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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2000 Aug;69(2):228–232. doi: 10.1136/jnnp.69.2.228

Homocysteine, folate, methylation, and monoamine metabolism in depression

T Bottiglieri 1, M Laundy 1, R Crellin 1, B Toone 1, M Carney 1, E Reynolds 1
PMCID: PMC1737050  PMID: 10896698

Abstract

OBJECTIVES—Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression.
METHODS—In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes.
RESULTS—Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls.
CONCLUSIONS—Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.



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Selected References

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  1. Baldessarini R. J. Neuropharmacology of S-adenosyl-L-methionine. Am J Med. 1987 Nov 20;83(5A):95–103. doi: 10.1016/0002-9343(87)90860-6. [DOI] [PubMed] [Google Scholar]
  2. Botez M. I., Young S. N., Bachevalier J., Gauthier S. Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid. Ann Neurol. 1982 Nov;12(5):479–484. doi: 10.1002/ana.410120512. [DOI] [PubMed] [Google Scholar]
  3. Botez M. I., Young S. N., Bachevalier J., Gauthier S. Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat. Nature. 1979 Mar 8;278(5700):182–183. doi: 10.1038/278182a0. [DOI] [PubMed] [Google Scholar]
  4. Bottiglieri T., Hyland K., Laundy M., Godfrey P., Carney M. W., Toone B. K., Reynolds E. H. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med. 1992 Nov;22(4):871–876. doi: 10.1017/s0033291700038447. [DOI] [PubMed] [Google Scholar]
  5. Bottiglieri T., Hyland K., Reynolds E. H. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994 Aug;48(2):137–152. doi: 10.2165/00003495-199448020-00002. [DOI] [PubMed] [Google Scholar]
  6. Bottiglieri T., Lim C. K., Peters T. J. Isocratic analysis of 3-methoxy-4-hydroxyphenyl glycol, 5-hydroxyindole-3-acetic acid and 4-hydroxy-3-methoxyphenylacetic acid in cerebrospinal fluid by high-performance liquid chromatography with amperometric detection. J Chromatogr. 1984 Nov 28;311(2):354–360. doi: 10.1016/s0378-4347(00)84729-5. [DOI] [PubMed] [Google Scholar]
  7. Carney M. W., Chary T. K., Laundy M., Bottiglieri T., Chanarin I., Reynolds E. H., Toone B. Red cell folate concentrations in psychiatric patients. J Affect Disord. 1990 Jul;19(3):207–213. doi: 10.1016/0165-0327(90)90093-n. [DOI] [PubMed] [Google Scholar]
  8. Coppen A., Chaudhry S., Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986 Jan-Feb;10(1):9–13. doi: 10.1016/0165-0327(86)90043-1. [DOI] [PubMed] [Google Scholar]
  9. Crellin R., Bottiglieri T., Reynolds E. H. Folates and psychiatric disorders. Clinical potential. Drugs. 1993 May;45(5):623–636. doi: 10.2165/00003495-199345050-00001. [DOI] [PubMed] [Google Scholar]
  10. Fava M., Borus J. S., Alpert J. E., Nierenberg A. A., Rosenbaum J. F., Bottiglieri T. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry. 1997 Mar;154(3):426–428. doi: 10.1176/ajp.154.3.426. [DOI] [PubMed] [Google Scholar]
  11. Giulidori P., Stramentinoli G. A radioenzymatic method for S-adenosyl-L-methionine determination in biological fluids. Anal Biochem. 1984 Feb;137(1):217–220. doi: 10.1016/0003-2697(84)90373-7. [DOI] [PubMed] [Google Scholar]
  12. Godfrey P. S., Toone B. K., Carney M. W., Flynn T. G., Bottiglieri T., Laundy M., Chanarin I., Reynolds E. H. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392–395. doi: 10.1016/0140-6736(90)91942-4. [DOI] [PubMed] [Google Scholar]
  13. Hyland K., Smith I., Bottiglieri T., Perry J., Wendel U., Clayton P. T., Leonard J. V. Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurology. 1988 Mar;38(3):459–462. doi: 10.1212/wnl.38.3.459. [DOI] [PubMed] [Google Scholar]
  14. Lindenbaum J., Healton E. B., Savage D. G., Brust J. C., Garrett T. J., Podell E. R., Marcell P. D., Stabler S. P., Allen R. H. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988 Jun 30;318(26):1720–1728. doi: 10.1056/NEJM198806303182604. [DOI] [PubMed] [Google Scholar]
  15. Lucock M. D., Green M., Levene M. I. Methylfolate modulates potassium evoked neuro-secretion: evidence for a role at the pteridine cofactor level of tyrosine 3-hydroxylase. Neurochem Res. 1995 Jun;20(6):727–736. doi: 10.1007/BF01705542. [DOI] [PubMed] [Google Scholar]
  16. Muir M., Chanarin I. Solid-phase vitamin B12 assays using polyacrylamide-bound intrinsic factor and polyacrylamide-bound R-binder. Br J Haematol. 1983 Mar;53(3):423–435. doi: 10.1111/j.1365-2141.1983.tb02043.x. [DOI] [PubMed] [Google Scholar]
  17. Reynolds E. H., Carney M. W., Toone B. K. Methylation and mood. Lancet. 1984 Jul 28;2(8396):196–198. doi: 10.1016/s0140-6736(84)90482-3. [DOI] [PubMed] [Google Scholar]
  18. Reynolds E. H., Preece J. M., Bailey J., Coppen A. Folate deficiency in depressive illness. Br J Psychiatry. 1970 Sep;117(538):287–292. [PubMed] [Google Scholar]
  19. Ruck A., Kramer S., Metz J., Brennan M. J. Methyltetrahydrofolate is a potent and selective agonist for kainic acid receptors. Nature. 1980 Oct 30;287(5785):852–853. doi: 10.1038/287852a0. [DOI] [PubMed] [Google Scholar]
  20. Shorvon S. D., Carney M. W., Chanarin I., Reynolds E. H. The neuropsychiatry of megaloblastic anaemia. Br Med J. 1980 Oct 18;281(6247):1036–1038. doi: 10.1136/bmj.281.6247.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Stabler S. P., Marcell P. D., Podell E. R., Allen R. H., Savage D. G., Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest. 1988 Feb;81(2):466–474. doi: 10.1172/JCI113343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ubbink J. B., Hayward Vermaak W. J., Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr. 1991 Apr 19;565(1-2):441–446. doi: 10.1016/0378-4347(91)80407-4. [DOI] [PubMed] [Google Scholar]
  23. Wang J. K., Andrews H., Thukral V. Presynaptic glutamate receptors regulate noradrenaline release from isolated nerve terminals. J Neurochem. 1992 Jan;58(1):204–211. doi: 10.1111/j.1471-4159.1992.tb09297.x. [DOI] [PubMed] [Google Scholar]

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