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The journal of nutrition, health & aging

, Volume 14, Issue 10, pp 829–833 | Cite as

The folic acid endophenotype and depression in an elderly population

  • N. Naumovski
  • M. Veysey
  • X. Ng
  • L. Boyd
  • L. Dufficy
  • B. Blades
  • C. Travers
  • P. Lewis
  • J. Sturm
  • M. Townley-Jones
  • Z. Yates
  • P. Roach
  • M. Lucock
JNHA: Clinical Neurosciences

Abstract

Objectives

Folate status and/or genes have been linked to depression in a number of studies. This may be via a direct action (or actions) on neuronal membranes or indirect effects through the metabolism of methyl groups involved in neurotransmitter synthesis. This study examines folate and related thiol metabolism that might underpin either phenomenon.

Design

Cohort study describing the relationship between several genetic and nutritional aspects of folic acid homeostasis and depression assessed by the HADS psychometric index in an elderly cohort.

Setting

New South Wales (Australia) retirement village.

Participants

118 elderly participants (age 65–90 years).

Results

Stepwise multiple regression was used to determine the best statistical model to predict depression; C677T-MTHFR (p=0.0103) was found to be positively associated with depression, while the thiol dipeptide Cys-Gly was negatively associated (p=0.0403). The statistical models used accounted for the major folate related indices (genetic and biochemical) that are most often evaluated in the context of health and disease. When only genetic data were examined for interactions, C677T-MTHFR was found to be negatively associated with the HADS Depression Index Score (p=0.0191).

Conclusion

The potential influence of Cys-Gly on this phenotype is novel, and of considerable interest given that it has been linked to altered spontaneous activity and sedation in an animal model. Cys-Gly is a recognised ligand at the N-methyl-D-aspartatic acid (NMDA) subclass of glutamate receptor, a system associated with depression. In addition, the C677T-MTHFR association adds further support to existing findings underscoring the potential role of folate in depression.

Key words

Folate depression homocysteine cysteinylglycine polymorphism MTHFR 

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References

  1. 1.
    Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhacement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392–395.CrossRefPubMedGoogle Scholar
  2. 2.
    Lucock MD. Synergy of genes and nutrients: the case of homocysteine Curr Opin Clin Nutr Metab Care 2006;9:748–756.CrossRefPubMedGoogle Scholar
  3. 3.
    Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1103–1112.CrossRefPubMedGoogle Scholar
  4. 4.
    Bailey LB, Gregory JF. Polymorphisms of methyleneterahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 1999;129:919–922.PubMedGoogle Scholar
  5. 5.
    Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol 2005;19:59–65.CrossRefPubMedGoogle Scholar
  6. 6.
    Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review. Am J Epidemiol 2007;165:1–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Ho PI, Ortiz D, Rogers E, Shea TB. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res 2002;70:694–702.CrossRefPubMedGoogle Scholar
  8. 8.
    Yamane H, Denbow DM, Furuse M. Screening of dipeptides having central functions for excitation and sedation. Mini Reviews in Medicinal Chemistry 2009;9:300–305.PubMedGoogle Scholar
  9. 9.
    Dufficy L, Naumovski N, Ng X, Blades B, Yates Z, Travers C, Lewis P, Sturm J, Veysey M, Roach PD, Lucock MD. G80A reduced folate carrier SNP influences the absorption and cellular translocation of dietary folate and its association with blood pressure in an elderly population. Life Sci 2006;79:957–966.CrossRefPubMedGoogle Scholar
  10. 10.
    Snaith RP, Zigmond AS, The Hospital Anxiety and Depression Scale Manual. 1994:NFER Nelson.Google Scholar
  11. 11.
    Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361–370.CrossRefPubMedGoogle Scholar
  12. 12.
    Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 2002;52:69–77.CrossRefPubMedGoogle Scholar
  13. 13.
    van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346:1070.CrossRefPubMedGoogle Scholar
  14. 14.
    van der Put NM, van der Molen EF, Kluijtmans LA, Heil SG, Trijbels JM, Eskes TK, Van Oppenraaij-Emmerzaal D, Banerjee R, Blom HJ. Sequence analysis of the coding region of human methionine synthase: Relevance to hyperhomocysteinaemia in NTD and vascular disease. Quarterly Journal of Medicine 1997;90:511–517.Google Scholar
  15. 15.
    van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural tube defects? Am J Human Genet 1998;62:1044–1051.CrossRefGoogle Scholar
  16. 16.
    Johnson WG, Stenroos ES, Spychala JR, Chatkupt S, Ming SX, Buyske S. New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet A. 2004;124;339–345.CrossRefGoogle Scholar
  17. 17.
    Winkelmayer WC, Eberle C, Sunder-Plassmann G, Födinger M. Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients. Kidney International 2003;63:2280–2285.CrossRefPubMedGoogle Scholar
  18. 18.
    Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, Gravel RA, Rozen R. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab 1999;67:317–323.CrossRefPubMedGoogle Scholar
  19. 19.
    Melse-Boonstra A, Lievers KJ, Blom HJ, Verhoef P. Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene. Am J Clin Nutr 2004;80:700–704.PubMedGoogle Scholar
  20. 20.
    Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol 1999;4:359–365.Google Scholar
  21. 21.
    Dringen R, Kranich O, Hamprecht B. The gamma-glutamyl transpeptidase inhibitor acivicin preserves glutathione released by astroglial cells in culture. Neurochem Res 1997;22:727–733.CrossRefPubMedGoogle Scholar
  22. 22.
    Dringen R, Pfeiffer B, Hamprecht B. Synthesis of the antioxidant glutathione in neurons: Supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 1999;19:562–569.PubMedGoogle Scholar
  23. 23.
    Dringen R, Hirrlinger JJ. Glutathione pathway in the brain. BiolChem 2003;384:505–516.Google Scholar
  24. 24.
    Mosharov E, Cranford MR, Banerjee R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transulfuration pathway and its regulation by redox changes. Biochemistry 2000;39:13005–13011.CrossRefPubMedGoogle Scholar
  25. 25.
    Rakofsky JJ, Holtzheimer PE, Nemeroff CB. Emerging targets for antidepressant therapies. Curr Opin Chem Biol 2009;13:1–12.CrossRefGoogle Scholar
  26. 26.
    Paul IA, Skolnick P, Glutamate and Depression — Clinical and Preclinical Studies. Ann N Y Acad Sci 2003;1003:250–272.CrossRefPubMedGoogle Scholar
  27. 27.
    Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228–232.CrossRefPubMedGoogle Scholar

Copyright information

© Serdi and Springer Verlag France 2010

Authors and Affiliations

  • N. Naumovski
    • 1
  • M. Veysey
    • 3
  • X. Ng
    • 1
  • L. Boyd
    • 1
  • L. Dufficy
    • 1
  • B. Blades
    • 1
    • 3
  • C. Travers
    • 4
  • P. Lewis
    • 4
  • J. Sturm
    • 3
  • M. Townley-Jones
    • 2
  • Z. Yates
    • 1
  • P. Roach
    • 1
  • M. Lucock
    • 1
  1. 1.School of Environmental & Life SciencesUniversity of NewcastleOurimbahAustralia
  2. 2.School of Mathematical & Physical SciencesUniversity of NewcastleOurimbahAustralia
  3. 3.Teaching & Research UnitNorthern Sydney Central Coast HealthGosfordAustralia
  4. 4.Public Health UnitNorthern Sydney Central Coast HealthGosfordAustralia

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