Nutrition and Depression: The Role of Folate

Jonathan E. Alpert, MD, PhD, Maurizio Fava, MD


Medscape Psychiatry & Mental Health eJournal. 1997;2(1) 

In This Article

Folate in the Treatment of Depression

An association between low folate levels and depression has suggested a potential role for folate in the treatment of depressive disorders. In support of this hypothesis, mood improvement has been observed in folate-deficient patients with epilepsy or gastrointestinal disorders.[16,17] In a retrospective survey, psychiatric patients treated with folic acid spent less time in the hospital and exhibited mood improvement and better social functioning than those with low folate levels who did not receive supplemental folate.[18]

In a double-blind, placebo-controlled trial involving patients with unipolar and bipolar mood disorders who were receiving lithium prophylaxis, administration of small daily doses of folic acid (200mcg) reduced the occurrence and duration of mood disorder symptoms.[19]

In a randomized, controlled trial of 24 depressed patients with RBC folate levels lower than 200ng/mL, addition of the folate derivative methyltetrahydrofolate (methylfolate) at a dosage of 15mg/day to ongoing treatment with standard agents (tricyclic antidepressants, monoamine oxidase inhibitors, or lithium) was associated with better clinical outcome at 3 and 6 months than addition of placebo.[9] Methylfolate was selected because it is actively transported into the CNS and concentrated in synaptic regions where it is involved in essential metabolic pathways.

In an open-label trial of 20 elderly patients with depressive disorders, of whom only 2 were frankly folate deficient, administration of methylfolate (50mg/day) alone, rather than as an adjunct to standard antidepressants, was associated with an 81% response rate over a 6-week period.[20]

Growing evidence suggests that folate may have a place as an adjunct to antidepressant pharmacotherapy and, perhaps, as a single agent in the treatment of depressed patients with borderline low or deficient folate levels. In a more speculative context, folates may have a place in the treatment of some depressed patients with serum or RBC folate concentrations in the normal range.

Because folate supplementation, in some studies, has made a positive contribution to the treatment outcome of psychiatric patients with conditions other than depression, including schizophrenia,[9,18] the question remains whether the potential benefits of folate and methylfolate reflect intrinsic antidepressant properties or are evidence for a more pervasive impact of folates on various aspects of neuropsychiatric function, among which the regulation of mood, sleep, appetite, drive, and concentration comprises an integral part.

Although the relationship between low folate level and depression is well supported, as is the importance of correcting folate deficiency in the treatment of depression, the potential neuropsychiatric morbidity associated with elevated folate levels among depressed patients remains unclear. Sleep alterations, malaise, irritability, and hyperactivity have been reported among healthy volunteers given supraphysiologic daily doses of folate (15mg).[21] Additionally, lowered serotonin (5-hydroxytryptamine) levels in the brains of rats fed diets oversupplemented with folate, as well as in rats receiving folate-deficient diets, have been reported.[22] These observations suggest that a curvilinear relationship may exist between folate dosing and antidepressant benefit such that administration of folate or methylfolate in quantities above or below a putative therapeutic window would be unlikely to benefit depressed patients and may contribute to depressive symptomatology.


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