One-carbon metabolism and bipolar disorder

Objective: Folate is one of the most widely used nutraceuticals for the treatment of mood disorders. In this article, we review folate metabolism, its relationship with bipolar disorder, and its therapeutic potential. Methods: We searched PubMed and the Cochrane Library for relevant articles up to and including the year 2012. Background information, proposed mechanisms of action, and results from clinical trials were reviewed. Results: Folate is an essential cofactor involved in methylation reactions, which are critical for monoamine synthesis and homocysteine regulation. Folate level is thought to be associated with mood disorders and limited response to antidepressants. Functional deficiency, due to a common genetic variant of the methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene, could also affect the presentation of bipolar disorder. Sodium valproate and lamotrigine, commonly used mood stabilizers for the treatment of bipolar disorder, can potentially interfere with folate and homocysteine metabolism. Previous studies consistently support the efficacy of folate in the treatment of depression; one study showed efficacy in the treatment of mania. Biologically active forms of folate formulations, which do not require biochemical conversion, could be beneficial in the treatment of bipolar disorder. Conclusions: Folate augmentation could be effective for the treatment of bipolar disorder. A common genetic variant of the MTHFR gene might impact the treatment effect of folate augmentation. The biologically active form of folate could potentially correct mood stabilizer-associated functional folate deficiency, help normalize monoamine synthesis, and improve outcomes.