The Effect of Folic Acid as An Adjuvant Therapy for Chronic Schizophrenia: A Study on

Glutathione Reductase
Innawati Jusuf , Hery Murtantyo Hutomo1*, Sri Woroasih 2, Alifiati Fitrikasari1
1

1
Psychiatry Department, Faculty of Medicine, Diponegoro University
Dekanat Lama Building 1st floor
Dr. Sutomo Street Number 16, Randusari, Semarang City, 50244, Indonesia.
*Correspondence: E-mail: [email protected], Tel. (+62)85357500070
2
RSJD dr. Amino Gondohutomo, Central Java
347 Brigjend. Sudiarto Street, Semarang City, 50611, Indonesia

ABSTRACT
Introduction: Schizophrenia is a severe mental disorder marked by psychiatric syndromes
consist of positive, negative and cognitive disorders. It significantly reduces patient’s quality of
life. Oxidative stress is known to play a role in schizophrenia’s pathophysiologies or hypotheses.
Glutathione (GSH) is the main antioxidant in the brain. In its formation process, Glutathione
Reductase (GR) enzyme is needed. Folic acid is a vitamin that prevents oxidative stress by
blocking hyperhomocysteinemia, a condition that increases free radicals decreases GSH levels.
Aim: This study is held to determine the effect of folic acid as adjuvant therapy on Glutathione
reductase level and PANSS score in chronic schizophrenic patients.
Methods: This research is a double-blind, randomized controlled trial with the pre-test and post-
test design. A total of 72 patients were included in this study, divided into treatment and control
groups. The study gave antipsychotics and 2 mg of folic acid for the treatment group, whereas
the control group got antipsychotics and a placebo. The study was conducted for 3 weeks during
hospitalization. PANSS score and GR level (pg/ml) were measured on the first day and after the
intervention was completed.
Results: In this study, there was a significant increase in glutathione reductase level and a
significant decrease in total PANSS score in both pre-test and post-test amongst the control and
treatment groups (p<0.001). To be precise, there was a significant decrease in general, positive,
and negative PANSS score on both pre and post-test for the control and treatment groups
(p=0.029; p=0.015; p<0.001 respectively).
Conclusion: Folic acid as an adjuvant therapy has an effect on increasing glutathione reductase
level and decreasing PANSS score in chronic schizophrenic patients.
Keywords: chronic schizophrenia, folic acid, glutathione reductase levels, PANSS score
INTRODUCTION
Schizophrenia is a severe mental disorder marked by psychiatric syndromes, such as

positive, negative and cognitive symptoms.[1] The 2018 Basic Health Research (Riskesdas)

shows that the prevalence of schizophrenia in Indonesia is 6.7/1000 households.[2]

Oxidative stress is known to be involved in schizophrenia pathophysiology or hypothesis.

[3] It is a condition that arises due to the excessive formation of free radicals such as reactive

oxygen species (ROS) and reactive nitrogen species (RNS), causing an imbalance between the

oxidation process and antioxidant availability.[4] Antioxidants play a role in balancing free

radicals in the body, such as reactive oxygen species (ROS), leading to oxidative stress reduction

and neuron damage prevention.[5]

Glutathione (GSH) is a major antioxidant in the brain and plays a key role against

oxidative stress. In its formation process, the glutathione reductase (GR) enzyme is needed.[6] In

schizophrenic patients, the GSH level declines as much as 40% in the frontal cortex area and

35% in blood plasma.[9] Studies found that declined GSH level was worsening the Total

Positive and Negative Symptom Scale (PANSS) Score.[10]

Folic acid is a vitamin that prevents oxidative process through a one-carbon cycle

metabolism by preventing hyperhomocysteinemia, a condition that increases free radicals, such

as ROS, and decreases GSH level.[7,8] Therefore, folate deficiency has been identified as a risk

factor for schizophrenia.[11]

To sum up, hyperhomocysteinemia can decrease the GSH and GR levels, which will

worsen schizophrenia symptoms. On the other hand, folic acid plays a role in preventing

hyperhomocysteinemia, leading to the GSH and GR level improvement, also schizophrenia

symptoms as well.[6,9,10] Hence, this study aims to determine the effect of adjuvant folic acid

on GR levels and PANSS score improvement in chronic schizophrenic patients.

METHODS
This study used a double-blind, randomized controlled trial with a pre-test and post-test

study design. It was conducted at the Dr. Amino Gondohutomo Regional Mental Hospital

Semarang. Blood samples for accessing the GSH level were examined at Central Laboratory

Diponegoro National Teaching Hospital Semarang. Data collection was carried out from January

1 to March 30, 2021. This research had obtained ethical clearance from the Health Research

Ethics Committee of Regional Mental Hospital Dr. Amino Gondohutomo, Central Java Province.

The ethical license number is No. 420/15161.

Research subjects were selected using consecutive sampling and must meet the following

inclusion criteria: schizophrenic patients aged 21-50 years old, diagnosed by PPDGJ III, have

suffered for at least two years, are receiving standard hospital treatments (psychotropics with or

without additional anticholinergics). Patients with a history of comorbid cardiac schizophrenia,

hypertension, anemia, diabetes mellitus, cardiovascular disease, alcohol and substance abuse are

excluded. Patients who suddenly refuse to follow procedure (given adjuvant therapy or taking

blood samples) and patients who went home at their request before the study ends are considered

to drop out. After selection, the patient's family is asked whether they are willing to participate in

the study and signing the informed consent form.

At first, the subjects were asked for their demographical data. Then after being

randomized using four blocks randomization method, they are divided into two groups, the

control and the treatment group. On the first day of treatment, both groups were assessed using

PANSS score and got their serum GR (Glutathione Reductase) level measured. GR serum was
measured using the Elabscience ELISA Kit. Catalog No. E-EL-H1339 96T. The control group

received standard antipsychotics and a placebo for three weeks. The treatment group received

standard antipsychotics and folic acid as adjuvant as much as 2 mg/day for three weeks. Both

groups were monitored and evaluated for adjuvant side effects and clinical conditions daily. In

the third week, all subjects were assessed for PANSS score and their serum GR (Glutathione

Reductase) level again.

RESULTS
Demographic Characteristics Analysis

This study examines demographic variables including age, gender, occupation, marital status,

education, length of illness, genetic history of mental disorder in the family, body mass index,

smoking, number of hospitalizations. A total of 72 people were included in this study. The

analysis of subjects’demographic characteristics was presented in <table 1>.

Table 1. The demographic characteristics of research subjects (n=72)
Mean±SD Median (min –
Demographic n %
max)
Age (years old) 33,78 ± 7,70 34 (21 – 50)
Gender
Male 50 69,4
Female 22 30,6
Working status (%)
Employed 28 38,9
Unemployed 44 61,1
Marital status
Single 36 50,0
Married 26 36,1
Divorced 10 13,9
Education level
Primary school 18 25,0
Junior high school 23 31,9
Senior high school 22 30,6
Diploma 3 4,2
Bachelor 6 8,3
Length of illness (years) 4,67 ± 2,97 4 (2 – 21)
Genetics
Present 10 13,9
Absent 62 86,1
Body Mass Index
Underweight 7 9,7
Normal 54 75,0
Overweight 6 8,3
Obese 5 6,9
Smoking (%)
Yes 50 69,4
No 22 30,6
Number of 3,40 ± 1,96 3 (1 – 10)
hospitalizations
The Differences in Glutathione Reductase Level Between the Control and the Treatment

Groups

The differences in glutathione reductase level values between the control and the treatment

groups was shown in <Table 2>.

Table 2. The Differences in Glutathione Reductase Level Between the Control and the
Treatment Groups
Glutathione reductase Groups
p
(pg/ml) Control Treatment
Pre test 1385.69 ± 948.43 1212.14 ± 907,76 0.362‡
Post test 2287.36 ± 2455.50 6719.75 ± 4712,20 <0.001‡*
Delta 901.67 ± 2169.73 5507.61 ± 4944,30 <0.001‡*
† †
P (pre vs post) 0.078 <0.001 *
‡ †
Note: * Significant (p < 0.05); Mann whitney; Wilcoxon

In this study, the mean GR serum value after intervention in the control group was

2287.36 ± 2455.50 and the treatment group was 6719.75 ± 4712.20 (significantly different,

p<0.001). The glutathione reductase level before and after intervention were significantly

increased in both control and treatment groups, with delta values as much as 901.67 ± 2169.73

and 5507.61 ± 4944.30, respectively. (significantly different, p<0.001)

The Differences in Total PANSS Score Between the Control and the Treatment Groups

The differences in total PANSS score between the control and the treatment groups was shown

in < Table 3>.

Table 3. Differences in Total PANSS Score Between the Control and the Treatment Groups
Groups
Total PANSS p
Treatment Control
Pre test 83.86 ± 17.27 87.69 ± 14.71 0.314§
Post test 49.14 ± 11.02 64.08 ± 11.79 <0.001§*
Delta 34.72 ± 13.18 23.61 ± 9.56 <0.001§*
P (pre vs post) <0.001¶* <0.001¶*
Note: * Significant (p < 0.05); § Independent t; ¶ Paired t
 The mean value of total PANSS score after intervention for the control group was

64.08±11.79 and the treatment group was 49.14 ± 11.02. Statistically, both showed a significant

difference (p<0.001). The mean value of the total PANSS score difference (delta) of the control

and the treatment groups was 23.61 ± 9.56 and 34.72 ± 13.18, respectively. There was a

significant decrease in the total PANSS score from 83.86 ± 17.27 to 49.14 ± 11.02 (p <0.001) in

the treatment group. The control group was also having a significant decreased on the total

PANSS score from 87.69 ± 14.71 to 64.08 ± 11.79 (p <0.001).

The Differences in Positive Symptoms of PANSS Score Between the Control and the

Treatment Groups

The difference in positive PANSS score between the control and the treatment groups was shown

in <table 4>.

Table 4. The difference in positive PANSS score between the control and the treatment
groups
Groups
Positive PANSS p
Treatment Control
Pre test 22.94 ± 4.76 23.56 ± 4.74 0.587§
Post test 12.11 ± 2.96 15.03 ± 2.96 <0.001§*
Delta 10.83 ± 4.12 8.53 ± 3.74 0.015§*
P (pre vs post) <0.001¶* <0.001¶*
Note: * Significant (p < 0.05); Independent t; ¶ Paired t
§

After intervention (post-test), there was a significant decrease in positive PANSS score in

both groups, where the positive PANSS score in the control and treatment groups were 15.03 ±

2.96 and 12.11 ± 2.96 respectively (p<0.001). The mean value of the total PANSS score

difference (delta) of the control was 8.53 ± 3.74, and the treatment groups was 10.83 ± 4.12.

Thus, statistically, both groups showed a significant difference (p=0.015). Table 4 also shows a

significant decrease of positive PANSS score in the treatment group, from 23.56 ± 4.74 to 15.03

± 2.96 (p<0.001).
The Difference in Negative Symptoms of PANSS Score Between the Control and the

Treatment Groups

The difference in the negative PANSS score between the control and the treatment

groups was shown in <table 5>.

Table 5. Difference in the negative PANSS score between the control and the treatment
groups
Negative Groups
p
PANSS Treatment Control
Pre test 19.28 ± 5.56 19.11 ± 6.48 0.907§
Post test 10.47 ± 3.65 14.89 ± 5.30 <0.001‡*
Delta -8.81 ± 3.91 4.22 ± 3.13 <0.001‡*
† ¶
p(pre vs post) <0.001 * <0.001 *
Note: * Significant (p < 0.05); § Independent t; ‡ Mann whitney; ¶ Paired t; † Wilcoxon.
The negative PANSS score mean score after intervention (post-test) in the treatment

group was 10.47 ± 3.65, and the control group was 14.89 ± 5.30. Statistically, both showed a

significant difference (p<0.001).

The mean score difference of negative PANSS score (delta) in the treatment was 8.81 ±

3.91, and the control group was 4.22 ± 3.13. Statistically, both showed a significant difference

(p<0.001).

<Table 5> also shows that the treatment group found a significant decrease in the

negative PANSS score, from 19.28 ± 5.56 to 10.47 ± 3.65 (p <0.001). The negative PANSS

score was significantly decreased in the control group, from 19.11 ± 6.48 to 14.89 ± 5.30 (p

<0.001).
The Difference in General Symptoms of PANSS Score Between the Control and the

Treatment Groups

The Difference in General PANSS Score Between the Control and the Treatment Groups was

shown in <Table 6>.

Table 6. The Difference in General PANSS Score Between the Control and the Treatment
Groups
Groups
General PANSS p
Treatment Control
Pre test 41.64 ± 11.33 45.03 ± 9.46 0.173§
Post test 26.56 ± 7.79 34.17 ± 6.78 <0.001§*
Delta 15.08 ± 9.42 10,86 ± 8.42 0.029‡*
P (pre vs post) <0.001¶* <0.001¶*
Note: * Significant (p < 0.05); § Independent t; ‡ Mann whitney; ¶ Paired t.

After the intervention (post-test), there was a decrease in the general PANSS score for

both groups, where the general PANSS score in the treatment group was 26.56 ± 7.79 and in the

control group was 34.17 ± 6.78. Thus, based on the statistical test, the difference in general

PANSS score after the intervention between the two groups showed significant results (p<0.001).

The mean value of the general PANSS score difference (delta) of the control was 10.86 ±

8.42 and the treatment group was 15.08 ± 9.42. Statistically, both showed a significant difference

(p=0.029).

<Table 6> also shows a significant decrease in the general PANSS score for the

treatment group, from 41.64 ± 11.33 to 26.56 ± 7.79 (p <0.001). There was a significant decrease

in the general PANSS score in the control group, from 45.03 ± 9.46 to 34.17 ± 6.78 (p <0.001).
DISCUSSION

The Description of Subjects’ Demographic Characteristics

In this study, the mean age of all subjects is 33.78 ± 7.70 years. This result is in

accordance with epidemiological studies in schizophrenic patients, declaring that schizophrenia

prevalence is high at the age range of 30 - 40 years old in both males and females.[12]

The research subjects in this study were dominated by males (69.4%). This result is

consistent with previous epidemiological studies showing that schizophrenia is more common in

men. Several studies showed a difference in schizophrenia symptoms between men and women.

They observed more severe negative symptoms in men compared to women. However, another

study found that the difference in symptoms between women and men was not significantly

different. [13,14]

Most subjects in this study were unemployed (61.1%). This result is in line with another

study conducted by Mark S. Ezeme (2016) on 172 schizophrenic patients in Nigeria, where more

people were unemployed (51.2%).[15]

Based on the marital status, the majority of the research subjects were single (50%), and

as many as 13.9% experienced a divorce. This result is similar to a study by Zargar W. et al.

(2018), finding that schizophrenia patients are more likely to be single.[12]

The subjects’ education level was dominated by junior high and high school graduates, as

much as 31.9%. This result is in accordance with previous studies in which high school

graduates dominated schizophrenia patients.[12,16]

The length of illness in this study was 2-21 years, with a mean value as much as 4.67 ±

2.97 years. Another study was stated that the earlier onset of the illness, meaning a longer
duration of illness, the patient's output will decrease, with the dominant symptoms that arise are

in the form of negative symptoms and cognitive disorders. [17]

In the genetic variables, most research subjects didn’t have a genetic history of mental

disorders in the family (86.1%). This result is not in accordance with previous research. In their

research, Mao Sheng Ran et al. (2017) shows that a family history of mental disorders, especially

those diagnosed with schizophrenia, is a strong determinant of developing schizophrenia risk.

[18]

This study is dominated by normal BMI, as much as 75%. This result isn’t in line with

previous research, which states that schizophrenic women suffer more from obesity, which may

be caused by long-term treatment of antipsychotics, mainly clozapine and olanzapine. [50]

Most research subjects (69.4%) are smoking. This study is similar to previous studies,

which stated that 62% of schizophrenic patients were smokers. One hypothesis that is plausible

to explain it is that smoking can reduce the symptoms of schizophrenia. [19]

The average number of hospitalizations in this study was 3.40 ± 1.96. This result is in

line with previous studies, stating that the longer onset of illness, the more hospitalizations were

required by the patient. [16]

Differences in Glutathione Reductase levels in Schizophrenic Patients

This study aligns with the previous theory, proclaiming that folic acid supplementation as

an adjuvant therapy plays a role in the GSH formation, especially in the one-carbon cycle. GSH

acts as a cellular redox buffer and is a major liver antioxidant. It also functions as a cofactor for

GPx family antioxidant enzymes that degrade H2O2 and alkyl hydroperoxides, yielding GSSG.

In addition, this study is also supported by research conducted by Aleksandrova (2020), stating
that there is a significant relationship between folic acid deficiency in blood with a decrease of

glutathione reductase level, glutathione level, and an increase in homocysteinemia (HHcy) in

hypertensive patients. [20]

In another study conducted by Joshua L, et al. (2013), which was conducted on chronic

schizophrenia patients, found a significant difference in terms of blood folic acid level between

the control group who received a placebo and the treatment group who received 2 mg of folic

acid and 400 mcg of B12. This folic acid level increment was starting at week 2.[21]

The Differences in Total PANSS Score Before and After Folic Acid Adjuvant Therapy

The study result obtained at Amino Gondohutomo Regional Mental Hospital regarding

the total PANSS score are in accordance with the research conducted by Xueqin Song, et al

(2014), which stated that folic acid supplementation could significantly reduce the total PANSS

score (p = 0.038). This result is also aligned with Nucifora's (2017) research, where a significant

relationship was found between the declined level of GSH enzyme, an antioxidant, in

schizophrenic patients and an increase in the total PANSS score (p = 0.033).[23] This study

supports the pathophysiology of antioxidant imbalance affecting the symptoms of schizophrenia.

Folic acid can prevent hyperhomocysteinemia by converting homocysteine into methionine in

the one-carbon cycle. Homocysteine can also enter the trans-sulfuration pathway leading to the

production of cysteine and GSH.[24,25]

The Differences in Positive PANSS Score Before and After Folic Acid Adjuvant Therapy

Another study conducted by Nucifora LC et al. (2017), supports the result of this study,

stating that there is a significant relationship between decreased GSH antioxidant enzymes in
schizophrenic patients with an increase in positive PANSS score (p = 0.013).[23] The role of

antioxidants in positive symptoms of schizophrenia is shown through this mechanism, whereas

the low level of glutathione in schizophrenic patients leads to GABA neurotransmitter

dysfunction and NMDA receptors disturbance in the prefrontal cortex. Dysfunction of this

neurotransmitter affects the feedback loop of the dopamine neurotransmitter. Positive symptoms

in schizophrenic patients are assumed to be due to dopamine neurotransmitter escalation in the

prefrontal cortex.26

The Differences in Negative PANSS Score Before and After Folic Acid Adjuvant Therapy

The study results conducted at the Amino Gondohutomo Regional Mental Hospital

regarding the Negative PANSS score are in accordance with a research done by Xueqin Song, et

al (2014), stating that folic acid supplementation can reduce negative PANSS score (p = 0.034).

[22] K. Langbein also supports this (2017), declared that there is a significant relationship

between decreased plasma glutathione reductase level and an increase in a negative PANSS

score. This occurs because there is a decrease in gray matter density in the orbitofrontal cortex, a

center for motivation, reward and decision making in schizophrenic patients.

The Differences in General PANSS Score Before and After Folic Acid Adjuvant Therapy

The current study results are supported by JL Roffman, et al (2017), who provided an L-

methylfolate intervention for 12 weeks. This intervention was able to reduce the general PANSS

score (p=0.02). [28] The general PANSS score reduction in the treatment group was lower than

in the control group. Thiress happened maybe due to the effect of folic acid as in the control
group, subjects only received antipsychotic, while in the treatment group, subjects received

antipsychotic accompanied by folic acid.

CONCLUSION

The use of folic acid as adjuvant therapy improves the psychiatric symptoms of chronic

schizophrenic patients and increases serum glutathione reductase level. The demographic

characteristics of chronic schizophrenic patients receiving treatments at Dr. Amino

Gondohutomo Regional Mental Hospital Semarang based on age, gender, occupation, marital

status, education, length of illness, genetic history of mental disorder in the family, body mass

index, smoking habit, number of hospitalizations are varied. However, there was a significant

improvement in the PANSS score between the treatment and control groups, and there was a

significant improvement in serum glutathione reductase levels between the treatment and control

groups.

ACKNOWLEDGEMENTS

The contribution of this research is described as following:

“Conceptualization, Hery, Innawati, Sri, Fitri; methodology, Hery, Innawati and Sri; software

Hery; validation, Innawati, Sri, Fitri and Hery; formal analysis, Hery, Innawati and Sri;

investigation, Innawati, Sri , Inawati and Widodo; resources, Hey; data accuracy, Hery; writing-

preparation of original draft, Hery; writing – reviewing and editing, Hery; visualization, Hery;

supervision, Innawati, sri and Fitri; project administration, Innawati and Fitri; fund acquisition,

Innawati and Sri. This work is supported by the Psychiatry Study Program of the Faculty of

Medicine, Diponegoro University. We would like to thank the RSJD dr. Amino Gondohutomo
Semarang and all the participants and their families. The author states there is no conflict of

interest.
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