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Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression

  • Jae-Min Kim (a1), Robert Stewart (a2), Sung-Wan Kim (a1), Su-Jin Yang (a1), Il-Seon Shin (a1) and Jin-Sang Yoon (a1)...
Abstract
Background

The role of folate, vitamin B12 and homocysteine levels in depression is not clear.

Aims

To investigate cross-sectional and prospective associations between folate, B12 and homocysteine levels and late-life depression.

Method

A total of 732 Korean people aged 65 years or over were evaluated at baseline. Of the 631 persons who were not depressed, 521 (83%) were followed over a period of 2–3 years and incident depression was ascertained with the Geriatric Mental State schedule. Serum folate, serum vitamin B12 and plasma homocysteine levels were assayed at both baseline and follow-up.

Results

Lower levels of folate and vitamin B12 and higher homocysteine levels at baseline were associated with a higher risk of incident depression at follow-up. Incident depression was associated with a decline in vitamin B12 and an increase in homocysteine levels over the follow-up period.

Conclusions

Lower folate, lower vitamin B12 and raised homocysteine levels may be risk factors for late-life depression.

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Copyright
Corresponding author
Professor JS Yoon, Department of Psychiatry and Depression Clinical Research Centre, Chonnam National University Medical School, Kwangju, Republic of Korea. Email: jsyoon@chonnam.ac.kr
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Declaration of interest

None. Funding detailed in Acknowledgements

Footnotes
References
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Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression

  • Jae-Min Kim (a1), Robert Stewart (a2), Sung-Wan Kim (a1), Su-Jin Yang (a1), Il-Seon Shin (a1) and Jin-Sang Yoon (a1)...
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eLetters

"Authors�� reply to One-carbon metabolism and depression: important link with polyunsaturated fatty

Jin-Sang Yoon, Professor
08 September 2008

As Assies & Fouwer appropriately point out, there has been growing evidence for an underlying metabolic link between the key components of one-carbon metabolism and polyunsaturated fatty acids(PUFAs) both in depression and dementia.1 However we do not fully agree with their recommendation for measuring these factors in combination. Our reasons are as follows. One of the main potential mood stabilizing effectsof PUFAs in depression is thought to be their dampening action against abnormal intracellular signal transduction by i) inhibiting G-protein mediated and phospholipase C-mediated hydrolysis of crucial membranephospholipids;2 ii) modulating the influx of calcium ions;3 and iii) reducing the activity of protein kinase C.4 In addition, PUFA actions are closely related to inflammatory and immune pathways, which are also potentially important in the pathogenesis of depression.5 Compared to these more established findings, the evidence for relationships between one-carbon metabolism and PUFAs in depression is relatively scanty. For these reasons, we cannot recommend measuring PUFAs in the context of one- carbon metabolism at the present time, particularly for clinical purposes.However, we do feel that Assises & Fouwer¡¯s suggestions should encourage future animal and clinical studies on these interesting researchissues.

References1. Das UN. Folic acid and polyunsaturated fatty acids improve cognitive function and prevent depression, dementia, and Alzheimer's disease--but how and why? Prostaglandins Leukot Essent Fatty Acids 2008; 78: 11-9.2. Sperling RI, Benincaso AI, Knoell CT, Larkin JK, Austen KF, Robinson DR. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993; 91: 651-60.3. Honen BN, Saint DA, Laver DR. Suppression of calcium sparks in rat ventricular myocytes and direct inhibition of sheep cardiac RyR channels by EPA, DHA and oleic acid. J Membr Biol 2003; 196: 95-103.4. Seung Kim HF, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB. Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro. Mol Psychiatry 2001; 6: 246-8.5. Maes M, Smith RS. Fatty acids, cytokines, and major depression. Biol Psychiatry 1998; 43: 313-4.
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Conflict of interest: None Declared

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One-carbon metabolism and depression: important link with polyunsaturated fatty acid metabolism

Johanna Assies, Senior Investigator Biological Psychiatry
02 July 2008

From their longitudinal study Kim et al concluded that lower levels of folate and vitamin B12 and raised homocysteine may be risk factors for late-life depression.1 We propose to include polyunsaturated fatty acids (pufas) in future studies that will test the potential role of the one-carbon metabolism in the etiology and persistence of depression, for several reasons. First, because the one carbon metabolism is intimately linked with the pufa metabolism.2 The methionine-homocysteine cycle produces methyl groups for the synthesis of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) catalyzed by PE methyltransferase. PC is critical for the delivery of important pufas such as docosahexaenoic acid (DHA, C22:6n-3) from the liver to the plasma and distribution to peripheral tissues. The PC/PE ratio also modulates the activity of Delta-5and Delta-6 desaturases involved in n-3 and n-6 PUFA synthesis. Moreover, plasma homocysteine was significantly inversely correlated with DHA, total n-3 and the ratio n-3/n-6 pufas in healthy male subjects.3 Secondly,these findings are relevant for psychiatry, as pufa’s, -particularly DHA and AA (arachidonic acid)- are key “building stones” that are required forhealthy functioning of nerve and brain cells. In patients with recurrent depression a decrease in n-3 pufas in erythrocyte membranes was found together with a significant positive association between the sum of plasman-6 pufas and homocysteine.4 There is also increasing evidence from cross-sectional studies and randomized controlled trials supporting the notion that an impaired pufa metabolism is directly linked to the onset of depression.5,6 Thirdly,both an impaired one-carbon and an impaired pufa metabolism might explain the positive associations between depression and the metabolic syndrome (acluster of risk factors for cardiovascular disease. Depressed patients areat risk for all components of the metabolic syndrome. Interestingly, the metabolic syndrome is associated with a rise in plasma homocysteine levelsand a decrease in DHA in plasma and cell membranes. Based on these findings, our opinion is that for a proper understanding of underlying mechanisms linking the one-carbon metabolism and depression, homocysteine,folate, B-vitamins should be measured in conjunction with dietary and laboratory analyses of pufa’s.

1 Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Yoon JS.: Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Br J Psychiatry 2008; 192: 268-274.

2 Selley ML. A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimers’disease. Neurobiology of Aging 2007; 28: 1834-39.

3 Li D, Mann NJ, Sinclair AJ. A significant inverse relationship between concentrations of plasma homocysteine and phospospholipid docosahexaenoic acid in healthy male subjects. Lipids 2006; 41 : 85-95.

4 Assies J , Lok A, Bockting CL, Weverling GJ, Lieverse R, Visser I, Abeling NGGM, Duran M, Schene A. Fatty acids and homocysteine levels in patients with recurrent depression: an explorative pilot study. Prostaglandins Leukot Essent Fatty Acids 2004; 70: 349-56.

5 Severus WE, Litman AB, Stoll AL. Omega 3 fatty acids, homocysteine,and the increased cardiovascular mortality in major depressive disorder. Harvard Rev Psychiatry 2001; 9: 280-93.

6 Pouwer F, Nijpels G, Beekman AT, Dekker JM, van Dam RJ, Heine RJ, Snoek FJ. Fat food for a bad mood. Can we treat and prevent depression in type 2 diabetes by means of ù-3 polyunsaturated fatty acids? Diabetic Medicine 2005; 22: 1465-75.
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