Invest Clin 64(3): 424 - 436, 2023 https://doi.org/10.54817/IC.v64n3a12

Corresponding author: Ximin Zhao. Department of Psychiatry, Zhoushan Second People’s Hospital, Zhoushan,

Zhejiang Province, China. Email: zhaoxmzsph@zcxecl.com

Clinical efficacy and safety of folic acid

and vitamin B

for the adjuvant treatment

of schizophrenia: a systematic review

and meta-analysis.

Kai Niu

, Ximin Zhao

, Ying Wei

and Yuefeng Wang

Department of Psychiatry, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang

Province, China.

Medical Record Statistics Office, Zhoushan Second People’s Hospital, Zhoushan,

Zhejiang Province, China.

Key words: folic acid; meta-analysis; schizophrenia; vitamin B

Abstract. Given the different effects of folate and vitamin B

on the ad-

juvant treatment of schizophrenia (SCH), their efficacy and safety as adjuvant

therapies for SCH were systematically evaluated by evidence-based medicine.

Publication retrieval was performed using authoritative databases such as the

Cochrane Library, PubMed, and Web of Science to screen randomized con-

trolled trials (RCTs). After the quality evaluation and data extraction of includ-

ed studies, eligible RCTs were systematically reviewed using Review Manager

5.2 software. In total, 14 RCTs were included. The results of the meta-analysis

revealed that as the adjuvant therapy for SCH, vitamin B

differed significantly

from folate in terms of anxiety relief rate [odds ratio (OR)=1.28, 95% con-

fidence interval (CI) (1.02, 1.61), p=0.03, I

=0%, Z=2.13]. However, there

were no significant differences in the incidence rate of mania [OR=1.13, 95%

CI (0.78,1.65), p=0.65, I

=36%, Z=0.65], total efficacy [OR=1.06, 95% CI

(0.72, 1.56), p=0.77, I

=0%, Z=0.30] and incidence rate of adverse reactions

[OR=1.15, 95% CI (0.88, 1.49), p=0.31, I

=0%, Z=1.03]. Although folate and

vitamin B

exhibit no significant differences in the adjuvant treatment of SCH,

vitamin B

exerts markedly fewer side effects than folate drugs, and it is of de-

terminant significance for the clinical adjuvant medication of SCH.

Adjuvant treatment of schizophrenia 425

Vol. 64(3): 424 - 436, 2023

Eficacia clínica y seguridad del ácido fólico y la vitamina B

como tratamiento adyuvante de la esquizofrenia: una revisión

sistemática y metanálisis.

Invest Clin 2023; 64 (3): 424 – 436

Palabras clave: ácido fólico; metanálisis; esquizofrenia; vitamina B

Resumen. En vista de los diferentes efectos del folato y la vitamina B

en el tratamiento adyuvante de la esquizofrenia (SCH), su eficacia y seguridad

como terapia adyuvante para SCH fueron evaluadas sistemáticamente mediante

la medicina basada en la evidencia. La recuperación de publicaciones se realizó

en base a bases de datos autorizadas como Cochrane Library, PubMed y Web

of Science para la selección de ensayos controlados aleatorios (ECA). Después

de la evaluación de la calidad y la extracción de datos de los estudios incluidos,

los ECA elegibles se revisaron sistemáticamente mediante el software Review

Manager 5.2. En total, se incluyeron 14 ECA. Los resultados del metanálisis

revelaron que, como terapia adyuvante para la SCH, la vitamina B

difería sig-

nificativamente del folato en términos de tasa de alivio de la ansiedad [odds

ratio (OR) = 1,28, intervalo de confianza (IC) del 95% (1,02, 1,61), p=0,03,

=0%, Z=2,13], pero no hubo diferencias significativas en la tasa de incidencia

de manía [OR=1,13, IC 95% (0,78,1,65), p=0,65, I

=36%, Z= 0,65], eficacia

total [OR=1,06, IC 95% (0,72, 1,56), p=0,77, I

=0%, Z=0,30] y tasa de inci-

dencia de reacciones adversas [OR=1,15, IC 95% (0,88, 1,49 ), p=0,31, I

=0%,

Z=1,03]. Aunque el folato y la vitamina B

no presentan diferencias significati-

vas en el tratamiento adyuvante de la SCH, la vitamina B

ejerce notablemente

menos efectos secundarios que los fármacos de folato y tiene una importancia

orientativa para la medicación adyuvante clínica de la SCH.

Received: 16-11-2022 Accepted: 15-04-2023

INTRODUCTION

Schizophrenia (SCH) is a chronic men-

tal disorder that involves social, cognitive,

and emotional problems and has a lifetime

prevalence of 1% in the population. As a

chronic disease, SCH is usually accompa-

nied by physical illness, malnutrition, and

reduced self-care practices, all of which can

cause vitamin deficiency

. Nutritional de-

ficiencies often coexist with SCH, which is

attributed to the patients’ tendency to have

higher calorie diets with saturated fat in-

stead of fiber foods such as fruits and veg-

etables. Previous studies have revealed de-

ficiencies of nutrients, such as folate and

vitamin B

in SCH patients resulting from

less time on outdoor activities

2,3

. Vitamin

and folate levels decline in patients with

SCH

. Alcoholism and drug addictions are

viewed as chronic diseases featured by re-

currence, in common with SCH. However,

the prevalence data of illicit drug addic-

tion worldwide are still lacking. Like SCH,

alcoholism, and drug addictions may cause

adverse effects on cognitive function and

426 Niu et al.

Investigación Clínica 64(3): 2023

induce malnutrition

. In addition, exces-

sive drinking is a common phenomenon in

developed countries, which affects nutrient

intake and metabolism, leading to malnu-

trition, and also causes damage to multiple

organs. Although folate and vitamin B

de-

ficiencies are frequently present in chronic

alcohol drinkers, the impact of long-term

drinking on vitamin B

and folate levels has

not yet reached a consensus. Thus, the data

about correlations of vitamin D and other

vitamin deficiencies with the risk of alco-

holism are also insufficient to support the

final conclusion

. Recently, vitamin B

has

been demonstrated to be vital for hemosta-

sis and multiple physiological functions, as

well as the pathogenesis of diseases such

as cancer, autoimmune disorder, senile de-

mentia, cognitive impairment, and SCH

It was also reported in another study that

vitamin B

acts as an essential player in

SCH and cognitive function and has immu-

nomodulatory, anti-inflammatory, and anti-

oxidant effects

. Homocysteine is thought

to be a pro-atherogenic molecule that has

toxic effects on endothelium, but its associ-

ations with diagnosis and prognostic evalu-

ation of SCH have not been systematically

analyzed and summarized

. Consistent

with vitamin B

, folate is a vitamin B used

to modulate cell division. Folate deficiency

is closely implicated in megaloblastic ane-

mia, cardiovascular disease, osteoporosis,

bone dysplasia, depression, and SCH, and

folate insufficiency during pregnancy may

cause fetal neural tube developmental de-

fects. SCH involves neurodegenerative pro-

cesses, although the impact extent of vita-

min deficiency on these processes remains

unclear

, and the potential deterioration

of such processes resulting from folate and

vitamin B

deficiencies cannot be ignored.

For this reason, efforts should be made to

identify patients at risk of specific vitamin

deficiencies and then provide prompt and

appropriate interventions.

Consequently motivated, the clinical ef-

ficacy and safety of folate and vitamin B12 as

adjuvant therapy in SCH were systematically

reviewed and meta-analyzed to guide the

clinical medication of SCH.

MATERIALS AND METHODS

Retrieval methods

Publication retrieval was performed us-

ing databases such as the Cochrane Library,

PubMed, Web of Science, and EMBASE, as

well as related websites for registration of

clinical trial institutions with “schizophre-

nia”, “cognitive impairment”, “SCH”, “fo-

late”, and “vitamin B

” as subject words

and trademark names of relevant drugs as

free words. In addition, relevant studies pub-

lished in English were retrieved to avoid bias

due to language restrictions (Fig. 1).

Inclusion criteria

The inclusion criteria of studies were

as follows: i) studies using randomized con-

trolled trials (RCTs), ii) those with research

subjects meeting the diagnostic criteria for

SCH following the Minnesota Multiphasic

Personality Inventory or schizophrenia scale

and also the ICD-11 diagnosis of schizophre-

nia

, iii) those researching comparisons of

efficacy and safety between folate and vita-

min B

as adjuvant therapies for SCH, iv)

those mainly evaluating indexes including

anxiety relief rate, incidence rate of mania,

total efficacy and incidence rate of adverse

reactions, v) those whose research subjects

had no history of drug abuse, and vi) those

including research subjects who underwent

6-12 weeks of treatment and were aged ≥8

years old and lack of folate or vitamin B

Exclusion criteria

The exclusion criteria involved: i) stud-

ies adopting non-RCTs, ii) repeated studies,

iii) studies with incomplete data, or iv) stud-

ies published for the second time.

Quality evaluation of studies

Evaluation was performed as required:

i) whether patients were ranked randomly

Adjuvant treatment of schizophrenia 427

Vol. 64(3): 424 - 436, 2023

(“yes” =2, ”unclear” =1, ”no” =0), ii) ran-

dom hiding (“yes” =2, ”unclear” =1, ”no”

=0), iii) blind trial (“yes” =2, ”clear” =1,

”no” =0), and iv) withdrawal or not with-

drawal (“yes” =1, ”no” =0). Data involving

author information and country, Jadad score,

type, patient’s age and gender, the dose of

study drugs, number of cycles, effective treat-

ment, total efficacy score after treatment,

and adverse reactions were extracted. Then

two commentators were responsible for com-

paring these data, where inconsistencies were

discussed, and missing information was sup-

plemented as far as possible.

Bias analysis of studies

Two investigators independently con-

ducted data extraction and cross-checking

to ensure the data’s accuracy. Quality evalu-

ation was conducted for RCTs with the Co-

chrane Handbook 5.0.2 as a reference. As

for the included studies, the presence or ab-

sence of publication bias was evaluated us-

ing a funnel chart (performed through the

Egger’s test), which illustrated that all stud-

ies were within the triangle area, without ob-

vious publication bias (Figs. 2 and 3).

Statistical analysis

The Review Manager 5.2 software [Co-

chrane Information Management System

(IMS)] provided by Cochrane Collaboration

was utilized for statistical analysis using the

hazard ratio of binary variables. The meta-

analysis analyzed the efficacy and incidence

rate of adverse reactions using relative risk

(RR) and 95% confidence interval (CI). Be-

sides, the chi-square test (the significance

level was set at p<0.05) and t-test expressed

by Z and P values for the hypothesis test

were applied, and p<0.05 was considered

statistically significant. The hypothesis test

results were displayed in the forest plot,

and the χ

test was employed to analyze

heterogeneity, divided into low, medium,

and high heterogeneity and represented by

=25%, 50%, and 75%, respectively. The in-

verted funnel chart was used and displayed

no obvious publication bias.

RESULTS

Basic information of included patients

A total of 123 studies were obtained by

the preliminary retrieval based on databases

such as PubMed, Cochrane Library, Web of

Fig. 1. Flow chart of literature retrieval.

428 Niu et al.

Investigación Clínica 64(3): 2023

Fig. 2. Quality evaluation chart of literatures.

Fig. 3. Funnel chart for analysis of literature publication bias.

Adjuvant treatment of schizophrenia 429

Vol. 64(3): 424 - 436, 2023

Science, and EMBASE. Furthermore, rel-

evant references were also retrieved to avoid

omission. Fourteen studies adopting RCTs

were included (Table 1)

12-25

Anxiety relief rate in SCH patients

undergoing adjuvant therapy with folate

and vitamin B

A heterogeneity test found that a low

level of heterogeneity existed in 14 studies

adopting RCTs for detecting anxiety relief

rates in SCH patients undergoing adjuvant

therapy with folate and vitamin B

, so fixed

models were utilized for meta-analysis. The

experimental group was given folate in com-

bination with vitamin B

, and the control

group was only given folate. The two groups

had significantly different remission rates

of anxiety [odds ratio (OR)=1.28, 95%

CI (1.02, 1.61), p=0.03, I

=0%, Z=2.13]

(Fig. 4).

Incidence rate of mania in SCH patients

undergoing adjuvant therapy with folate

and vitamin B

A heterogeneity test was conducted and

revealed that 14 studies adopting RCTs for

investigating the incidence rate of mania

in SCH patients undergoing adjuvant ther-

apy with folate and vitamin B

exhibited a

low level of heterogeneity, which could be

subject to meta-analysis with fixed models.

The results manifested that there was no

significant difference in the incidence rate

of mania in SCH patients undergoing adju-

vant therapy with folate and vitamin B

be-

tween the experimental group and the con-

trol group [OR=1.13, 95% CI (0.78, 1.65),

p=0.65, I

=36%, Z=0.65] (Fig. 5).

Total efficacy of folate and vitamin B

in the adjuvant treatment of SCH

A heterogeneity test was performed and

manifested that 14 studies adopting RCTs

for examining the total efficacy of adjuvant

therapy with folate and vitamin B

for SCH

showed a low level of heterogeneity, which

were subject to meta-analysis with fixed

models. The results demonstrated that the

total efficacy of adjuvant therapy with folate

and vitamin B

for SCH showed no signifi-

cant difference between the experimental

group and the control group [OR=1.06, 95%

CI (0.72, 1.56), p=0.77, I

=0%, Z=0.30]

(Fig. 6).

Incidence rate of adverse reactions of

folate and vitamin B

in the adjuvant

treatment of SCH

Through a heterogeneity test, it was

uncovered that 14 studies adopting RCTs

for detecting the incidence rate of adverse

reactions of folate and vitamin B

in the

adjuvant treatment of SCH had a low level

of heterogeneity, so fixed models were used

for meta-analysis. The results confirmed that

the incidence rate of adverse reactions of ad-

juvant therapy with folate and vitamin B

for

SCH exhibited no significant difference be-

tween the experimental group and the con-

trol group [OR=1.15, 95% CI (0.88,1.49),

p=0.31, I

=0%, Z=1.03] (Fig. 7).

DISCUSSION

Folate and vitamin B

have immuno-

modulatory, anti-inflammatory, and antioxi-

dant properties. It has been reported that the

incidence of vitamin D deficiency is raised

in patients newly diagnosed with SCH

. An-

other study demonstrated that vitamin B

is not only associated with malnutrition but

also correlated with the occurrence of dis-

ease and increased incidence rate of auto-

immune thyroid diseases. Consequently, the

loss of the neuroprotective effect of vitamin

may be implicated in the pathogenesis

of SCH

. Like SCH, substance use disorder

(SUD) is a chronic disease usually related to

malnutrition. In a study about associations

of folate and vitamin B

levels with the se-

verity of symptoms in patients with SCH,

those with low levels of vitamin B

may be at

particular risk of poor prognosis. A previous

study also revealed lower folate levels in SCH

patients than in healthy controls

. Howev-

430 Niu et al.

Investigación Clínica 64(3): 2023

Table 1

Basic information of patients in 14 literatures adopting RCTs.

Study item Age

Gender

(Male)

Observation index of outcome

Experimental

group (N)

Control

group (N)

NOS

score

Study

type

Yazici et al. 2019 41.44±12.28 57.14% Anxiety relief rate, incidence rate of mania, etc. 119/189 109/189 8 RCT

Yazici et al. 2019 40.63±13.50 100% Anxiety relief rate, incidence rate of mania, etc. 24/30 23/28 7 RCT

Altun et al. 2018 9.33±1.80 76.67% Anxiety relief rate, incidence rate of mania, etc. 23/30 25/30 8 RCT

Hope et al. 2020 30.0±9.0 55.78% Anxiety relief rate, incidence rate of mania, etc. 420/ 483 401/483 8 RCT

Allott et al. 2019 20.2±3.0 65.40% Anxiety relief rate, incidence rate of mania, etc. 88/120 76/120 8 RCT

Topal et al. 2022 8.5±3.1 73.90% Anxiety relief rate, incidence rate of mania, etc. 178/203 180/203 7 RCT

Ramaekers et al. 2014 19.5±2.56 78.20% Anxiety relief rate, incidence rate of mania, etc. 12/18 13/18 9 RCT

Chen et al. 2021 44.3±10.7 49.60% Anxiety relief rate, incidence rate of mania, etc. 125/232 117/232 9 RCT

Misiak et al. 2014 26.0±5.3 58.97% Anxiety relief rate, incidence rate of mania, etc. 27/39 31/39 7 RCT

Kale et al. 2010 33.57±8.35 56.32% Anxiety relief rate, incidence rate of mania, etc. 23/31 26/48 8 RCT

Roffman et al. 2013 45.3±1.1 71.0% Anxiety relief rate, incidence rate of mania, etc. 31/56 28/56 8 RCT

Saedisomeolia et al. 2011 37.25±16.0 66.44% Anxiety relief rate, incidence rate of mania, etc. 44/60 41/60 8 RCT

Misiak et al. 2016 28.51±8.6 68.44% Anxiety relief rate, incidence rate of mania, etc. 117/135 121/146 9 RCT

Misiak et al. 2015 25.12±4.48 43.22% Anxiety relief rate, incidence rate of mania, etc. 34/83 36/83 7 RCT

Adjuvant treatment of schizophrenia 431

Vol. 64(3): 424 - 436, 2023

Fig. 4. Meta-analysis of anxiety relief rate in SCH patients undergoing adjuvant therapy between the two

groups.

Fig. 5. Meta-analysis of incidence rate of mania in SCH patients undergoing adjuvant therapy between the

two groups.

Fig. 6. Meta-analysis of total efficacy of adjuvant therapy for SCH between the two groups.

432 Niu et al.

Investigación Clínica 64(3): 2023

er, these findings have not been reported in

other studies. Consistent with previous stud-

ies, folate, and vitamin B

are relatively de-

ficient in older adults, verifying associations

with gender and age

29-31

It has long been considered that ab-

normal one-carbon metabolism is one of

the mechanisms for the neuropathology and

psychopathology of SCH

. The changes in

levels of one-carbon metabolic components

(folate and vitamin B

), homocysteine, and

docosahexaenoic acid (DHA) are primarily

found in patients receiving drug adminis-

tration. For instance, daily administration

of 2 mg folate plus 1 mg vitamin B

for 12

weeks can significantly reduce the serum

homocysteine level (p<0.0001)

. In a rel-

evant study, the impact of change levels of

one-carbon metabolic components (folate

and vitamin B

) on the severity of SCH was

reported, and the subsequent alterations

of homocysteine and DHA in phospholipids

were also notably correlated with the patho-

genesis of SCH

. In a study conducted by

Satoskar et al.

, the associations of folate

and vitamin B

deficiencies with the patho-

genesis and prognosis of SCH patients were

investigated, and the mechanism of one-car-

bon metabolism was also further explored.

In the study, the clinical efficacy and safety

of agents were analyzed between first-epi-

sode psychosis (FEP) patients (n=31) and

healthy controls (HC, n=48), and folate and

vitamin B

were matched with confound-

ing factors such as race, diet, and lifestyle,

to reduce variability. Compared with HC,

the DHA level in patients with FEP notice-

ably declined. The unique cohort used in the

study provided an extensive mechanism for

changing one-carbon metabolism (disturbed

folate-vitamin B

-DHA balance). Besides,

the increased level of homocysteine contrib-

utes to the mechanism research on the neu-

ropathology of SCH, and the data mentioned

above may be of great significance for the

psychopathology of SCH

36-39

The limitations of this meta-analysis

include: i) Potential publication bias existed

because of too few studies and small sample

size. ii) There were few studies included and

no subgroup analysis for comparison of ef-

ficacy. iii) Only therapeutic effects at the

end of treatment were evaluated, but long-

term effects were not assessed. iii) We only

included adult SCH patients over the age of

18, whose results would be inapplicable to

adolescents.

Vitamin B

and folate levels are nota-

bly lower in patients with SCH

40,41

. Herein,

further analysis on the clinical efficacy and

Fig. 7. Meta-analysis of incidence rate of adverse reactions in SCH patients undergoing adjuvant therapy

between the two groups.

Adjuvant treatment of schizophrenia 433

Vol. 64(3): 424 - 436, 2023

safety of adjuvant therapy with folate and vi-

tamin B

for SCH revealed that vitamin B

differed significantly from folate in terms of

anxiety relief rate (p<0.05). However, there

were no significant differences in the inci-

dence rate of mania, total efficacy, and in-

cidence rate of adverse reactions (p>0.05).

Although vitamin deficiency commonly oc-

curs in patients with SCH, vitamin B

has

notably fewer side effects than folate drugs,

which is consistent with the findings of Roff-

man et al.

. Hence, this meta-analysis is of

great guiding significance for the adjuvant

clinical medication of SCH.

ACKNOWLEDGMENTS

This study was not financially supported.

Conflict of interest

The authors declare no conflict of interest.

Authors ORCID

• Kai Niu (KN):

0000-0003-0314-9735

• Ximin Zhao (XZ):

0000-0001-5924-0058

• Ying Wei (YW):

0000-0001-7642-3614

• Yuefeng Wang(YFW):

0000-0001-9064-3525

Authors’ contribution

Study design: KN, XZ; Data collection:

YW, YFW; Data analysis: YW, YFW; Writing:

KN, XZ. KN

and

XZ contributed equally to

this study.

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