Skip to main content Accessibility help

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)...



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


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


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.


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.


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

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

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

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

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

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

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


Corresponding author

Professor JS Yoon, Department of Psychiatry and Depression Clinical Research Centre, Chonnam National University Medical School, Kwangju, Republic of Korea. Email:


Hide All

Declaration of interest

None. Funding detailed in Acknowledgements



Hide All
1 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: 618–26.
2 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: 228–32.
3 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: 251–7.
4 Tiemeier, H, van Tuijl, HR, Hofman, A, Meijer, J, Kiliaan, AJ, Breteler, MM. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry 2002; 159: 2099–101.
5 Prince, M, Acosta, D, Chiu, H, Scazufca, M, Varghese, M, 10/66 Dementia Research Group. Dementia diagnosis in developing countries: a cross-cultural validation study. Lancet 2002; 361: 909–17.
6 Kim, JM, Stewart, R, Shin, IS, Yoon, JS. Vascular disease/risk and late-life depression in a Korean community population. Br J Psychiatry 2004; 185: 102–7.
7 Copeland, JRM, Dewey, ME, Griffiths-Jones, HM. A computerized psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECAT. Psychol Med 1986; 16: 8999.
8 Kim, JM, Stewart, R, Prince, M, Yoon, JS. Diagnosing dementia in a developing nation: an evaluation of the GMS-AGECAT algorithm in an older Korean population. Int J Geriatr Psychiatry 2003; 18: 331–6.
9 Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJ, den Heijer, M, Kluijtmans, LA, van den Heuvel, LP, Rozen, R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–13.
10 Park, JH, Kwon, YC. Modification of the mini-mental state examination for use in the elderly in a non-western society: Part I. Development of Korean version of Mini-Mental State Examination. Int J Geriatr Psychiatry 1990; 5: 381–7.
11 Kim, JM, Stewart, R, Glozier, N, Prince, M, Kim, SW, Yang, SJ, Shin, IS, Yoon, JS. Physical health, depression and cognitive function as correlates of disability in an older Korean population. Int J Geriatr Psychiatry 2005; 20: 160–7.
12 National Institute of Alcohol Abuse and Alcoholism. The Physicians' Guide to Helping Patients with Alcohol Problems: 953769. National Institutes of Health, 1995.
13 Kim, JM, Stewart, R, Kim, SW, Yang, SJ, Shin, IS, Yoon, JS. Vascular risk factors and incident late-life depression in a Korean population. Br J Psychiatry 2006; 189: 2630.
14 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: 352–60.
15 Penninx, BW, Guralnik, JM, Ferrucci, L, Fried, LP, Allen, RH, Stabler, SP. Vitamin B12 deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry 2000; 157: 715–21.
16 Lindeman, RD, Romero, LJ, Koehler, KM, Liang, HC, LaRue, A, Baumgartner, RN, Garry, PJ. Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions. J Am Coll Nutr 2000; 19: 6876.
17 Almeida, OP, Lautenschlager, N, Flicker, L, Leedman, P, Vasikaran, S, Gelavis, A, Ludlow, J. Association between homocysteine, depression, and cognitive function in community-dwelling older women from Australia. J Am Geriatr Soc 2004; 52: 327–8.
18 Ramos, MI, Allen, LH, Haan, MN, Green, R, Miller, JW. Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification. Am J Clin Nutr 2004; 80: 1024–8.
19 Tolmunen, T, Hintikka, J, Voutilainen, S, Ruusunen, A, Alfthan, G, Nyysonen, K, Viinamaki, H, Kaplan, GA, Salonen, JT. Associations between depressive symptoms and serum concentrations of homocysteine in men: a population study. Am J Clin Nutr 2004; 80: 1574–8.
20 Levitt, AJ, Joffe, RT. Folate, vitamin B12, and life course of depressive illness. Biol Psychiatry 1989; 25: 867–72.
21 Park, SY, Paik, HY, Skinner, JD, Spindler, AA, Park, HR. Nutrient intake of Korean-American, Korean, and American adolescents. J Am Diet Assoc 2004; 104: 242–5.
22 Mischoulon, D, Burger, JK, Spillmann, MK, Worthington, JJ, Fava, M, Alpert, JE. Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression. J Psychosom Res 2000; 49: 183–7.
23 Mischoulon, D, Fava, M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr 2002; 76: S115861.
24 Gultepe, M, Ozcan, O, Avsar, K, Cetin, M, Ozdemir, AS, Gok, M. Urine methylmalonic acid measurements for the assessment of cobalamin deficiency related to neuropsychiatric disorders. Clin Biochem 2003; 36: 275–82.
25 Marengoni, A, Cossi, S, Martinis, MD, Calabrese, PA, Orini, S, Grassi, V. Homocysteine and disability in hospitalized geriatric patients. Metabolism 2004; 53: 1016–20.
26 Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288: 2015–22.
27 Stewart, R, Asonganyi, B, Sherwood, R. Plasma homocysteine and cognitive impairment in an older British African-Caribbean population. J Am Geriatr Soc 2002; 50: 1227–32.
28 Kunugi, H, Fukuda, R, Hattori, M, Kato, T, Tatsumi, M, Sakai, T, Hirose, T, Nanko, S. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry 1998; 3: 435–7.
29 Arinami, T, Yamada, N, Yamakawa-Kobayashi, K, Hamaguchi, H, Toru, M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet 1997; 74: 526–8.
30 Bonna, KH, Njolstad, I, Ueland, PM, Schirmer, H, Tverdal, A, Steigen, T, Wang, H, Nordrehaug, JE, Arnesen, E, Rasmussen, K; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578–88.


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

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)...
Submit a response


"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.
... More

Conflict of interest: None Declared

Write a reply

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.
... More

Conflict of interest: None Declared

Write a reply


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *