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Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression

  • Osvaldo P. Almeida (a1) (a2) (a3), Andrew H. Ford (a1) (a2) (a3) and Leon Flicker (a1) (a4) (a5)



Folate and vitamin B12 insufficiencies have been associated with increased risk of depression. This systematic review aimed to clarify if, compared with placebo, treatment with folate and/or vitamin B12 reduces depression scale scores, increases remission, and prevents the onset of clinically significant symptoms of depression in people at risk.


This systematic review searched the PubMed, PsychInfo, Embase, and Cochrane databases from inception to 6 June 2014, using the following terms and strategy: (vitamin B12 or vitamin B9 or folate or folic acid or cobalamin or cyanocobalamin) and (depression or depressive disorder or depressive symptoms) and (randomized controlled trial or RCT). The electronic search was supplemented by manual search. Two independent reviewers assessed all papers retrieved for eligibility and bias, and extracted crude data. Review Manager 5 was used to manage and analyze the data.


Two hundred and sixty-nine manuscripts were identified, of which 52 were RCTs and 11 fulfilled criteria for review. We found that the short-term use of vitamins (days to a few weeks) does not contribute to improve depressive symptoms in adults with major depression treated with antidepressants (5 studies, standardized mean difference = −0.12, 95% confidence interval – 95% CI = −0.45, 0.22), but more prolonged consumption (several weeks to years) may decrease the risk of relapse (1 study, odds ratio (OR) = 0.33, 95% CI = 0.12, 0.94) and the onset of clinically significant symptoms in people at risk (2 studies, risk ratio = 0.65, 95% CI = 0.43, 0.98).


The number of available trials remains small and heterogeneity between studies high. The results of these meta-analyses suggest that treatment with folate and vitamin B12 does not decrease the severity of depressive symptoms over a short period of time, but may be helpful in the long-term management of special populations.


Corresponding author

Correspondence should be addressed to: Osvaldo P. Almeida, Professor, WA Centre for Health & Ageing (M573), University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. Phone: +61-8-9224 2855. Email:


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