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Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues

J Clin Psychiatry 2009;70(suppl 5):12-17
10.4088/JCP.8157su1c.03

Supplementation with folate may help reduce depressive symptoms. Folate, a naturally occurring B vitamin, is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate and l-methylfolate),and folinic acid. Some forms may be more bioavailable than others inpatients with a genetic polymorphism and in those who take particular medications or use alcohol. Folic acid augmentation in depressed patients may reduce residual symptoms. The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism. Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor. Evidence for the efficacy of folate in improving cognitive symptoms is equivocal, but most studies used folic acid. Although the studies reviewed have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B12deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks.Several forms of folate appear to be safe and efficacious in some individuals with major depressive disorder, but more information is needed about dosage and populations most suited to folate therapy.


From the Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston.

This article is derived from the planning teleconference series “The Use of Complementary and Alternative Medicines to Achieve Remission in Major Depressive Disorder,” which was held in May 2009 and supported by an educational grant from Pamlab, LLC.

Financial disclosure appears at the end of the article.

Corresponding author: Maurizio Fava, MD, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 351, Boston, MA 02114 (mfava@partners.org).