Investigating the Association of Vitamin B12 and Folate with Neuropsychiatric Diseases with Special Reference to Schizophrenia: Integrated Evidence Syntheses and Policy Evaluation

Abstract

Background For their integral roles in DNA/ RNA synthesis, homocysteine metabolism, and numerous methylation reactions, folate and vitamin B12 are hypothesized to be associated with the risk of neuropsychiatric diseases. However, compared to other health outcomes, these vitamins have been less studied in the context of schizophrenia. Objectives We set out to (1) identify health effects of vitamin B12, (2) investigate an association between folate and vitamin B12 and schizophrenia, (3) examine a causal nature of the association, and (4) assess the impact of relevant public health policies on schizophrenia. Methods Umbrella reviews were conducted to address the objectives (1) and (2). For objective (3), we conducted a systematic review and meta-analysis of genetic association studies examining the relationship between gene polymorphisms involved in folate metabolism and schizophrenia. For objective (4), we evaluated the impact of folic acid fortification on changes in schizophrenia rates over the past 30 years in 194 jurisdictions. Results We found a suggestive level of evidence on the relationship between vitamin B12 status and neurological outcomes. For schizophrenia, higher plasma/serum folate concentrations or the variant MTHFR 677TT genotype were each associated with decreased and increased risk, respectively. Our meta-analysis further identified significant roles of the MTHFR C677T and A1298C polymorphisms at an aggregate level. Mandatory folic acid fortification and the duration of fortification policies were independently associated with declines in the prevalence rates of schizophrenia in individuals aged 15-39 years. Conclusion The current evidence suggests that the folate and vitamin B12 inadequacy is associated with the risk of schizophrenia and that this relationship may be causal. Mandatory folic acid fortification may be a beneficial strategy for lowering prevalence of schizophrenia among individuals at ages of typical onset. More research on combined or interactive effects of these vitamins or relevant genotypes will advance our current knowledge.