Skip to main content Accessibility help
×
×
Home

Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

  • David Mischoulon (a1), Stefania Lamon-Fava (a2), Jacob Selhub (a2), Judith Katz (a1), George I. Papakostas (a1), Dan V. Iosifescu (a1), Albert S. Yeung (a1), Christina M. Dording (a1), Amy H. Farabaugh (a1), Alisabet J. Clain (a1), Lee Baer (a1), Jonathan E. Alpert (a1), Andrew A. Nierenberg (a1) and Maurizio Fava (a1)...
Abstract
Objective

To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response.

Methods

We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined.

Results

Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C = 41%, C/T = 47%, T/T = 11%, A/A = 66%, A/G = 29%, G/G = 4%). In the fluoxetine-treated subsample (n = 49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response.

Conclusion

The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.

Copyright
Corresponding author
*Address correspondence to: David Mischoulon, MD, PhD, 1 Bowdoin Square, 6th Floor, Massachusetts General Hospital, Boston, MA 02114, Tel. 617-724-5198; Fax 617-724-3028. (Email dmischoulon@partners.org)
References
Hide All
1.Mischoulon, D, Raab, MF. The role of folate in depression and dementia. J Clin Psychiatry. 2007; 68(Supplement 10): 2833.
2.Fava, M, Borus, JS, Alpert, JE, Nierenberg, AA, Rosenbaum, JF, Bottiglieri, T. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry. 1997; 154(3): 426428.
3.Papakostas, GI, Petersen, T, Mischoulon, D, Ryan, JL, Nierenberg, AA, Bottiglieri, T, Rosenbaum, JF, Alpert, JE, Fava, M. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004; 65(8): 10901095.
4.Papakostas, GI, Petersen, T, Lebowitz, BD, Mischoulon, D, Ryan, JL, Nierenberg, AA, Bottiglieri, T, Alpert, JE, Rosenbaum, JF, Fava, M. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol. 2005; 8(4): 523528.
5.Coppen, A, Bailey, J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000; 60(2): 121130.
6.Alpert, JE, Mischoulon, D, Rubenstein, GEF, Bottonari, K, Nierenberg, AA, Fava, M. Folinic acid (leucovorin) as an adjunctive treatment for SSRI-refractory depression. Annals of Clinical Psychiatry. 2002; 14(1): 3338.
7.McGuffin, P, Knight, J, Breen, G, Brewster, S, Boyd, PR, Craddock, N, Gill, M, Korszun, A, Maier, W, Middleton, L, Mors, O, Owen, MJ, Perry, J, Preisig, M, Reich, T, Rice, J, Rietschel, M, Jones, L, Sham, P, Farmer, AE. Whole genome linkage scan of recurrent depressive disorder from the depression network study. Hum Mol Genet. 2005; 14(22): 33373345.
8.Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJH, den Heiger, M, Kluijtmans, LAJ, van den Heuvel, LP, Rozen, R. A candidate genetic risk factor for vascular disease: a common mutation in methylene tetrahydrofolate reductase. Nature Genetics. 1995; 10(1): 111113.
9.Arinami, T, Yamada, N, Yamakawa-Kobayashi, K, Hamaguchi, H, Toru, M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997; 74(5): 526528.
10.Kunugi, H, Fukuda, R, Hattori, M, Kato, T, Tatsumi, M, Sakai, T, Hirose, T. Nanko SC677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry. 1998; 3(5): 435437.
11.Hickie, I, Naismith, S, Ward, PB, Turner, K, Scott, E, Mitchell, P, Wilhelm, K. Parker G. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry. 2005 Mar; 186: 197202.
12.Naismith, S, Hickie, I, Ward, PB, Turner, K, Scott, E, Little, C, Mitchell, P, Wilhelm, K, Parker, G. Caudate nucleus volumes and genetic determinants of homocysteine metabolism in the prediction of psychomotor speed in older persons with depression. Am J Psychiatry. 2002; 159(12): 20962098.
13.Bjelland, I, Tell, GS, Vollset, SE, Refsum, H, Ueland, PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003; 60(6): 618626.
14.Kelly, CB, McDonnell, AP, Johnston, TG, Mulholland, C, Cooper, SJ, McMaster, D, Evans, A, Whitehead, AS. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004; 18(4): 567571.
15.Tan, EC, Chong, SA, Lim, LC, Chan, AO, Teo, YY, Tan, CH, Mahendran, R. Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders. Psychiatr Genet. 2004; 14(4): 227231.
16.Almeida, OP, Flicker, L, Lautenschlager, NT, Leedman, P, Vasikaran, S, van Bockxmeer, FM. Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging. 2005; 26(2): 251257.
17.Reif, A, Pfuhlmann, B, Lesch, KP. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29(7): 11621168.
18.Chen, CS, Tsai, JC, Tsang, HY, Kuo, YT, Lin, HF, Chiang, IC, Devanand, DP. Homocysteine levels, MTHFR C677T genotype, and MRI hyperintensities in late-onset major depressive disorder. Am J Geriatr Psychiatry. 2005; 13(10): 869875.
19.Lewis, SJ, Lawlor, DA, Davey Smith, G, Araya, R, Timpson, N, Day, IN, Ebrahim, S. The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis. Mol Psychiatry. 2006; 11(4): 352360.
20.Zintzaras, E. C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies. Psychiatr Genet. 2006; 16(3): 105115.
21.Refsum, H, Nurk, E, Smith, AD, Ueland, PM, Gjesdal, CG, Bjelland, I, Tverdal, A, Tell, GS, Nygard, O, Vollset, SE. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006; 136(6 Suppl): 1731S1740S.
22.Gilbody, S, Lewis, S, Lightfoot, T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007; 165(1): 113.
23.Gaysina, 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(6): 699706.
24.Leclerc, D, Campeau, E, Goyette, P, Adjalla, CE, Christensen, B, Ross, M, Eydoux, P, Rosenblatt, DS, Rozen, R, Gravel, RA. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet. 1996; 5(12): 18671874.
25.Ashavaid, TF, Shalia, KK, Kondkar, AA, Todur, SP, Nair, KG, Nair, SR. Gene polymorphism and coronary risk factors in Indian population. Clin Chem Lab Med. 2002; 40(10): 975985.
26.Zhu, W, Dao, J, Cheng, J, Zhao, R. [Relations of methionine synthase gene variation with congenital heart disease] [Article in Chinese] Wei Sheng Yan Jiu. 2004; 33(1): 6669.
27.Laraqui, A, Allami, A, Carrie, A, Coiffard, AS, Benkouka, F, Benjouad, A, Bendriss, A, Kadiri, N, Bennouar, N, Benomar, A, Guedira, A, Raisonnier, A, Fellati, S, Srairi, JE, Benomar, M. Influence of methionine synthase (A2756G) and methionine synthase reductase (A66G) polymorphisms on plasma homocysteine levels and relation to risk of coronary artery disease. Acta Cardiol. 2006; 61(1): 5161.
28.Dai, C, Zhang, G. [Study on homocysteine metabolism related enzymes gene mutations in Chinese patients with ischemic cardiovascular and cerebrovascular diseases] [Article in Chinese] Zhonghua Xue Ye Xue Za Zhi. 2001; 22(9): 484487.
29.Salomon, O, Rosenberg, N, Zivelin, A, Steinberg, DM, Kornbrot, N, Dardik, R, Inbal, A, Seligsohn, U. Methionine synthase A2756G and methylenetetrahydrofolate reductase A1298C polymorphisms are not risk factors for idiopathic venous thromboembolism. Hematol J. 2001; 2(1): 3841.
30.De Marco, P, Calevo, MG, Moroni, A, Arata, L, Merello, E, Finnell, RH, Zhu, H, Andreussi, L, Cama, A, Capra, V. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet. 2002; 47(6): 319324.
31.Zhang, G, Dai, C. [Correlation analysis between plasma homocysteine level and polymorphism of homocysteine metabolism related enzymes in ischemic cerebrovascular or cardiovascular diseases] Zhonghua Xue Ye Xue Za Zhi. 2002; 23(3): 126129.
32.Zhu, WL, Cheng, J, Dao, JJ, Zhao, RB, Yan, LY, Li, SQ, Li, Y. Polymorphism of methionine synthase gene in nuclear families of congenital heart disease. Biomed Environ Sci. 2004; 17(1): 5764.
33.Gueant-Rodriguez, RM, Juilliere, Y, Candito, M, Adjalla, CE, Gibelin, P, Herbeth, B, Van Obberghen, E, Gueant, JL. Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population. Thromb Haemost. 2005; 94(3): 510515.
34.Helfenstein, T, Fonseca, FA, Relvas, WG, Santos, AO, Dabela, ML, Matheus, SC, D'Almeida, V, Tufik, S, Souza, FG, Rodrigues, PR, Taglieri, R, Sousa, EF, Izar, MC. Prevalence of myocardial infarction is related to hyperhomocysteinemia but not influenced by C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms in diabetic and non-diabetic subjects. Clin Chim Acta. 2005; 355(1–2): 165172.
35.Yates, Z, Lucock, M. Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism. Haematologica. 2002; 87(7): 751756.
36.Miriuka, SG, Langman, LJ, Evrovski, J, Miner, SE, D'Mello, N, Delgado, DH, Wong, BY, Ross, HJ, Cole, DE. Genetic polymorphisms predisposing to hyperhomocysteinemia in cardiac transplant patients. Transpl Int. 2005; 18(1): 2935.
37.Yu, HD, Zheng, H, Qi, H, Lian, JH, He, Y. Dong ZM. [Study on the association of polymorphisms in homocysteine metabolism related enzymes with deep venous thrombosis] [Article in Chinese] Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006; 23(6): 635639.
38.Miriuka, SG, Langman, LJ, Keren, ES, Miner, SE, Mamer, OA, Delgado, DH, Evrovski, J, Ross, HJ, Cole, DE. Effects of folic acid fortification and multivitamin therapy on homocysteine and vitamin B(12) status in cardiac transplant recipients. J Heart Lung Transplant. 2004; 23(4): 405412.
39.Tsai, MY, Welge, BG, Hanson, NQ, Bignell, MK, Vessey, J, Schwichtenberg, K, Yang, F, Bullemer, FE, Rasmussen, R, Graham, KJ. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases. Atherosclerosis. 1999; 143(1): 163170.
40.D'Angelo, A, Coppola, A, Madonna, P, Fermo, I, Pagano, A, Mazzola, G, Galli, L, Cerbone, AM. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events. Thromb Haemost. 2000; 83(4): 563570.
41.Hiraoka, M, Kato, K, Saito, Y, Yasuda, K, Kagawa, Y. Gene-nutrient and gene-gene interactions of controlled folate intake by Japanese women. Biochem Biophys Res Commun. 2004; 316(4): 12101216.
42.McGrath, PJ, Stewart, JW, Quitkin, FM, Chen, Y, Alpert, JE, Nierenberg, AA, Fava, M, Cheng, J, Petkova, E. Predictors of relapse in a prospective study of fluoxetine treatment of major depression. Am J Psychiatry. 2006; 163(9): 15421548.
43.Perlis, RH, Purcell, S, Fagerness, J, Cusin, C, Yamaki, L, Fava, M, and Smoller, JW. Clinical and genetic dissection of anger expression and CREB1 polymorphisms in major depressive disorder. Biol Psychiatry. 2007; 62(5): 536540.
44.Mischoulon, D, McColl, R, Howarth, S, Lagomasino, IT, Alpert, JE, Nierenberg, AA, Fava, M. Management of major depression in the primary care setting. Psychotherapy and Psychosomatics. 2001; 70(2): 103107.
45.First, MB, Spitzer, RL, Gibbon, M, Williams, JBW. Structured Clinical Interview for DSM-IV Axis I disorders-patient edition (SCID-I/P, version 2.0). New York, NY: Biometrics Research Department, New York State Psychiatric Institute; 1995.
46.Araki, A, Sako, Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 1987; 422: 4352.
47.Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23: 5662.
48.Cohen, J. Statistical Power Analysis for the Behavioral Sciences, 2nd Edition. Hillsdale, NJ: Lawrence Erlbaum; 1988.
49.Faul, F, Erdfelder, E, Lang, A-G, Buchner, A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods. 2007; 39(2): 175191.
50.Mischoulon, D, Burger, JK, Spillmann, MK, Worthington, JJ, Fava, M, Alpert, JE. Anemia and macrocytosis in the prediction of serum folate and B12, and outcome in major depression. J Psychosom Res. 2000; 49(3): 183187.
51.Pfeiffer, CM, Johnson, CL, Jain, RB, Yetley, EA, Picciano, MF, Rader, JI, Fisher, KD, Mulinare, J, Osterloh, JD. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004. Am J Clin Nutr. 2007; 86(3): 718727.
52. Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. Nutr J. 2012 Jan 10;11:2. MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults.
53.Waśkiewicz, A, Piotrowski, W, Broda, G, Sobczyk-Kopcioł, A, Płoski, R. Impact of MTHFR C677T gene polymorphism and vitamins intake on homocysteine concentration in the Polish adult population. Kardiol Pol. 2011; 69(12): 12591264.
54. Sensoy N, Soysal Y, Kahraman A, Doğan N, Imirzalioğlu N. Modulator Effects of the Methylenetetrahydrofolate Reductase C677T Polymorphism on Response to Vitamin B12 Therapy and Homocysteine Metabolism. DNA Cell Biol. 2011 Nov 15. [Epub ahead of print]
55.Sukla, KK, Raman, R. Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population. Eur J Clin Nutr. 2012 Jan; 66(1): 111118, doi: 10.1038/ejcn.2011.152.
56.Crider, KS, Zhu, JH, Hao, L, Yang, QH, Yang, TP, Gindler, J, Maneval, DR, Quinlivan, EP, Li, Z, Bailey, LB, Berry, RJ. MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am J Clin Nutr. 2011 Jun; 93(6): 13651372.
57.Serretti, A, Kato, M, Kennedy, JL. Pharmacogenetic studies in depression: a proposal for methodologic guidelines. Pharmacogenomics J. 2008; 8(2): 90100.
58.Tchantchou, F, Graves, M, Shea, TB. Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: modulation by apolipoprotein E-deficiency. Nutritional Neuroscience. 2006; 9(1-2): 1724.
59.Kim, HS, Fay, JC. Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds. Proceedings of the National Academy of Sciences USA. 2007; 104(49): 1938719391.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed