What is MTHFR and why is it important?
MTHFR is an enzyme required to convert folic acid into an active form called
L-methylfolate that is usable by our bodies. L-methylfolate plays an important role in making neurotransmitters such as serotonin, dopamine, and norepinephrine, which help regulate mood.
Some people carry a mutation in the MTHFR gene, which limits their ability to create L-methylfolate. The GeneSight MTHFR test shows whether or not a person has this mutation.
How do doctors treat people with reduced MTHFR activity?
There are two possible treatment options for people with reduced MTHFR activity; both are oral supplements:
- L-methylfolate: Studies have shown that using L-methylfolate alone1–4 or in addition to an antidepressant4–6 can help reduce depressive symptoms. One study has shown that depressed patients with variation in MTHFR may benefit more from taking L-methylfolate.7
- Folic acid: While this is a possible treatment option, healthcare providers and researchers are split on whether it is an effective one. Studies evaluating the effect of folic acid alone on depression response have produced mixed results.8–10 Some studies show that folic acid in addition to an antidepressant helps improve depression11–13, while other studies show no benefit14–16.
How can consumers take L-methylfolate or folic acid?
L-methylfolate is available over the counter or as a prescription. Folic acid is generally available in 400 mcg in a multivitamin or 800 mcg in a prenatal vitamin. Note: Assurex Health does not make dosing recommendations; please check with your healthcare provider on whether this is right for you.
Are there any risks to taking folic acid supplements?
There may be some potential risks with high doses of folic acid. Although studies have produced mixed results17–23, high doses of folic acid may mask symptoms of vitamin B12 deficiency (i.e., anemia). Some studies have also shown that high intake of folic acid may intensify the neurologic effects of vitamin B12 deficiency (i.e., cognitive impairment).17,24,25
While more research needs to be conducted, folic acid and L-methylfolate dietary supplements may help with depressive symptoms. Please talk to your healthcare provider to find out if this is right for you.
For more information on how the GeneSight test can help you and your physician, visit genesight.com, email us at firstname.lastname@example.org, or phone 855.891.9415.
This document is for educational purposes related to pharmacogenomics and personalized medicine only and should not be considered medical advice. The information is based on scientific opinion from industry experts and is intended to provide additional information to healthcare providers. These materials may be changed, improved, or updated without notice. Assurex Health is not responsible for any errors or omissions contained in third party content. We encourage you to contact us for specific scientific advice regarding our GeneSight® tests. You may print a copy of this document for your own personal noncommercial use. You may not copy any part of this document for any other purpose, and you may not modify any part of this document without the permission of Assurex Health. “GeneSight,” “Assurex” and associated logos are registered trademarks of Assurex Health, Inc. © 2018 Assurex Health, Inc. All rights reserved.
- Guaraldi, G. P., Fava, M., Mazzi, F. & La Greca, P. An Open Trial of Methyltetrahydrofolate in Elderly Depressed Patients. Ann. Clin. Psychiatry 5, 101–105 (1993).
- Passeri, M., Cucinotta, D., Abate, G. & Senin, U. Oral 5’methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging Clin. Exp. Res. 5, 63–71 (1993).
- Di Palma, C., Urani, R., Agricola, R., Giorgetti, V. & Dalla Verde, G. Is methylfolate effective in relieving major depression in ceronic alcoholics? A hypothesis of treatment. Curr. Ther. Res. – Clin. Exp. 55, 559–568 (1994).
- Shelton, R. C., Manning, J. S. & Barrentine, L. W. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord 15, 1–9 (2013).
- Godfrey, P., Toone, B., Carney, M., Flynn, T. & Bottiglieri, T. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392–395 (1990).
- Papakostas, G. I. et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am. J. Psychiatry 169, 1267–74 (2012).
- Papakostas, G. I. et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J. Clin. Psychiatry 75, 855–63 (2014).
- Loria-Kohen, V. et al. A pilot study of folic acid supplementation for improving homocysteine levels, cognitive and depressive status in eating disorders. Nutr. Hosp. 28, 807–15 (2013).
- Adhikari, P. M. et al. Effect of vitamin B12 and folic acid supplementation on neuropsychiatric symptoms and immune response in HIV-positive patients. J. Neurosci. Rural Pract. 7, 362–367 (2016).
- de Koning, E. J. et al. Effects of Two-Year Vitamin B 12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations : Additional Results from the B-PROOF Study, an RCT. (2016). doi:10.3390/nu8110748
- Coppen, A. & Bailey, J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J. Affect. Disord. 60, 121–30 (2000).
- Resler, G. et al. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation 15, 145–152 (2008).
- Venkatasubramanian, R., Naveen, C. & Pandey, R. S. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J. Affect. Disord. 150, 644–648 (2013).
- Basoglu, C. et al. Adjuvant folate treatment to essitalopram and serum homocystein, folate, vitamin B-12 levels in patients with major depressive disorder. [Turkish]. Bull. Clin. Psychopharmacol. 19, 135–142 (2009).
- Bedson, E. et al. Folate augmentation of treatment – evaluation for depression (FolATED): randomised trial and economic evaluation. Health Technol. Assess. (Rockv). 18, (2014).
- Sarris, J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am. J. Psychiatry appiajp201615091228 (2016). doi:10.1176/appi.ajp.2016.15091228
- Morris, M. S., Jacques, P. F., Rosenberg, I. H. & Selhub, J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85, 193–200 (2007).
- Mills, J. L. et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am. J. Clin. Nutr. 77, 1474–1477 (2003).
- Ray, J. G., Vermeulen, M. J., Langman, L. J., Boss, S. C. & Cole, D. E. C. Persistence of vitamin B12 insufficiency among elderly women after folic acid food fortification. Clin. Biochem. 36, 387–391 (2003).
- Metz, J., McNeil, A. R. & Levin, M. The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate. Clin. Lab. Haem. 26, 323–325 (2004).
- Liu, S. et al. A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects. BMC Pregnancy Childbirth 4, (2004).
- Wyckoff, K. F. & Ganji, V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post-folic acid fortification period than in the pre-folic acid fortification period. Am. J. Clin. Nutr. 86, 1187–92 (2007).
- Qi, Y. P. et al. The prevalence of low serum vitamin B12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J Nutr 144, 170–176 (2014).
- Morris, M., Selhub, J. & Jacques, P. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham Heart Study. J Am Geriatr Soc 60, 1457–1464 (2012).
- Moore, E. M., Ames, D., Mander, A. G., Carne, R. P. & Brodaty, H. Among Vitamin B12 Deficient Older People, High Folate Levels are Associated with Worse Cognitive Function: Combined Data from Three Cohorts. J. Alzheimer’s Dis. 39, 661–668 (2014).