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remethylation of homocysteine, thus reducing the body’s production of SAM-e, which
may have serious effects on mood.
Recent genetic studies may explain why some individuals respond better to folate
supplementation than others. The methylene tetrahydrofolate reductase (MTHFR) gene
limits the conversions of folic acid to L-methyltetrahydrofolate (known as methylfolate),
the biologically active form. Genetic variations in the MTHFR gene may reduce the
ability to benefit fully from oral folate supplements, and may be related to folate
deficiency. Both Lake and Spiegel and Brown and Gerbarg emphasize this critical
genetic factor. Individuals who do not respond adequately to folate supplements can be
tested for MTHFR variants. Those found to be positive for the variants can be treated
with methylfolate which avoids the need for conversion.
The 2000 Coppen and Bailey study^4 showed that 93% of women had a good response to
a mixture of folate and the antidepressant fluoxetine (Prozac), while only 61% of the
group of women who received only placebo in addition to fluoxetine had a good
response. The dose was 500 mcg per day.
Women in the Coppen and Bailey study achieved a 20.6% reduction of homocysteine
on fluoxitine and folate, while the men got no apparent benefit.
Like Brown et al., Mischoulon and Rosenbaum cite Bottiglieri’s research on the effect of
folate deficiency on the cycle that furnishes the body with SAM-e, and the resultant
deficiency of SAM-e and elevation of homocysteine levels that are associated with
depression.^5 But they concede that supplementation with folate may not release or
furnish SAM-e or lower homocysteine.
Although the link with vitamin B12 deficiency is not so strong or clear, at least in
younger people, a 2007 meta-analysis by Gilbody et al.^6 is cited by Mischoulon and
Rosenbaum for the proposition that there is a “robust” relationship between low
folate and depression, but much more so in women than in men.^7
The 1997 Fava et al. study cited by both Fugh-Berman and Cott and Brown et al., is cited
by Mischoulon and Rosenbaum for the proposition that pretreatment folate status was