Evidence for Folate in Combination With Antidepressants at Initiation of Therapy

Maurizio Fava, MD, and David Mischoulon, MD, PhD

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston

The Need for Combination or Augmentation Therapy

Antidepressant monotherapy tends to produce relatively low remission rates,1 and residual symptoms are common among people who have achieved remission from depression.2 The use of combination or augmentation therapies from the start of treatment may accelerate antidepressant response through the synergy of different mechanisms of action.3 Augmenting antidepressants with a form of folate, a naturally occurring B vitamin, may provide beneficial effects for depressive symptoms. In addition, folate deficiency has been associated with the presence of depression, may hinder response to antidepressants, and may contribute to relapse of depression.4–6

Mechanism of Action of Folate in Depression

Three commercially available folate formulations, folic acid, 5-MTHF (also known as methylfolate and l-methylfolate), and folinic acid, may have a role in improving MDD remission rates. Via the one-carbon cycle, folic acid and folinic acid are converted into l-methylfolate. This active form of folate can cross the blood-brain barrier and activate the enzymes needed to synthesize dopamine, norepinephrine, and serotonin,7 which are the trimonoamine neurotransmitters known to be involved in depression (AV 1AV 1)).8 Additionally, MTHFR, an enzyme needed to convert folate forms to l-methylfolate, is affected by the C677T polymorphism, a genetic variation common in patients with depression that can impair the conversion to l-methylfolate.9

Evidence for Folate in Depression

Folic acid. Two randomized, controlled studies10,11 have examined folic acid as augmentation therapy for depression. The first study10 found that folate may reduce residual symptoms of depression, particularly in individuals with low folate levels. The second study, by Coppen and Bailey,11 found a significantly greater response rate with women (but not men) who received folic acid plus an antidepressant versus placebo (AV 2AV 2).

5-MTHF. Five studies12–16 have examined 5-MTHF monotherapy or augmentation in depression. In monotherapy double-blind trials, this form of folate was found to have a response rate similar to that of amitriptyline12 and higher than that of trazodone.13 The other 2 monotherapy trials15,16 were open studies, and both found evidence that 5-MTHF was an effective treatment with rapid onset of action. In a placebo-controlled augmentation trial, Godfrey et al14 found a significantly greater reduction in overall clinical outcome scores with adjunctive methylfolate than with placebo (AV 3AV 3).

Folinic acid. Folinic acid, or leucovorin, is an adjuvant chemotherapy agent with limited evidence in depression. An 8-week open, prospective trial17 found that an SSRI plus folinic acid significantly reduced HDRS scores for previous partial and nonresponders to SSRIs (P < .01). And, among completers, 31% achieved response and 19% achieved remission.


Initiating Combination Therapy With Folate

In a review of combination and augmentation strategies, Fava and Rush3 proposed a new paradigm for the treatment of depression—combination therapy at the initiation of treatment. By carefully choosing medications with synergistic mechanisms of action, clinicians may help to increase rates of response and remission and decrease the risk for relapse. An agent such as folate, which is necessary to synthesize the trimonoamine neurotransmitters implicated in depression, may enhance the effects of a traditional antidepressant.

Since folate exists in a variety of forms, clinicians must select the best dosage and form for augmentation. In the study by Coppen and Bailey,11 109 patients with depression received either 500 μg/d of folic acid or placebo in addition to 20 mg/d of fluoxetine from the start of treatment. The lack of separation between folic acid and placebo response rates for men may be due to an insufficient dosage of folic acid (see AV 2AV 2). Additionally, folic acid lowers plasma homocysteine levels, and the MTHFR C677T polymorphism impairs homocysteine metabolism. Therefore, 5-MTHF may be a more suitable form of folate supplementation for some patients because MTHFR is not needed for 5-MTHF to penetrate the blood-brain barrier. For example, the study by Godfrey et al14 found that folate-deficient patients with MDD (n = 24) who were given 15 mg/d of MTHF in addition to psychotropic treatment experienced a greater reduction of symptoms than patients receiving a placebo augmentation (see AV 3AV 3).

Safety Concerns With Folate Supplementation

Overall, folate is generally well tolerated. Historically, the greatest concern with folate supplementation has been its ability to mask vitamin B12 deficiency. Inadequate B12 results in anemia identical to that caused by folate deficiency; however, inadequate B12 also causes irreversible damage to the central and peripheral nervous systems.18 Folic acid supplementation corrects the anemia of B12 deficiency, delaying diagnosis but concealing the continuing lack of B12, thus leaving the patient vulnerable to permanent nervous system damage. However, 5-MTHF is unable to synthesize DNA and is, therefore, not expected to mask B12 deficiency.19

Cancer risk has also been a concern with folate supplementation.19–21 A recent article by Ebbing and colleagues20 suggested increased cancer incidence and mortality after treatment with folic acid and vitamin B12. However, close scrutiny of the evidence presented by Ebbing et al20 has suggested that those claims are not well supported.19,21,22 The benefits of folate supplementation may outweigh the risks of cancer. However, caution should be used in at-risk patients, such as those with a family history of colorectal cancer.19,22

Another concern is that folate doses >800 µg/d can result in high levels of unmetabolized serum folic acid, reducing the amount of brain l-methylfolate and leading to decreased monoamine levels, an outcome that potentially increases the risk of or exacerbates depression. Again, the findings are mixed, but, in individuals in whom this is a concern, 5-MTHF may be less likely to incur these risks.19,22

For Clinical Use

  • Be aware that folate plays an important role in synthesizing the trimonoamine neurotransmitters known to be involved in depression
  • Consider folate supplementation when initiating treatment for patients with depression and low or normal folate levels
  • Some forms of folate may be more effective than others in particular patient populations, but more rigorous study is needed

Drug Names

fluoxetine (Prozac and others)


5-MTHF=5-methyltetrahydrofolate, BH4=tetrahydrobyopterin, DHF=dihydrofolate, F=folic acid, HDRS=Hamilton Depression Rating Scales, L-MF=l-methylfolate, MDD=major depressive disorder, MTHFR=methylenetetrahydrofolate reductase, SSRI=selective serotonin reuptake inhibitor

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