Psychiatry Research 288 (2020) 112959

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

Review article

Vitamin D deficiency and Schizophrenia in Adults: A Systematic Review and T

Meta-analysis of Observational Studies
⁎
Jia-lian Zhua, Wen-wen Luoa, Xuan Chenga, Yun Lia, Qi-zhi Zhanga, Wen-xing Penga,b,
a
Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
b
Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China

A B S T R A C T

Schizophrenia is a heterogeneous disorder in which there is an interaction between genetic and environmental factors. Accumulating data show that there may be an
association between vitamin D deficiency and schizophrenia. We conducted an updated meta-analysis to investigate the relationship between schizophrenia and
blood vitamin D level. All published observational articles have been searched from five databases until September 2019. In total, 36 articles with a total of 12528
participants were included in this study. Patients with schizophrenia have significantly lower levels of vitamin D than controls. The subgroup analyses based on study
design, hospitalization status, quality score, type of biomarker [25-hydroxyvitamin D or 25-hydroxyvitamin D3], and the country did not explain between-study
heterogeneity; however, meta-regression on match factors indicted that match of BMI could account for some degree of heterogeneity. No significant differences in
publication bias were observed. Also, subjects with schizophrenia were more likely to have vitamin D deficiency or insufficiency compared to controls. In conclusion,
our analyses are consistent with the hypothesis that vitamin D deficiency is associated with schizophrenia. More well-designed randomized control trials are needed
to determine whether this association is causal.

1. Background also recognized as a ‘‘neurodevelopmental’’ disorder (Mackay-

Vitamin D (Vit D) is an important hormone that is widely known for
its essential role in calcium absorption and bone health (Wacker and
Holick, 2013). Data support a role for Vit D within the central nervous
system as a neuroprotective and dopamine modulating steroid
(Kesby et al., 2011). However, Vit D deficiency is becoming a common
problem in many countries. It is estimated that 1 billion people have Vit
D deficiency or insufficiency worldwide (Holick, 2007). Many studies
have highlighted hypovitaminosis D as a potential environmental risk
factor for various conditions such as multiple sclerosis, asthma, cardi-
ovascular diseases, and, more recently, psychiatric disorders
(Ebers et al., 2004; Kocovska et al., 2017). A large study recently im-
plicated vitamin D status related to the risk of brain disorders including
schizophrenia or psychosis (Cui et al., 2015). Patients with schizo-
phrenia, in particular, are more likely to be deficient than individuals
with other psychiatric disorders (Belvederi Murri et al., 2013;
Berg et al., 2010). Incidence of Vit D deficiency was found both in-
creased in animal models (e.g., the litter of vitamin-D depleted preg-
nant female rats) and in humans with developing schizophrenia
(McGrath et al., 2010a).
Evidence from epidemiology suggests that the etiology of schizo-
phrenia is associated with both the influence of genetic factors specific
to the individual and the impact of the environment. Schizophrenia is
Sim et al., 2004) and numerous pieces of epidemiological evidence
implicate low levels of maternal Vit D as a potential risk factor for
schizophrenia. Firstly, data on different geographical regions suggest
that for those born in late winter and early spring in those final ge-
stations was during the winter months have an increased risk of de-
veloping schizophrenia later in life (Miller, 2013; Torrey et al., 1997;
Wang and Zhang, 2017) and this risk is larger at high latitudes that
feature greater seasonal fluctuations (Davies et al., 2003). Based on
clues from maternal sera, low prenatal Vit D also has been proposed to
increase the risk of schizophrenia (McGrath et al., 2003). Secondly, the
incidence of schizophrenia is significantly higher for those living in
urban compared to those in rural (Marcelis et al., 1999). Finally, there
is a greatly increased risk of schizophrenia for the children of dark-
skinned migrants who move to cold climates(Cantor-Graae and
Selten, 2005). Moreover, studies from the Netherlands (Selten et al.,
2001), Denmark (Cantor-Graae et al., 2003), and Sweden
(Zolkowska et al., 2001) have shown an increased risk of schizophrenia
in migrants, especially those with dark skin.
For hypovitaminosis D is more prominent during winter and spring,
at high latitudes, in the urban environment, and individuals with dark
skin, there is an infer that Vit D plays a vital role in schizophrenia. For
the production of Vit D is strongly and consistently associated with the
duration of the photoperiod, which is affected by latitude and season

⁎
Corresponding author: Department of Pharmacy, the Second Xiangya Hospital, Central South University, #139, Middle Renmin Road, Changsha, Hunan 410011,
P.R. China
E-mail address: pwx.csu@csu.edu.cn (W.-x. Peng).

https://doi.org/10.1016/j.psychres.2020.112959
Received 4 January 2020; Received in revised form 25 March 2020; Accepted 27 March 2020
Available online 18 April 2020
0165-1781/ © 2020 Elsevier B.V. All rights reserved.
J.-l. Zhu, et al.
(Holick, 1995; Webb et al., 1988). In the city, exposure to sunlight has
been reduced in built environment compared to the country that could
increase the risk of Vit D deficiency (Mackay-Sim et al., 2004). Besides,
deficits in nutrients and vitamin D in long-term schizophrenia were
observed from illness onset and were associated with worse sympto-
mology (Firth et al., 2018). A review conducted on the relationship
between schizophrenia and prenatal nutrition deficiency, which include
Vit D, lends weight to this candidate (Brown and Susser, 2008). Adults
with schizophrenia also have been found to have lower serum Vit D
levels than the general population (Berg et al., 2010; Crews et al.,
2013).
A study conducted Vit D status on neonatal and risk of schizo-
phrenia demonstrated that low Vit D concentrations had a significantly
increased risk of schizophrenia (up to twofold) compared to neonates
with concentrations ranging between 40.5 and 50.9 nmol/L.
Interestingly, neonates with excessive concentrations of Vit D also had
an elevated risk for this disorder (McGrath et al., 2010b). While most of
the epidemiological data or systematic review only reported that hy-
povitaminosis D is associated with schizophrenia (Eserian and
Kalleian, 2013; McGrath et al., 2010a; Valipour et al., 2014). Another
study in the neonatal population found that Vit D supplementation
during the first year of life was associated with reduced risk of schi-
zophrenia in males but not females (McGrath et al., 2004a). Some even
have failed to find a significant association between Vit D and schizo-
phrenia (Norelli et al., 2010). The conclusion on the prevalence of
schizophrenia between males and females was also inconsistent
(Aleman et al., 2003; McGrath et al., 2004b; Saha et al., 2005). Cur-
rently, there is a disparity between the causality tests for genetic risk of
schizophrenia and lowers serum Vit D (Taylor et al., 2016) and recent
clinical evidence for Vit D supplementation in schizophrenia
(Krivoy et al., 2017). Vit D supplementation may improve to some
extent the cognitive performance in schizophrenia patients. However,
further studies are needed to confirm the preventive effect on reducing
the incidence of schizophrenia using a larger sample and larger doses of
vitamin D supplementation. Therefore, we undertook an updated sys-
tematic review and meta-analysis to investigate whether Vit D defi-
ciency is associated with schizophrenia.
2. Methods
2.1. Search strategy
Systematic research on all published articles was retrieved by
searching PubMed, the Cochrane Library, Embase, ISI (Web of Science)
and Scopus databases using the following combination of descriptors:
(schizophrenia OR psychotic disorders OR mental disorders OR psy-
chiatric) AND (vitamin D OR 25-hydroxyvitamin D OR calcidiol OR
cholecalciferol OR hydroxycholecalciferols OR ergocalciferols OR 25-
hydroxyvitamin D2 OR dihydrotachysterol OR calcifediol OR dihy-
droxycholecalciferols OR calcitriol) from inception to April 2019. The
references list of retrieved articles was also manually reviewed to
identify relevant studies missed by the search strategy.
2.2. Inclusion and Exclusion criteria
The eligible studies must meet the following inclusion criteria: (1)
original studies to evaluate the association between 25-hydroxyvitamin
D [25(OH)D] or 25-hydroxyvitamin D3 [25(OH)D3] status and the risk
of schizophrenia; (2) observational studies conducted on humans and
had measured the peripheral blood Vit D levels of schizophrenic pa-
tients and control or prevalence of Vit D deficiency or insufficiency
(VDD or VDI) of subjects. Studies conducted on the animal, pregnant
women, review and Randomized Controlled Trials which explored the
association between the use of Vit D supplements and the incidence of
schizophrenia were excluded. None restrictions of study design, bio-
markers of Vit D status, ethnicity, disease stage or severity. One study
2
Psychiatry Research 288 (2020) 112959
that had measured only 1,25-dihydroxy vitamin D were excluded from
the systematic review (Kishimoto et al., 2008). Three studies with the
cutoff point of 8.16 (Eyles et al., 2018), 10 (Nefzi et al., 2018) or 12 ng/
mL (Shukurova et al., 2015) and seven studies had no cutoff point of
VDD or lack of relevant data (Berg et al., 2010; Boerman et al., 2013;
Hummer et al., 2005; McGrath et al., 2010b; Rylander and
Verhulst, 2013; Wyszogrodzka-Kucharska and Rabe-Jablonska, 2006;
Yoo et al., 2018) was excluded from this meta-analysis. We also found
two other abstracts that seemed to have overlapped sample sizes
(Agarwal, 2013a, b); therefore, we included only the one with a larger
sample size (Agarwal, 2013a). One study compared the difference be-
tween highland and lowland of Vit D of patients who lived in Tanah
Karo also excluded(Akbar et al., 2018).
2.3. Data extraction and Outcomes
Data extraction was independently performed by two reviewers (JL
Z and WW L) and any discrepancies between the reviewers were re-
solved by intercessor until consensus was reached. The remaining ar-
ticles were browsed full text to determine whether they met the in-
clusion criteria or not. Required items of information were extracted
from the published papers (Tables 1 and 2). The primary outcome of the
study was the mean concentration of 25(OH)D. For consistency, Vit D
present in nmol/L were converted to ng/mL by using the conversion
factor (1 ng/mL = 2.5 nmol/L). Three studies reported medians and the
interquartile range of Vit D levels(Abdullah et al., 2012; Humble et al.,
2010; Yuksel et al., 2014), we calculated the mean and SD using re-
quired formulas (Hozo et al., 2005). One study (Partti et al., 2010)
reported mean and 95% CI instead of SD, or means and SD of two
groups such as male and female (Rey-Sánchez et al., 2009), respec-
tively, we converted them to mean and SD according to the Cochrane
Handbook for Systematic Reviews of Interventions. The secondary
outcomes were the number of samples positive or ORs for VDD or VDI
and differences between sex of serum Vit D in schizophrenic patients.
VDD was defined as a serum 25(OH)D, a stable marker of Vit D status,
the concentration of ≤ 20 ng/mL, which has been widely used in re-
lative studies as the cut-off point for VDD (Bouillon et al., 2007). VDI
was defined as a concentration of 25(OH)D ≤ 30 ng/mL based on most
of the included studies.
2.4. Quality assessment of studies
In the current analysis, the Newcastle-Ottawa scale (Stang, 2010)
was used to examine the quality of case-control studies. A maximum of
nine scores can be awarded to each study included in this meta-ana-
lysis. The quality score of greater than 6 as high-quality studies and
those with a score of 6 or fewer points were considered as low-quality
studies.
For cross-section studies included in this meta-analysis, we used an
11-item checklist which was recommended by the Agency for
Healthcare Research and Quality (AHRQ) (Hu et al., 2015). An item
would be scored “0” if it was answered “NO” or “UNCLEAR”; if it was
answered “YES”, then the item scored “1”. Article quality was assessed
as follows: low quality = 0-3; moderate quality = 4-7; high
quality = 8-11.
2.5. Statistical analysis
Stata, version 14.0 (Stata Corp) were applied to collect relevant data
and analysis in this meta-analysis. For outcomes, we chose weighted
mean difference (WMD) to assess continuous variables (i.e. periphery
blood levels of vitamin D), while risk difference (RD) or odds ratio to
evaluate dichotomous outcomes such as VDD or VDI. Each numerical
outcome value was presented with a 95% confidence interval (95% CI)
as well. The standard error (SE) of the incidence of VDD or VDI was
calculated for meta-analysis of the prevalence of VDD and VDI. Of note,
 J.-l. Zhu, et al.

Table 1
Baseline Characteristics for Case-control Studies and Cohort studies included in Meta-analysis
Study ID Number of Cases (%male) Age (mean in/out Diagnosis Ethnicity or Biomarkers Of Measurement of Categories of VDD and VDD or VDI Mean level of VD (ng/ml) Matching
SZ C or range) patient tool Country VD VD VDI (ng/ml) SZ C SZ C factors

Higuchi-1987 12(42%) 5(100%) 18-57 in Japan 25(OH)D3 HPLC CPBA 12.6 ± 2.2 22.3 ± 1.4 ①
Schneider-2000 34(56%) 31(61%) 21-81 in DSM-III-R Germany 25(OH)D3 IA 35.1 ± 26.1 45.9 ± 19.8
Bergemann- 72(0%) 71(0%) 20-46 in DSM-IV Germany 25(OH)D 16.3 ± 7.9 24.6 ± 11.5 ①
2008 ICD-10
Rey-Sánchez- 73(66%) 73(66%) 61 in DSM-IV Spain 25(OH)D3 RIA deficient:<15 F:19 F:20.42 ± 26.05 F:33.12 ± 19.42 ①,④,⑥
2009 CIE-10 M:33 M:15.12 ± 11.96 M:18.13 ± 15.43
Norelli-2010 40 20 18-65 in DSM-IV White 25(OH)D deficient:<20 23 9 19.5 ± 9.3 22.7 ± 13.0 ①,②,③,④
Black insufficient:<30 33 16
Cha-2011 14 32 DSM-IV South Korea 25(OH)D RIA deficient:<20 2 0
insufficient:<30 5 1
Clelland-2014 64(48%) 90(49%) 18-65 in DSM IV African- 25(OH)D CLIA insufficient:<30 44 42 31.63 ± 22.64 37.06 ± 22.7 ③,④,⑦
American
Caucasian
Hispanic
Bogers-2016 80 29 42 both Caucasian 25(OH)D3 deficient:<20 63 17
non-Caucasian
Itzhaky-2012 50(68%) 50(26%) 19-65 in PANSS Israel 25(OH)D CLIA deficient:<15 28 12 15.0 ± 7.3 20.2 ± 7.8 ①
insufficient:<30 20 31

3
Yuksel-2014 41(65.9%) 40(48%) 17-66 in DSM-IV-TR Turkey 25(OH)D EI deficient:<10 35 12 7.92 ± 2.89 14.94 ± 4.95 ①,②
40(50%) out insufficient:<20 40 22 14.99 ± 4.89
Graham-2015 20(60%) 20(60%) 17-33 Out SCID Caucasian 25(OH)D CLIA deficient:<30 11 28.2 ± 12.6 29.9 ± 14.3 ①,②,③
African-
American
Zhu-2015 93(44%) 93(56%) 18-65 out DSM-IV Yellow 25(OH)D RIA 10.55 ± 5.32 17.48 ± 6.08 ①,②,④
Bulut-2016 80(53%) 74(53%) 18-55 out DSM-IV TR Turkey 25(OH)D EI deficient:<10 20 6 23.46 ± 13.98 23.69 ± 9.61 ①,②
insufficient:<20 11 21
Akinlade-2017 60 30 19-55 in DSM-IV Ibadan 25(OH)D ELISA deficient:<20 35 2 19.75 ± 5.19 28.06 ± 5.63 ①
ICD-10 insufficient:<30 24 17
Kulaksizoglu- 64(56%) 54(57%) 18-65 out DSM-IV-TR Turkey 25(OH)D CLIA 10.06 ± 2.64 10.86 ± 3.45
2017
Yazici, AB-2019 189 109 41.4 in DSM-Ⅴ Turkey 25(OH)D ELFA deficient:<20 126 56 F:15.44 ± 8.8 F:17.78 ± 7.35 ①
insufficient:<30 41 38 M:19.41 ± 10.04 M:23.97 ± 12.51
sufficient:>30 22 15 17.52 ± 9.65 21.26 ± 10.9
Yazici, E-2019 in:30 28 19-65 both DSM-IV Turkey 25(OH)D ELISA in:16.20 ± 17.93 13.69 ± 4.91
0ut:30 DSM-Ⅴ out:11.37 ± 4.58
Malik-2019 80 40 18-65 both DSM-IV-TR Pakistan 25(OH)D deficient:<10 35 12 ①,②
insufficient:<20 29 20
sufficient:>20 6 8

①age; ②gender; ③ethnicity; ④BMI; ⑤education served; ⑥gonadal status; ⑦season of recruitment; R: Cohort Study
SZ, schizophrenia; C, control; VD, Vitamin D; VDD, Vitamin D deficient; VDI, Vitamin D insufficient; CPBA, competitive protein-binding assay; IA, Immunoassay; RIA, Radioimmunoassay; CLIA, Chemiluminescence
immunoassay; RLM, Routine laboratory methods; EI, Electroluminescence; LC-MS/MS, Liquid chromatography-tandem mass spectrometry; NM, not mentioned; ELFA, Enzyme-linked fluorescent immunoassay
Psychiatry Research 288 (2020) 112959
 J.-l. Zhu, et al.

Table 2
Baseline Characteristics for Cross-section studies included in Meta-analysis
Study ID Number of Cases (%male) Age (mean or in/outpatient Diagnosis tool Country Outcomes Measurement of Categories of VDD and Number of VDD or Mean level of VD (ng/ml)
range) VD VDI VDI
SZ C (ng/ml) SZ C SZ C

Humber-2010 20(40%) 97(54%) 43.7 out ICD-10 USA 25(OH)D RIA 14.6 ± 5.1 19.7 ± 5.9
Partti-2010 48(42%) 6193(45%) 52 out SCID Finland 25(OH)D RIA 15.6 ± 12.4 17.5 ± 13.2
Doknic-2011 26(46%) 35(31%) 32 out DSM-IV Serbia 25(OH)D CLIA 9.22 ± 1.12 28.76 ± 3.32
Abdullah-2012 185 105 40 in ICD-9 codes Russia/ Whites and 25(OH)D CLIA low:<32 164 97 21.2 ± 9.4 20.2 ± 11.0
295 nonwhites
Menkes-2012 49 53 18-65 in New Zealand 25(OH)D3 ECLIA deficient:<10 13 6 14.6 ± 5.8 23.8 ± 11.1
insufficient:<20 29 27
Murie-2012 25 8 19-69 in Chinese 25(OH)D LC-MS/MS deficient:<10 14 5
insufficient:<20 9 3
Agarwal, 63 out USA 25(OH)D deficient:<10 10
2013a insufficient:<20 22
sufficient:<30 14
Jamilian-2013 100(68%) 100(50%) 35.5 in DSM-4-TR Iran 25(OH)D RLM 18.8 ± 4.56 21.32 ± 4.18
Cieslak-2014 22(59%) both USA 25(OH)D insufficient:<30 20 17.3 ± 8.9
Grados-2015 13 17 In Spain 25(OH)D CLIA deficient:<20 12.87 ± 17.2 21.45 ± 17.2

4
insufficient:<30
Bazzano-2016 61 52 18-65 in USA 25(OH)D deficient:<20 19 32 21.8 ± 11.9 23.5 ± 10.2
insufficient:<30 13 28
Boerman-2016 202 118 out DSM-IV Holland 25(OH)D CLIA deficient:<12 70 27 17.8 ± 11.0 21.18 ± 11.3
insufficient:<20 65 37
sufficient:<30 45 30
optimum:>30 22 24
Lally-2016 324(60%) 96 43.8 out ICD-10 UK/Black; White Asian; 25(OH)D CLIA deficient:<10 11.5 ± 6.7 14.3 ± 8.1
Mixed insufficient:<20
Salavert-2017 22(73%) 22(27%) 18-65 in DSM-IV European 25(OH)D CLIA deficient:<20 19 8 13.14 ± 5.96 22.63 ± 7.65
Bruins-2018 1531 309 45 out Netherlands 25(OH)D LC-MS insufficient:<20 972 182
RDM
Patel-2018 18 61 40.6 in ICD-10 UK/Black; White Asian; 25(OH)D CLIA deficient:<12 11.8 ± 10.3 13.0 ± 13.4
(18-79) Mixed insufficient:<20
sufficient:>20
Yoo-2018 302(56%) 40.7 in Korea 25(OH)D insufficient:<20 236 15.5 ± 6.4
(18-82) sufficient:>20 66
Zoghbi-2019 196(60%) DSM-Ⅴ Lebanon 25(OH)D CLIA deficient:<10 22
insufficient:<20 89
sufficient>20 85

T, total; SZ, schizophrenia; CLIA, Chemiluminescence immunoassay; ECLIA: electrochemiluminescence immunoassay; RIA, Radioimmunoassay; RDM: the Roche Diagnostic method
Psychiatry Research 288 (2020) 112959
J.-l. Zhu, et al.
Figure 1. Flow chart of literature searching
when the incidence of VDD obeys normal distribution, and n*P, n*(1-P)
were both bigger than 5, RD was used for evaluating, otherwise we used
odds ratio (OR) to assess the prevalence of VDD or VDI. Differences in
the prevalence of VDD and VDI between schizophrenia and controls
were assessed by odds ratio. Summary estimates with their corre-
sponding SDs were derived by the method of Der Simonian and Laird by
using a random-effects model, which incorporates between-study
variability. Heterogeneity across studies was assessed using the Q-sta-
tistic. Meta-regression and subgroup analyses were performed to find
the source of heterogeneity using a random-effects model. Publication
bias was detected by Egger's test and Begg's test, P<0.05 was con-
sidered a significant publication bias. In addition, the sensitivity ana-
lysis was conducted to test the stability of results by Stata 12.0
5
Psychiatry Research 288 (2020) 112959
software.
3. Results
3.1. Study characteristics
The detailed steps of the literature search flow and screening pro-
cess were depicted in Figure 1. A total of 16869 articles were identified
via a primary search of the aforementioned literature databases, from
which 2359 citations were removed because of duplication. Screening
of article title and abstract by separate two researchers (JL Zhu and WW
Luo), 14395 citations were removed due not to meet the inclusion
criteria and 112 potential related articles were reminded
J.-l. Zhu, et al.
approximately. Further assessment of full text and abstract, 36 articles
did not match on the schizophrenic patients, 15 articles conducted on
capable of Vit D supplementation to schizophrenia, 10 articles without
full text or abstract, and 11 articles lack outcomes or relevant data.
Ultimately, a total of 36 articles included 18 case-control (17 full-text
articles and one abstracts) and 18 cross-section studies (16 full-text
articles and two abstracts) were considered in this meta-analysis.
Studies characteristics were summarized in Table 1-2. Sample sizes
of included studies ranged from 17 to 6193 persons, and in total 12528
participants. The age span is from 17 to 79. These papers were pub-
lished between 1987 and 2019; most of the diagnosis tools of schizo-
phrenia were DSM-IV and ICD-10. No matter measured 25(OH)D or
25(OH)D3 and their measurements. Quality assessment of studies
showed that 6 of case-control studies (Bergemann et al., 2008;
Bogers et al., 2016; Cha et al., 2011; Higuchi et al., 1987;
Kulaksizoglu and Kulaksizoglu, 2017; Schneider et al., 2000) were
considered as low-quality and the rest (Akinlade et al., 2017;
Bulut et al., 2016; Clelland et al., 2014; Graham et al., 2015;
Itzhaky et al., 2012; Malik et al., 2019; Norelli et al., 2010; Rey-
Sánchez et al., 2009; Yazici et al., 2019a; Yazici et al., 2019b;
Yuksel et al., 2014; Zhu et al., 2015)were high-quality studies. The
quality score of cross-section studies showed that 7 of 18 were high-
quality(Abdullah et al., 2012; Doknic et al., 2011; Humble et al., 2010;
Jamilian et al., 2013; Partti et al., 2010; Patel and Minajagi, 2018;
Zoghbi et al., 2019), and the rest of the studies (Agarwal, 2013a;
Bazzano et al., 2016; Boerman et al., 2016; Bruins et al., 2018;
Cieslak et al., 2014 ; Grados et al., 2015; Lally et al., 2016;
Menkes et al., 2012; Murie et al., 2012; Salavert et al., 2017; Yoo et al.,
2018) were moderate-quality.
3.2. Mean concentration of Vit D and schizophrenia
Twenty-seven study populations from 31 studies (Abdullah et al.,
2012; Akinlade et al., 2017; Bazzano et al., 2016; Bergemann et al.,
2008; Boerman et al., 2016; Bulut et al., 2016; Clelland et al., 2014;
Doknic et al., 2011; Grados et al., 2015; Graham et al., 2015;
Higuchi et al., 1987; Humble et al., 2010; Itzhaky et al., 2012;
Jamilian et al., 2013; Kulaksizoglu and Kulaksizoglu, 2017; Lally et al.,
2016; Menkes et al., 2012; Norelli et al., 2010; Partti et al., 2010;
Patel and Minajagi, 2018; Rey-Sánchez et al., 2009; Salavert et al.,
2017; Schneider et al., 2000; Yazici et al., 2019a; Yazici et al., 2019b;
Yuksel et al., 2014; Zhu et al., 2015) were included in the meta-analysis
of the mean level of 25(OH)D. As shown in Figure 2, the results in-
dicated that there were statistically significant differences in the mean
concentration of 25(OH)D between schizophrenia and control group
(WMD= -4.68, 95% CI [-7.02, -2.35], P<0.001). However, between
study-heterogeneity was significant (Q test, P<0.0001, I2=96.1%). Of
note, the control group in the case-control and cohort studies consisted
of healthy subjects with no history of psychiatric disorders while in the
cross-sectional studies, psychiatric patients but non-schizophrenic were
considered to be the control group. Consequently, we were able to
conclude that, compared with healthy subjects or other psychiatric
patients, peripheral blood mean level of 25(OH)D achieved inferior in
schizophrenia patients.
To explore the source of heterogeneity, subgroup analysis (based on
study design, country, biomarker, quality score and hospitalized status)
was conducted. As shown in Table 3, we found that the mean con-
centration of Vit D between schizophrenia and controls was significant
in case-control studies, European and non-European countries and
studies that included inpatients. The mean difference of blood levels of
Vit D between schizophrenic patients and the control group was not
significant in cross-sectional studies and those that included out-
patients. The subgroup analysis on biomarkers of Vit D [25(OH)D vs.
25(OH)D3], quality score (high, moderate and low-quality) revealed
that the mean difference of Vit D was significantly different between
schizophrenia and controls. The subgroup differences showed that
6
Psychiatry Research 288 (2020) 112959
study design, quality score, country, type of biomarker and hospitali-
zation status could not account for some degree of between-study het-
erogeneity.
A meta-regression on matching factors (conducted on age, gender,
ethnicity and body mass index (BMI) of controls) revealed that match of
BMI could explain the between-study heterogeneity (P=0.018, I2 re-
sidual=91.68%). After introducing it into the meta-regression analysis
model, the variance component between-study decreased from 38.46 to
14.29, indicating that 62.8% of the sources of heterogeneity can be
explained. Findings from sensitivity analysis revealed that no individual
studies significantly affected the mean concentration of Vit D, which
indicated statistically robust results. Publication bias was examined
both qualitatively (funnel-plot asymmetry) and quantitatively (Begg's
test [z=1.95, P=0.342>0.05] and Egger's test [t=0.95,
P=0.352>0.10]). Overall, no evidence of publication bias was ob-
served.
3.3. Prevalence of VDD or VDI in schizophrenic patients
The definition of Vit D deficiency in schizophrenia patients was
different among studies. For these differences, we did a subgroup
analysis. Fifteen studies with the VDD defined as lower than 20 ng/mL
(Agarwal, 2013a; Akinlade et al., 2017; Bazzano et al., 2016;
Boerman et al., 2016; Bogers et al., 2016; Bruins et al., 2018;
Bulut et al., 2016; Malik et al., 2019; Menkes et al., 2012; Norelli et al.,
2010; Salavert et al., 2017; Yazici et al., 2019a; Yoo et al., 2018;
Yuksel et al., 2014; Zoghbi et al., 2019) and nine studies with the VDI
defined as lower than 30 ng/mL(Abdullah et al., 2012; Agarwal, 2013a;
Bazzano et al., 2016; Bogers et al., 2016; Cha et al., 2011; Graham et al.,
2015; Norelli et al., 2010; Yazici et al., 2019a; Yuksel et al., 2014) were
included in this meta-analysis. One study had considered the cutoff
point of 32 ng/mL for VDD, and we summarized it into a group of VDI
(Abdullah et al., 2012). Of note, one citation has the result of all
schizophrenic patients have the VDI (lower than 30 ng/mL), which
could not include in the comparison (Nefzi et al., 2018). Results implied
that the overall prevalence of VDD and VDI in schizophrenic patients
was 68% (95%CI [58%–77%]) and 76% (95%CI [68%, 83%])
(Figure 3), respectively. Heterogeneity between study was significant
(Q test, P <0.001; I2=97.3% and 86.8%) and heterogeneity between
subgroup wasn't significant (Q test, P=0.24; I2=26.7%).
3.4. Odds Ratios from meta-analysis
To further investigate the differences of the prevalence of VDD or
VDI between schizophrenia and controls, we calculated the OR of
thirteen studies on VDD (Akinlade et al., 2017; Bazzano et al., 2016;
Boerman et al., 2016; Bogers et al., 2016; Bruins et al., 2018;
Bulut et al., 2016; Cha et al., 2011; Menkes et al., 2012; Murie et al.,
2012; Norelli et al., 2010; Salavert et al., 2017; Yazici et al., 2019a;
Yuksel et al., 2014) and nine studies on VDI (Abdullah et al., 2012;
Akinlade et al., 2017; Bazzano et al., 2016; Boerman et al., 2016;
Cha et al., 2011; Clelland et al., 2014; Itzhaky et al., 2012; Norelli et al.,
2010; Yazici et al., 2019a), respectively. The meta-analysis demon-
strated that the odds ratio of VDD and VDI was 2.09, 95%CI [1.48,
2.95] and 2.43, 95%CI [1.40, 4.23], respectively (Figure 4 and 5).
Heterogeneity was significant (I2=59%, P=0.004 or I2=62%,
P=0.006). Subgroup analysis revealed that study design could not ex-
plain the between-study heterogeneity (I2=0% and 41.4%). Meta-re-
gression on odds ratio of VDD and VDI also provided that the study
design could not explain the between-study heterogeneity (P=0.771,
I2=58.87% and P=0.323, I2=65.05%).
4. Discussion
In the present meta-analysis, the authors discussed the correlations
between schizophrenia and Vit D. No matter type of schizophrenia and
J.-l. Zhu, et al. Psychiatry Research 288 (2020) 112959

Figure 2. Forest plot of Mean Difference of 25(OH)D in schizophrenic patients vs. control participants
(1), (3): Females; (2), (4): Males; (5): inpatient; (6): outpatient; (7): remission schizophrenia; (8): acute episode schizophrenia

stage of schizophrenia, mean concentration of Vit D in individuals
unveiled that significant reductions in mean among people with schi-
zophrenia than controls (WMD=-4.68,95%CI [-7.02, -2.35],
P<0.0001). Our findings on the prevalence of deficiency (<20 ng/ml)
and insufficiency (<30 ng/ml) both indicated that hypovitaminosis D
was quite common in schizophrenia (70%, 95%CI [63%, 78%],
P<0.0001). The odds ratio showed that subjects with schizophrenia
were increased risk of VDD 2.09 times and 2.21 times of VDI compared
to controls.
There are four case-control studies included in this meta-analysis
discussed the gender difference of 25(OH)D between schizophrenic
patients and healthy subjects. Three of them reported females have

Table 3
Subgroup analysis on mean serum level of vitamin D and schizophrenia
Subgroup Number of Studies Participants, n Heterogeneity Subtotal [95% CI] Subgroup Differences

Study design 31 3652 P<0.01, I2=96.1% -4.68 [-7.02, -2.35] P=0.86, I2=0%
Case-control Study 19 1841 P<0.01, I2=87.3% -4.47 [-6.34, -2.59]
Cross-section Study 12 1811 P<0.01, I2=98.1% -4.95 [-9.92, 0.03]
Hospitalization status P=0.81, I2=0%
Out 7 697 P<0.01, I2=98.6% -5.23 [-12.27, 1.80]
In 24 2955 P<0.01, I2=84.4% -4.33 [-5.84, -2.82]
Country P=0.16, I2=50.2%
European 12 1529 P<0.01, I2=97.1% -7.19 [-12.15, -2.22]
Non-European 19 2123 P<0.01, I2=87.3% -3.41 [-5.03, -1.78]
Biomarker of vitamin D P=0.19, I2=42.0%
25(OH)D 26 3322 P<0.01, I2=96.7% -4.22 [-6.83, -1.61]
25(OH)D3 5 330 P=0.022, I2=64.9% -7.18 [-10.74, -3.61]
Quality score P=0.72, I2=0%
High 21 2386 P<0.01, I2=96.9% -4.22[-7.44, -1.01]
moderate 6 923 P=0.056, I2=53.6% -4.27[-6.30, -2.24]
low 4 343 P<0.01, I2=96.3% -6.88[-12.96, -0.80]

7
J.-l. Zhu, et al.
Figure 3. Forest plot of Prevalence of VDD and VDI in schizophrenic patients
higher serum 25(OH)D concentration than males (Cieslak et al., 2014 ;
Graham et al., 2015; Rey-Sánchez et al., 2009), only one was the op-
posite(Yazici et al., 2019a). Evidence from systematic review provided
a gender difference in the risk of developing schizophrenia
(Aleman et al., 2003; McGrath et al., 2004b), while Saha et al support
that there was no significant difference between female and male
(Saha et al., 2005). Meanwhile, Graham reported that Caucasian sub-
jects had a significantly higher 25(OH)D levels compared with African
American subjects (P<0.001)(Graham et al., 2015). For the different
components of schizophrenic patients of four case-control studies, we
discussed them separately on mean (Rey-Sánchez et al., 2009;
Yazici et al., 2019a; Yazici et al., 2019b; Yuksel et al., 2014). Subgroup
analysis based on study design, country, hospitalization status, type of
biomarker and quality score indicated that they could not explain some
degree of heterogeneity. In our meta-regression based on matching
factors, such as age, gender, ethnicity, and BMI revealed that match of
BMI could explain the between-study heterogeneity (P=0.018, I2 re-
sidual=91.68%). In observational studies, one of the primary sources
of bias is confounding. Potential confounders in Vit D studies are the
season of birth, latitude and the geographical location (Chiang et al.,
2016), as they are factors that will affect the duration and intensity of
sunlight exposure. Other factors such as age, gender, ethnicity, smoking
status, alcohol use, and BMI could also influence the blood concentra-
tion of Vit D.
Evidence from both epidemiological and pre-clinical studies to in-
dicate that Vit D deficiency might be an important risk factor for
schizophrenia. However, schizophrenia is a heterogeneous group of
8
Psychiatry Research 288 (2020) 112959
disorders with unknown etiology. The neurodevelopmental hypothesis
informed that at the cellular level, schizophrenia is associated with
subtle abnormalities in the cytoarchitecture of different brain regions
(Piper et al., 2012). Schizophrenic patients show a clear dysfunction in
dopamine (DA) systems is thought to be a key feature of schizophrenia.
Animal models on Vit D deficiency support that Vit D hormone prevents
abnormal dopaminergic phenotypes via its early neuroprotective ac-
tions on fetal DA neurons(Luan et al., 2018). Studies firmly established
that Vit D deficiency affects brain cell proliferation, differentiation, and
gross brain structure, it also produces long-lasting cellular changes and
alterations in behavior in the adult offspring(Kesby et al., 2013;
Schoenrock and Tarantino, 2016). Patrick proposed a model that Vit D
and the omega-3 fatty acids, in combination with genetic factors and at
key periods during development, would lead to dysfunctional serotonin
activation and function and may be one underlying mechanism that
contributes to neuropsychiatric disorders including schizophrenia
(Patrick and Ames, 2015).
In the database, there is one systemic review examined the asso-
ciation of Vit D deficiency with schizophrenia, which was published in
2014, contained 8 cross-section studies and 10 case-control studies
(Valipour et al., 2014). To conducted an updated meta-analysis, we
formulated a more stringent inclusion strategy and data was unified
with a standard algorithm. In comparison, our study has compared the
same outcomes as the previous research except we explored the asso-
ciation of gender with blood level of 25(OH)D. For gender differences in
the risk of a particular disorder can yield important clues regarding its
pathogenesis and evidence. In addition, the quality of studies included
J.-l. Zhu, et al. Psychiatry Research 288 (2020) 112959

Figure 4. Forest plot of Odds Ratio of VDD in Schizophrenia vs. Controls

Figure 5. Forest plot of Odds Ratio of VDI in Schizophrenia vs. Controls

9
J.-l. Zhu, et al.
in the previous meta-analysis was examined by Newcastle-Ottawa scale,
no matter type of article. In our study, we used an 11-item checklist
which was recommended by the AHRQ to assess the quality of cross-
section studies. Previous literature(Ford et al., 2005; Harris et al., 2013)
has described older age and dark skin as potential risk factors associated
with vitamin D deficiency.
At the same time, the limitations of our study should be considered.
Firstly, the 36 documents included are all observational studies. Eight
case-control studies have potential selection bias or not stated; only 3
studies chose community controls. Most of cross-section studies had not
explained any patient exclusions from analysis or described how con-
founding was assessed and/or controlled. And the quality of literature is
relatively general. Secondly, all of the studies included in this research
and published by the database had some publication bias. Size of
sample, age or ethnicity of population, different latitudes or elevations
and the outcomes of studies could affect the publication bias. Finally,
due to the lack of sufficient information about the gender and age of
population, we were unable to conduct subgroup analysis according to
these included studies. Therefore, it is uncertain whether these dis-
crepancies may influence the result to a certain extent and the results
should be interpreted with caution.
In conclusion, there is a strong association between Vit D deficiency
and schizophrenia. Our meta-analysis showed that schizophrenic pa-
tients have a lower level of Vit D than healthy controls or other psy-
chiatric patients. And the incidence of schizophrenia was higher in
people with Vit D deficiency. Against this background, we can under-
stand the association of Vit D and schizophrenia where causality re-
mains to be elucidated. More well-designed cohort study or randomized
controlled trials are needed to explore their deeper connections.
Abbreviations
Vit D: vitamin D; 25(OH)D: 25-hydroxyvitamin D; VDD: vitamin D
deficiency; VDI: vitamin D insufficiency; BMI: body mass index; AHRQ:
Agency for Healthcare Research and Quality; MD: mean difference; RD:
risk difference; 95%CI: 95% confidence interval; SE: standard error; OR:
odds ratio; WMD: weighted mean difference; SZ, schizophrenia; C,
control; VD, Vitamin D; VDD, Vitamin D deficient; VDI, Vitamin D in-
sufficient; IA, Immunoassay; RIA, Radioimmunoassay; CLIA,
Chemiluminescence immunoassay; RLM, Routine laboratory methods;
EI, Electroluminescence; LC-MS/MS, Liquid chromatography-tandem
mass spectrometry; NM, not mentioned; ELFA, Enzyme-linked fluor-
escent immunoassay; T, total; SZ, schizophrenia; CLIA,
Chemiluminescence immunoassay; ECLIA: electrochemiluminescence
immunoassay; RIA, Radioimmunoassay; RDM: the Roche Diagnostic
method
CRediT authorship contribution statement
Jia-lian Zhu: Conceptualization, Data curation, Formal analysis,
Methodology, Supervision, Validation, Writing - original draft. Wen-
wen Luo: Data curation, Supervision, Validation, Writing - original
draft. Xuan Cheng: Project administration, Resources, Software. Yun
Li: Project administration, Resources, Software. Qi-zhi Zhang:
Investigation, Visualization. Wen-xing Peng: Conceptualization,
Funding acquisition, Writing - review & editing.
Conflict of interest
The authors declare that they have no conflicts of interest.
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