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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Shoffel‐Havakuk, H., Lava, C. X., Reuven, Y., Moog, D., O'Dell, K. D., Reder, L. S., Hapner, E. R., & Johns, M. M. E. (2020) · JAMA Otolaryngology–Head & Neck Surgery · doi:10.1001/jamaoto.2020.4026 · Cited by 6
Pathophysiology of Mood Disorders and Mechanisms of Action of Antidepressants and Mood Stabilizers
Fišar, Z. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7940-6_6 · Cited by 7
Rôle de l’homocystéine en pathologie
de jaeger, C., Fraoucene, N., Voronska, E., & Cherin, P. (2010) · Médecine & longévité · doi:10.1016/j.mlong.2010.03.002 · Cited by 6
Über den möglichen Einfluss der Ernährung auf die psychische Gesundheit
Hausteiner, C., Bornschein, S., Zilker, T., Förstl, H., & Graßmann, J. (2007) · Der Nervenarzt · doi:10.1007/s00115-007-2265-5 · Cited by 6
Detectar la depresión antes, durante y después de la gestación con el perfil anímico del embarazo
Campagne, D. M. (2004) · Progresos de Obstetricia y Ginecología · doi:10.1016/s0304-5013(04)75956-7 · Cited by 6
Collaborative depression care, screening, diagnosis and specificity of depression treatments in the primary care setting
Alexander, J. L., Richardson, G., Grypma, L., & Hunkeler, E. M. (2007) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.7.11s.s59 · Cited by 6
Half-baked? B vitamins and depression
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“Indeed, it has been proposed that vitamin B-12 has a stronger causal relation to depression than does folate (8), although, interestingly, low folate but not low vitamin B-12 significantly delays time to onset of clinical improvement in patients with depression compared with depressed patients with normal folate conce…”
Background
Valeriana jatamansi jones improves depressive behavior in CUMS mice by modulating vitamin B12-related ileal homeostasis
Lv, P., Xiang, F., Zhang, S., Lei, D., Zhou, C., Wei, G., & Yan, Z. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.119392 · Cited by 5
Subjective well-being in older adults: folate and vitamin B12independently predict positive affect
Edney, L. C., Burns, N. R., & Danthiir, V. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515002949 · Cited by 5
“Homocysteine is an amino acid that, at high levels, is associated with adverse health outcomes such as CVD((5)) and depression((6)); SAMe is a methyl donor with potential antidepressant properties due to its involvement in the metabolism of neurotransmitters such”
Background
POSITIVE PSYCHIATRY, POSITIVE PSYCHOLOGY AND MINDFULNESS: A COMMON VIEW
Marques, I. A., Balreira, M. L., & Temótio, J. (2018) · Psicologia Saúde & Doenças · doi:10.15309/18psd190215 · Cited by 5
Homocysteine as a potential indicator of endothelial dysfunction and cardiovascular risk in female patients with borderline personality disorder
Kern, K., Sinningen, K., Engemann, L., Maiß, C., Hanusch, B., Mügge, A., Lücke, T., & Brüne, M. (2022) · Borderline Personality Disorder and Emotion Dysregulation · doi:10.1186/s40479-021-00171-9 · Cited by 6
Nutrition and Depression
Gebretsadik, M., & Grossberg, G. T. (2007) · Nutrition and disease prevention · doi:10.1201/9781420005493.ch22 · Cited by 5
Nutritional-Based Nutraceuticals in the Treatment of Anxiety
Camfield, D. (2016) · Springer eBooks · doi:10.1007/978-3-319-42307-4_5 · Cited by 5
Exposure to Nitrous Oxide May Be Associated With High Homocysteine Plasma Levels and a Risk for Clinical Depression
Levine, J., & Chengappa, K. R. (2007) · Journal of Clinical Psychopharmacology · doi:10.1097/01.jcp.0000264982.02239.48 · Cited by 5
Nutrition and Late-Life Depression
Payne, M. E. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-385-5_26 · Cited by 5
“A study of vitamin status among older individuals living in Rotterdam (n ¼ 806) also found that B12 deficiency was associated with depression, after controlling for cardiovascular disease and functional disability ( 59 ).”
Background
The Use of Natural Products and Supplements in Late-Life Mood and Cognitive Disorders
Varteresian, T. C., Merrill, D. A., & Lavretsky, H. (2013) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.11.1.15 · Cited by 4
Is Depression Related to Low Folate Levels in People with Epilepsy? An Observational Study and Meta-analysis
Ramanujam, B., Bajaj, B. K., Kaur, K., Anand, K. S., & Buxi, G. (2017) · Journal of Neurosciences in Rural Practice · doi:10.4103/jnrp.jnrp_468_16 · Cited by 4
“suggests that the relation between folate and pterins is altered in the depressed elderly, though they found no association between the concentration of biopterin or neopterin with depressive symptoms or depressive disorders.[29]”
Background
Depression and one carbon metabolic pathway: A study among a mendelian population from North India
Kaur, G., Gaur, R., Thakur, M. K., & Saraswathy, K. N. (2018) · Current Psychology · doi:10.1007/s12144-018-0056-8 · Cited by 4
A retrospective examination of adjunctive L-methylfolate in children and adolescents with unipolar depression
Bopp, E. A., Poweleit, E. A., Cox, M. O., Farrow, J. E., Strawn, J. R., Durán, L. R. P., Prows, C. A., DelBello, M. P., & Ramsey, L. B. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.06.039 · Cited by 4
Evaluation of Factors of Importance for Clinical Dementia Diagnosis
Nägga, K., Garcia, J., Zetterberg, H., Blennow, K., Gottfries, J., & Marcusson, J. O. (2005) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000084554 · Cited by 4
A new look at vitamin B12 deficiency
Nettina, S. M. (2009) · The Nurse Practitioner · doi:10.1097/01.npr.0000363588.59740.6f · Cited by 4
Suicidal ideation in a sample with a first-episode of restrictive eating disorders: The role of biomarkers
del Barrio, A. G., de Santayana, G. P., Ruiz-Guerrero, F., Gonzalez, P. B., Giraldo, G. C., Gómez, J. G., & García‐Unzueta, M. T. (2022) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2021.100305 · Cited by 4
Serum folate and homocysteine as biomarkers for suicide risk in major depressive disorder: insights in males and younger patients
Zhang, A., Qin, Y., Wang, H., Lyu, N., Zhao, Q., Zhang, L., & Huang, J. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-07183-7 · Cited by 4
“Similarly, the Rotterdam Study in older adults reported that, after adjusting for multiple variables, neither low folate nor high HCY levels were significantly associated with depressive symptoms [20].”
Methyltetrahydrofolate reductase polymorphism, folic acid, and B12 in a sample of patients with depressive and anxiety symptoms
Fathy, H., El-Mawella, S. M. A., Abdou, H., Adel, A., & Abdou, A. (2011) · Middle East Current Psychiatry · doi:10.1097/01.xme.0000395563.70945.52 · Cited by 3
Catechol-O-methyltransferase inhibitors
Pfeiffer, R. F. (2013) · CRC Press eBooks · doi:10.1201/b14361-25 · Cited by 3
N-Terminal pro-Brain Natriuretic Peptide, Homocysteine and Methylenetetrahydrofolate Reductase Gene Polymorphism in Elderly Depressed and Mild Cognitive Impairment Patients
El‐Batch, M., Eissa, M., Farouk, G., & Attia, M. A. (2008) · Bulletin of Egyptian Society for Physiological Sciences · doi:10.21608/besps.2008.37030 · Cited by 3
“Furthermore, it has been suggested that homocysteic acid and cysteine sulfinic acid, as metabolites of Hcy, may inhibit the S-adenosylmethionine–dependent methylation of biogenic amines and phospholipids, thus, an elevated plasma Hcy concentration may merely be a marker of impaired monoamine metabolism, which causes d…”
BackgroundResult
Improvement of cognitive performance by a nutraceutical formulation: Underlying mechanisms revealed by laboratory studies
Shea, T. B. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.039 · Cited by 3
Vitamin Disorders
Hajjar, R. R., & Nahhas, Z. (2007) · Nutrition and disease prevention · doi:10.1201/9781420005493.ch10 · Cited by 3
Depressive symptoms are associated with food insufficiency and nutritional deficiencies in poor community-dwelling elderly people
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Combining Medications to Achieve Remission
Zajecka, J., & Goldstein, C. (2009) · doi:10.3109/9781420084887-5 · Cited by 3
Adults with depressive symptoms have lower odds of dietary supplement use
Meshkat, S., Tassone, V. K., Pang, H. Y. M., Wu, M., Jung, H., Lou, W. Y. W., & Bhat, V. (2024) · PLoS ONE · doi:10.1371/journal.pone.0302637 · Cited by 3
From Micro to Macro: Understanding the Far‐Reaching Consequences of B12 Deficiency on Women's Health
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Nutritional Aspects of Eating Disorders, Addictions, and Substance Use Disorders
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Western Diet and Behavior: The Columbus Concept
Wilczyńska-Kwiatek, A., Meester, F. D., Singh, R. B., & Łapiński, Ł. (2010) · Humana Press eBooks · doi:10.1007/978-1-60327-571-2_1 · Cited by 2
“These vitamins, minerals, antioxidants, flavonoids, and ω-3 fatty acids should be adequately available, as dietary deficiencies in them are associated with psychological disorders [53, 61, 62].”
Background
L’algue Klamath et ses propriétés nutritionnelles. Un extrait spécifique aux effets neuromodulateurs et neuroprotecteurs
Menvielle-Bourg, F. J., Vitacca, A., & Scoglio, S. (2011) · Phytothérapie · doi:10.1007/s10298-011-0627-4 · Cited by 2

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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