Folate, vitamin B12, and homocysteine in major depressive disorder
Abstract
OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment.
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Low serum folate is associated with depression and resistance to antidepressant treatment.
“low serum folate has been associated with depression and with resistance to antidepressant treatment”
From Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications (2013) · cites this paper as Fava et al., 1997
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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 · see citing works
“Randomized trials have shown that folate and other nutritional supplementations have a significant effect in treating the treatment-resistant depression [19,20].”
Depressive symptoms and risk for malnutrition among hospitalized elderly people
German, L., Feldblum, I., Bilenko, N., Castel, H., Harman‐Boehm, I., & Shahar, D. R. (2008) · The journal of nutrition health & aging · doi:10.1007/bf02982661 · Cited by 88 · see citing works
“Another hypothesis is that undernutrition may affect depression through biological changes: lack of consumption of important macro-and micronutrients may result in lower immune functioning or cause neurohormonal or neurotransmitter changes (40).”
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 · see citing works
“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).”
Kelly, C. B., McDonnell, A. P., Johnston, T., Mulholland, C. C., Cooper, S. J., McMaster, D., Evans, A., & Whitehead, A. S. (2004) · Journal of Psychopharmacology · doi:10.1177/0269881104047285 · Cited by 88 · see citing works
“Low plasma folate also appears to predict a poor response to antidepressant treatment (Fava et al., 1997).”
BackgroundAlmeida, O. P., Ford, A. H., Hirani, V., Singh, V., VANBOCKXMEER, F., McCaul, K. A., & Flicker, L. A. (2014) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.114.145177 · Cited by 87 · see citing works
Mahdavifar, B., Hosseinzadeh, M., Salehi‐Abargouei, A., Mirzaei, M., & Vafa, M. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.03.055 · Cited by 84 · see citing works
Predictors of response to antidepressants
Nierenberg, A. A. (2003) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(02)00105-3 · Cited by 84 · see citing works
“These negative predictors included very early age of onset; comorbid anxiety disorder [22]; current alcohol use (not abuse) [23]; persistent nonresponse in the first 4 to 5 weeks [24]; alcohol use and dropout in long-term follow-up; and low folate levels [25].”
BackgroundSelf-citationTolmunen, 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 · see citing works
“Bottiglieri et al (14) recorded increased plasma tHcy concentrations in 52% of depressed inpatients by using the same cutoff as we did, whereas Fava et al (6) observed increased tHcy concentrations in 20% of depressed outpatients (cutoff: 13.”
BackgroundMethodResultInfluentialFolic 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 · see citing works
“…SFA levels relative relevant study to microbiolocal assay controls Bio-Rad Laboratory Levitt and Joffe, 1989 157% Quanta-Phase I Bio-Rad Laboratory Fava et al., 1997 73% Quanta-Phase II Diagnostic Products Lee et al., 1998 130% Corporation Dual Count Folate Kit Copyright # 2004 John Wiley & Sons,…”
BackgroundNg, 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 · see citing works
Folate 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 80 · see citing works
“In study of 213 adult outpatients with MDD, Fava et al., 75 found low folate levels to be associated with the presence of melancholic depression.”
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 · see citing works
“In addition, depressed patients with low blood levels of folate had a poorer response to anti-depressive treatment (Fava et al., 1997).”
BackgroundResler, 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 · see citing works
Assies, J., Lok, A., Bockting, C. L., Weverling, G. J., Lieverse, R., Visser, I., Abeling, N. G. G. M., Duran, M., & Schene, A. H. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.12.009 · Cited by 72 · see citing works
Alpert, M., Silva, R. R., & Pouget, E. R. (2003) · Journal of Clinical Psychopharmacology · doi:10.1097/01.jcp.0000084024.22282.cd · Cited by 72 · see citing works
Stahl, S. M. (2007) · CNS Spectrums · doi:10.1017/s1092852900015418 · Cited by 71 · see citing works
Vitamin 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 · see citing works
Effective Mood Stabilization With a Chelated Mineral Supplement
Kaplan, B. J., Simpson, J. S., Ferre, R., Gorman, C. P., McMullen, D. M., & Crawford, S. G. (2001) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v62n1204 · Cited by 71 · see citing works
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 · see citing works
Neuropharmacology of depression in aging and age-related diseases
Gareri, P., Fazio, P. D., & Sarro, G. D. (2002) · Ageing Research Reviews · doi:10.1016/s0047-6374(01)00370-0 · Cited by 71 · see citing works
Dharmayani, P. N. A., Juergens, M., Allman-Farinelli, M. A., & Mihrshahi, S. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18020780 · Cited by 68 · see citing works
Liwinski, T., & Lang, U. E. (2023) · Nutrients · doi:10.3390/nu15173859 · Cited by 74 · see citing works
“Numerous studies have provided evidence suggesting a potential association be-tween folate deficiency and depression [22,59–63].”
BackgroundCognitive Function in an Elderly Population
Vogiatzoglou, A., Smith, A. D., Nurk, E., Drevon, C. A., Ueland, P. M., Vollset, S. E., Nygaard, H. A., Engedal, K., Tell, G. S., & Refsum, H. (2012) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3182761b6c · Cited by 68 · see citing works
The Role of Vitamins in Autism Spectrum Disorder: What Do We Know?
Bjørklund, G., Waly, M. I., Al-Farsi, Y. M., Saad, K., Dadar, M., Rahman, M. M., Elhoufey, A. A., Chirumbolo, S., Jóźwik-Pruska, J., & Kałużna‐Czaplińska, J. (2019) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1237-5 · Cited by 70 · see citing works
Dittmann, S., Seemüller, F., Schwarz, M., Kleindienst, N., Stampfer, R., Zach, J., Born, C., Bernhard, B., Fast, K., Grunze, H., et al. (2007) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00412.x · Cited by 66 · see citing works
Lazarou, C., & Kapsou, M. (2010) · Complementary Therapies in Clinical Practice · doi:10.1016/j.ctcp.2010.01.003 · Cited by 64 · see citing works
Folate and brain function in the elderly
D’Anci, K. E., & Rosenberg, I. H. (2004) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/00075197-200411000-00011 · Cited by 63 · see citing works
Do Vitamins or Minerals (Apart From Lithium) Have Mood-Stabilizing Effects?
Popper, C. W. (2001) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v62n1203 · Cited by 61 · see citing works
“Recent work on folic acid (vitamin B9) suggests that low levels may be associated with depressive symptomatology and poor response to antidepressant medication.(1,2) Less is known about the role of trace elements, but there is considerable evidence that these too may be essential for normal brain function.”
BackgroundCatatonia and other psychiatric symptoms with vitamin B12 deficiency
Berry, N., Sagar, R., & Tripathi, B. M. (2003) · Acta Psychiatrica Scandinavica · doi:10.1034/j.1600-0447.2003.00089.x · Cited by 60 · see citing works
“Certain studies (12, 13) point out that this narrow window of opportunity is approximately 1 year or even lesser, although there a few reports of complete remission of very long standing psychiatric symptoms (7).”
Background
- Authors
- D, M. F. M., Borus, J. S., Alpert, J. E., Nierenberg, A. A., Rosenbaum, J. F., & Bottiglieri, T.
- Affiliations
- Massachusetts General Hospital (US)
- Venue
- American Journal of Psychiatry
- Published
- 1997-03-01
- Volume
- 154
- Issue
- 3
- Pages
- 426-428
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W1794181152
- Cited by
- 287
- References
- 15
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 10 · 2016: 10 · 2015: 6 · 2014: 11 · 2013: 14 · 2012: 12
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01mh048483-01a1)
- National Institute of Mental Health (MH-48483)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- folic acid, vitamin B12, homocysteine, major depressive disorder, endogenous depression, fluoxetine, antidepressant response, serum metabolites, treatment-resistant depression
- MeSH terms
- Adolescent, Adult, Ambulatory Care, Depressive Disorder, Female, Fluoxetine, Folic Acid, Folic Acid Deficiency, Homocysteine, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Vitamin B 12, Vitamin B 12 Deficiency, Treatment Outcome
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