L-Methylfolate Augments the Antidepressant Effects of SSRIs in Treatment-Resistant Major Depression

September 14, 2011 · Posted in Current Treatments, Potential Treatments 

Folate occurs naturally in foods such as broccoli

The B vitamin folate has been shown to be a useful augmentation treatment for patients who are nonresponsive or only partially responsive to selective serotonin reuptake inhibitor (SSRI) antidepressants. Treatment with folate works even in those who are not folate-deficient at baseline.

When folate is broken down in the body by reductase enzymes, it turns into the active form L-methylfolate, and crosses the blood-brain barrier. Maurizio Fava and colleagues at Massachusetts General Hospital (MGH) performed two placebo-controlled, randomized studies of L-methylfolate for depression. There was significantly greater improvement when SSRIs were augmented with L-methylfolate than when they were augmented with placebo. The results were significant with the use of 15mg of L-methylfolate, but not with 7.5mg, suggesting dose-related effects.

Editor’s note: These data add to the literature suggesting the importance of using folate or L-methylfolate as adjunctive treatments to antidepressants in unipolar depressed patients. Alec Coppen and colleagues have reviewed the literature, mostly from Europe, that shows that regular folate (usually in the 400 to 800ug/day range) is a significant augmenting agent for patients with inadequate responses to antidepressants. Based on this literature, it is generally recommended that in those with difficult-to-treat depression, women should take 1mg/day of folate and men should take 2mg/day (as per the suggestion of Andy Stoll of MGH).

L-methylfolate may have additional advantages, since it is four times more potent than folate when taken directly. There is a proprietary preparation of L-methylfolate (Deplin, available by prescription only at 7.5mg or 15mg). L-methylfolate is also available from some health food stores in a generic version containing 1mg of the compound. Given the findings by Fava that 15mg (but not 7.5mg) of adjunctive L-methylfolate was an effective augmentation for SSRIs, relatively higher doses of L-methylfolate may be more effective than the 1-2mg of regular folate often used in European studies.

However, multiple studies have shown folate is more effective than placebo for augmenting antidepressants, and it remains to be studied directly whether L-methylfolate would be more effective in those without the reductase deficiency.

Side Note: Fifteen percent of the general population has a common gene defect that interferes with the ability of their tetrahydrofolate reductase enzyme to function at full capacity. For these people, taking L-methylfolate instead of folate is necessary.

In those with this deficiency, folate is unable to be converted to L-methylfolate and thus facilitate the metabolic pathway by which homocysteine, which has negative effects on central nervous system function and cognition, is turned into to s-adenosyl methionine (SAMe), which has positive antidepressant effects in unipolar depression as shown in multiple placebo-controlled clinical trials.


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