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One-carbon metabolism and depression: important link with polyunsaturated fatty acid metabolism
- Johanna Assies, François Pouwer, CoRPS (Center of Research on Psychology in Somatic disease), Department of Medical Psychology, Tilburg University, The Netherlands (2 July 2008)
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"Authors¡¯ reply to One-carbon metabolism and depression: important link with polyunsaturated fatty
- Jin-Sang Yoon, Jae-Min Kim, Robert Stewart, Sung-Wan Kim, Su-Jin Yang, Il-Seon Shin, Jin-Sang Yoon (8 September 2008)
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Johanna Assies, Senior Investigator Biological Psychiatry Academic Psychiatric Centre, University of Amsterdam, The Netherlands, François Pouwer, CoRPS (Center of Research on Psychology in Somatic disease), Department of Medical Psychology, Tilburg University, The Netherlands
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j.assies{at}amc.uva.nl Johanna Assies, et al.
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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-5 and 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 for healthy 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 plasma n-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 (a cluster of risk factors for cardiovascular disease. Depressed patients are at risk for all components of the metabolic syndrome. Interestingly, the metabolic syndrome is associated with a rise in plasma homocysteine levels and 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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Jin-Sang Yoon, Professor Chonnam National University, Jae-Min Kim, Robert Stewart, Sung-Wan Kim, Su-Jin Yang, Il-Seon Shin, Jin-Sang Yoon
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jsyoon{at}chonnam.ac.kr Jin-Sang Yoon, et al.
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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 effects of 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 membrane phospholipids;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 research issues. References 1. 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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