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

Published online by Cambridge University Press:  04 May 2012

David Mischoulon ,
Stefania Lamon-Fava ,
Jacob Selhub ,
Judith Katz ,
George I. Papakostas ,
Dan V. Iosifescu ,
Albert S. Yeung ,
Christina M. Dording ,
Amy H. Farabaugh  and
Alisabet J. Clain
...Show all authors
David Mischoulon*
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Stefania Lamon-Fava
Affiliation:
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
Jacob Selhub
Affiliation:
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
Judith Katz
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
George I. Papakostas
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Dan V. Iosifescu
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Albert S. Yeung
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Christina M. Dording
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Amy H. Farabaugh
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Alisabet J. Clain
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Lee Baer
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Jonathan E. Alpert
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Andrew A. Nierenberg
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Maurizio Fava
Affiliation:
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
*
*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 [email protected])
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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.

Keywords

Methylene Tetrahydrofolate ReductaseMTHFRMethionine SynthaseMSC677TA2756Gdepressionantidepressantfluoxetine
Type
Original Research
Information
CNS Spectrums , Volume 17 , Issue 2 , June 2012 , pp. 76 - 86
Copyright
Copyright © Cambridge University Press 2012

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References

1.Mischoulon, D, Raab, MF. The role of folate in depression and dementia. J Clin Psychiatry. 2007; 68(Supplement 10): 28–33.Google Scholar
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): 426–428.Google ScholarPubMed
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): 1090–1095.CrossRefGoogle ScholarPubMed
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): 523–528.CrossRefGoogle ScholarPubMed
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): 121–130.CrossRefGoogle ScholarPubMed
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): 33–38.CrossRefGoogle ScholarPubMed
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): 3337–3345.CrossRefGoogle ScholarPubMed
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): 111–113.CrossRefGoogle Scholar
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): 526–528.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
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): 435–437.CrossRefGoogle ScholarPubMed
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: 197–202.CrossRefGoogle ScholarPubMed
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): 2096–2098.CrossRefGoogle ScholarPubMed
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): 618–626.CrossRefGoogle ScholarPubMed
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): 567–571.CrossRefGoogle ScholarPubMed
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): 227–231.CrossRefGoogle ScholarPubMed
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): 251–257.CrossRefGoogle Scholar
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): 1162–1168.CrossRefGoogle ScholarPubMed
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): 869–875.CrossRefGoogle ScholarPubMed
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): 352–360.CrossRefGoogle ScholarPubMed
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): 105–115.CrossRefGoogle ScholarPubMed
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): 1731S–1740S.CrossRefGoogle ScholarPubMed
22.Gilbody, S, Lewis, S, Lightfoot, T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007; 165(1): 1–13.CrossRefGoogle ScholarPubMed
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): 699–706.CrossRefGoogle ScholarPubMed
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): 1867–1874.CrossRefGoogle ScholarPubMed
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): 975–985.CrossRefGoogle ScholarPubMed
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): 66–69.Google Scholar
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): 51–61.CrossRefGoogle ScholarPubMed
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): 484–487.Google Scholar
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): 38–41.CrossRefGoogle Scholar
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): 319–324.CrossRefGoogle ScholarPubMed
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): 126–129.Google ScholarPubMed
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): 57–64.Google ScholarPubMed
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): 510–515.Google ScholarPubMed
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): 165–172.CrossRefGoogle Scholar
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): 751–756.Google ScholarPubMed
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): 29–35.CrossRefGoogle ScholarPubMed
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): 635–639.Google Scholar
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): 405–412.CrossRefGoogle Scholar
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): 163–170.CrossRefGoogle ScholarPubMed
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): 563–570.Google ScholarPubMed
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): 1210–1216.CrossRefGoogle ScholarPubMed
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): 1542–1548.CrossRefGoogle Scholar
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): 536–540.CrossRefGoogle ScholarPubMed
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): 103–107.CrossRefGoogle ScholarPubMed
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.Google Scholar
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: 43–52.CrossRefGoogle ScholarPubMed
47.Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23: 56–62.CrossRefGoogle ScholarPubMed
48.Cohen, J. Statistical Power Analysis for the Behavioral Sciences, 2nd Edition. Hillsdale, NJ: Lawrence Erlbaum; 1988.Google Scholar
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): 175–191.CrossRefGoogle Scholar
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): 183–187.CrossRefGoogle ScholarPubMed
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): 718–727.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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): 1259–1264.Google ScholarPubMed
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]CrossRefGoogle Scholar
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): 111–118, doi: 10.1038/ejcn.2011.152.CrossRefGoogle Scholar
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): 1365–1372.CrossRefGoogle Scholar
57.Serretti, A, Kato, M, Kennedy, JL. Pharmacogenetic studies in depression: a proposal for methodologic guidelines. Pharmacogenomics J. 2008; 8(2): 90–100.CrossRefGoogle ScholarPubMed
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): 17–24.CrossRefGoogle ScholarPubMed
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): 19387–19391.CrossRefGoogle ScholarPubMed