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Vitamin B12, Folate, and Homocysteine in Depression: The Rotterdam Study
Open accessAbstract
OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. METHOD: The authors screened 3,884 elderly people for depressive symptoms. Subjects with positive screening results had psychiatric workups. Folate, vitamin B(12), and homocysteine blood levels were compared in 278 persons with depressive symptoms, including 112 with depressive disorders, and 416 randomly selected reference subjects. Adjustments were made for age, gender, cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.
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“A population-based study in 3884 elderly men and women with depressive disorders found that those with vitamin B12 deficiency were almost 70% more likely to experience depression than those with normal vitamin B12 status [170].”
From Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence (2020) · cites this paper as [170]
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“Vitamin B12 may be causally related to depression, whereas the relation with folate could be due to physical comorbidity (Tiemeier et al. 2002).”
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Hofman, A., Breteler, M. M. B., van Duijn, C. M., Janssen, H. L. A., Krestin, G. P., Kuipers, E. J., Stricker, B. H. C., Tiemeier, H., Uitterlinden, A. G., Vingerling, J. R., et al. (2009) · European Journal of Epidemiology · doi:10.1007/s10654-009-9386-z · Cited by 244
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BackgroundResultClinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study
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Almeida, O. P., McCaul, K. A., Hankey, G. J., Norman, P. E., Jamrozik, K. D., & Flicker, L. A. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.11.1286 · Cited by 166
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Venkatramanan, S., Armata, I. E., Strupp, B. J., & Finkelstein, J. L. (2016) · Advances in Nutrition · doi:10.3945/an.115.012021 · Cited by 138
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“Recent studies show that people with folate and/or vitamin B12 deficiency are more likely to develop depression (Tiemeier et al., 2002).”
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Wong, C. W. (2015) · Hong Kong Medical Journal · doi:10.12809/hkmj144383 · Cited by 140
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“Although, serum levels of vitamin E were not related to depressive symptoms in older Rotterdam residents (34), depressed aged people in our study reported lower intake of vitamin E compared to non-depressed participants.”
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Papakostas, G. I., Alpert, J. E., & D, M. F. M. (2003) · Current Psychiatry Reports · doi:10.1007/s11920-003-0085-2 · Cited by 96
“Studies also report a relationship between elevated homocysteine levels and depressive disorders in the elderly [ 14 ].”
BackgroundInfluentialREVIEW: Biological risk factors for late life depression
Tiemeier, H. W. (2003) · European Journal of Epidemiology · doi:10.1023/a:1025388203548 · Cited by 95
“Population-based studies performed in elderly populations were able to confirm only low vitamin B12 levels and to a lesser extent the ratio of omega-6/ omega-3 fatty acids as being independently associated with depression [81, 82].”
BackgroundRodríguez‐Oroz, M., Lage, P. M., Sanchez-Mut, J. V., Lamet, I., Pagonabarraga, J., Toledo, J. B., García‐García, D., Clavero, P., Samaranch, L., Irurzun, C., et al. (2009) · Movement Disorders · doi:10.1002/mds.22522 · Cited by 95
“(Hcy) levels represent a risk factor for cognitive decline and dementia in the general population(3) and have been associated with mild cognitive impairment (MCI),(4) Alzheimer’s disease (AD),(4,5) vascular dementia,(6) and depression.(7) In patients with PD, levodopa (Ldopa) treatment leads to increased Hcy plasma le…”
BackgroundKwok, T. C. Y., Wu, Y., Lee, J., Lee, R., Yung, C. Y., Choi, G., Lee, V. W. Y., Harrison, J., Lam, L. C. W., & Mok, V. (2019) · Clinical Nutrition · doi:10.1016/j.clnu.2019.11.005 · Cited by 98
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High vitamin B12 level and good treatment outcome may be associated in major depressive disorder
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“A Dutch study (n = 3884) suggested that B12 deficiency but not folate deficiency is independently related to depressive disorders [6].”
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Sugden, C. (2006) · Nutrition Research Reviews · doi:10.1079/nrr2006119 · Cited by 93
“Cobalamin-deficient subjects were significantly more likely to have a depressive disorder than controls (adjusted OR 1·69; P ¼ 0·02; 95% CI 1·10, 2·56) (Tiemeier et al. 2002).”
BackgroundEsnafoğlu, E., & ÖZTURAN, D. D. (2020) · Child and Adolescent Mental Health · doi:10.1111/camh.12387 · Cited by 92
Vitamin B12 Supplementation in Treating Major Depressive Disorder: A Randomized Controlled Trial
Syed, E. U., Wasay, M., & Awan, S. (2013) · The Open Neurology Journal · doi:10.2174/1874205x01307010044 · Cited by 90
“High B12 levels in serum are associated with good treatment response, high homocysteine levels which are common in folate / B12 deficiency and in those suffering from depression are associated with poor response to anti depressant treatment [15-17].”
Reif, A., Pfuhlmann, B., & Lesch, K. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2005.06.027 · Cited by 88
“Comparatively few studies aimed to investigate a possible involvement of HCY in depression (Fava et al., 1997; Bottiglieri et al., 2000; Penninx et al., 2000; Naismith et al., 2002; Tiemeier et al., 2002).”
Changes in folate, vitamin B12 and homocysteine associated with incident dementia
Kim, J.-M., Stewart, R., Kim, S.-W., Shin, I.-S., Yang, S.-J., Shin, H.-Y., & Yoon, J.-S. (2008) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2007.131482 · Cited by 85
Pereira, R. D. S. (2006) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2006.00359.x · Cited by 84
Tolmunen, T., Hintikka, J., Voutilainen, S., Ruusunen, A. A., Alfthan, G., Nyyssönen, K., Viinamäki, H. T., Kaplan, G. A., & Salonen, J. T. (2004) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/80.6.1574 · Cited by 83
“Several studies failed to support an independent role for elevated tHcy concentrations in depression: 3 studies found no association between tHcy and depression (6, 18, 19), and a population-based study showed the disappearance of an association between tHcy and depression after correction for cardiovascular disease r…”
MethodResultFolic acid: neurochemistry, metabolism and relationship to depression
Paul, R. T. P., McDonnell, A. P., & Kelly, C. B. (2004) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.614 · Cited by 82
Vitamin B12 deficiency. Recognizing subtle symptoms in older adults.
Dharmarajan, T. S., Adiga, G. U., & Norkus, E. P. (2003) · PubMed · Cited by 79
Wu, Y., Zhang, L., Li, S., & Zhang, D. (2021) · Nutrition Reviews · doi:10.1093/nutrit/nuab014 · Cited by 80
Ng, T. P., Feng, L., Niti, M., Kua, E. H., & Yap, K.-B. (2009) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2009.02229.x · Cited by 80
“0mmol/L) used in other studies.(15) Group comparisons of categorical and continuous variables were performed using the chi-square test or analysis of variance, as appropriate.”
MethodFolate and Unipolar Depression
Morris, D. W., Trivedi, M. H., & Rush, A. J. (2008) · The Journal of Alternative and Complementary Medicine · doi:10.1089/acm.2007.0663 · Cited by 81
Walker, J. G., Mackinnon, A. J., Batterham, P. J., Jorm, A. F., Hickie, I. B., McCarthy, A., Fenech, M. F., & Christensen, H. M. (2010) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.109.075291 · Cited by 79
Food Insecurity and Risk of Depression Among Refugees and Immigrants in South Africa
Maharaj, V., Tomita, A. M., Thela, L. T., Mhlongo, M., & Burns, J. K. (2016) · Journal of Immigrant and Minority Health · doi:10.1007/s10903-016-0370-x · Cited by 79
“Refugees represent an ‘‘at risk’’ population for nutrient deficiencies, such as vitamin B12 and iron [9–11], which could predispose them to depression [12].”
Haskell‐Ramsay, C. F., Robertson, B. C., Jones, E., Forster, J. S., Jones, R., Wilde, A., Maggini, S., & Kennedy, D. O. (2010) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.1144 · Cited by 79
“…of one or more B vitamins and/or homocysteine are related to depression (Bjelland et al., 2003; Kim et al., 2008; Sanchez-Villegas et al., 2009; Tiemeier et al., 2002), and cognitive function (Durga et al., 2006; Duthie et al., 2002; Elias et al., 2006, 2008; Feng et al., 2006; Kado et al.,…”
BackgroundGillespie, N. A., Kirk, K. M., Evans, D. M., Heath, A. C., Hickie, I. B., & Martin, N. G. (2004) · Twin Research · doi:10.1375/13690520460741435 · Cited by 77
“For example, recent studies suggest associations between homocysteine and depression in persons residing in the community (den Heijer et al., 2003; Tiemeier et al., 2002).”
BackgroundSingle-Subject Studies in Translational Nutrition Research
Schork, N. J., & Goetz, L. H. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064717 · Cited by 79
Kamphuis, M. H., Geerlings, M. I., Grobbee, D. E., & Kromhout, D. (2007) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1602804 · Cited by 74
“Studies that investigated the association of blood levels of B6-9-12 vitamins and homocysteine with depression in the elderly showed inconsistent results (Penninx et al., 2000; Tiemeier et al., 2002; Almeida et al., 2004; Hvas et al., 2004a; Sachdev et al., 2005; Williams et al., 2005).”
BackgroundResultInfluentialFood insecurity and housing instability in vulnerable families
King, C. (2016) · Review of Economics of the Household · doi:10.1007/s11150-016-9335-z · Cited by 81
“…increase the risk of maternal depression through the accumulation of stress from experiencing food insufficiency (Heflin et al. 2005; Whitaker et al. 2006), or through multiple nutritional deficiencies such as in vitamin B12 and folate (Alpert and Fava 1997; Reynolds 2002; Tiermeier et al. 2002).”
Considering the Case for Vitamin B 12 Fortification of Flour
Allen, L. H., Rosenberg, I. H., Oakley, G. P., & Omenn, G. S. (2010) · Food and Nutrition Bulletin · doi:10.1177/15648265100311s104 · Cited by 75
“Vitamin B12 deficiency was a risk factor for depression in several studies [46].”
BackgroundNutrition and the psychoneuroimmunology of postpartum depression
Ellsworth-Bowers, E. R., & Corwin, E. J. (2012) · Nutrition Research Reviews · doi:10.1017/s0954422412000091 · Cited by 79
Resler, G., Lavie, R., Campos, J., Mata, S., Urbina, M., García, A., Apitz, R. J., & Lima, L. (2008) · NeuroImmunoModulation · doi:10.1159/000151527 · Cited by 73
Gariballa, S., & Forster, S. (2007) · Clinical Nutrition · doi:10.1016/j.clnu.2007.06.007 · Cited by 85
Metformin and Vitamin B12 Deficiency: Where Do We Stand?
Ahmed, M. A. (2016) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3pk7p · Cited by 78
“386 symptoms may take many forms, including peripheral neuropathy (PN) which generally manifests as numbness and paresthesia (41), optic neuropathy (33), and neuropsychiatric disorders such as chronic fatigue syndrome, psychosis, mood disorders (42) or depressive symptoms (43).”
BackgroundVitamin B12 and folate serum levels in newly admitted psychiatric patients
Lerner, V., Kanevsky, M., Dwolatzky, T., Rouach, T., Kamin, R., & Miodownik, C. (2005) · Clinical Nutrition · doi:10.1016/j.clnu.2005.08.014 · Cited by 71
Vitamin B6Is Associated with Depressive Symptomatology in Massachusetts Elders
Merete, C., Falcón, L. M., & Tucker, K. L. (2008) · Journal of the American College of Nutrition · doi:10.1080/07315724.2008.10719720 · Cited by 71
“In comparison to nondepressed patients, depressed patients have been shown to be deficient in vitamin B12 and folate [1,3,16].”
ResultCancer-Related Stress and Complementary and Alternative Medicine: A Review
Chandwani, K. D., Ryan, J. L., Peppone, L. J., Janelsins, M. C., Sprod, L. K., Devine, K. A., Trevino, L. A., Gewandter, J. S., Morrow, G. R., & Mustian, K. M. (2012) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2012/979213 · Cited by 72
“[139] H.”
Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease
O’Suilleabhain, P. E., Bottiglieri, T., Dewey, R. B., Sharma, S., & Diaz-Arrastia, R. R. (2004) · Movement Disorders · doi:10.1002/mds.20253 · Cited by 71
Metadata
- Authors
- Tiemeier, H., van Tuijl, H. R., Hofman, A., Meijer, J., Kiliaan, A. J., & Breteler, M. M. B.
- Affiliations
- Erasmus MC (NL)
- Venue
- American Journal of Psychiatry
- Published
- 2002-12-01
- Volume
- 159
- Issue
- 12
- Pages
- 2099-2101
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2131673402
- Cited by
- 408
- References
- 6
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 13 · 2023: 4 · 2022: 12 · 2021: 12 · 2020: 41 · 2019: 7 · 2018: 18 · 2017: 11 · 2016: 16 · 2015: 14 · 2014: 27 · 2013: 22 · 2012: 19
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- vitamin B12, folic acid, homocysteine, hyperhomocysteinemia, depression, depressive disorders, vitamin B12 deficiency, folate deficiency, older adults, functional disability, cardiovascular disease, comorbidities
- MeSH terms
- Aged, Chromatography, High Pressure Liquid, Depressive Disorder, Female, Folic Acid Deficiency, Humans, Male, Middle Aged, Population Surveillance, Vitamin B 12 Deficiency, Hyperhomocysteinemia
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