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Iran Red Crescent Med J. 2017 February; 19(2):e33243. doi: 10.5812/ircmj.33243.

Published online 2016 August 4. Research Article

Acid Folic Supplementation in Major Depressive Disorder Treatment:

A Double-Blind Randomized Clinical Trial
Zahra Sepehrmanesh,1 Abdollah Omidi,2 and Narges Gholampoor1,*
1
Department of Psychiatry, Kashan University of Medical Sciences, Kashan, IR Iran
2
Department of Psychology, Kashan University of Medical Sciences, Kashan, IR Iran
*
Corresponding author: Narges Gholampoor, Department of Psychiatry, Kargarnezhad Hospital, Kashan University of Medical Sciences, Kashan, IR Iran. Tel: +98-3155540021,
Fax: +98-3155540111, E-mail: [email protected]

Received 2015 September 25; Revised 2016 June 19; Accepted 2016 July 17.

Abstract

Background: Augmentation therapy involves the addition of a second drug, such as mood stabilizers, antipsychotics, and nutri-
tional supplements, to a primary antidepressant treatment. Studies on adding folic acid to a preexisting antidepressive regimen as
a form of augmentation therapy have had different and even controversial results.
Objectives: This study aimed to determine the effects that adding folic acid to a pharmaceutical diet with citalopram has on the
treatment of depression.
Methods: This double-blind randomized clinical trial was conducted in Kashan, Iran on 90 patients who suffered from depression.
Patients were allocated to study groups using random permuted blocks. One group (n = 45) received a dosage of 20 mg citalopram
in combination with 2.5 mg folic acid on a daily basis, and the other group (n = 45) received the same daily dose of citalopram with a
placebo for eight weeks. To measure the severity of each patient’s depression, the Beck depression inventory II (BDI-II) questionnaire
was used prior to starting the antidepressant therapy and was repeated four, six, and eight weeks after beginning the treatment. A
reduction from the original BDI-II scores that was greater than 50% was considered to be a response to treatment.
Results: The average depression scores before treatment were 30.11 ± 10.41 in the intervention group and 31.24 ± 10.26 in the control
group (P = 0.6). At the end of the study, the depression scores in the intervention and the control groups were 13.31 ± 6.57 and 19.11
± 8.59, respectively (P < 0.001). A reduction in the average depression scores of the intervention group was statistically significant
after six and eight weeks (P = 0.01 and P = 0.001, respectively). At the end of the study, the frequency of response to treatment was
73.3% in the intervention group and 40.0% in the control group (P < 0.001).
Conclusions: Folic acid, when used as a complementary therapy, can improve a patient’s response to antidepressants used for the
treatment of major depression.

Keywords: Major Depressive Disorder, Citalopram, Folic Acid, Augmentation Therapy

1. Background are not always successful because of unpleasant side ef-

fects. Therefore, developing safer and more effective meth-
Major depressive disorder (MDD) is a chronic mental ods for the treatment of refractory depression would be ad-
disorder with an estimated lifetime prevalence of 13% - 17% vantageous (8).
in the United States (1, 2). Depression is the leading cause of
Previous studies have investigated the role of nutri-
disability in developed countries and has been predicted
tional factors in treating neuropsychiatric disorders (9-11).
to become the most significant cause of disability world-
These studies have shown that a considerable portion of
wide by 2020 (3). MDD causes a huge economic burden
patients with psychiatric disorders, including MDD, have
for health systems, with the imposed burden in European
been reported as having low levels of different vitamins,
countries reaching €118 billion, most of which is related to
especially folate (12, 13). Augmentation therapy using fo-
indirect costs, such as absence from work (4, 5).
late, vitamin B12, omega-3 fatty acids, and zinc supplemen-
Although new therapeutic options have emerged in re-
tation are new methods that have been suggested to im-
cent years, there are still many patients who do not re-
prove depression and a patient’s response to a therapeutic
spond to first-line antidepressants (6, 7). Several strate-
regimen with fewer side effects (14-16).
gies have been proposed for patients with refractory de-
pression, including increasing the dosage of the antide- Few studies have examined the effects of folic acid sup-
pressant, switching the patient to new-generation medi- plementation as an augmentation of the treatment of ma-
cations, and adding another antidepressant medication to jor depression, and the results achieved by the few stud-
the patient’s current treatment. However, these methods ies that exist are not univocal. Additionally, the concurrent

Copyright © 2016, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial
4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the
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Sepehrmanesh Z et al.

use of citalopram with folic acid in treating MDD has not survey. The total number of recruited cases was 100. How-
yet been evaluated. ever, five cases were omitted because of antidepressant us-
age within the last four weeks, three cases had psychosis,
and two cases were put aside because of a history of manic
2. Objectives episodes. Thus, the final sample size of the study was 90
cases (Figure 1).
Considering the existing controversies, in this study,
The demographic and clinical data of the patients,
we evaluated the effects of the concurrent administration
such as age, sex, education level, marital status, history of
of citalopram and folate in the treatment of MDD.
depression, treatment with SSRIs, and history of anxiety
disorders, were recorded in a predesigned checklist.
3. Methods The patients were divided into two equal groups, an in-
tervention group and a control group, using the permuted
3.1. Study Participants block randomization method. For this purpose, 15 blocks
with a block size of six were used, and the blocks were clas-
This double-blind randomized clinical trial was con-
sified by order of numbers. Both patients and researchers
ducted on 90 patients who were referred to the psychiatric
were blind to the treatment allocation. The only person
clinic of Kashan University of Medical Sciences in Iran. The
who knew the allocation was the nurse who was in charge
study site was a psychiatric clinic affiliated with the gov-
of delivering the medications.
ernment that is the main referral center in the area. This
All ethical principles were respected in accordance
clinic provides outpatient psychiatric and psychological
with Resolution 196/96 on research involving human sub-
services to children and adults.
jects. The ethics committee of Kashan University of Med-
The calculation to determine the required sample size
ical Sciences approved the study and supervised all its
for this study was based on the results of a study performed
stages (approval code: p/29/5/1/458). This study was also
by Venkatasubramanian et al. who evaluated the effects of
recorded in the Iran Center of Clinical Trials Registration
the coadministration of fluoxetine and a different dosage
database (IRCT2014082518922N1). After being informed of
of folic acid (17). In their study, the frequency of response
the study objectives, all participants signed a written con-
to treatment was reported to be 52.6% in patients who re-
sent form.
ceived high doses of folic acid and 21.7% in those receiving
low-dose folic acid. With a power of 80% and Z1-α/2 = 1.96
and with the use of the following equation, we concluded 3.2. Clinical Assessments
that the required sample size of each group in our study
All study participants were visited by a psychiatrist at
was 39. To allow for a 10% loss of participants, the sample
the beginning of the study and at two-week intervals. In ev-
size was adjusted to 45 in each study group (Equation 1).
ery visit, patients were checked for exclusion criteria, treat-
z1 − α
+ z1−β

2
pq ment adherence, and possible side effects.
2
n= (1) To measure the severity of each patient’s depression
(p1 − p2 )2
and anxiety, all participants were asked to complete the
Participants were recruited via convenience sampling second version of the Beck Depression Inventory question-
from those referred to our outpatient psychiatric clinic naire (BDI-II) and the Hamilton anxiety rating scale ques-
who were depressed according to the Diagnostic and Sta- tionnaire (HAM-A) prior to group allocation. The BDI-II was
tistical Manual of Mental Disorders IV Text Revision. For completed again four, six and eight weeks after the onset
this purpose, all patients who met the inclusion and ex- of the study. The HAM-A was also completed by all patients
clusion criteria were enrolled until completion of the re- at the end of the treatment (the eighth week). Lower BDI-
quired sample size (n = 90). All patients were residents of II scores were considered to be the result of the study. Pa-
Kashan city. tients were divided according to their BDI-II scores into
The inclusion criteria were an age of 20 - 50 years and mild (14 - 19), moderate (20 - 28), and severe (29 - 63) de-
a Beck depression inventory score greater than 12. The pression categories. A decrease more of than 50% in a pa-
exclusion criteria were the use of antidepressants within tient’s primary BDI-II score was reported as a response to
the last four weeks, signs of psychosis, mental retarda- treatment.
tion, a history of manic episodes, a history of taking psy- A developed checklist was used for collecting data. The
chotropic drugs, and certain medical problems (anemia, checklist consisted of two parts. The first part gathered
pregnancy, chronic diseases, etc.). Patients experiencing the subjects’ demographic data, such as age, sex, height,
severe drug reactions at any stage were excluded from the weight, marital status, education level, and history of MDD

2 Iran Red Crescent Med J. 2017; 19(2):e33243.

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Sepehrmanesh Z et al.

Enrollment
Assessed for Eligibility (n = 100)

Excluded (n = 10)
• Meeting Exclusion Criteria (n = 10)
Anti Depressant Usage History (n = 5)
Psychosis Signs (n = 3)
Manic History (n = 2)

Randomized (n = 90)

Allocation
Allocated to Citalopram and Folic Acid Treatment Allocated to Citalopram and Folic Acid Treatment
(n = 45) (n = 45)

Analysis
Analysed (n = 45) Analysed (n = 45)

Figure 1. Study Flow Chart

and anxiety disorders. The second part contained clini- 3.4. Statistical Analysis
cal information, including BDI-II scores (which were ob-
The data were analyzed using SPSS software version 16
tained prior to the onset of the study and four, six, and
for Windows. The descriptive part of the analysis was re-
eight weeks into the treatment) and HAM-A (which were
ported as absolute and relative frequency. The results of
obtained before and after the treatment). The content va-
the quantitative data analysis were expressed as mean ±
lidity of the checklist was approved by four psychiatry and
standard deviation. The Kolmogorov-Smirnov test was ap-
psychology experts. The checklist’s reliability was deter-
plied to assess the data distribution. A chi-squared test, an
mined using the interobserver method: In an initial pilot
independent t-test, a paired t-test, and a repeated measures
study, the questionnaire was completed for five patients in
ANOVA were used for data analysis. Before analyzing the
each group by three researchers not involved in creating
data using the repeated measures ANOVA, assumptions,
the checklist. Then, the degree and significance of agree-
including the type of data, randomness, normality, and
ment between observers was calculated (r = 0.87).
sphericity, were checked. Since Mauchly’s Test of Sphericity
indicated that the assumption of sphericity had been vio-
lated (P < 0.001), the Huynh-Feldt correction was applied.
3.3. Medications
All tests were two-tailed. The level of significance for all
tests was considered to be P < 0.05.
All patients received 20 mg citalopram tablets (Sobhan
Pharmaceutical Company, Iran) per day for eight weeks.
The patients in the intervention group also received 2.5 mg 4. Results
folic acid (Sobhan Pharmaceutical Company, Iran) per day,
and patients in the control group were given an identical- In this study, 90 patients in two groups were surveyed,
looking placebo in addition to the citalopram. The drugs and all patients completed the treatment course. Of the 90
were given once every two weeks at the time of the psychia- patients, 56 (62.2%) patients were female. The average age
trist’s visit. Patient adherence to treatment and side effects of the patients was 35.73 ± 9.57 years; the minimum age
were looked for at each appointment. was 20 years old and the maximum was 50 years old.

Iran Red Crescent Med J. 2017; 19(2):e33243. 3

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Sepehrmanesh Z et al.

The demographic and clinical characteristics of the pa- Table 1. Patient Demographics and Clinical Characteristicsa
tients are shown according to treatment group in Table 1.
The baseline clinical characteristics of the patients are also Variable Group P Value
shown in Table 1. The average depression scores of the pa- Acid Folic Placebo
tients before treatment was 30.11 ± 10.41 in the interven-
Age 35.11 ± 8.62 36.35 ± 10.49 0.54
tion group and 31.24 ± 10.26 in the placebo group (P = 0.6).
The mean HAM-A anxiety score before treatment was 34.24 Sex 0.38

± 9.09 in the intervention group and 35.82 ± 9.57 in the Male 19 (42.2) 15 (33.3)

placebo group. This difference between the scores of the Female 26 (57.8) 30 (66.7)
two groups before intervention was not statistically signif-
Marital status 0.9
icant (P = 0.42). The treatment outcomes are shown in Ta-
Single 12 (26.7) 10 (22.2)
ble 2. The repeated measures ANOVA showed that the re-
duction in depression scores were different between the Married 27 (60) 29 (64.4)

groups (P < 0.001) (Figure 2). Divorced 3 (6.7) 2 (4.4)

Widow 3 (6.7) 4 (8.9)

Education 0.69
35.00 Group
Case Primary school 12 (26.7) 11 (24.4)
Control
Middle School 15 (33.3) 13 (28.9)
30.00
High school diploma 12 (26.7) 17 (37.8)
Mean Depression Score

Academic degree 6 (13.3) 4 (8.9)

25.00
MDD history 0.16

No 29 (64.4) 35 (77.8)
20.00 Yes 16 (35.6) 10 (22.2)

Anxiety disorders 0.38

15.00 No 27 (60) 31 (68.9)

Yes 18 (40) 14 (31.1)

10.00 Depression severity 0.96

Before 4
th
6
th
8
th Mild 9 (20.0) 8 (17.8)
Intervention Week Week Week
Moderate 10 (22.2) 10 (22.2)

Figure 2. Repeated Measures Analysis of Depression Scores Severe 26 (57.8) 27 (60.0)

BDI-II score 30.11 ± 10.41 31.24 ± 10.26 0.6

Hamilton score 34.24 ± 9.01 35.82 ± 9.57 0.42

a
5. Discussion Values are expressed as mean ± standard deviation or No. (%).

The present study was designed to investigate the ef-

fects of the coadministration of folic acid and citalopram late is an effective adjunctive therapy in the treatment of
in patients with MDD. Prescribing 2.5 mg of folic acid as a patients with MDD that is resistant to SSRIs (23).
supplement increased the antidepressant action of citalo- Other studies have reported opposite findings. Chris-
pram. tensen et al. disagree with the idea of the potentiation of
Previous studies have investigated the potential effect antidepressants with folate + B12 supplementation (24).
of folate augmentation of antidepressants. Passeri et al. One review study addressed the effects of supplements
compared folate with trazodone added to standard med- on the improvement of the therapeutic effects of antide-
ication for the treatment of depression in patients with pressant drugs. This study did not find sufficient evidence
dementia (18). Another survey confirmed that folic acid to support the positive effects of folic acid (25). These con-
greatly improved the effect of fluoxetine in the treatment tradictions may be caused by the differences in prescribed
of major depression (19). Similar results that are consistent folic acid doses, the treatment duration, and the methods
with our findings have been reported in other studies as used to measure the patients’ clinical response.
well (20-22). Papakostas et al. confirmed that L-methyl fo- Our study indicated that the response to treatment was

4 Iran Red Crescent Med J. 2017; 19(2):e33243.

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Sepehrmanesh Z et al.

Table 2. Treatment Outcomesa folate but that higher doses were reported to be more ef-
fective in women than in men (17).
Variables Groups P Value Currently, there is no valid reason for explaining these
Folic Acid Placebo
differences, but psychosocial factors, genetics, individual
differences in drug metabolism and pharmacokinetics,
BDI-II score
and food and drug habits may play a role.
4th week 24.44 ± 9.19 27.38 ± 9.57 0.14
We found that there were statistically significant dif-
6th week 18.24 ± 7.97 23.0 ± 9.08 0.01 ferences between the two groups in the responses of pa-
8th week 13.31 ± 6.57 19.11 ± 8.59 0.001 tients of both genders who were less than 35 years old to
Response frequency
the treatment, but of the patients who were older than 35
years old, a similar response was observed only in male pa-
4th week 0 0 -
tients. This aspect of study has not previously received at-
6th week 10 (22.2) 5 (11.1) 0.16
tention (31). Since folic acid deficiency is more common
8th week 33 (73.3) 18 (40.0) 0.001 in the older population, elderly people would rationally
Depression scores reduction benefit more from receiving folic acid than younger peo-
4th week 5.67 ± 3.62 3.87 ± 4.07 0.03
ple. Alternatively, age-related reductions in intestinal folic
acid absorption might be the reason for these results (32).
6th week 11.87 ± 4.88 8.24 ± 5.87 0.002
However, since our study subjects were not selected from
8th week 16.8 ± 5.77 12.13 ± 6.55 0.001 an older population, this possibility seems less likely.
Final depression severity 0.04 According to current studies, the effects of the coad-
Mild 13 (61.9) 10 (30.3) ministration of folate on improving the treatment of de-
Moderate 7 (33.3) 15 (45.5)
pression are noticeable and well proved. Folic acid is es-
sential for various functions of the human body, includ-
Severe 1 (4.8) 8 (24.2)
ing processes related to the nervous system. Studies con-
21.93 ± 9.41 27.18 ± 11.16 0.02
Final Hamilton score
ducted over the last few decades have shown that patients
a
Values are expressed as mean ± standard deviation or No. (%). with folic acid deficiency revealed psychological symp-
toms, such as depression and cognitive impairment (33,
34).
significantly higher in both men and women in the folic Folate level is thought to be associated with vari-
acid and citalopram group compared with the placebo ous mood disorders. Previous studies have shown lower
group. To our knowledge, only one study has mentioned plasma and red blood cell folate in patients with depres-
the effect of gender on the response to the augmentation sion. Lower levels of folic acid have also been related to
of treatment with folic acid. Coppen et al. reported that longer and more severe depressive phases in bipolar pa-
men need relatively higher doses of folic acid to achieve tients (15, 35). In a group of studies that evaluated folic
the positive effects (19). The role of gender was noticed by acid levels in depressed patients, individuals with depres-
other studies that surveyed the relationship between folic sion had the lowest serum levels of all patients studied,
acid and depression. Sanchez-Villegas et al. pointed out and only individuals with alcohol dependence had similar
that an inverse association exists between the amount of folic acid levels (36). Folic acid levels are thought to fluctu-
folic acid intake and the prevalence of depression among ate depending on the type of mood disorder. For example,
men, especially smokers, but no similar relationship was the percentage of individuals with low folic acid levels was
found among women (26). In another study, Astorg et al. higher among patients with melancholic depression com-
observed a strong correlation between high levels of folic pared to those with nonmelancholic depression (37).
acid and reduced incidence of depressive episodes among There have been very few studies conducted on the lev-
men, but this association was not seen in women (27). Sim- els of folate and depression in the general population. Tol-
ilar results have been reported by Murakami et al. (28). On munen et al. examined 2682 Finnish men between 42 and
the other hand, two other studies stated that the relation- 60 years old. The participants were divided into three cat-
ship between folic acid intake and occurrence of depres- egories depending on dietary folate intake (38). After con-
sive symptoms was observed only in women (29, 30). trolling for confounding variables, such as smoking, alco-
Another study evaluating the effects of two differ- hol consumption, body mass index, and socioeconomic
ent doses of folic acid on the efficiency of fluoxetine for status, people who had low levels of folate in their diet were
the treatment of depression showed that both men and found to be more likely to be affected by depression 67%
women would benefit from treatment augmentation with higher compared to those who had higher levels of folate

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Sepehrmanesh Z et al.

intake (38). cate that oxidative stress and reduced antioxidant func-
Another study conducted by Morris et al. in the United tion play a role in depression (45). Previous studies have
States involved 3010 individuals selected from the general well demonstrated that folic acid increases the total an-
population who were between 15 and 39 years old. Follow- tioxidant capacity in the body. Thus, it can be hypothesized
ing an adjustment for confounding factors, people with de- that folic acid acts via modifying and reducing oxidative
pression were determined to have significantly lower lev- stress to enhance the treatment of patients with MDD (46,
els of serum folate. Additionally, people with dysthymia 47).
showed lower levels of folate serum than the normal pop- To best of our knowledge, ours is the first study to ad-
ulation (39). The consistent results of these two studies, dress the effects of adding folic acid to citalopram for the
which targeted two different age ranges, demonstrates a treatment of depression. One advantage of our study is
causal relationship between folic acid and depression. that it investigated depression and anxiety disorders si-
Whether poor nutrition is a symptom of depression multaneously.
causes folate deficiency or primary folate deficiency pro- Not measuring the folic acid levels in serum and in red
duces depression, folate prescription would be beneficial blood cells is one of the limitations of this study. Other lim-
and folic acid supplementation would improve the treat- itations include not measuring the levels of oxidants and
ment process of depression even in patients without folic the total antioxidant capacity before and after the folate
acid deficiency (34, 37, 39, 40). prescription, which made it impossible to evaluate the ef-
Although the pre- and posttreatment serum levels of fect of folate on oxidant and antioxidant status, and lack of
folic acid were not measured in our study, favorable clin- a long-term follow-up period to determine the relapse rate
ical responses were observed after the coadministration in the study groups.
of folic acid with the standard treatment of depression. Further studies are needed to enable more confident
Based on previous surveys, high doses of folic acid (15 conclusions about the mechanism via measuring the exact
mg) might cause side effects, including sleep disturbances, levels of folic acid. Additionally, more work is required to
fatigue, restlessness, and hyperactivity, in healthy volun- compare different antidepressant regimens with or with-
teers. Large doses of folate have been reported to be asso- out folic acid and also to ascertain the optimum therapeu-
ciated with low levels of serotonin in the brain within ani- tic dose of folate.
mal models. Therefore, ascertaining the effective and safe
therapeutic doses of folic acid and its interactions with a Acknowledgments
variety of antidepressant treatment regimens is crucial.
Hypotheses have been proposed to explain the role of The authors are grateful for the participation of the pa-
folate deficiency in pathogenesis of mood disorders, es- tients in this study and for the personnel of the psychiatric
pecially MDD, but the exact mechanism of this vitamin ward of Kashan’s Kargarnezhad Hospital.
in the development and treatment of depression is not
yet fully understood. Folate assists in the formation of Footnotes
the cofactor for tyrosine hydroxylase and tryptophan hy-
droxylase, which are important enzymes in the synthe- Funding/Support: Funding support for this study was
sis of monoamines that are related to depression, includ- provided by the Kashan University of Medical Sciences,
ing dopamine, serotonin, and epinephrine (41). Another grant number 92003.
possible pathway that explains the role of folate in patho- Authors’ Contribution: Development of the original
genesis of MDD involves homocysteine metabolism. Ho- idea: Zahra Sepehrmanesh; study concept and design:
mocysteine is a nonprotein amino acid that is produced Zahra Sepehrmanesh and Narges Gholampoor; data collec-
as a result of a one-carbon metabolism pathway. Several tion: Narges Gholampoor; preparation of the manuscript:
enzymes are involved in the catabolism of homocysteine, Zahra Sepehrmanesh and Narges Gholampoor; revision
such as methylenetetrahydrofolate reductase. This en- of the manuscript: Zahra Sepehrmanesh and Abdollah
zyme requires sufficient amounts of folic acid in order to Omidi.
function properly (42). Folic acid deficiency results in ele-
vated homocysteine levels, the presence of which has been
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