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The effects of folic acid
supplementation on depression in
adults: a systematic review and
meta-analysis of randomized
controlled trials
Parniyan Khalili
Clinical Psychology Department, Semnan University, Semnan, Iran
Omid Asbaghi
Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Ladan Aghakhani
Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Cain C.T. Clark
Centre for Intelligent Healthcare, Coventry University, Coventry, UK, and
Neda Haghighat
Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Abstract
Purpose –This study aims, a systematic review and meta-analysis, to evaluate the effects of folic acid
(folate) on patients with depression.
Design/methodology/approach –Related articles were found by searching PubMed, SCOPUS, Web of
science and Cochrane’s Library, from inception to January 2022. Weighted mean differences (WMD) were
pooled using a random-effects model. Heterogeneity, sensitivity analysis and publication bias were reported
using standard methods.
Findings –Pooled analysis of six randomized controlled trials revealed that folic acid supplementation
decreased the depression score in the Beck Depression Inventory (WMD: 3.9; 95% CI: 5.3 to 2.4,
p<0.001) compared with control group, without heterogeneity (I2 = 0.0%, p= 1.000). It also lowered the
depression score in the Hamilton (HAM) Depression Inventory (WMD: 3.5 mg/dL; 95% CI: 4.6 to
2.4, p<0.001) compared with control group, with moderate heterogeneity (I2 = 71.8%, p= 0.007).
Moreover, subgroup analysis showed that the folic acid supplementation reduced HAM in all
subgroups. Meta-regression analysis demonstrated that there is no evidence of a significant linear
relationship between dose and duration of folic acid supplementation and changes in HAM. Also, based
on the non-linear dose response, no evidence of a relationship between dose and duration of folic acid
supplementation and changes in HAM was found.
Originality/value –Folic acid supplementation could possibly have an effect on lowering depression in
patients. However, the clinical trials thus far are insufficient for clinical guidelines and practice.
Keywords Folic acid, Depression, Meta-analysis
Paper type Research paper
The authors thank the Laparoscopy research center of Shiraz University of Medical Sciences.
Folic acid
supplementa
tion
Received 12 February2022
Revised 29 June2022
Accepted 29 June2022
Nutrition & Food Science
© Emerald Publishing Limited
0034-6659
DOI 10.1108/NFS-02-2022-0043
The current issue and full text archive of this journal is available on Emerald Insight at:
https://www.emerald.com/insight/0034-6659.htm
1. Introduction
Over the past two decades, epidemiological and experimental studies have shown the
relevance of nutritional factors on mental health issues, such as depression (Schefft et al.,
2017;Lazarou and Kapsou, 2010). Several studies have reported low folate levels in plasma,
serum and red blood cells among patients with major depression (Abou-Saleh and Coppen,
2006). The correlation between folic acid deficiency and mental illness was first published
by Carney in 1967 (Carney, 1967), who found that there is a high incidence of folate
deficiency occurring in patients with depression (29%–30%), organic psychosis (24%) and
schizophrenia (20%) (Pourghassem Gargari et al., 2012).
Furthermore, the results of several studies have also shown that the effectiveness
of the antidepressant medication is influenced by initial folate levels, as treatment
is less effective when folate is deficient (Stanger et al., 2009;Papakostas et al.,2004),
and response to antidepressant medication might be enhanced by concurrent
folic acid supplementation (Williams et al.,2007). Folate plays a vital role in the
development, differentiation and functioning of the central nervous system (CNS)
(Stanger et al., 2009) and has other beneficial effects on health (Asbaghi et al., 2021a,
2021b,2021c,2021d,2021e).Oneofthemainfunctionsoffolateisitsroleinthe1-
carbon cycle. As part of this process, the methylenetetrahydrofolate reductase
(MTHFR) converts folate into methyltetrahydrofolate (MTHF), using vitamin B12,
which is combined with homocysteine and then produces S-adenosylmethionine
(SAMe) (Mischoulon and Raab, 2007). SAM contributes to the methylation of
neurotransmitters implicated in depression, such as serotonin, dopamine and
noradrenalin (de Koning et al., 2016).
Folate deficiency also affects other biological mechanisms that cause depression;
indeed, in people with low folate status, homocysteine levels are higher since folate is
involved in remethylating homocysteine to methionine and research suggests that
homocysteine levels are positively correlated with depression symptoms severity and
levels (Bender et al., 2017;Froese et al., 2019). A putative hypothesis for these
relationships is that high homocysteine levels are associated with cerebral vascular
disease and neurotransmitter deficiencies, which may lead to depression (Ebesunun
et al., 2012). Previously, several systematic reviews and meta-analyses have examined
the relationship between low folate status and depression (Gilbody et al.,2007;Taylor
et al.,2004;Roberts et al., 2018). The results of a recent systematic review showed
that adjunctive folate is effective and safe for major depressive disorder (MDD)
(Zheng et al., 2020). However, further research is needed to determine if folate status
contributes to depression. Therefore, we conducted the present meta-analysis to
examine the efficacy of folic acid in treating depression.
2. Materials and methods
The current study was conducted according to the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) guidelines (Moher et al.,2009).
2.1 Literature search
Without any limitations on time and publication language, the following databases were
used to identify suitable studies: PubMed, SCOPUS, Web of science and Cochrane’s Library.
Search terms were related to folate and its constituent’s“folate”OR “folic acid”OR “Vitamin
M”OR “Vitamin B9”OR “Folacin”OR “Folvite”OR “Pteroylglutamic Acid”OR “folates”OR
“tetrahydrofolates”OR “Formyltetrahydrofolates”) AND (Depression OR “mental health”
NFS
OR depressive). The search strategy identified articles published since journal inception and
up to January 2022.
2.2 Study selection
All of the articles were transformed into EndNote (version X7, for Windows, Thomson
Reuters, Philadelphia, PA, USA) by a researcher (P.K.) who conducted a literature search.
After the elimination of duplications, two independent authors (N.H. and P.K.) separately
analyzed all titles and abstracts of the remaining articles, to ascertain whether these studies
were eligible for our meta-analysis based on the inclusion criteria. Any disagreements
between the two investigators were settled by a panel discussion.
2.3 Inclusion criteria
All of the studies needed to be randomized controlled trials (RCTs), including crossover
studies, in adults (<18 years), in addition to the following criteria: the effects of folic
acid on depression have been measured in all articles; Beck Depression Inventory (BDI)
and Hamilton (HAM) Depression Inventory were used to assess depression; means and
standard deviation have been reported; finally, studies with observational and animal
study designs, and acute interventions that were not in the form of randomized
allocation or placebo-control groups, were excluded.
2.4 Data extraction
The studies were independently screened and extracted by two authors, and a third author
resolved any disagreements. The following data were extracted using a standardized
extraction form: first-named author, date, study design, the sample size in both intervention
and control groups, total study period and follow-up, the characteristics of the target
population, such as age, sex, comorbidities, intervention features (including dose, type and
duration of exposure), adverse events and depression, before and after the intervention.
2.5 Quality assessment
The quality assessments were performed using the Cochrane Collaboration’stool
(Higgins et al., 2011) by two authors (P.K. and N.H.), independently. Cochrane
Collaboration’s tool includes various different domains: sequence generation, allocation
concealment, blinding of participants and staff, blinding of the outcome assessment,
missing outcome measures, selective outcome reporting and other biases. For each item
in the tool, the assessment of the risk of bias is in two parts. Each domain was categorized
withalow,highandunclearriskofbias.BasedonCochraneCollaboration’s tool, the
quality of each publication was considered as good (low risk of bias for >2 domains), fair
(low risk of bias for two domains) or weak (low risk of bias for <2domains).
2.6 Data synthesis and statistical analysis
The mean 6standard deviation (SD) of change in BP was used to calculate the effect size
within intervention and control groups, using a random-effects model (DerSimonian and
Laird, 1986). Depression was expressed as the weighted mean difference (WMD) and 95%
confidence intervals (CIs). The I-square and Q tests were used to assess the heterogeneity
among studies (Higgins et al., 2003). Subgroup analysis, based on folate dosage, duration
and type of intervention and baseline depression, was conducted to detect potential sources
of heterogeneity (Higgins and Thompson, 2002). The standard formula was applied to
convert all other statistics to mean 6SD, while Hozo et al.’s system was applied to convert
Folic acid
supplementa
tion
median and 95% CIs to mean and SD (Hozo et al., 2005). The following formula was used to
convert standard errors of the mean (SEM): SDs by SEM Hn(nis the number of
participants in each group). Additionally, when mean changes were not reported, we
calculated them by using this formula: mean change = final values baseline values, and
SD changes were calculated by following formula (Borenstein et al.,2011):
SD change ¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
½ðSD baselineÞ^2 þðSD final ^2 ð2R SD baseline SD
p
All units were converted to the most frequently used unit. Also, we enforced the meta-
regression to differentiate the confounders and linear relations among the effect
size and sample size, duration of intervention and intervention dosage (Mitchell,
2012). We accomplished sensitivity analysis to find the effect of each particular study
on the overall estimation (Tobias, 1999). The possibility of publication bias was
checked through Egger’s regression test and the visually inspected funnel plot test
(Egger et al.,1997). All analyses were performed using the STATA version 12 (Stata
Corporation, College Station, TX, USA), with statistical significance accepted,
apriori,atp<0.05.
Figure 1.
Flowchart of study
selection
dentification
Screening
Eligibility
Included
Records identified after databases search (n= 4642)
PubMed (162), Scopus (2896), Web of science
(1273), and the Cochrane library (311)
Studies screened (n = 3792 )
Studies excluded after duplicates
removal (n = 850 )
3783 articles were excluded after
evaluating the title and abstract: no
relevant to the subject
Full text article for eligibility (n = 9 )
Studies included in quantitative synthesis
(meta-analysis): (n=6)
Records excluded
Insufficient data (n= 3)
u
ll
t
e
x
NFS
3. Results
3.1 Study selection
The study selection process is reported in Figure 1. After searching the listed databases
(PubMed (162), Scopus (2896), Web of Science (1273) and the Cochrane library (311)), 4,642 were
found. Of these, 850 duplicates were excluded, and 3,792 articles remained for screening based
on title and abstract. After that, nine eligible articles were selected for full-text
assessment. Finally, three trials were excluded due to insufficient data, and six trials
(Zou et al. 2019;Coppen and Bailey, 2000;Loria-Kohen et al., 2013;Resler et al.,2008;
Sepehrmanesh et al., 2016;Venkatasubramanian et al., 2013) were included in this meta-
analysis (Figure 1).
3.2 Study characteristics
Table 1 presents the characteristics of included articles, all of which were RCTs, published
between 2000 and 2019, that were conducted in Iran (Sepehrmanesh et al., 2016), Spain
(Loria-Kohen et al.,2013), Venezuela (Resler et al.,2008), the UK (Coppen and Bailey, 2000),
India (Venkatasubramanian et al.,2013) and China (Zou et al., 2019). The length of the
intervention varied from 6 to 24weeks, and the dosages of folic acid supplementation were
between 0.5 and 10 mg. A cohort of 152 participants was collated in the intervention group
and 156 participants in the control group. The participants of these studies were classified
as having major depression (Zou et al.,2019;Coppen and Bailey, 2000;Resler et al.,2008;
Sepehrmanesh et al.,2016;Venkatasubramanian et al.,2013) or with an eating disorder
(Loria-Kohen et al., 2013). All of the studies enrolled both sexes (Zou et al., 2019;Coppen
and Bailey, 2000;Loria-Kohen et al., 2013;Resler et al., 2008;Sepehrmanesh et al., 2016),
and only one was exclusively conducted on women (Venkatasubramanian et al.,2013).
Three studies used folic acid and fluoxetine (Coppen and Bailey, 2000;Resler et al.,
2008;Venkatasubramanian et al., 2013), one study used folic acid and sertraline (Zou
et al., 2019), one study used folic acid and citalopram (Sepehrmanesh et al., 2016)and
one of them just used folic acid (Loria-Kohen et al., 2013).
3.3 The effect of folic acid supplementation on HAM
The results of the pooled data from five effect sizes (Zou et al., 2019;Coppen and Bailey,
2000;Resler et al., 2008;Sepehrmanesh et al., 2016;Venkatasubramanian et al.,2013)
indicated that folic acid supplementation reduced HAM (WMD: 3.5 mg/dL; 95% CI: 4.6
to 2.4, p<0.001) compared with control group, with moderate heterogeneity (I
2
= 71.8%,
p= 0.007) (Figure 2(a)). Moreover, subgroup analysis showed that the folic acid
supplementation reduced HAM in all subgroups (Table 2).
3.4 The effect of folic acid supplementation on Beck Depression Inventory
The results of the pooled data from three effect sizes (Loria-Kohen et al.,2013;Sepehrmanesh
et al.,2016;Venkatasubramanian et al., 2013) indicated that folic acid supplementation
reduced BDI (WMD: 3.9; 95% CI: 5.3 to 2.4, p<0.001) compared with control group,
without heterogeneity (I
2
= 0.0%, p= 1.000) (Figure 2(b)).
3.4.1 Publication bias sensitivity analysis. Publication bias assessment based on Egger’s
regression test indicated no evidence of bias for BDI and HAM. Also, the funnel plots test
illustrated concordant results (Figure 3(a) and 3(b)). Moreover, sensitivity analysis showed
that none of the studies significantly affected the overall outcome.
3.4.2 Linear and non-linear dose response. There is no evidence of a significant linear
relationship between dose and duration of folic acid supplementation and changes in HAM
(Figure 4(a) and 4(b)). Also, based on a non-linear dose response, no evidence of a
Folic acid
supplementa
tion
Reference Study design
Participant’s characteristic Sample size Trial
duration
(week)
Intervention
Disorder
Means
BMI
Means age
IG CG
Acid folic
dose (mg/d) Control groupIG CG
Sepehrmanesh et al.,
2016
Parallel, R,
PC, DB
MDD nr 35.11 68.62 36.35 610.49 45
(m:19)
45
(m:15)
8 2.5 mg folic
acid þ20 mg
citalopram
placebo þ20 mg
citalopram
Loria-Kohen et al.,
2013
Parallel, R,
PC, DB
Eating
disorders
18.9 63.5 22.3 67.6 26.7 610 12 10 24 5 mg folic acid placebo
Resler et al., 2008 Parallel, R,
PC, B
Major
depression
nr 34.13 62.05 34.13 62.05 14 13 6 10 mg folic
acid þ20 mg
fluoxetine
fluoxetine þplacebo
Coppen et al., 2000 Parallel, R,
PC, DB
Major
depression
nr 41.9 612 44.3 614.6 51
(m:18)
58
(m:22)
10 0.5mg folic
acid þ20 mg
fluoxetine
fluoxetine þplacebo
Venkatasubramanian
et al., 2013
Parallel, R, C,
DB
Depression nr 31.7 67.2 34.6 65.7 15
(m:0)
15
(m:0)
6 1.5 mg folic
acid þ20 mg
fluoxetine
20 mg
fluoxetine þ5mg
folic acid
Zou et al., 2019 Parallel, R, C,
B
Depression nr 31.4 64.9 30.5 64.6 15 15 8 2 mg folic acid þ
sertraline
sertraline
Notes: Abbreviations: IG, intervention group; CG, control group; DB, double-blinded; SB, single-blinded; PC, placebo-controlled; CO, controlled; RA, randomized;
NR, not reported; m, Male; NR, not reported. Values are mean 6SD
Table 1.
Characteristic of
included studies in
meta-analysis
NFS
Figure 2.
Forest plots
presenting mean
difference (MD) and
95% confidence
intervals for the
impact of folic acid
supplementation on
(a) HAM and (b) BDI
Overall, DL (I
2
= 71.8%, p = 0.007)
Zou et al. 2019
Venkatasubramanian et al.2013
Coppen et al. 2000
Resler et al. 2008
Sepehrmanesh et al. 2016
author
–3.58 (– 4.69, –2.47)
–5.24 (–7.53, –2.95)
–3.34 (–4.20, –2.48)
–2.30 (–3.83, –0.77)
–4.65 (–5.35, –3.95)
–1.67 (–4.37, 1.03)
Effect (95% CI)
100.00
13.61
26.91
19.91
28.49
11.08
Weight
%
–10 0 10
Note: Weights are from random-effects model
Overall, IV (I
2
= 0.0%, p = 0.789)
Venkatasubramanian et al.2013
Loria- Kohen et al. 2013
Sepeh rmanesh et al. 2016
author
–
3.92 (
–
5.39,
–
2.44)
–
3.54 (
–
5.42,
–
1.66)
–
3.80 (
–
9.57, 1.97)
–
4.67 (
–
7.29,
–
2.05)
Effect (95% CI)
100.00
61.74
6.52
31.74
Weight
%
–
10 010
(a)
(b)
Table 2.
Cochrane risk of bias
assessment
Studies
Random
sequence
generation
Allocation
concealment
Selective
reporting
Other
sources
of bias
Blinding
(participants
and personnel)
Blinding
(outcome
assessment)
Incomplete
outcome
data
Sepehrmanesh et al., 2016 LULLL UL
Loria-Kohen et al., 2013 UUHLL UL
Resler et al., 2008 LUHLU UL
Coppen et al., 2000 L U H L L U L
Venkatasubramanian
et al., 2013
LULLL UL
Zou et al.. 2019 L U H L L U L
Notes: L: low risk of bias; U: unclear risk of bias and H: high risk of bias
Folic acid
supplementa
tion
relationship between dose and duration of folic acid supplementation and changes in HAM
was found (Figure 5(a) and 5(b))(Table 3).
4. Discussion
The current meta-analysis, involving six RCTs with a total of 308 participants, revealed that
folic acid supplementation (0.5–10 mg/d) elicited positive changes in depression test scores,
Figure 3.
The funnel plot test
illustrating visual
publication bias in
related between folic
acid and (a) HAM and
(b) BDI
0
0.5
1
1.5
Standard error of effect size
–6–4–2 0
Effect size
Funnel plot with pseudo 95% confidence limits
0
12
3
Standard error of effect size
–10 –5 0 5
Effect size
Funnel plot with pseudo 95% confidence limits
(a)
(b)
NFS
over a period of 6–24weeks, in people with a depressive disorder. Of note, folate has been
shown to have an inverse correlation with the duration of depressive episodes and length of
hospital stays, suggesting that folate contributes to treatment outcomes (Alpert et al.,2002).
Although, Schefft and colleagues’meta-analysis (Schefft et al., 2017) reported that the
overall effect of folic acid supplementation vs antidepressant medications was not
significant. Another meta-analysis conducted by Almeida et al. (2015) found that folate and/
or vitamin B12 treatment did not reduce the severity of depressive symptoms in individuals
with or without a depressive disorder for several weeks.
Figure 4.
Linear meta
regression between
changing in HAM
and (a) dose
of intervention and
(b) duration of
intervention for HAM
0 2 4 6 810
Dose (mg/d)
–5 –4 –3 –2 –1
Effect size
510 15 20 25
Duration (week)
–5 –4 –3 –2 –1
Effect size
(a)
(b)
Folic acid
supplementa
tion
However, recently, Zheng et al. (2020) conducted a systematic review based on 16 RCTs
involving 1,520 patients with major mental illnesses (schizophrenia, bipolar disorder and
MDD), and found that folate supplementation improved depressive symptoms in patients
with MDD and bipolar disorder, but not in those with schizophrenia.
Indeed, previous research has suggested that low folate levels play a major role in the
developing and progression of depression. For example, a meta-analysis by Gilbody et al. (2007)
based on case-control and cross-sectional studies, involving 15,315 participants, showed a
significant association between low folate status and depression. Bender et al. (2017) have also
Figure 5.
Non-linear dose
response between
changing in HAM
and (a) dose of
intervention and
(b) duration of
intervention for HAM
–
60
–
40
–
20 0 20
0 2 4 6 810
Dose (mg/d)
95% CI predicted HAM_change_int
HAM_change_int
–
60
–
40
–
20 020
5 10 15 20 25
Duration (week)
95% CI predicted HAM_change_int
HAM_change_int
(b)
(a)
NFS
conducted a meta-analysis, based on 43 studies, and found that dietary intake of folate and
serum folate levels are significantly different among patients with depression (vs non-
depressant), suggesting that depressed people had considerably lower levels of serum folate than
those who were not depressed.
Moreover, according to previous research, a decreased folate intake or status can lead to
higher levelsof homocysteine in the blood, which contributes to vascular disease of the brain,
and transmitter alterations, consequently leading to depression (Miyaki et al.,2012).
Elevated homocysteine levels in the blood are related to numerous psychiatric and
neurological diseases, such as depression, schizophrenia, Alzheimer’s and Parkinson’s
(Bottiglieri, 2005). Also, Wang et al. (2017), in a meta-analysis study, demonstrated that folic
acid supplementation could prevent hyperhomocysteinemia.
Homocysteine concentrations increased by low folate status or intake are related to lower
levels of methionine, and, therefore, lower SAM levels. SAM is considered necessary to regulate
mood because it has been demonstrated to increase cerebrospinal fluid levels of 5-
hydroxyindoleacetic acid, the main serotonin metabolite, in people with depression (Williams
et al.,2007). Furthermore, folic acid increases the level of omega-3 polyunsaturated fatty acids
(PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which may
help prevent dementia and Alzheimer’s disease (Das, 2008).
Coppen and Bailey (2000) found that folic acid supplementation significantly improves
antidepressant response, albeit only in women. The authors contend that the improvement
was associated with plasma homocysteine and not plasma folate. They also posit that the
lack of response among men was likely caused by the slight plasma folate increase, which
was insufficient to affect plasma homocysteine levels, suggesting that men might need a
higher dose of folic acid to achieve a better response rate.
Further, Venkatasubramanian et al. (2013) reported that female patients with depression
who take 5 mg/d of folic acid with fluoxetine have a greater response than those taking
1.5 mg/d. However, our meta-analysis showed no significant linear or non-linear relationship
between dose and duration of folic acid supplementation and changes in depressive
symptoms.
The present study has several limitations that should be addressed. First, the sample
sizes and follow-up periods of several included studies were small, which may decrease the
statistical power. Second, included studies did not report dietary folate intake or fortified
Table 3.
Subgroup analyses of
folic acid
supplementation on
depression in adults
NO WMD (95%CI) p-value
heterogeneity
P heterogeneity I
2
(%)
Subgroup analyses of folic acid supplementation on HAM
Overall effect 5 3.5 (4.6, 2.4) <0.001 0.007 71.8
Duration (week)
<824.0 (5.3, 2.7) <0.001 0.02 81.4
833.0 (5.0, 1.0) 0.003 0.06 63.0
Dose (mg/d)
<223.0 (3.9, 2.0) <0.001 0.24 25.4
234.1 (5.7, 2.5) <0.001 0.09 58.3
Subgroup analyses of folic acid supplementation on BDI
Overall effect 3 3.9 (5.3, 2.4) <0.001 1.000 0.0%
Notes: Abbreviations: CI: confidence interval, WMD: weighted mean differences, HAM: Hamilton
depression inventory and BDI: Beck depression inventory
Folic acid
supplementa
tion
foods with folic acid;as a result, some individuals may be consuming significantly less/more
folate. Clearly, these are issues that should beaddressed in further research.
5. Conclusion
Folic acid supplementation appears to have an effect on lowering depression in patients.
However, the evidence from clinical trials thus far is insufficient for clinical guidelines and
practice.
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Corresponding author
Neda Haghighat can be contacted at: neda.hag@gmail.com
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