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August 2009

Folate and Depression
L-methylfolate (Deplin) shows theoretical promise as an augmenting strategy for treatment-resistant depression, but so far there is little clinical evidence of its efficacy.

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Folate and Depression

August 2009

Considerable interest has been generated lately in the topic of folate and depression and, more specifically, in the role of L-methylfolate (Deplin) for modulating trimonoamines and augmenting antidepressants.1 L-methylfolate is available in the United States by prescription as a "medicinal food." Manufactured by Pamlab, it is indicated for individuals with major depressive disorder (MDD) "who present with suboptimal folate levels in the cerebrospinal fluid, plasma, and/or red blood cells, with particular emphasis as an adjunctive treatment (augmentation) for individuals who have not fully remitted following an adequate trial of an antidepressant."2

Folate is metabolized to its biologically active form, [6S]-5-methyltetrahydrofolate, better known as L-methylfolate. A critical enzyme in this conversion is 5,10-methylenetetrahydrofolate reductase (MTHFR), which exists in at least two genetically polymorphic forms (C677T and A1298C) that reduce enzyme activity and impair conversion to L-methylfolate.3 Whether these polymorphisms are associated with an increased risk of depression is not fully resolved. Gilbody et al, in a meta-analysis, found an increased risk (odds ratio 1.36) associated with the C677T homozygous TT variant.4 They also found an increased risk for schizophrenia (OR=1.44) and bipolar disorder (OR=1.82). On the other hand, a large case-control study and a meta-analysis were not supportive of such an association.5 The study, which involved MTHFR C677T genotyping of patients with recurrent MDD (n=1222) and normal controls (n=835), found no significant differences in allele frequencies or genotype. The meta-analysis, which included this study and three earlier case-control studies, also found no association between depression and the TT genotype.

Folate is important for DNA synthesis (deficiencies are associated with megaloblastic anemia), methylation reactions in the central nervous system, and more specifically for modulating synthesis of serotonin, norepinephrine, and dopamine through effects on tetrahydrobiopterin (BH4).6 Numerous studies have found an association between folate deficiency and depression, although scientific rigor is lacking in many of them.7 Association, of course, is not synonymous with causality, and reverse causality (depression leading to folate deficiency) may be a confounding factor.

Just how effective folate is as a treatment for depression either used alone or as an adjunct to a conventional antidepressant remains open to question. I concluded recently: "Overall, treatment studies with folate are few and variable in design, detail, duration, sample size, dose, and preparation used. It is a little difficult to go overboard recommending folate as an augmentation of conventional antidepressants, and it appears to have little future as a monotherapy."3 In other words, there is a genuine need to enlarge the evidence database. The good news is that Papakostas and others at the Massachusetts General Hospital are conducting an 8-week, multicenter, double-blind, placebo-controlled study to evaluate L-methylfolate as augmentation in 150 selective serotonin reuptake inhibitor (SSRI)-resistant patients with MDD.8 The L-methylfolate group will receive 7.5 mg/day for the first 4 weeks and then 15 mg/day for the remaining 4 weeks. A second group will receive placebo for the first 4 weeks followed by 7.5 mg/day of L-methylfolate, while a third group will remain on placebo for the whole study. Completers will have the option of an additional 12 months of open-label treatment with L-methylfolate. As of May 11, 2009, the study was described as "ongoing, but not recruiting patients."8 The outcome of this study should be instructive. If the results are favorable to L-methylfolate, it would be of interest to know if pretreatment serum and/or red blood cell folate levels or MTHFR C677T status played a role in the outcome.

Smith et al, in an effort to stimulate debate about whether mandatory folic acid fortification of flour should be introduced in the United Kingdom as it was in the United States and Canada a decade ago, ask whether folic acid is good for everyone.9 They raise concerns that high concentrations of unmetabolized folic acid in the body might facilitate "progression and growth of preneoplastic cells and subclinical cancers," impair natural killer cell cytotoxicity, reduce antifolate drug effectiveness, increase the risk of cognitive dysfunction in the elderly, and adversely affect certain types of cardiovascular disease. For example, a recent study in the United States and Canada found that 1 mg/day of folic acid supplementation did not reduce the risk of colorectal adenomas and may have increased the risk of multiple adenomas and advanced lesions.10 A secondary analysis of this study found a significantly increased incidence of prostate cancer over a 10-year period in the folic acid group (9.7% vs. 3.3% with placebo).11

The plot thickens when it comes to L-methylfolate, the reduced biologically active form of folate, for which there is support, at least in theory, for it not carrying the potentially negative baggage of folic acid. At present, there is a paucity of direct comparative clinical studies that might answer the question of whether L-methylfolate has efficacy and safety advantages over folic acid.

Recently, an Expert Review Supplement provided favorable comment on L-methylfolate for treating depressive disorders, stating that "it appears to be the optimal compound for augmentation."12 The supplement was supported by Pamlab and seems overly optimistic in view of the rather sparse supporting database. My views are more in keeping with Mischoulon et al, who write: "It is not yet clear whether folates will ultimately be shown to be safe and effective adjunctive agents in treating depression. . . . In the absence of larger, controlled clinical trials, we recommend that physicians proceed with usual caution when prescribing any type of folate supplementation."13

In conclusion, L-methylfolate shows considerable theoretical but, thus far, limited clinical promise as an augmenting strategy for treatment-resistant depression. For those of us favorably inclined towards evidence-based medicine, we look forward to the forthcoming expansion of the folate database.

by James W. Jefferson, MD

Clinical Professor of Psychiatry, University of Wisconsin School of Medicine and Public Health; Distinguished Senior Scientist, Madison Institute of Medicine, Inc.; Director, Healthcare Technology Systems, Inc.

1Stahl SM: Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr 2007;12:739-744.

2PamLab, LLC: Deplin® tablets. Package insert. 04/09. Available at Accessed June 23, 2009.

3Jefferson JW: Folate for depression: Fabulous facilitator or fantastic flop? Psychopharm Rev 2007;42:75-82.

4Gilbody S, Lewis S, Lightfoot T: Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: A HuGE review. Am J Epidemiol 2007;165:1-13.

5Gaysina D, Cohen S, Craddock N, Farmer A, Hoda F, Korszun A, Owen MJ, Craig IW, McGuffin P: No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: Results of the depression case control (DeCC) study and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2008;147B:699-706.

6Stahl SM: L-methylfolate: A vitamin for your monoamines. J Clin Psychiatry 2008;69:1352-1353.

7Gilbody S, Lightfoot T, Sheldon T: Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health 2007;61:631-637.

8A study of 6(S)-5-MTHF among serotonin reuptake inhibitor (SSRI)-resistant outpatients with major depressive disorder (MDD). Available at Identifier NCT00321152. Accessed June 23, 2009.

9Smith AD, Kim YI, Refsum H: Is folic acid good for everyone? Am J Clin Nutr 2008;87:517-533.

10Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER; Polyp Prevention Study Group: Folic acid for the prevention of colorectal adenomas. JAMA 2007;297:2351-2359.

11Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA: Folic acid and risk of prostate cancer: Results from a randomized clinical trial. J Natl Cancer Inst 2009;101:432-435.

12Farah A: The role of L-methylfolate in depressive disorders. Primary Psychiatry 2009;16(Suppl 1):1-8.

13Mischoulon D, Fava M, Stahl SM: Folate supplementation: Is it safe and effective? (Reply to Letter to the Editor) J Clin Psychiatry 2009;70:767-768.

Disclosure: Dr Jefferson recently received a consultation honorarium and a free lunch from Pamlab. This article was written without any financial support.