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INTRODUCTION
Schizophrenia (SCH) is a chronic mental disorder that involves social, cognitive, and emotional problems and has a lifetime prevalence of 1% in the population. As a chronic disease, SCH is usually accompanied by physical illness, malnutrition, and reduced self-care practices, all of which can cause vitamin deficiency 1. Nutritional deficiencies often coexist with SCH, which is attributed to the patients’ tendency to have higher calorie diets with saturated fat instead of fiber foods such as fruits and vegetables. Previous studies have revealed deficiencies of nutrients, such as folate and vitamin B12 in SCH patients resulting from less time on outdoor activities 2,3. Vitamin B12 and folate levels decline in patients with SCH 4. Alcoholism and drug addictions are viewed as chronic diseases featured by recurrence, in common with SCH. However, the prevalence data of illicit drug addiction worldwide are still lacking. Like SCH, alcoholism, and drug addictions may cause adverse effects on cognitive function and induce malnutrition 5. In addition, excessive drinking is a common phenomenon in developed countries, which affects nutrient intake and metabolism, leading to malnutrition, and also causes damage to multiple organs. Although folate and vitamin B12 deficiencies are frequently present in chronic alcohol drinkers, the impact of long-term drinking on vitamin B12 and folate levels has not yet reached a consensus. Thus, the data about correlations of vitamin D and other vitamin deficiencies with the risk of alcoholism are also insufficient to support the final conclusion 6. Recently, vitamin B12 has been demonstrated to be vital for hemostasis and multiple physiological functions, as well as the pathogenesis of diseases such as cancer, autoimmune disorder, senile dementia, cognitive impairment, and SCH 7. It was also reported in another study that vitamin B12 acts as an essential player in SCH and cognitive function and has immunomodulatory, anti-inflammatory, and antioxidant effects 8. Homocysteine is thought to be a pro-atherogenic molecule that has toxic effects on endothelium, but its associations with diagnosis and prognostic evaluation of SCH have not been systematically analyzed and summarized 9. Consistent with vitamin B12, folate is a vitamin B used to modulate cell division. Folate deficiency is closely implicated in megaloblastic anemia, cardiovascular disease, osteoporosis, bone dysplasia, depression, and SCH, and folate insufficiency during pregnancy may cause fetal neural tube developmental defects. SCH involves neurodegenerative processes, although the impact extent of vitamin deficiency on these processes remains unclear10, and the potential deterioration of such processes resulting from folate and vitamin B12 deficiencies cannot be ignored. For this reason, efforts should be made to identify patients at risk of specific vitamin deficiencies and then provide prompt and appropriate interventions.
Consequently motivated, the clinical efficacy and safety of folate and vitamin B12 as adjuvant therapy in SCH were systematically reviewed and meta-analyzed to guide the clinical medication of SCH.
MATERIALS AND METHODS
Retrieval methods
Publication retrieval was performed using databases such as the Cochrane Library, PubMed, Web of Science, and EMBASE, as well as related websites for registration of clinical trial institutions with “schizophrenia”, “cognitive impairment”, “SCH”, “folate”, and “vitamin B12” as subject words and trademark names of relevant drugs as free words. In addition, relevant studies published in English were retrieved to avoid bias due to language restrictions (Fig. 1).
Inclusion criteria
The inclusion criteria of studies were as follows: i) studies using randomized controlled trials (RCTs), ii) those with research subjects meeting the diagnostic criteria for SCH following the Minnesota Multiphasic Personality Inventory or schizophrenia scale and also the ICD-11 diagnosis of schizophrenia 11, iii) those researching comparisons of efficacy and safety between folate and vitamin B12 as adjuvant therapies for SCH, iv) those mainly evaluating indexes including anxiety relief rate, incidence rate of mania, total efficacy and incidence rate of adverse reactions, v) those whose research subjects had no history of drug abuse, and vi) those including research subjects who underwent 6-12 weeks of treatment and were aged ≥8 years old and lack of folate or vitamin B12.
Exclusion criteria
The exclusion criteria involved: i) studies adopting non-RCTs, ii) repeated studies, iii) studies with incomplete data, or iv) studies published for the second time.
Quality evaluation of studies
Evaluation was performed as required: i) whether patients were ranked randomly (“yes” =2, ”unclear” =1, ”no” =0), ii) random hiding (“yes” =2, ”unclear” =1, ”no” =0), iii) blind trial (“yes” =2, ”clear” =1, ”no” =0), and iv) withdrawal or not with-drawal (“yes” =1, ”no” =0). Data involving author information and country, Jadad score, type, patient’s age and gender, the dose of study drugs, number of cycles, effective treatment, total efficacy score after treatment, and adverse reactions were extracted. Then two commentators were responsible for comparing these data, where inconsistencies were discussed, and missing information was supplemented as far as possible.
Bias analysis of studies
Two investigators independently conducted data extraction and cross-checking to ensure the data’s accuracy. Quality evaluation was conducted for RCTs with the Cochrane Handbook 5.0.2 as a reference. As for the included studies, the presence or absence of publication bias was evaluated using a funnel chart (performed through the Egger’s test), which illustrated that all studies were within the triangle area, without obvious publication bias (Figs. 2 and 3).
Statistical analysis
The Review Manager 5.2 software [Cochrane Information Management System (IMS)] provided by Cochrane Collaboration was utilized for statistical analysis using the hazard ratio of binary variables. The meta-analysis analyzed the efficacy and incidence rate of adverse reactions using relative risk (RR) and 95% confidence interval (CI). Besides, the chi-square test (the significance level was set at p<0.05) and t-test expressed by Z and P values for the hypothesis test were applied, and p<0.05 was considered statistically significant. The hypothesis test results were displayed in the forest plot, and the χ2 test was employed to analyze heterogeneity, divided into low, medium, and high heterogeneity and represented by I 2 =25%, 50%, and 75%, respectively. The inverted funnel chart was used and displayed no obvious publication bias.
RESULTS
Basic information of included patients
A total of 123 studies were obtained by the preliminary retrieval based on databases such as PubMed, Cochrane Library, Web of Science, and EMBASE. Furthermore, relevant references were also retrieved to avoid omission. Fourteen studies adopting RCTs were included (Table 1) 12-25.
Table 1 Basic information of patients in 14 literatures adopting RCTs.
| Study item | Age | Gender (Male) | Observation index of outcome | Experimental group (N) | Control group (N) | NOS Score | Study type |
|---|---|---|---|---|---|---|---|
| Yazici et al. 2019 | 41.44±12.28 | 57.14% | Anxiety relief rate, incidence rate of mania, etc. | 119/189 | 109/189 | 8 | RCT |
| Yazici et al. 2019 | 40.63±13.50 | 100% | Anxiety relief rate, incidence rate of mania, etc. | 24/30 | 23/28 | 7 | RCT |
| Altun et al. 2018 | 9.33±1.80 | 76.67% | Anxiety relief rate, incidence rate of mania, etc. | 23/30 | 25/30 | 8 | RCT |
| Hope et al. 2020 | 30.0±9.0 | 55.78% | Anxiety relief rate, incidence rate of mania, etc. | 420/ 483 | 401/483 | 8 | RCT |
| Allott et al. 2019 | 20.2±3.0 | 65.40% | Anxiety relief rate, incidence rate of mania, etc. | 88/120 | 76/120 | 8 | RCT |
| Topal et al. 2022 | 8.5±3.1 | 73.90% | Anxiety relief rate, incidence rate of mania, etc. | 178/203 | 180/203 | 7 | RCT |
| Ramaekers et al. 2014 | 19.5±2.56 | 78.20% | Anxiety relief rate, incidence rate of mania, etc. | 12/18 | 13/18 | 9 | RCT |
| Chen et al. 2021 | 44.3±10.7 | 49.60% | Anxiety relief rate, incidence rate of mania, etc. | 125/232 | 117/232 | 9 | RCT |
| Misiak et al. 2014 | 26.0±5.3 | 58.97% | Anxiety relief rate, incidence rate of mania, etc. | 27/39 | 31/39 | 7 | RCT |
| Kale et al. 2010 | 33.57±8.35 | 56.32% | Anxiety relief rate, incidence rate of mania, etc. | 23/31 | 26/48 | 8 | RCT |
| Roffman et al. 2013 | 45.3±1.1 | 71.0% | Anxiety relief rate, incidence rate of mania, etc. | 31/56 | 28/56 | 8 | RCT |
| Saedisomeolia et al. 2011 | 37.25±16.0 | 66.44% | Anxiety relief rate, incidence rate of mania, etc. | 44/60 | 41/60 | 8 | RCT |
| Misiak et al. 2016 | 28.51±8.6 | 68.44% | Anxiety relief rate, incidence rate of mania, etc. | 117/135 | 121/146 | 9 | RCT |
| Misiak et al. 2015 | 25.12±4.48 | 43.22% | Anxiety relief rate, incidence rate of mania, etc. | 34/83 | 36/83 | 7 | RCT |
Anxiety relief rate in SCH patients undergoing adjuvant therapy with folate and vitamin B12
A heterogeneity test found that a low level of heterogeneity existed in 14 studies adopting RCTs for detecting anxiety relief rates in SCH patients undergoing adjuvant therapy with folate and vitamin B12, so fixed models were utilized for meta-analysis. The experimental group was given folate in combination with vitamin B12, and the control group was only given folate. The two groups had significantly different remission rates of anxiety [odds ratio (OR)=1.28, 95% CI (1.02, 1.61), p=0.03, I 2 =0%, Z=2.13] (Fig. 4).
Incidence rate of mania in SCH patients undergoing adjuvant therapy with folate and vitamin B12
A heterogeneity test was conducted and revealed that 14 studies adopting RCTs for investigating the incidence rate of mania in SCH patients undergoing adjuvant therapy with folate and vitamin B12 exhibited a low level of heterogeneity, which could be subject to meta-analysis with fixed models. The results manifested that there was no significant difference in the incidence rate of mania in SCH patients undergoing adjuvant therapy with folate and vitamin B12 between the experimental group and the control group [OR=1.13, 95% CI (0.78, 1.65), p=0.65, I 2 =36%, Z=0.65] (Fig. 5).
Total efficacy of folate and vitamin B12 in the adjuvant treatment of SCH
A heterogeneity test was performed and manifested that 14 studies adopting RCTs for examining the total efficacy of adjuvant therapy with folate and vitamin B12 for SCH showed a low level of heterogeneity, which were subject to meta-analysis with fixed models. The results demonstrated that the total efficacy of adjuvant therapy with folate and vitamin B12 for SCH showed no significant difference between the experimental group and the control group [OR=1.06, 95% CI (0.72, 1.56), p=0.77, I 2 =0%, Z=0.30] (Fig. 6).
Incidence rate of adverse reactions of folate and vitamin B12 in the adjuvant treatment of SCH
Through a heterogeneity test, it was uncovered that 14 studies adopting RCTs for detecting the incidence rate of adverse reactions of folate and vitamin B12 in the adjuvant treatment of SCH had a low level of heterogeneity, so fixed models were used for meta-analysis. The results confirmed that the incidence rate of adverse reactions of adjuvant therapy with folate and vitamin B12 for SCH exhibited no significant difference between the experimental group and the control group [OR=1.15, 95% CI (0.88,1.49), p=0.31, I 2 =0%, Z=1.03] (Fig. 7).
DISCUSSION
Folate and vitamin B12 have immunomodulatory, anti-inflammatory, and antioxidant properties. It has been reported that the incidence of vitamin D deficiency is raised in patients newly diagnosed with SCH26. Another study demonstrated that vitamin B12 is not only associated with malnutrition but also correlated with the occurrence of disease and increased incidence rate of autoimmune thyroid diseases. Consequently, the loss of the neuroprotective effect of vitamin B12 may be implicated in the pathogenesis of SCH 27. Like SCH, substance use disorder (SUD) is a chronic disease usually related to malnutrition. In a study about associations of folate and vitamin B12 levels with the severity of symptoms in patients with SCH, those with low levels of vitamin B12 may be at particular risk of poor prognosis. A previous study also revealed lower folate levels in SCH patients than in healthy controls 28. However, these findings have not been reported in other studies. Consistent with previous studies, folate, and vitamin B12 are relatively deficient in older adults, verifying associations with gender and age 29-31.
It has long been considered that abnormal one-carbon metabolism is one of the mechanisms for the neuropathology and psychopathology of SCH 32. The changes in levels of one-carbon metabolic components (folate and vitamin B12), homocysteine, and docosahexaenoic acid (DHA) are primarily found in patients receiving drug administration. For instance, daily administration of 2 mg folate plus 1 mg vitamin B12 for 12 weeks can significantly reduce the serum homocysteine level (p<0.0001) 33. In a relevant study, the impact of change levels of one-carbon metabolic components (folate and vitamin B12) on the severity of SCH was reported, and the subsequent alterations of homocysteine and DHA in phospholipids were also notably correlated with the pathogenesis of SCH 34. In a study conducted by Satoskar et al. 35, the associations of folate and vitamin B12 deficiencies with the pathogenesis and prognosis of SCH patients were investigated, and the mechanism of one-carbon metabolism was also further explored. In the study, the clinical efficacy and safety of agents were analyzed between first-episode psychosis (FEP) patients (n=31) and healthy controls (HC, n=48), and folate and vitamin B12 were matched with confounding factors such as race, diet, and lifestyle, to reduce variability. Compared with HC, the DHA level in patients with FEP noticeably declined. The unique cohort used in the study provided an extensive mechanism for changing one-carbon metabolism (disturbed folate-vitamin B12-DHA balance). Besides, the increased level of homocysteine contributes to the mechanism research on the neuropathology of SCH, and the data mentioned above may be of great significance for the psychopathology of SCH 36-39.
The limitations of this meta-analysis include: i) Potential publication bias existed because of too few studies and small sample size. ii) There were few studies included and no subgroup analysis for comparison of efficacy. iii) Only therapeutic effects at the end of treatment were evaluated, but longterm effects were not assessed. iii) We only included adult SCH patients over the age of 18, whose results would be inapplicable to adolescents.
Vitamin B12 and folate levels are notably lower in patients with SCH 40,41. Herein, further analysis on the clinical efficacy and safety of adjuvant therapy with folate and vitamin B12 for SCH revealed that vitamin B12 differed significantly from folate in terms of anxiety relief rate (p<0.05). However, there were no significant differences in the incidence rate of mania, total efficacy, and incidence rate of adverse reactions (p>0.05). Although vitamin deficiency commonly occurs in patients with SCH, vitamin B12 has notably fewer side effects than folate drugs, which is consistent with the findings of Roffman et al. 42. Hence, this meta-analysis is of great guiding significance for the adjuvant clinical medication of SCH.
