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.
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Medication changes based on MTHFR: What is the evidence?

Some evidence supports the use of active folate supplementation to improve symptoms of MDD.

Shelton et al³conducted an observational study that assessed the effects of adding L-methylfolate (brand name: Deplin), 7.5 or 15 mg, to existing antidepressant therapy in 502 patients with MDD who had baseline PHQ-9 scores of at least 5. After an average 95 days of therapy, PHQ-9 scores were reduced by a mean of 8.5 points, with 67.9% of patients achieving at least a 50% reduction in PHQ-9 scores. The study did not take into account patients’ MTHFR genotype or differentiate results between the 2 doses of L-methylfolate.³

Papakostas et al¹³ performed 2 randomized, double-blind, parallel-sequential, placebo-controlled trials of L-methylfolate for patients with MDD. The first compared L-methylfolate, 7.5 and 15 mg, to placebo, without regard to MTHFR genotype.¹³ There was no significant difference between the 7.5-mg dose and placebo, or the 15-mg dose and placebo. However, among the group receiving the 15-mg dose, the response rate was 24%, vs 9% in the placebo group, which approached significance (P = .1). Papakostas et al¹³ followed up with a smaller trial comparing the 15-mg dose alone to placebo, and found the response rate was 32.3% in patients treated with L-methylfolate compared with 14.6% in the placebo group (P = .04).¹³

Although the Shelton et al³ and Papakostas et al¹³ studies showed some improvement in depressive symptom scores among patients who received L-methylfolate supplementation, an important consideration is if MTHFR genotype may predict patient response to this therapy.

Papakostas et al¹⁴ performed a post hoc analysis of their earlier study to assess potential associations amongst multiple other biomarkers of inflammation and metabolic disturbances hypothesized by the authors to be associated with MDD, as well as body mass index (BMI), with treatment outcome.¹⁴ When change in the Hamilton Depression Rating Scale-28 (HDRS-28) was analyzed by C677T and A1298C variant groups (677 CT vs TT and 1298 AC vs CC), no statistically significant improvements were identified (C677T mean change from baseline −3.8 points, P = .087; A1298C mean change from baseline −0.5 points, P = .807).¹⁴ However, statistically significant improvements in HDRS-28 scores were observed compared with baseline when the C677T genotype was pooled with other biomarkers, including methionine synthase (MTR 2756 AG/GG, −23.3 points vs baseline, P < .001) and a voltage-dependent calcium channel (CACNAIC AG/AA, −9 points vs baseline, P < .001), as well as with BMI ≥ 30 kg/m² (−9.9 points vs baseline, P = .001).¹⁴

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Impact of the MTHFR C677T genetic variant on depression

References

Medication changes based on MTHFR: What is the evidence?

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