Women with depression should be offered folic acid

We disagree with Nahas and Sheikh’s conclusion that there is insufficient evidence to recommend folate for major depressive disorder (MDD).¹ Our review of the same studies cited in their review of alternative medicines for depression leads us to the opposite conclusion and reveals misinterpretations of the data. We outline these studies here so that readers can draw their own conclusions.

In a 10-week randomized, blinded trial, Coppen and Bailey measured the effect of folate when combined with fluoxetine for the treatment of major depression (N = 127).² The relatively unimpressive average improvement, noted by Nahas and Sheikh, is shown to be the result of a sex-specific response variable. Based on intention to treat and per protocol analyses, response and remission rates as well as end-point depression scores in the folate plus fluoxetine group were shown to be clinically superior for women but not men (Table 1).² Only around 3 to 4 women need to be treated with folic acid for 1 to achieve treatment response or remission. This highly clinically meaningful result has also been overlooked in recent depression guidelines.^3,4 It is worth noting that mean folate levels were low but within the normal range at baseline in the study and, as such, response was not linked to overt folate deficiency.

Nahas and Sheikh also cited an earlier 52-week randomized blinded trial by Coppen et al that measured the effect of folate augmentation of “affectively very well” lithium clinic patients with unipolar depression (n = 53), bipolar disorder (n = 17), and schizoaffective disorder (n = 5).⁵ The investigators indicated that the affective morbidity of study participants was so low that it was difficult to assess the value of any additional therapy. In the unipolar depression group, the Beck Depression Inventory (BDI) average score at baseline was approximately 8, indicating minimal symptoms. Therefore, this trial was not designed to assess the antidepressant effect of folate in MDD. Nonetheless, a significant improvement in BDI was observed in the unipolar depression folate group (P < .02) but not the placebo group (Table 2). Unfortunately, a subgroup analysis based on sex was not reported. These data are not consistent with Nahas and Sheikh’s conclusion of no difference in BDI scores between groups.

The third cited trial enrolled only people with folate deficiency (red-cell folate < 200 μg/L) who met the diagnostic criteria for depression (n = 24) or schizophrenia (n = 17).⁶ There were no enrolment criteria based on depression severity and no baseline depression data were provided. A hint that depression severity was minor at baseline were the 1-month Hamilton Depression Rating Scale scores of less than 10 in both groups. For these reasons, the trial is not applicable to address the question of folate augmentation for the routine patient with MDD starting a course of antidepressants. Moreover, a sex-specific subanalysis was not reported.

Finally, Nahas and Sheikh refer to but discount Passeri and colleagues’ randomized comparison of folate versus trazodone added to standard psychotropic medication for the treatment of depression in cognitively impaired patients.⁷ We believe that the absence of a placebo group prevents any conclusion from being formed regarding the effectiveness of either agent in depressed elderly patients with mild to moderate dementia.

Based on the Coppen and Bailey randomized trial² (the only trial to test adjunctive folate in clinically depressed patients), folate provides a clinically meaningful benefit to women initiating standard antidepressant medication when used in a typical supplementary dose of 0.5 μg daily. The muted benefit found in other trials might represent the average of nonresponders (men) and responders (women) with MDD as well as their low burden of depressive symptoms. Folate’s use is made more attractive by its safety profile, low cost, and potential for providing other benefits. The use of folate in sexually active women of childbearing age might add the further benefit of protecting against neural tube defects to the fetus if pregnancy occurs. With baseline folate measures being unnecessary, not recommending folate to this group of women is difficult to justify. In contrast to Nahas and Sheikh, we believe the evidence to date supports its routine use in clinical practice in women with depression and we encourage depression guideline developers to reconsider its place in therapy.

• Copyright© the College of Family Physicians of Canada