Vitamins and plant ingredients

Vitamin B12, homocysteine and depressive symptoms: a longitudinal study among older adults



The roles of vitamin B12 and homocysteine concentration in depression are not clear. We investigated cross-sectional and prospective associations of serum vitamin B12 and plasma homocysteine with depressive symptoms in Dutch older adults.


In the Longitudinal Aging Study Amsterdam (LASA), blood was collected in 1995/1996 among 1352 men and women aged 65 years. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) six times from 1995/1996 to 2011/2012. Multiple linear regression and mixed models were used to assess whether vitamin B12 and homocysteine were associated with severity at baseline and course of depressive symptoms over 16 years. Cox regression analyses were performed for the associations with incidence of depression (CES-D 16 and/or antidepressant use). All analyses were adjusted for sociodemographic characteristics and lifestyle factors.


Vitamin B12 was neither cross-sectionally (n=1205) nor prospectively (n=1012) associated with depressive symptoms (adjusted β for CES-D over time, lowest versus highest quartile: −0.04 (95% confidence interval (CI): −0.15−0.06)). We also found no association with incident depression (n=853), except for a higher risk of depression over time in younger participants (aged 64.8–73.4 years; continuous vitamin B12, adjusted hazard ratio per s.d.: 1.38 (95% CI: 1.10–1.72)). For homocysteine, no associations were found, except for a lower risk of depression in younger participants.


Our study did not confirm earlier shown associations of serum vitamin B12 and plasma homocysteine with severity and course of depressive symptoms and incidence of depression in older adults. Further research into the influence of homocysteine metabolism on mental health is needed.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Hoey L, Strain JJ, McNulty H . Studies of biomarker responses to intervention with vitamin B-12: a systematic review of randomized controlled trials. Am J Clin Nutr 2009; 89: 1981s–1996s.

    CAS  Article  Google Scholar 

  2. 2

    Stover PJ . Vitamin B12 and older adults. Curr Opin Clin Nutr Metab Care 2010; 13: 24–27.

    CAS  Article  Google Scholar 

  3. 3

    Hughes CF, Ward M, Hoey L, McNulty H . Vitamin B12 and ageing: current issues and interaction with folate. Ann Clin Biochem 2013; 50: 315–329.

    Article  Google Scholar 

  4. 4

    Aparicio-Ugarriza R, Palacios G, Alder M, Gonzalez-Gross M . A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clin Chem Lab Med 2014; 53: 1149–1159.

    Google Scholar 

  5. 5

    Devalia V, Hamilton MS, Molloy AM . Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166: 496–513.

    CAS  Article  Google Scholar 

  6. 6

    Djernes JK . Prevalence and predictors of depression in populations of elderly: a review. Acta Psychiatry Scand 2006; 113: 372–387.

    CAS  Article  Google Scholar 

  7. 7

    Coppen A, Bolander-Gouaille C . Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol 2005; 19: 59–65.

    CAS  Article  Google Scholar 

  8. 8

    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.

    CAS  Article  Google Scholar 

  9. 9

    Bottiglieri T . Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1103–1112.

    CAS  Article  Google Scholar 

  10. 10

    Belmaker RH, Agam G . Major depressive disorder. N Engl J Med 2008; 358: 55–68.

    CAS  Article  Google Scholar 

  11. 11

    Ford AH, Flicker L, Thomas J, Norman P, Jamrozik K, Almeida OP . Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry 2008; 69: 1203–1209.

    CAS  Article  Google Scholar 

  12. 12

    Christensen H, Aiken A, Batterham PJ, Walker J, Mackinnon AJ, Fenech M et al. No clear potentiation of antidepressant medication effects by folic acid+vitamin B12 in a large community sample. J Affect Disord 2011; 130: 37–45.

    CAS  Article  Google Scholar 

  13. 13

    Okereke OI, Cook NR, Albert CM, Van Denburgh M, Buring JE, Manson JE . Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women. Br J Psychiatry 2015; 206: 324–331.

    Article  Google Scholar 

  14. 14

    Almeida OP, Ford AH, Hirani V, Singh V, vanBockxmeer FM, McCaul K et al. B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial. Br J Psychiatry 2014; 205: 450–457.

    Article  Google Scholar 

  15. 15

    Hvas AM, Juul S, Lauritzen L, Nexo E, Ellegaard J . No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord 2004; 81: 269–273.

    CAS  Article  Google Scholar 

  16. 16

    Syed EU, Wasay M, Awan S . Vitamin B12 supplementation in treating major depressive disorder: a randomized controlled trial. Open Neurol J 2013; 7: 44–48.

    CAS  Article  Google Scholar 

  17. 17

    Almeida OP, Ford AH, Flicker L . Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. Int Psychogeriatr 2015; 27: 727–737.

    Article  Google Scholar 

  18. 18

    Moorthy D, Peter I, Scott TM, Parnell LD, Lai C-Q, Crott JW et al. Status of vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. J Nutr 2012; 142: 1554–1560.

    CAS  Article  Google Scholar 

  19. 19

    Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP . Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry 2000; 157: 715–721.

    CAS  Article  Google Scholar 

  20. 20

    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: 2099–2101.

    Article  Google Scholar 

  21. 21

    Ng TP, Feng L, Niti M, Kua EH, Yap KB . Folate, vitamin B12, homocysteine, and depressive symptoms in a population sample of older Chinese adults. J Am Geriatr Soc 2009; 57: 871–876.

    Article  Google Scholar 

  22. 22

    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.

    Article  Google Scholar 

  23. 23

    Eussen SJ, Ferry M, Hininger I, Haller J, Matthys C, Dirren H . Five year changes in mental health and associations with vitamin B12/folate status of elderly Europeans. J Nutr Health Aging 2002; 6: 43–50.

    CAS  PubMed  Google Scholar 

  24. 24

    Lindeman RD, Romero LJ, Koehler KM, Liang HC, LaRue A, Baumgartner RN et al. 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: 68–76.

    CAS  Article  Google Scholar 

  25. 25

    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: 618–626.

    CAS  Article  Google Scholar 

  26. 26

    Sachdev PS, Parslow RA, Lux O, Salonikas C, Wen W, Naidoo D et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med 2005; 35: 529–538.

    Article  Google Scholar 

  27. 27

    Beydoun MA, Shroff MR, Beydoun HA, Zonderman AB . Serum folate, vitamin B-12, and homocysteine and their association with depressive symptoms among U.S. adults. Psychosom Med 2010; 72: 862–873.

    CAS  Article  Google Scholar 

  28. 28

    Morris MS, Fava M, Jacques PF, Selhub J, Rosenberg IH . Depression and folate status in the US Population. Psychother Psychosom 2003; 72: 80–87.

    Article  Google Scholar 

  29. 29

    Petridou ET, Kousoulis AA, Michelakos T, Papathoma P, Dessypris N, Papadopoulos FC et al. Folate and B12 serum levels in association with depression in the aged: a systematic review and meta-analysis. Aging Mental Health 2015; pp 1–9.

  30. 30

    Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC . Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr 2010; 92: 330–335.

    CAS  Article  Google Scholar 

  31. 31

    Gougeon L, Payette H, Morais JA, Gaudreau P, Shatenstein B, Gray-Donald K . Intakes of folate, vitamin B6 and B12 and risk of depression in community-dwelling older adults: the Quebec Longitudinal Study on Nutrition and Aging. Eur J Clin Nutr 2016; 70: 380–385.

    CAS  Article  Google Scholar 

  32. 32

    Almeida OP, McCaul K, Hankey GJ, Norman P, Jamrozik K, Flicker L . Homocysteine and depression in later life. Arch Gen Psychiatry 2008; 65: 1286–1294.

    CAS  Article  Google Scholar 

  33. 33

    Nabi H, Bochud M, Glaus J, Lasserre AM, Waeber G, Vollenweider P et al. Association of serum homocysteine with major depressive disorder: Results from a large population-based study. Psychoneuroendocrinology 2013; 38: 2309–2318.

    CAS  Article  Google Scholar 

  34. 34

    Kamphuis MH, Geerlings MI, Grobbee DE, Kromhout D . Dietary intake of B(6-9-12) vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study. Eur J Clin Nutr 2008; 62: 939–945.

    CAS  Article  Google Scholar 

  35. 35

    Deeg DJH, van Tilburg T, Smit JH, de Leeuw ED . Attrition in the Longitudinal Aging Study Amsterdam: the effect of differential inclusion in side studies. J Clin Epidemiol 2002; 55: 319–328.

    Article  Google Scholar 

  36. 36

    Huisman M, Poppelaars J, van der Horst M, Beekman AT, Brug J, van Tilburg TG et al. Cohort profile: the Longitudinal Aging Study Amsterdam. Int J Epidemiol 2011; 40: 868–876.

    Article  Google Scholar 

  37. 37

    Hoogendijk EO, Deeg DJH, Poppelaars J, van der Horst M, Broese van Groenou MI, Comijs HC et al. The Longitudinal Aging Study Amsterdam: cohort update 2016 and major findings. Eur J Epidemiol 2016; 31: 927–945.

    Article  Google Scholar 

  38. 38

    Radloff LS . The CES-D scale: a self-report depression scale for research in the general population. Appl Psych Meas 1977; 1: 385–401.

    Article  Google Scholar 

  39. 39

    Beekman ATF, Deeg DJH, Van Limbeek J, Braam AW, De Vries MZ, Van Tilburg W . Criterion validity of the Center for Epidemiologic Studies Depression scale (CES-D): results from a community-based sample of older subjects in the Netherlands. Psychol Med 1997; 27: 231–235.

    CAS  Article  Google Scholar 

  40. 40

    Dhonukshe-Rutten RA, Pluijm SM, de Groot LC, Lips P, Smit JH, van Staveren WA . Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people. J Bone Miner Res 2005; 20: 921–929.

    CAS  Article  Google Scholar 

  41. 41

    Garretsen HFL. . Probleemdrinken: Prevalentiebepaling, Beïnvloedende Factoren en Preventiemogelijkheden, Theoretische Overwegingen en Onderzoek in Rotterdam. Swets & Zeitlinger: Lisse, The Netherlands, 1983.

    Google Scholar 

  42. 42

    Stel VS, Smit JH, Pluijm SM, Visser M, Deeg DJ, Lips P . Comparison of the LASA Physical Activity Questionnaire with a 7-day diary and pedometer. J Clin Epidemiol 2004; 57: 252–258.

    Article  Google Scholar 

  43. 43

    Seppälä J, Koponen H, Kautiainen H, Eriksson JG, Kampman O, Leiviska J et al. Association between vitamin b12 levels and melancholic depressive symptoms: a Finnish population-based study. BMC Psychiatry 2013; 13: 1–8.

    Article  Google Scholar 

Download references


The Longitudinal Aging Study Amsterdam is supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care. Funding for this paper was provided by the European Union FP7 MooDFOOD Project ‘Multi-country cOllaborative project on the rOle of Diet, FOod-related behaviour, and Obesity in the prevention of Depression’ (grant agreement no. 613598).

Author information



Corresponding author

Correspondence to L E M Elstgeest.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Elstgeest, L., Brouwer, I., Penninx, B. et al. Vitamin B12, homocysteine and depressive symptoms: a longitudinal study among older adults. Eur J Clin Nutr 71, 468–475 (2017).

Download citation

Further reading