Folate in the form of l-methyl folate enhances antidepressant response

This is the third post in a series on complementary and integrative treatments of depressed mood. The previous post reviewed the evidence for SAMe (S-adenosylmethionine). In this post I briefly review the evidence for folate in depressed mood. Future posts will take a look at omega-3 fatty acids, vitamin D, the supplement DHEA and other non-pharmacologic approaches to fighting the winter blues.

Antidepressant mechanism of action

The mechanism of action by which folate affects mood has not been definitively established however its antidepressant effects are probably related to the central role this vitamin plays in the synthesis of neurotransmitters involved in mood regulation, including serotonin, dopamine and norepinephrine. Specifically, folate is a co-factor in the re-methylation of homocysteine into S-adenosylmethionine, required steps in synthesis of serotonin, dopamine and norepinephrine.

Folate in the diet is converted in the body to l-methylfolate, the only form of this vitamin that can cross the blood-brain barrier and contribute to neurotransmitter synthesis. It has been suggested that a significant percentage (perhaps as many as 75%) of individuals who fail to respond to antidepressants (so-called refractory depressed mood or treatment-resistant depression) may have a genetic mutation in the enzyme required for conversion of dietary folate into l-methylfolate, resulting in abnormal low levels of l-methylfolate in the brain and correspondingly low levels of neurotransmitters involved in mood regulation. Emerging research findings suggest that individuals with treatment-resistant depression respond better when high dose folate in the form of l-methylfolate (7.5 to 15mg/day) is added to their antidepressant regimen (Duprey 2016).

Folate enhances antidepressant response

Findings from controlled trials support that folate is an effective adjunctive treatment of depressed mood. One study found that the efficacy of fluoxetine (Prozac) and other antidepressants is significantly enhanced by the addition of daily folate. In another study the response of depressed patients treated with a SSRI antidepressant taken together with l-methylfolate (0.5-1mg/day) was as much as 30% greater than patients treated with a SSRI only (Papakostas 2004). An early systematic review of three controlled studies involving a total of 247 subjects concluded that “folate may have a potential role as a supplement to other (i.e., antidepressant) treatments” of depressed mood however findings were inconsistent (Taylor 2003). Patients who took folate 1mg with an antidepressant experienced incrementally greater reductions in depressed mood compared to those taking an antidepressant alone. However, one study included in the review failed to show a differential effect when folate was combined with trazodone, a widely used antidepressant. The significance of these findings was limited by small number of studies done and small study size. Shelton et al (Shelton 2013) provide a review of more recent research findings, which support that l-methylfolate augmentation is safe and results in statistically significant improvement in response compared to individuals taking an antidepressant alone (Shelton 2013).

Bottom line

In view of the high incidence of treatment non-response to antidepressants, the fact that the majority of non-responders may lack the enzyme required to convert dietary folate into its active form (i.e. l-methylfolate) needed for neurotransmitter synthesis, and consistent positive findings of l-methylfolate augmentation in this population, taking l-methyl folate together with an antidepressant is a reasonable integrative approach for managing depressed mood.

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