Influence of supplementation with vitamins B9 (folic acid) and B12 (cobalamin) in the treatment of patients with antidepressants: a narrative review




B-complex vitamins; Homocysteine; Depression; Drugs; Health teaching.


In Brazil, about 5.8% of the population is diagnosed with depression, and only 1/3 of these patients are undergoing treatment, due to the adverse effects of antidepressant medications that have driven new therapeutic strategies. In such patients, high concentrations of homocysteine, an amino acid with neurodegenerative properties, have been observed. Thus, therapeutic options that provide the maintenance of serum homocysteine levels within the reference values are becoming targets for the treatment of depression alone or in association with the usual antidepressants. This narrative review aims to evaluate the influence of supplementation with vitamins B9 (folic acid) and B12 (cobalamin) in the treatment of patients with antidepressants. It has been identified that these vitamins are important nutrients for the synthesis of neurotransmitters, as well as the reduction of homocysteine levels in the brain. Patients with depression, and being treated or not with antidepressants, achieved a significant improvement in their clinical condition when they received the supplementation of these two micronutrients, because they potentiated the effects of antidepressants, and decreased homocysteine levels in the blood circulation and the severity of depressive symptoms, mainly in those patients with high plasma homocysteine concentrations. It was concluded that the low cost of acquiring vitamins B9 and B12 is an important factor, and has raised the possibility of its inclusion in the treatment guidelines for depression in order to improve the efficiency of medicines and decrease the severity of symptoms.


AbcMed. (2018). Hiper-homocisteinemia - o que é isso?

Almeida, O. P., McCaul, K., Hankey, G. J., Norman, P., Jamrozik, K., & Flicker, L. (2008). Homocysteine and depression in later life. Archives of General Psychiatry, 65, 1286-1294. DOI:10.1001/archpsyc.65.11.1286.

American Psychiatric Association. (1980). Diagnostic and Statistical Manual of Mental Disorders. 3. ed. Washington: American Psychiatric Association.

American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders. 4. ed. Washington: American Psychiatric Association.

Angst, J. (1992). How recurrent and predictible is depressive illness? In: Montgomery, S., Rouillon, F. Long-term treatment in depression. New York: John Wiley & Sons.

Araújo, S. H. R. (2011). Adaptação transcultural da GRID Hamilton Rating Scale for Depression (GRID-HAMD) para o português brasileiro e avaliação do impacto de um treinamento sobre a confiabilidade interavaliadores. Dissertação (Mestrado) - Processos Interativos dos Órgãos e Sistemas. Instituto de Ciências da Saúde, Universidade Federal da Bahia.

Arias, B., Gutiérrez, B., Pintor, L., Gastó, C., & Fañanás, L. (2001). Variability in the 5-HT2A receptor gene is associated with seasonal pattern in major depression. Molecular Psychiatry, 6, 239-242. DOI:10.1038/

Bottiglieri, T. (2005). Homocysteine and folate metabolism in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29, 1103-1112. DOI: 10.1016/j.pnpbp.2005.06.021.

Bouwman, V., Adriaanse, M. C., Riet, E. v., Snoek, F. J., Dekker, J. M., & Nijpels, G. (2010). Depression, anxiety and glucose metabolism in the general dutch population: the new Hoorn study. PLoS One, 5, e9971. DOI: 10.1371/journal.pone.0009971.

Brasil. (2017). 1º boletim quadrimestral sobre benefícios por incapacidade de 2017: Adoecimento mental e trabalho: a concessão de benefícios por incapacidade relacionados a transtornos mentais e comportamentais entre 2012 e 2016. Brasília: Secretaria de Previdência, 2017.

Brigitta, B. (2002). Pathophysiology of depression and mechanisms of treatment. Dialogues in Clinical Neurosciense, 4, 7-20. DOI: 10.31887/DCNS.2002.4.1/bbondy.

Campbell, S., & MacQueen, G. (2006). An update on regional brain volume differences associated with mood disorders. Current Opinion in Psychiatry, 19, 25-33. DOI: 10.1097/01.yco.0000194371.47685.f2.

Cantoni, G. L. (1985). The role of S-adenosylhomocysteine in the biological utilization of S-adenosylmethionine. Progress in Clinical and Biological Research, 198, 47-65.

Coppen, A., & Bailey, J. (2000). Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo-controlled trial. Journal of Affective Disorders, 60, 121-130. DOI: 10.1016/s0165-0327(00)00153-1.

Cunha, V. R., Bastos, G, A. N., & Duca, G. F. (2012). Prevalência de depressão e fatores associados em comunidade de baixa renda de Porto Alegre, Rio Grande do Sul. Revista Brasileira de Epidemiologia, 15, 346-354.

D’Incao, D. B., & Gastaud, M. B. (2015). Investigando a associação entre sintomas e queixas depressivas com as estações do ano. Fractal: Revista de Psicologia, 27, 152-159.

Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., & Lanctôt, K. L. (2010). A meta-analysis of cytokines in major depression. Biological Psychiatry, 67, 446-457. DOI: 10.1016/j.biopsych.2009.09.033.

Duan, W., Ladenheim, B., Cutler, R. G., Kruman, I. I., Cadet, J. L., & Mattson, M. P. (2001). Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. Journal of Neurochemistry, 80, 101-110. DOI: 10.1046/j.0022-3042.2001.00676.x.

Fleck, M. P. A., Lafer, B., Sougey, E. B., Porto, J. A., Brasil, M. A., & Juruena, M. F. (2003). Diretrizes da Associação Médica Brasileira para o tratamento da depressão. Brazilian Journal of Psychiatry, 25, 114-122.

Flugge, G. (1995). Dynamics of central nervous 5-HT1A-receptors under psychosocial stress. The Journal of Neuroscience, 15, 7132-7140.

Frey, A., Lampert, A., Dietz, K., Striebich, S., Locher, C., Fedorenko, O. et al. (2007). Thyrotropin serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychobiology, 56, 123-126. DOI: 10.1159/000112954.

Global Burden of Disease Study 2013 Collaborators. (2015). Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries,1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet, 386, 743-800. DOI: 10.1016/S0140-6736(15)60692-4.

Green, R. C., Cupples, L. A., Kurz, A., Auerbach, S., Go, R., Sadovnick, D. et al. (2003). Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Archives of Neurology, 60, 753-759. DOI:10.1001/archneur.60.5.753.

Hesdorffer, D. C., Hauser, W. A., Annegers J. F., & Cascino, G. (2000). Major depression is a risk factor for seizures in older adults. Annals of Neurology, 47, 246-249.

Holsboer, F., & Ising M. (2010). Stress hormone regulation: biological role and translation into therapy. Annual Review of Psychology, 61, 81-109. DOI: 10.1146/annurev.psych.093008.100321.

Howland, R. D., & Mycek, M. J. (2007). Farmacologia ilustrada. 3. ed. Porto Alegre: Artmed.

Kruman, I. I., Culmsee, C., Chan, S. L., Kruman, Y., Guo, Z., Penix, L. et al. (2000). Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. Journal of Neuroscience, 20, 6920-6926. DOI: 10.1523/JNEUROSCI.20-18-06920.2000.

Kumar, A., Haroon, E., Darwin, C., Pham, D., Ajilore, O., Rodriguez, G. et al. (2008). Gray matter prefrontal changes in type 2 diabetes detected using MRI. Journal of Magnetic Resonance Imaging, 27, 14-19. DOI: 10.1002/jmri.21224.

Lam, R. L., Schneider, J. L., Zhao, W., & Corley, D. A. (2013). Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA: The Journal of the American Medical Association, 310, 2435-2442. DOI: 10.1001/jama.2013.280490.

Lee, E-S. Y., Chen, H., Soliman, K. F. A., & Charlton, C. G. (2005). Effects of homocysteine on the dopaminergic system and behavior in rodents. Neurotoxicology, 26, 361-371. DOI: 10.1016/j.neuro.2005.01.008.

Lewy, A. J., Sack, R. L., Singer, C. M., White, D. M., & Hoban, T. M. (1988). Winter depression and the phase shift hypothesis for the therapeutic effect of bright light: history, theory and experimental evidence. Journal of Biological Rhythms, 3, 121-134. DOI: 10.1177/074873048800300203.

Linnebank, M., Moskau, S., Semmler, A., Widman, G., Stoffel-Wagner, B., Weller, M. et al. (2011). Antiepileptic drugs interact with folate and vitamin B12 serum levels. Annals of Neurology, 69, 352-359. DOI: 10.1002/ana.22229.

Malhi, G. S., & Mann, J. J. (2018). Depression. The Lancet, 392, 2299-2312.

Musselman, D. L., Evans, D. L., & Nemeroff, C. B. (1998). The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Archives of General Psychiatry, 55, 580-592. DOI: 10.1001/archpsyc.55.7.580.

Nerbass, F. B., Draibe, S. A., & Cuppari, L. (2005). Hiperhomocisteinemia na insuficiência renal crônica. Revista de Nutrição, 18, 239-249.

Nihalani, N., Simionescu, M., & Dunlop, B. W. (2016). Depression: treatment strategies and management. 2. ed. Boca Raton: CRS Press.

Nouwen, A., Lloyd, C. E., & Pouwer, F. (2009). Depression and type 2 diabetes over the lifespan: a meta-analysis. Response to Mezuk et al. Diabetes Care, 32, e56. DOI: 10.2337/dc09-0027.

Papakostas, G. I., Shelton, R. C., Zajecka, J. M., Etemad, B., Rickels, K.,Clain, A. et al. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. The American Journal of Psychiatry, 169, 1267-1274. DOI: 10.1176/appi.ajp.2012.11071114.

Rang, H. P., Dale, M. M., Ritter, J. M., & Moore, P. K. (2016). Farmacologia. 8. ed. Rio de Janeiro: Elsevier.

Sunden, S. L., Renduchintala, M. S., Park, E. I., Miklasz, S. D., & Garrow, T. A. (1997). Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Archives of Biochemistry and Biophysics, 345, 171-174. DOI: 10.1006/abbi.1997.0246.

Syed, E. U., Wasay, M., & Awan, S. (2013). Vitamin B12 supplementation in treating major depressive disorder: a randomized controlled trial. The Open Neurology Journal, 7, 44-48. DOI: 10.2174/1874205X01307010044.

Thorn, L., Evans, P., Cannon, A., Hucklebridge, F., & Clow, A. (2011). Seasonal differences in the diurnal pattern of cortisol secretion in healthy participants and those with self-assessed seasonal affective disorder. Psychoneuroendocrinology, 36, 816-823. DOI: 10.1016/j.psyneuen.2010.11.003.

Weissman, M. M., Bland, R. C., Canino, G. J., Faravelli, C., Greenwald, S., & Hwu, F. G. (1996). Cross-national epidemiology of major depression and bipolar disorder. Journal of the American Medical Association, 276, 293-299.

Wong, M. L., & Licinio, J. (2001). Research and treatment approaches to depression. Nature Reviews Neuroscience, 2, 343-351. DOI: 10.1038/35072566.

World Health Organization. (1997). CID-10. Classificação Estatística Internacional de Doenças e Problemas Relacionados à Saúde. 10 rev. São Paulo: Edusp, v.1.

World Health Organization. (2012). Depression: a Global Crisis. World Mental Health. Geneva: Ed World Health Organization.

World Health Organization. (2017). Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: Ed World Health Organization.

Wulffele, M. G., Kooy, A., Lehert, P., Bets, D., Ogterop, J. C., Van der Burg, B. B. et al. (2003). Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: A randomized, placebo-controlled trial. Journal of Internal Medicine, 254, 455-463. DOI:10.1046/j.1365-2796.2003.01213.x.



How to Cite

SOUSA, L. J. de R. .; PAULA, C. A. de .; ALMEIDA, M. E. F. de . Influence of supplementation with vitamins B9 (folic acid) and B12 (cobalamin) in the treatment of patients with antidepressants: a narrative review. Research, Society and Development, [S. l.], v. 11, n. 7, p. e3611729445, 2022. DOI: 10.33448/rsd-v11i7.29445. Disponível em: Acesso em: 4 mar. 2024.



Review Article