Evidence for the Use of l-Methylfolate Combined With Antidepressants in MDD

Maurizio Fava, MD (Chair)

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

Richard C. Shelton, MD

Department of Psychiatry, Vanderbilt School of Medicine, Nashville, Tennessee

John M. Zajecka, MD

Department of Psychiatry, Rush University Medical Center, Chicago, Illinois

Three investigators met to discuss their poster showing new research results for the use of adjunctive l-methylfolate in patients with MDD. Download the poster.


Dr Fava: Depression is a leading cause of disability worldwide,1 and, despite the availability of numerous antidepressant monotherapies, the goal of remission is challenging to achieve in clinical practice.2 The largest clinical trial conducted in depression to date, STAR*D,3 suggested that only about 1 in 3 patients will achieve remission with their first antidepressant treatment.

Clinicians need to consider which next-step strategies to suggest for patients who do not achieve remission or response with the initial treatment. For lack of response, switching antidepressants is often the best strategy, but, in patients with partial improvement, augmentation strategies may be used to address residual depressive symptoms. The existing antidepressant therapy is typically maintained at the same dose. Initially, lithium or thyroid hormone augmentations were tested, but, more recently, studies of augmentation with atypical antipsychotics have led to an indication for adjunctive treatment of depression for aripiprazole, quetiapine, and the olanzapine/fluoxetine combination.4

Other augmentation therapy options may be found within the area of complementary and alternative medicine. Among these treatments, one of the best studied is folate, which has been examined in several clinical studies in depression since the 1980s.5 The literature suggests that l-methylfolate (also known as 5-methylenetetrahydrofolate [5-MTHF] and methylfolate), which is the active form of folate that crosses the blood-brain barrier, may have intrinsic antidepressant effects or may augment the efficacy of antidepressants.

Study of l-Methylfolate as Adjunctive Therapy With SSRIs


Dr Fava: My colleagues and I undertook a placebo-controlled study of l-methylfolate added to ongoing antidepressant therapy in patients with MDD who had inadequately responded to an SSRI. We recently presented a poster6 summarizing the results of 2 multicenter trials conducted in succession across the same academic centers in the United States. Both trials used a sequential parallel comparison design (SPCD) that allows examination of drug-placebo differences in 2 phases of 30 days each. Some patients received only adjunctive placebo in both phases, some received adjunctive placebo in the first phase and adjunctive l-methylfolate in the second phase, and some received adjunctive l-methylfolate in both phases (AV 1AV 1).

In the first trial, the first phase examined the efficacy of adjunctive l-methylfolate, 7.5 mg/d, versus adjunctive placebo. We observed that patients who received 7.5 mg/d of l-methylfolate did not differ in outcome from those who received placebo.

In the second phase of the first trial, patients who had received 7.5 mg/d of l-methylfolate in the first phase received a dose of 15 mg/d (see AV 1AV 1). The response rate in the patients who had not responded to 7.5 mg/d in the first phase and received 15 mg/d in the second phase was numerically greater (24%) than the response rate in those who received adjunctive placebo in both phases and had not responded in the first phase (9%). Therefore, although the first trial did not support the use of 7.5 mg/d of l-methylfolate, it suggested that 15 mg/d may be effective.

The second trial using the same study design (SPCD) was then initiated to examine the efficacy of adjunctive l-methylfolate, 15 mg/d, versus placebo (see AV 1AV 1). The results of both phases of the second trial showed a robust effect of l-methylfolate, 15 mg/d, compared with placebo. When the data from both phases were pooled, statistical significance was achieved in the difference between active drug and placebo for HDRS-17 response rates (P=.04) and reduction in HDRS-17 mean scores (P=.05). Of the side effects reported in our study,6 only gastrointestinal effects occurred significantly more frequently with l-methylfolate than with placebo (P=.03).

These findings suggest that l-methylfolate, at a dose of 15 mg/d, has a significant adjunctive effect compared with placebo among patients with MDD who have responded inadequately to antidepressant treatment. Further studies are needed to replicate these findings.

Dr Zajecka: The clinical information to be extrapolated from these data is that, for patients with MDD who are inadequately responsive to an SSRI and who have responded suboptimally to 7.5 mg/d of adjunctive l-methylfolate, increasing the dose to 15 mg/d may be the first intervention. Considering the safety and tolerability of l-methylfolate, a dose of 15 mg/d may also be an optimal starting dose for many patients.

Place of l-Methylfolate Among Other Augmentation Strategies

Dr Shelton: To put this study6 into context, we need to compare it with previous augmentation studies. For example, placebo response rates vary considerably between clinical trials, so to evaluate these results we have to compare them with drug-placebo differences in other augmentation trials. Data from this study can be compared with data from studies of augmentation with atypical antipsychotics in which those agents were shown to be effective compared with placebo in MDD unresponsive to standard antidepressant therapy. In our study,6 the magnitude of effect—ie, the drug effect minus the placebo effect—of l-methylfolate was equivalent to or greater than the effect sizes shown in atypical antipsychotic augmentation studies.4


Although more research is needed, the efficacy results of this study6 and the relative safety and tolerability of l-methylfolate in comparison with atypical antipsychotic medications (AV 2AV 2)4 raise the question, “Where might we put l-methylfolate in a treatment algorithm?” Augmentation with l-methylfolate might precede atypical antipsychotic augmentation therapy.

Dr Zajecka: This study6 provides support for a treatment effect of l-methylfolate as adjunctive therapy, and, based on current evidence regarding safety and tolerability, I agree that l-methylfolate should be considered early in the course of treatment. We should remember that the patients in this study would not necessarily have been considered treatment-refractory by psychiatrists. However, the data suggest that l-methylfolate could be considered an appropriate adjunctive treatment after a patient’s depression has failed to respond adequately to 1 or 2 trials of first-line monotherapy.


Types of Folate and Mechanism of Action


Dr Shelton: Decades of research on folic acid in depression indicate that folate depletion is associated with increased depression risk and decreased response to antidepressant therapies.5 I sometimes encounter confusion as to whether folic acid could be used as an alternative for l-methylfolate. People often do not understand that problems with folic acid absorption can prevent this substitution (AV 3AV 3).5 The hope that folic acid fortification in foods would alleviate depression has faded7 because many people are not able to adequately convert folic acid into its active form and because a high level of folate in plasma may interfere with uptake of l-methylfolate.8,9 Giving patients folic acid may therefore decrease the availability of l-methylfolate in the brain.8

Dr Zajecka: That is a good reminder. In this study, we used the bioavailable form of folate—l-methylfolate—which crosses the blood-brain barrier (see AV 3AV 3). Some people have a genetic polymorphism or predisposition that reduces the ability to convert folic acid into the bioavailable form. Other patients who may have folic acid absorption problems include those with chronic illnesses, who drink alcohol, who are malnourished, or who take certain medications (including some anticonvulsants) that may decrease the ability of folic acid to work optimally in the brain.10 Clinicians need to remain cognizant of the full range of adjunctive therapy choices when treating these patients.

Residual Symptoms

Dr Zajecka: Data11 suggest that failure to achieve asymptomatic remission of depression is among the most relevant predictors of relapse, so clinicians should maintain efforts to identify and treat patients’ residual symptoms. The STAR*D trial showed that patients have a broad range of residual symptoms.12,13 Clinicians should caution against treating just the individual symptoms of depression rather than the core depressive syndrome. I think l-methylfolate is an example of one way to address the overall syndrome, given its pathophysiologic association with depression.5

Dr Shelton: I agree. An analysis13 of the STAR*D data showed that more than 90% of patients whose depression had remitted, according to the definition of remission used in the study, had at least 1 residual symptom; a greater number of residual symptoms was associated with greater risk of relapse. Unfortunately, practicing clinicians may target individual residual symptoms (eg, sleep disturbance or low energy) with nonantidepressant therapies but leave the overall syndrome of depression inadequately addressed. Although there are times when addressing symptoms individually is appropriate, some adjunctive therapies can be used not only to target individual symptoms but also to attempt to resolve the full syndrome of depression. Dr Zajecka made a good point that we need to take an overall syndromic view, because when people have incomplete remission of their symptoms, they have continued impairment and are much more likely to relapse into a depressed state.


Dr Zajecka: Patient variability occurs in absorption of folic acid in the central nervous system, making it sensible to use l-methylfolate, the bioavailable form. Data on the potential efficacy and safety and tolerability of l-methylfolate suggest that it is a promising addition to the choices of adjunctive therapy for depression.

For Clinical Use


  • Adjunctive l-methylfolate has shown greater efficacy than placebo in the treatment of depressive symptoms that are inadequately responsive to SSRI monotherapy
  • l-methylfolate appears to be safe and well tolerated, and could be used as adjunctive therapy early in treatment to address the depressive syndrome rather than individual residual symptoms


Drug Names

aripiprazole (Abilify), lithium (Lithobid and others), l-methylfolate (Deplin), olanzapine/fluoxetine (Symbyax), quetiapine (Seroquel)


BH4 = tetrahydrobiopterin, DHF = dihydrofolate, DHFR = dihydrofolate reductase, HDRS-17 = 17-Item Hamilton Depression Rating Scale, MDD = major depressive disorder, MTHF = methylenetetrahydrofolate, MTHFR = methylenetetrahydrofolate reductase, NNT = number needed to treat, NNH = number needed to harm, LHH = likelihood to be helped or harmed, SPCD = sequential parallel comparison design, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, THF = tetrahydrofolate, XR = extended release

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