health, Peking University and The Medicine Inter-
episode of patients. Our findings of geographic area have revealed disciplinary Seed Fund (BMU20140435) by Health Science Center,
that the folate level significantly decreased in schizophrenia pa- Peking University. The funding agents had no role in the design and
tients from Asian populations, but no significantly statistical dif- conduct of the study; collection, management, analysis, interpretation
ferences in European, African and American populations, which of the data; preparation, review, or approval of the manuscript.
may be due to differences of the racial, alimentary, treatment,
living standard, lifestyle or economic level. Owing to limited
number of studies, our results concerning subgroup analysis Acknowledgments
should be interpreted with caution. More cohort or experimental
studies are needed to confirm the causality (Mitchell et al., 2014). Thanks to the researchers of the original studies included in our
There are several limitations existing in our meta-analysis. Firstly, meta-analysis. The authors alone are responsible for the content
the sample size was relatively small for some stratified analyses. The and writing of the paper. We thank team members for their sup-
literatures included in our study were not comprehensive, as we failed port and contributions to this study.
to obtain the literature except for English and Chinese. Secondly, we
did not find any cohort study to confirm the causality between schi-
zophrenia and low folate level. Thirdly, we failed to find the factors to Appendix A. Supporting information
explain the existed heterogeneity in our meta-analysis.
In conclusion, our study indicates that schizophrenia patients Supplementary data associated with this article can be found in the
have lower folate levels. More epidemiological and laboratory online version at http://dx.doi.org/10.1016/j.psychres.2016.03.003.
studies are still needed to confirm whether it is necessary to
supplement folate in schizophrenia patients.
References

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