Savvy Psychopharmacology

Impact of the MTHFR C677T genetic variant on depression

Current Psychiatry. 2020 October;19(10):41-45,51,53 | doi:10.12788/cp.0052

References

1. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488.
2. Jadavji N, Wieske F, Dirnagl U, et al. Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and gamma-aminobutyric acid in brain tissue. Molecular Genetics and Metabolism Reports. 2015;3(Issue C):1-4.
3. Shelton R, Manning J, Barrentine L, et al. Assessing effects of L-methylfolate in depression management: results of a real-world patient experience trial. Prim Care Companion CNS Disord. 2013;15(4):pii:PCC.13m01520. doi: 10.4088/PCC.13m01520.
4. Brustolin S, Giugliani R, Felix T. Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res. 2010;43(1):1-7.
5. Blom H, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34:75-81.
6. Moorthy D, Peter I, Scott T, et al. Status of vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. J Nutr. 2012;142:1554-1560.
7. Lievers K, Boers G, Verhoef P, et al. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med (Berl). 2001;79(9):522-528.
8. Jiang W, Xu J, Lu X, et al. Association between MTHFR C677T polymorphism and depression: a meta-analysis in the Chinese population. Psychol Health Med. 2015;21(6):675-685.
9. Bousman C, Potiriadis M, Everall I, et al. Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: a five-year prospective cohort study of primary care attendees. Am J Med Genet B Neuropsychiatr Genet. 2014;165B(1):68-76.
10. Schiepers O, Van Boxtel M, de Groot R, et al. Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(7):1682-1688.
11. Lizer M, Bogdan R, Kidd R. Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients. J Psychiatr Pract. 2011;17(6):404-409.
12. Bjelland I, Tell G, Vollset S, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
13. Papakostas G, Shelton R, Zajecka J, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.
14. Papakostas G, Shelton R, Zajecka J, 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. 2014;75(8):855-863.
15. Mech A, Farah A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2016;77(5):668-671.
16. Godfrey P, Toone B, Carney M, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336(8712):392-395.

Mech and Farah¹⁵ performed a randomized, double-blind, placebo-controlled study of the use of EnLyte, a supplement containing 7-mg L-methylfolate, in patients with at least 1 variant of MTHFR (either C677T or A1298C) over an 8-week period. In addition to L-methylfolate, this supplement contains other active ingredients, including leucovorin (or folinic acid), magnesium ascorbate, and ferrous glycine cysteinate. Montgomery-Åsberg Depression Scale (MADRS) scores improved by 12 points in patients who received the supplement and by 1.3 points in patients who received placebo. However, because the supplement contained many ingredients, the response observed in this study cannot be attributed to L-methylfolate alone.¹⁵

Table 2^3,13,15,16contains summaries of these and other selected studies assessing active folate supplementation in MDD.

CASE CONTINUED

Over the next several weeks, Ms. T experiences some modest improvement in mood while taking L-methylfolate and her antidepressant regimen, and she experiences no notable adverse effects. Unfortunately, after 3 months, Ms. T discontinues the supplement due to the cost.

The value of MTHFR testing

Ms. T’s case is an example of how clinicians may respond to MTHFR pharmacogenetic testing. Although L-methylfolate has shown some benefit in several randomized clinical trials, available data do not confirm the relevance of MTHFR functional status to symptom response. Additionally, there is likely interplay among multiple factors affecting patients’ response to L-methylfolate. Larger randomized trials prospectively assessing other pharmacogenetic and lifestyle factors may shed more light on which patients would benefit.

Based on available data, the decision to prescribe L-methylfolate should not necessarily hinge on MTHFR genetics alone. Both patients and clinicians must be aware of the potentially prohibitive cost if L-methylfolate is recommended, as prescription insurance may not provide coverage (eg, a recent search on GoodRx.com showed that generic L-methylfolate was approximately $40 for 30 tablets; prices may vary). Additionally, clinicians should be aware that L-methylfolate is regulated as a medical food product and is not subject to strict quality standards required for prescription medications. Future prospective studies assessing the use of L-methylfolate specifically in patients with a MTHFR variants while investigating other relevant covariates may help identify which specific patient populations would benefit from supplementation.

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Impact of the MTHFR C677T genetic variant on depression

References

CASE CONTINUED

The value of MTHFR testing

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