Cited by 408Folate and B Vitamins ResearchTryptophan and brain disordersTreatment of Major Depression

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Vitamin B12, Folate, and Homocysteine in Depression: The Rotterdam Study

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Tiemeier, Henning, van Tuijl, H. Ruud, Hofman, Albert, Meijer, John, Kiliaan, Amanda J., Breteler, Monique M.B.·2002·American Journal of Psychiatry

DOI 10.1176/appi.ajp.159.12.2099

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Abstract

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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Background
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Background
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Background
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Background
Nutritional strategies for dealing with depression
Manosso, L. M., Moretti, M., & Rodrigues, A. L. S. (2013) · Food & Function · doi:10.1039/c3fo60246j · Cited by 39
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“Recently, data from the Rotterdam study ( Tiemeier et al., 2002 ) argued for a relationship of an impaired homocysteine pathway in depression.”
Background
Association of Vitamin B12 Deficiency with Fatigue and Depression after Lacunar Stroke
Huijts, M., Duits, A., Staals, J., & van Oostenbrugge, R. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030519 · Cited by 35
“Since depression is found to be related to low vitamin B12 levels in the elderly population [12], we also adjusted for age.”
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Background
Vitamins and psychological functioning: a mobile phone assessment of the effects of a B vitamin complex, vitamin C and minerals on cognitive performance and subjective mood and energy
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“…2007), the results of numerous studies demonstrate a potential relationship between these vitamins and/or levels of homocysteine and depression (Tiemeier et al., 2002; Bjelland et al., 2003; Kim et al., 2008; Sanchez‐Villegas et al., 2009) and cognitive performance (La Rue et al., 1997; Duthie…”
Result
Vitamin B12, homocysteine and depressive symptoms: a longitudinal study among older adults
Elstgeest, L. E. M., Brouwer, I. A., Penninx, B. W. J. H., van Schoor, N. M., & Visser, M. (2017) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2016.224 · Cited by 33
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Folate Augmentation of Treatment – Evaluation for Depression (FolATED): protocol of a randomised controlled trial
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“A recent cohort study demonstrated that hyperhomocysteinaemia (plasma level >15 μmol/L), but not total serum folate or vitamin B12, is significantly related to depression severity (odds ratio = 1.90; 95% confidence interval = 1.11–3.25)[ 10 ].”
Influential
The association between serum vitamin B12 deficiency and tension-type headache in Turkish children
Çalık, M., Aktas, M. S., Çeçen, E., Pişkin, İ. E., Ayaydın, H., Örnek, Z., Karaca, M., Solmaz, A., & Ay, H. (2018) · Neurological Sciences · doi:10.1007/s10072-018-3286-5 · Cited by 31
“a higher rate of depression in vitamin B12 deficient elderly patients due to socioeconomic and health factors [41].”
Background
Plasma homocysteine levels in depression and schizophrenia in South Indian Tamilian population
Narayan, S. K., Verman, A., Kattimani, S., Ananthanarayanan, P., & Adithan, C. (2014) · Indian Journal of Psychiatry · doi:10.4103/0019-5545.124746 · Cited by 31
“Hordoland Hcys study, [9] King’s College study, [41] Rotterdam study, [10]”
Vascular Nutritional Correlates of Late-Life Depression
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Kendrick, T., Dunn, N., Robinson, S., Oestmann, A., Godfrey, K., Cooper, C., Inskip, H., & the Southampton Women’s Survey Study Group (2008) · Journal of Epidemiology and Community Health · doi:10.1136/jech.2007.069765 · Cited by 29
S‐Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders
Kuželički, N. K. (2016) · Drug Development Research · doi:10.1002/ddr.21345 · Cited by 29
“Namely, individuals with deficient trans-sulfuration and/or remethylation pathways, as well as folate and/or vitamin B12 deficiency might not be able to eliminate excessive homocysteine and might be at risk of cardiovascular events when taking SAM for longer periods of time.”
Background
Natural Products and Supplements for Geriatric Depression and Cognitive Disorders: An Evaluation of the Research
Varteresian, T. C., & Lavretsky, H. (2014) · Current Psychiatry Reports · doi:10.1007/s11920-014-0456-x · Cited by 29
Blood profile holds clues to role of infection in a premonitory state for idiopathic parkinsonism and of gastrointestinal infection in established disease
Charlett, A., Dobbs, R. J., Dobbs, S. M., Weller, C., Ibrahim, M. A. A., Dew, T. K., Sherwood, R. A., Oxlade, N. L., Plant, J., Bowthorpe, J., et al. (2009) · Gut Pathogens · doi:10.1186/1757-4749-1-20 · Cited by 29
“Hyperhomocysteinemia is associated with cardiovascular risk and conditions which overlap with parkinsonism: dementing illnesses [54] and depression [55].”
Background
Intake of B vitamins in childhood and adult life in relation to psychological distress among women in a British birth cohort
Mishra, G. D., McNaughton, S. A., O'Connell, M. A., Prynne, C. J., & Kuh, D. J. (2008) · Public Health Nutrition · doi:10.1017/s1368980008002413 · Cited by 28
“Thiamin 0?05 0?5 0?8 0?4 Low 22 (4, 40) 9 (28, 27) 4 (214, 22) 12 (26, 30) Middle 16 (22, 35) 0?2 (218, 18) 21 (219, 17) 4 (214, 22) High Reference Reference Reference Reference Riboflavin 0?8 0?5 0?6 0?4 Low 7 (212, 26) 6 (211, 24) 25 (223, 13) 11 (27, 29) Middle 5 (213, 23) 25 (223, 13) 16 (22, 34) 12 (26, 29) High…”
Background
Association between uremic toxins and depression in patients with chronic kidney disease undergoing maintenance hemodialysis
Hsu, H.-J., Yen, C.-H., Chen, C., Wu, I., Lee, C., Sun, C., Chang, S., Chou, C., Hsieh, M.-F., Chen, C., et al. (2012) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2012.08.009 · Cited by 29
“The causes of the higher prevalence of depression in CKD patients are uncertain, but may be related to the higher prevalence of comorbid chronic diseases, complications of anemia and vitamin B12 deficiency, genetic factors, greater mental stress and hyperinflammatory status [10–13].”
Background
Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part I)
Iosifescu, D. V., Papakostas, G. I., Lyoo, I. K., Lee, H. K., Renshaw, P. F., Alpert, J. E., Nierenberg, A. A., & D, M. F. M. (2005) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2005.09.003 · Cited by 28
Natural Food Folate and Late-Life Depression
Payne, M. E., Jamerson, B. D., Potocky, C. F., Ashley‐Koch, A. E., Speer, M. C., & Steffens, D. C. (2009) · Journal of Nutrition for the Elderly · doi:10.1080/01639360903417181 · Cited by 27
“Depressed individuals have been found to exhibit poorer folate status (plasma and erythrocyte levels) than non-depressed individuals in some clinical and epidemiological studies ( 16-19 ), while several epidemiological studies have failed to demonstrate any relationship between folate status and late-life depression (…”
Result
Serum Folate and Depressive Symptoms Among Japanese Men and Women: A Cross-Sectional and Prospective Study
Nanri, A., Hayabuchi, H., Ohta, M., Sato, M., Mishima, N., & Mizoue, T. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.04.040 · Cited by 27
Clinical course in Parkinson's disease with elevated homocysteine
O’Suilleabhain, P. E., Oberle, R., Bartis, C., Dewey, R. B., Bottiglieri, T., & Diaz-Arrastia, R. R. (2005) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2005.10.002 · Cited by 27
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Age-associated B vitamin deficiency as a determinant of chronic diseases
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“Moreover, elderly individuals deficient in vitamin B12 can develop neuropsychiatric abnormalities, such as depression, that are not seen in folate deficiency, suggesting effects specific to cobalamin metabolic, environmental or genetic factors (Tiemeier et al. 2002).”
Background
Influence of the MTHFR C677T Polymorphism on Magnetic Resonance Imaging Hyperintensity Volume and Cognition in Geriatric Depression
Hong, E. D., Taylor, W. D., McQuoid, D. R., Potter, G. G., Payne, M. E., Ashley‐Koch, A. E., & Steffens, D. C. (2009) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e3181aad5b2 · Cited by 27
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Biological understanding of the cardiovascular risk associated with major depression and panic disorder is important
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“Homo- Int J Geriatr Psychiatry 2011; 26: 307–313 cysteine has been implicated in cross-sectional studies of depression and depressive symptoms (Tiemeier et al., 2002) and higher levels of homocysteine are associated with higher incident depression (Kim et al., 2008).”
BackgroundInfluential
Cross-Sectional Analysis of the Correlation Between Daily Nutrient Intake Assessed by 7-Day Food Records and Biomarkers of Dietary Intake Among Participants of the NU-AGE Study
Ostan, R., Guidarelli, G., Giampieri, E., Lanzarini, C., Berendsen, A. A. M., Januszko, O., Jennings, A., Lyon-Belgy, N., Caumon, E., Gillings, R., et al. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01359 · Cited by 27
“Indeed, low intake of folate and vitamin B12 are associated with high homocysteine levels considered a risk factor for cardiovascular disease, dementia and depression (Tiemeier et al., 2002; Moretti et al., 2004; Zakai et al., 2007; Kim et al., 2008; Smith et al., 2018).”
Background
Acute vitamin B12 supplementation evokes antidepressant response and alters Ntrk-2
Trautmann, C., Bock, A., Urbach, A., Hübner, C. A., & Engmann, O. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108112 · Cited by 25
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Laird, E. J., O’Halloran, A. M., Molloy, A. M., Healy, M., Hernández, B., O’Connor, D. M. A., Kenny, R. A., & Briggs, R. (2021) · British Journal Of Nutrition · doi:10.1017/s0007114521004748 · Cited by 29
“Another study in older adults observed a similar increased risk of depression with low B12 status(13), while a further four studies in similar cohorts observed no such association(17,36–38).”
Result
Serum homocysteine levels are correlated with behavioral and psychological symptoms of Alzheimer’s disease
Lee, & Kim, H. (2014) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s68980 · Cited by 25
High intake of folic acid or complex of B vitamins provides anti-Parkinsonism effect: No role for serum level of homocysteine
Haghdoost-Yazdi, H., Fraidouni, N., Faraji, A., Jahanihashemi, H., & Sarookhani, M. R. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.05.011 · Cited by 25
“Also, elevated plasma Hcy level is a risk factor for cognitive decline and dementia in the general population and has been associated with mild cognitive impairment, Alzheimer's disease (AD), vascular dementia and depression [10] [11] [12] [13] [14].”
Nutrition and Late-Life Depression: Etiological Considerations
Payne, M. E. (2010) · Aging Health · doi:10.2217/ahe.09.90 · Cited by 25
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Background
No relation between folate and homocysteine levels and depression in early pregnant women.
Watanabe, H., Suganuma, N., Hayashi, A., Hirowatari, Y., Hirowatari, T., & Ohsawa, M. (2010) · PubMed · Cited by 23
Use of Proton Pump Inhibitors and Risk of Major Depressive Disorder: A Nationwide Population-Based Study
Huang, W.-S., Bai, Y., Hsu, J.-W., Huang, K., Tsai, C.-F., Su, T., Li, C., Lin, W.-C., Tsai, S., Pan, T., et al. (2018) · Psychotherapy and Psychosomatics · doi:10.1159/000485190 · Cited by 23
Plasma pterins and folate in late life depression: The Rotterdam Study
Tiemeier, H. W., Fekkes, D., Albert Hofman, D., van Tuijl, H. R., Kiliaan, A. J., & Breteler, M. M. B. (2006) · Psychiatry Research · doi:10.1016/j.psychres.2005.07.035 · Cited by 23
Testing homocysteine-induced neurotransmitter deficiency, and depression of mood hypothesis in clinical practice
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Hyperhomocysteinemia Is a Result, Rather than a Cause, of Depression under Chronic Stress
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Background
The B-VITAGE trial: A randomized trial of homocysteine lowering treatment of depression in later life
Ford, A. H., Flicker, L. A., McCaul, K. A., van Bockxmeer, F., Hegarty, S., Hirani, V., Fenner, S. G., & Almeida, O. P. (2010) · Trials · doi:10.1186/1745-6215-11-8 · Cited by 23
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Background
Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application
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“Although it remains unclear whether raised homocysteine is a causal factor or merely a biomarker for deficiencies in folate and other B vitamins, inadequate intake of these nutrients has convincingly been linked to MDD in some patients (Tiemeier et al. 2002; Bottiglieri 2005).”
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Authors: Tiemeier, H., van Tuijl, H. R., Hofman, A., Meijer, J., Kiliaan, A. J., & Breteler, M. M. B.
Affiliations: Erasmus MC (NL)
ORCID: Tiemeier, Henning
Kiliaan, Amanda J.
Breteler, Monique M.B.
Venue: American Journal of Psychiatry
Publisher: American Psychiatric Association Publishing
Published: 2002-12-01
Volume: 159
Issue: 12
Pages: 2099-2101
ISSN: 0002-953X (ISSN-L)
1535-7228
DOI: 10.1176/appi.ajp.159.12.2099
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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Vitamin B12, Folate, and Homocysteine in Depression: The Rotterdam Study

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