Folate for Depression

Background

Folic acid is a common and familiar vitamin (vitamin B9), both as a stand-alone product and as an ingredient in multivitamins. Health care professionals are noticing another form of folate, L-methylfolate (i.e., methylfolate, methyltetrahydrofolate, 5-MTHF) in supplements and medical foods. Methylfolate can be found in several U.S. prenatal vitamins (e.g., OptiNate), other multivitamins (e.g., Optimized Folate), and in medical foods (e.g., CerefolinNAC, Deplin) promoted to enhance memory or mood. This article explains folate forms and functions, then reviews evidence of folate’s role in the treatment of depression.

Folate Forms, Functions, and Failures

In humans, folate is necessary for DNA synthesis and normal cellular maturation and division. For example, folate deficiency causes abnormal red blood cell precursors, megaloblasts, to form in the bone marrow. Megaloblasts are unable to mature into normal red blood cells, and are destroyed by macrophages in the bone marrow. Hence, folate deficiency can cause megaloblastic anemia. Folic acid is also necessary for normal fetal neural tube development and synthesis of serotonin, norepinephrine, and dopamine.¹

Folate is the general term that refers to a variety of chemical forms of folic acid. Folic acid is the form found in vitamins and fortified foods. Dietary folate is a mixture of folates. These various forms of folate undergo multistep enzymatic change in the small intestine wall to L-methylfolate which participates in methylation reactions. A malfunction in any of the enzymes necessary for this transformation could result in deficient L-methylfolate levels. There is some preliminary evidence that a mutation of the gene responsible for production of the enzyme involved in the last step of this cascade, methyltetrahydrofolate reductase (MTHFR) is associated with depression, presumably due to inability to make adequate amounts of neurotransmitters.² This genetic mutation (677C/T mutation) is also associated with heart disease risk, seemingly due to inadequate levels of L-methylfolate, which may have a beneficial effect on endothelial function. Furthermore, certain medications (e.g., methotrexate, lamotrigine, etc) can inhibit enzymes in this pathway. Because L-methylfolate bypasses this conversion cascade, it is said to be a more “bioefficient” form of folate than folic acid.¹ Leucovorin (folinic acid) is a reduced form of folic acid that is better able to cross the blood brain barrier than folic acid. However, use of leucovorin does not bypass the need for MTHFR.³

Folate and Depression

Folic acid is required for the production of neurotransmitters including serotonin.^4,5 Folic acid deficiency is common among patients with depression.^6-8 And people with low folate status or lower dietary folate intake have a higher risk for depression.^9,10 Lower folate levels also link to poor response rates for patients taking antidepressants.^7,11

Taking folates with conventional antidepressants might improve treatment response. In a small study (n=127), patients who met DSM-III criteria for depression and who had a HAM-D score of 20 or more were randomized to folic acid 500 mcg daily or placebo. All patients also received fluoxetine 20 mg daily. Folic acid levels were increased in women more than in men. Almost all women in the folate group had a response (i.e., more than a 50% reduction in HAM-D) vs about 60% of women in the placebo group (p<0.005). Men did not benefit. These results suggest a higher folic acid dose may be required in men for efficacy in augmenting antidepressant response.¹²

Another study included a subgroup of patients with a DSM-III diagnosis of depression (n=24), plus folate deficiency or borderline folate deficiency (i.e., red cell folate <200 mcg/mL).¹³ Patients were randomized to 7.5 mg of L-methylfolate daily (given as racemic methylfolate 15 mg) or placebo for six months.^2,13 All patients also received standard pharmacotherapy. “Clinical outcome scores” improved significantly more in the methylfolate group than in the placebo-treated patients.¹³

L-methylfolate 25 mg daily (given as racemic methylfolate 50 mg) was compared to trazodone 100 mg daily in an elderly population with mild to moderate dementia, depression, and folate deficiency or borderline folate deficiency (n=96).^14,15 Similar improvement from baseline in HAM-D occurred with both treatments.¹⁴

A chart review of patients (n=95) given L-methylfolate 7.5 mg or 15 mg plus an SSRI or SNRI for depression was conducted. These patients were compared to matched controls (n=147) also taking an SSRI or SNRI for depression. Patients in both groups had a Clinical Global Impression-Severity (CGI-S) score of four to five (moderate to markedly severe). Patients had to have been taking their antidepressant or antidepressant/L-methylfolate for at least 60 days. Patients taking folic acid >400 mcg daily were excluded. Within 60 days, almost 20% of L-methylfolate patients had improvement in the CGI-S of two points or more (i.e., major improvement) vs about 7% of the patients who did not receive L-methylfolate.¹⁶

Folinic acid (leucovorin) 15 mg daily for two weeks, followed by 30 mg daily for six weeks, was added to SSRIs in patients with treatment-resistant depression (i.e., partial or no response after four weeks) in a small (n=33) open-label study.¹⁶ About 30% of patients responded (i.e., had more than a 50% reduction in HAM-D), while remission rates approached 20%.¹⁷

Conclusion

Although evidence of benefit is modest, increasing folate might be worth a try as an adjunct to antidepressants, especially in folate-deficient patients [Evidence level B; lower quality RCTs; case control study].^12-14,16 Folic acid is inexpensive and has little downside for most patients. Suggest at least 500 mcg/day of folic acid to augment antidepressants. But daily amounts of 800 mcg or greater should be discouraged in seniors due to evidence of cancer risk with high-dose folic acid in this population.¹

Patients might ask about claims that Deplin (L-methylfolate) (U.S.), a medical food, improves the efficacy of antidepressants. Tell them there is no proof that L-methylfolate is safer or more effective than folic acid, and it is more expensive.

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this PL Detail-Document: Melanie Cupp, Pharm.D., BCPS

References

1. PL Detail Document, L-Methyfolate, Pharmacist’s Letter/Prescriber’s Letter. March 2009.
2. Farah A. The role of L-methylfolate in depressive disorders. CNS Spectr 2009;141(1 Suppl 2):2-7.
3. Blehaut H, Mircher C, Ravel, et al. Effect of leucovorin (folinic acid) on the developmental quotient of children with Down’s syndrome (trisomy 21) and influence of thyroid status. PLoS One 2010;5(1):e8394.
4. Taylor MJ, Carney S, Geddes J, Goodwin G. Folate for depressive disorders. Cochrane Database Syst Rev 2003;(2):CD003390.
5. Coppen A, Swade C, Jones SA, et al. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord 1989;16:103-7.
6. Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-32.
7. Alpert M, Silva RR, Pouget ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J Clin Psychopharmacol 2003;23:309-13.
8. Tiemeier H, van Tuijl HR, Hofman A, et al. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry 2002;159:2099-101.
9. Morris MS, Fava M, Jacques PF, et al. Depression and folate status in the US Population. Psychother Psychosom 2003;72:80-7.
10. Tolmunen T, Voutilainen S, Hintikka J, et al. Dietary folate and depressive symptoms are associated in middle-aged Finnish men. J Nutr 2003;133:3233-6.
11. Fava M, Borus JS, Alpert JE, et al. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997;154:426-8.
12. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord 2000;60:121-30.
13. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392-5.
14. Passeri M, Cucinotta D, Abate G, et al. Oral 5’-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study [abstract]. Aging (Milano) 1993;5:63-71.
15. Shelton RC. The role of L-methylfolate in depressive disorders: commentary. Prim Psychiatry 2009;16(Suppl 1):8.
16. Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate plus SSRI or SNRI from treatment initiation compared to SSRI or SNRI monotherapy in a major depressive episode. Innov Clin Neurosci 2011;8:19-28.
17. Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid (leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry 2002;14:33-8.

Cite this document as follows: PL Detail-Document, Folate for Depression. Pharmacist’s Letter/Prescriber’s Letter. October 2011.

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