Can depressed people benefit from folic acid supplementation?

Townsend Letter for Doctors and Patients, Jan, 2001 by Alan R. Gaby

One hundred twenty-seven patients with a new episode of major depression (i.e., the first episode in at least 6 months) were treated with 20 mg/day of fluoxetine (Prozac) and were randomly assigned to receive, in double-blind fashion, either 500 mcg/day of folic acid or placebo for 10 weeks. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (HRS; 17-item version) score for depression of 20 or more. Among the 109 patients completing the trial, there was a significantly greater improvement in the folic acid group than in the placebo group. This improvement was confined to the women, in whom the mean HRS score at the end of the trial was 6.8 in the folic acid group vs. 11.7 in the placebo group (p[less than]0.001). Of the women who received folic acid, 93.9% showed a good response (defined as a greater than 50% reduction in HRS score), compared with 61.1% of those receiving placebo (p[less than]0.005). For men, the "good response" rates were 61.1% and 63.6%, r espectively. Possible or probable side effects due to fluoxetine were reported by 12.9% of patients receiving folic acid, compared with 29.7% of those receiving placebo (p[less than]0.05).

Comment: These results indicate that supplementation with folic acid may increase the efficacy and reduce the side effects of fluoxetine in women, but not men, with depression. Patients with depression have consistently been found to have low plasma and RBC folate levels, and low plasma folate has been associated with a poor response to antidepressant medications. In the present study, the lack of efficacy in men may have been due to an inadequate dose. That possibility is supported by two observations. First, although plasma folate levels increased in folic acid-supplemented men, the increase was less pronounced than in women. Second, plasma homocysteine levels did not decline in folic acid-supplemented men, whereas these levels decreased significantly by 20.6% in women. Since folic acid supplementation is known to decrease homocysteine levels, it appears that men have a higher requirement for this vitamin than women.

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.