Last summer, we posted a blog about using folate to treat (and perhaps prevent) depression in women of childbearing age.  Supporting that recommendation are the several reports indicating that people with lower folate levels are at higher risk of major depression or may experience more severe depressive symptoms.  Other studies have indicated that in folate-deficient patients, antidepressants may be less effective or may take longer to take effect.

But is folate an effective treatment for depression? A recent report indicates that augmentation with L-methylfolate may be effective for treating patients with depression who are partial- or non-response to selective serotonin reuptake inhibitors (SSRIs).  In this multicenter trial, 75 patients with SSRI-resistant major depressive disorder were randomly assigned to receive: (1) l-methylfolate for 60 days (15 mg/day); (2) placebo for 30 days followed by L-methylfolate (15 mg/day) for 30 days; or (3) placebo for 60 days. In all groups SSRI dosages were kept constant throughout the study.

Adjunctive treatment with l-methylfolate at 15 mg/day showed significantly increased response rates and decreased the severity of depressive symptoms.  (It seems as if lower doses of l-methylfolate were not effective.  A somewhat larger trial included in this report failed to show any improvement when l-methylfolate was used at a lower dose of 7.5 mg/day.)  L-methylfolate was well tolerated, with rates of adverse events similar to those reported in the placebo group.

In an earlier double-blind placebo-controlled study of folic acid (500 mcg/day) added to fluoxetine, Coppen and Bailey found that adjunctive folic acid was effective in women but not in men. In three other studies where patients with major depression were selected without regard to folate deficiency, it seems that positive results were seen only when higher doses of l-methylfolate (above 10 mg/day) were used.

Pregnancy and L-methylfolate

As there has been an increasing interest in the use of folate to treat depression, we have received more questions regarding the use of L-methylfolate (sold as Deplin) during pregnancy either alone or in combination with an antidepressant.  We all know that folate is important for pregnant women.  Because women with low folate levels are at increased risk of having a child with a neural tube defects (NTDs) and other types of malformations, the U. S. Public Health Service and CDC recommend that all women of childbearing age consume 0.4 mg (400 mcg) of folic acid daily.  (Most prenatal vitamins contain 0.8 mg or 800 mcg of folic acid.)

Folate is typically taken in its synthetic form (as in vitamin supplements) or as naturally occurring dihydrofolate in foods. For those of you interested in the nitty gritty details of folate metabolism, these folates are converted to the active form of l-methylfolate by 5,10-methylenetetrahydrofolate reductase (MTHFR). Importantly the MTHFR gene has various polymorphisms that affect this conversion.  About half of all Caucasians have a less efficient form of the MTHFR gene, and the prevalence may be even higher in certain groups (e.g., Californian Hispanics, African Americans). Those individuals with these less efficient forms of the MTHFR gene may be more prone to folate deficiency; however, taking l-methylfolate bypasses the MTHFR enzyme and leads to higher levels of the biologically active l-methylfolate.

It’s Safe: But How Much?

Because l-methylfolate is the naturally occurring, biologically active form of folic acid, synthesized by the human body, it is safe to take during pregnancy.  Where things get a bit murky is determining how much is safe during pregnancy.  When we make recommendations regarding the use of vitamin supplements, we refer to the Recommended Dietary Allowance (RDA) to determine what amount to use.  The upper limit established for synthetic forms of folate in dietary supplements and fortified foods is 1000 mcg for pregnant and lactating women.  While the amount of l-methylfolate used in the Coppen and Bailey study (500 mcg/day) does not exceed the recommended limit, most studies demonstrating efficacy for l-methylfolate uses doses that are 10 to 15 times higher than the recommended limit.

Some might wonder if l-methylfolate may be better for treating depression than conventional antidepressants during pregnancy; however, we cannot say that using high doses of l-methylfolate in pregnancy is safer.  No published studies have assessed the safety of high doses of l-methylfolate in pregnancy.  Yet there are certain situations where higher doses of folate may be used during pregnancy (usually 4 to 5 mg) “under medical supervision” (e.g., if a woman has given birth to a child with a neural tube defect in a previous pregnancy).

Given the uncertainty regarding the use of high doses of folate during pregnancy, antidepressants remain the first choice when pharmacologic treatment of depression is indicated.  But there are other situations where the decision might not be so straightforward.  What if you have a patient who responded to antidepressant only when augmented with l-methylfolate?  Or what if you have a pregnant woman with a partial response to an SSRI?  Would you opt to augment with l-methylfolate before you would consider augmenting with lithium or an atypical antipsychotic agent?

Ruta Nonacs, MD PhD

Bentley S, et al. Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis. Clin Ther. 2011;33:204–210.

Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121–130. doi: 10.1016/S0165-0327(00)00153-1.

Morrell MJ. Folic acid and epilepsy. Epilepsy Curr. 2002;2:31–4