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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 39  |  Issue : 2  |  Page : 89-94

Folate, vitamin B12, and negative symptoms in schizophrenia


1 Psychiatric Department, Cairo University, Cairo, Egypt
2 Psychiatric Department, South Valley University, Qena, Egypt

Date of Submission31-Oct-2017
Date of Acceptance06-Dec-2017
Date of Web Publication2-May-2018

Correspondence Address:
Hoda A Hussein
Faculty of Medicine, Psychiatry Department, Cairo University, Cairo, 11728
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejpsy.ejpsy_39_17

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  Abstract 


Introduction Negative symptomatology has been demonstrated to be the most relevant predictor of increased future socio-occupational dysfunction and poorer quality of life. Negative symptoms and functional outcomes have consistently been linked, with several studies reporting worse functional outcomes in individuals with more prominent negative symptoms. Folate deficiency has been identified as a risk factor for schizophrenia and its negative symptoms.
Aim The aim of this study was to assess the serum levels of folate and vitamin B12 in a sample of schizophrenic patients and their relation to negative symptoms in these patients.
Patients and methods It is a cross-sectional study aiming to assess the serum level of folate and vitamin B12 in schizophrenic patients. All patients were recruited from the Kuwait Center for Mental Health after taking approval from the scientific and ethics committee of the hospital. The study was conducted in the period from January 2016 to April 2016; the total number of patients was 41 after applying the inclusion and exclusion criteria. We applied the Positive and Negative Syndrome Scale and the Scale for the Assessment of Negative Symptoms; serum levels of vitamin B12 and folate were measured by radioimmunoassay technique.
Results About 41.5% of the patients have low folate level and about 39% of the patients have low B12 level. There are significant positive correlations between severity of negative symptoms and duration of illness and number of hospital admissions. Also there are significant positive correlations between serum levels of vitamin B12 and folate. There are significant negative correlations between serum levels of vitamin B12. All negative symptoms were assessed by the Scale for the Assessment of Negative Symptoms (affective flattening, alogia, attention, aviolation, and anhedonia). We cannot find a significant correlation between serum levels of folic acid and negative symptoms.
Conclusion Folate and vitamin B12 deficiency may be a risk factor for schizophrenia and negative symptoms; so we suggest to evaluate the serum vitamin B12 and folate levels for schizophrenic patients followed by dietary supplementation for patients with low vitamin B12 or folate.

Keywords: folate, negative symptoms, schizophrenia, vitamin B12


How to cite this article:
Abd El Mawella SM, Hussein HA, Ahmed T. Folate, vitamin B12, and negative symptoms in schizophrenia. Egypt J Psychiatr 2018;39:89-94

How to cite this URL:
Abd El Mawella SM, Hussein HA, Ahmed T. Folate, vitamin B12, and negative symptoms in schizophrenia. Egypt J Psychiatr [serial online] 2018 [cited 2018 Sep 20];39:89-94. Available from: http://new.ejpsy.eg.net/text.asp?2018/39/2/89/231702




  Introduction Top


Schizophrenia is a chronic psychiatric disorder characterized by positive symptoms (delusions, hallucinations, and disorganization), negative symptoms (social withdrawal, loss of emotional expressiveness and apathy), and cognitive impairment. Considerable disability is associated with negative symptoms and cognitive deficits, for which effective treatment is not available (Roffman et al., 2013)

Negative symptomatology has been demonstrated to be the most relevant predictor of increased future socio-occupational dysfunction and poorer quality of life (Bobes et al., 2010). Negative symptoms and functional outcomes have consistently been linked, with several studies reporting worse functional outcomes in individuals with more prominent negative symptoms (Milev et al., 2005; Blanchard et al., 2005; Rosenheck et al., 2006), these studies have reported correlations between negative symptoms and impairments in occupational functioning, household integration, relationships, and recreational activities.

Folate deficiency has been identified as a risk factor for schizophrenia, a cross-sectional study found decreased blood folate levels in patients with schizophrenia (Brown et al., 2007). Another study reported an inverse correlation between serum folate concentrations and negative symptoms among patients with schizophrenia while no correlation was found between positive symptoms and folate levels (Goff et al., 2004)

Silver (2000) reported that out of 644 bedridden psychotic patients, 78.3% of schizophrenic patients had vitamin B12 deficiency. The metabolism of cobalamin and folic acid is interrelated and both are necessary in several pathways in the human central nervous system, cobalamine and folate facilitate the production of adenosylmethionine (SAM), the exceptional donor of a methylgroup for various reactions of methylation, by promoting the conversion of homocysteine into methionine. (Stabler et al., 1988).

Some studies have clearly indicated the contribution of folic acid, vitamin B12 and homocysteine to altered single-carbon metabolism and its role in etiology of schizophrenia (Monji et al., 2005), decreased plasma folate may act as a risk factor for schizophrenia. Therefore, it is suggested to evaluate the serum cobalamin and folate levels for all newly admitted schizophrenic patients. (Ahmad et al., 2011)


  Aim Top


This study was conducted to assess the serum levels of folate and vitamin B12 in a sample of schizophrenic patients and their relation to negative symptoms in these patients.


  Patients and methods Top


It is a cross-sectional study aiming to assess the serum level of folate and vitamin B12 in schizophrenic patients; all patients were recruited from the Kuwait Center for Mental Health after taking approval from the scientific and ethics committee of the hospital. The study was conducted from January 2016 to April 2016; the total number of patients was 41 after applying inclusion and exclusion criteria.

Inclusion criteria were: both sexes, age 18-50 years, given written informed consent after explaining the aim of study, diagnosis was done according to DSM5. (APA, 2013).

All patients with known general acute or chronic medical conditions such as those with abnormal bleeding, digestive, infectious, parasitic or heart diseases, diabetes mellitus, hyperthyroidism were excluded from the study. Pregnant and lactating women during the previous year, vegetarians, patients with submentality, patients with substance abuse especially cigarette smoking as it decreases the level of folate, and patients with dietary supplementation by folate or multivitamins were also excluded.
  1. Psychiatric assessment:
  2. Sociodemographic data and detailed medical and psychiatric history were gathered for all patients using a semistructured interview. were diagnosed according to DSM5 (APA, 2013)
  3. The Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) was applied for the patients. Each scale comprises seven symptoms that are rated on a 1 (absent) to 7 (extreme) metric. The PANSS is a medical scale used for measuring symptom severity of patients with schizophrenia. As 1 rather than 0 is given as the lowest score for each item, the patient cannot score lower than 30 for the total PANSS score. Scores are often given separately for the positive scale, negative scale, and general psychopathology scale.
  4. The Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 2000) is a rating scale to measure negative symptoms in schizophrenia. SANS is split into five domains, and within each domain separate symptoms are rated from 0 (absent) to 5 (severe). SANS assesses five symptom complexes to obtain clinical ratings of negative symptoms in patients with schizophrenia. They are: affective blunting, alogia (impoverished thinking), avolition/apathy, anhedonia/asociality, and disturbance of attention. The final symptom complexes seem to have less obvious relevance to negative symptoms than the other four complexes. Assessments are conducted on a six-point scale (0=not at all to 5=severe).
  5. Laboratory assessment:


Serum folate and B12: Fasting samples were collected on plain tubes for the assay of serum vitamin B12 and folic acid. Serum was separated and frozen at −20°C until the time of analysis. Simultaneous assay of vitamin B12 and folic acid by the radioimmunoassay was carried out. The normal level for folate is 3.6–20 ng/ml and the normal level for vitamin B12 is 180–914 pg/ml.

Statistical analysis

Data were statistically described in terms of mean±SD, median and range, or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables between the study groups was done using Student’s t-test for independent samples. Comparison of numerical variables between more than two groups were compared using Kruskal–Wallis test. Correlation between various variables was done using Pearson’s moment correlation equation for linear relation in normally distributed variables and Spearman’s rank correlation equation for non-normal variables/nonlinear monotonic relation. P values of less than 0.05 were considered statistically significant. All statistical calculations were done using the computer program, the statistical package for the social sciences (SPSS Inc., Chicago, Illinois, USA) release 15 for Microsoft Windows (2006).


  Results Top


[Table 1] and [Table 2] show the demographic data and current medications of the patients. [Table 3] shows that 41.5% of the patients have low serum folate level, whereas 39% of the patients have low vitamin B12 level. [Table 4] shows the clinical data of the patients, and mean and standard deviation of serum folic acid and vitamin B12. [Table 5] shows that the most frequently negative symptoms assessed by SANS are flat affect, followed by alogia and anhedonia, then avolition, and lastly attention disturbance. [Table 6] shows the correlations between negative symptoms assessed by SANS and the clinical data of patients. [Table 7] shows the correlations between serum level of folic acid and vitamin B12 and scales of PANSS and SANS.
Table 1 Demographic data and family history of psychiatric disorders

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Table 2 Medications received by the patients

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Table 3 Level of folic acid and vitamin B12

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Table 4 Age, clinical data of the patients, and levels of folic acid and vitamin B12

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Table 5 Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms scores

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Table 6 Correlation between clinical data and scores of Scale for the Assessment of Negative Symptoms

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Table 7 Correlation of folic acid and vitamin B12 with Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms

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  Discussion Top


Schizophrenia is a chronic psychiatric disorder associated with marked disability. This disability is caused mainly by negative symptoms and cognitive deficit (Roffman et al., 2013). This study was conducted to assess the relationship between the negative symptoms and serum level of folate and vitamin B12.

In this study, we found that about 41.5% of the patients with low serum folate level and about 39% of the patient with low serum vitamin B12 level. This percentage is lesser than what recorded by Goff et al. (2004) on a group of schizophrenic patients, as they noted that all patients had a lower level of folate compared with a population of people without schizophrenia. In addition, the study was done by Ahmad et al. (2011) on 60 schizophrenic patients compared with the control group and found that a lower plasma folate level is found in schizophrenic patients compared with the healthy controls. They also detected that cobalamin deficiency in schizophrenic patients (13.3%) was significantly lower than the controls (23.3%). Another study found reduced folate and cobalamin levels, among schizophrenic patients (Silver et al., 2000). The difference in the percentage of serum folate level from other studies may be explained by the difference in culture as our patients from the Gulf area have different food habits.

In contrast, Reif et al. (2005) found that that the mean serum cobalamin concentrations were similar in schizophrenic patients and controls. In a survey in Mexico, the mean serum cobalamin levels in schizophrenic patients (409.75±243.79) were higher than healthy controls (407.71±210.18) García et al. (2010).

We detected a significant positive correlation between severity of the negative symptoms and duration of illness. That was proved by a study that investigated negative and positive symptoms longitudinally in 39 young schizophrenic patients at two follow-up assessments ∼2.5 and 5 years after hospital discharge. Negative symptoms, such as flat affect and poverty of speech, were found to be effective prognostic signs in schizophrenic patients for predicting later poor functioning at the second follow-up (Pogue-Geile, & Martin, 1985).

We also found a positive correlation between severity of negative symptoms and number of hospital admissions. This is also approved by Patel et al. (2015) who found that the negative symptoms were associated with an increased number of hospital admissions and increased duration of admission.

In this study, we could not find significant correlations between serum level of folic acid and negative symptoms of schizophrenia, although Roffman et al. (2013) and Goff et al. (2004) have reported an inverse correlation between serum folate concentrations and negative symptoms among patients with schizophrenia. However, we found a significant negative correlation between negative symptoms and vitamin B12, and a significant positive correlation between vitamin B12 and folic acid.

Long lists of psychiatric illness or symptoms have been documented to be caused by vitamin B12 deficiency (Demise, 1991). Also, there is a case report study of a young adult who presented with predominant negative symptoms without other psychotic and manic symptoms followed by neurological symptoms consistent with vitamin B12 deficiency. The symptoms showed complete remission after vitamin B12 supplementation (Sahoo et al., 2011) which is suggestive of a role for vitamin B12 in negative symptoms of schizophrenia.

This study suggests the introduction of folate and B12 for the treatment of schizophrenia, which is supported by a new placebo-controlled study of 140 patients with schizophrenia. A research team based at Massachusetts General Hospital found improvement across all participants when folate and vitamin B12 were added to their regular treatments. But the results were most significant in those carrying specific variants in genes involved with folate metabolism (Baker, 2013).

Roffman et al. (2013) studied 140 patients with schizophrenia at community mental health centres, and randomized them to receive daily doses of either folate and vitamin B12 or placebo for 16 weeks. All participants were taking antipsychotic medications − which have been shown to alleviate positive symptoms, Roffman et al. (2013) showed that those receiving folate and vitamin B12 showed improvement in negative symptoms, however they said that the degree of improvement was not statistically significant compared with the placebo.

The last question is that folate and vitamin B12 deficiency in schizophrenic patients may be a primary cause for negative symptoms or secondary to schizophrenic process itself; people with schizophrenia, and particularly those with prominent negative symptoms, may have difficulty eating green leafy vegetables. Thus, decreased folate could actually be a symptom of negative symptoms rather than a possible cause, and at the same time decreased plasma folate may act as a risk factor for schizophrenia. However this attracts our attention to the importance of correction of folate and vitamin B12 deficiency. So we suggest evaluating the serum cobalamin and folate levels for schizophrenic patients.

Study limitations

  1. Small number of the sample because we excluded smoker patients which is uncommon in schizophrenia.
  2. No control group.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ahmad S, Mahmoud D, Ali MM et al. (2011). Folate and vitamin B12 status in schizophrenic patients. J res Med Sci 16(Suppl 1):S437–S441.  Back to cited text no. 1
    
2.
Andreasen NC. (2000). Scale for the assesment of negative symptoms: SANS. Lowa: the University of Lowa.  Back to cited text no. 2
    
3.
APA (2013). American Psychiatric Association, American Psychiatric Association Inc; 5th ed. Washington. Diagnostic and Statistical Manual of Mental Disorders DSM-5.  Back to cited text no. 3
    
4.
Baker S. (2013). Folate and vitamin B12 treat schizophrenia symptoms By, Health Sciences Editor tags, vitamin B12, folate, schizophrenia.  Back to cited text no. 4
    
5.
Blanchard JJ, Horan WP, Collins LM. (2005). Examining the latent structure of negative symptoms: is there a distinct subtype of negative symptom schizophrenia? Schizophr Res 77:151–165.  Back to cited text no. 5
    
6.
Bobes J, Arango C, Garcia- Garcia M, Rejas J, CLAMORS Study Collaborative Group (2010). Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS Study. J Clin Psychiatry 71:280–2.  Back to cited text no. 6
    
7.
Brown AS, Bottiglieri T, Schaefer CA et al. (2007). Elevated prenatal homocysteine levels as a risk factor for schizophrenia. Arch Gen Psychiatry 64:31–39.  Back to cited text no. 7
    
8.
Demise J. (1991). Subtle vitamin deficiency and psychiatry: A largely unnoticed and devastating relationship. Med Hypothesis 34:131–40.  Back to cited text no. 8
    
9.
García MR, Pérez MJ, López CB et al. (2010). Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677T polymorphism, are risk factors for schizophrenia. J Psychiatr Res 44:441–6.  Back to cited text no. 9
    
10.
Goff DC, Bottiglieri T, Arning E et al. (2004). Folate, Homocystein, and Negative Symptoms in Schizophrenia. The American Journal of Psychiatry 161:1705–1708.  Back to cited text no. 10
    
11.
Kay SR, Fiszbein A, Opler LA. (1987). Positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13:261–276.  Back to cited text no. 11
    
12.
Milev P, Ho BC, Arndt S, Andreasen NC. (2005). Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry 162:495–506.  Back to cited text no. 12
    
13.
Monji A, Yanagimoto K, Maekawa T et al. (2005). Plasma folate and homocysteine levels may be related to interictal “schizophrenia-like” psychosis in patients with epilepsy. J Clin Psychopharmacol 25:3–5.  Back to cited text no. 13
    
14.
Patel R, Jayatilleke N, Broadbent M et al. (2015). Negative symptoms in schizophrenia: a study in a large clinical sample of patients using a novel automated method. BMJ Open 5:e007619.  Back to cited text no. 14
    
15.
Pogue-Geile MF, Martin H. (1985). Negative Symptoms in Schizophrenia: Their Longitudinal Course and Prognostic Importance. Schizophrenia Bulletin 11:427–439.  Back to cited text no. 15
    
16.
Reif A, Pfuhlmann B, Lesch KP. (2005). Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry 29:1162–8.  Back to cited text no. 16
    
17.
Roffman JL, Lamberti JS, Achtyes E et al. (2013). Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA Psychiatry 70:481–489.  Back to cited text no. 17
    
18.
Rosenheck R, Leslie D, Keefe R. (2006). Barriers to employment for people with schizophrenia. Am J Psychiatry 163:411–417.  Back to cited text no. 18
    
19.
Sahoo MK, Avasthi A, Singh A. (2011). Negative symptoms presenting as neuropsychiatric manifestation of vitamin B12 deficiency. Indian J Psychiatry 53:370–371.  Back to cited text no. 19
    
20.
Silver H. (2000). Vitamin B12 levels are low in hospitalized psychiatric patients. Isr J Psychiatry Relat Sci 37(1): 41–5.  Back to cited text no. 20
    
21.
Stabler SP, Marcell PD, Pdell ER et al. (1988). Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 81:466–74  Back to cited text no. 21
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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