Effects of Vitamin B12 and Folic Acid Supplementation on Negative Symptoms as the Primary Outcome and Positive and Cognitive Symptoms as Secondary Outcomes in Schizophrenia: A Randomized Controlled Trial
Abstract
Objective: Persistent negative symptoms in chronic schizophrenia often show limited responsiveness to antipsychotic therapy. The present study evaluated whether supplementation with vitamin B12 and folic acid improves negative symptoms as the primary endpoint, while also examining effects on positive symptoms and global cognitive functioning as secondary outcomes.
Method: In this randomized, double-blind, placebo-controlled trial, 88 inpatients with chronic schizophrenia receiving stable risperidone therapy were assigned to one of four groups: vitamin B12 (1 mg/day), folic acid (1 mg/day), combined vitamin B12 plus folic acid (1 mg/day each), and placebo for eight weeks. Negative symptoms were measured using the Scale for the Assessment of Negative Symptoms (SANS), positive symptoms using the Scale for the Assessment of Positive Symptoms (SAPS), and cognitive function using the Mini-Mental State Examination (MMSE). Serum concentrations of vitamin B12 and folate were assessed at baseline and after the intervention.
Results: Supplementation with vitamin B12 and/or folic acid led to significant increases in serum concentrations of the corresponding vitamins (P < 0.001). All supplementation groups demonstrated significant and clinically meaningful reductions in negative symptom severity compared with placebo, with large effect sizes. In contrast, no significant changes were detected in positive symptoms or global cognitive performance.
Conclusion: Adjunctive vitamin B12 and folic acid supplementation significantly reduced negative symptom severity in chronic schizophrenia, without affecting positive symptoms or global cognition. Targeted correction of vitamin deficiencies may represent a valuable adjunctive approach for persistent negative symptoms.
1. Davidson M, Carpenter WT, Jr. Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence. Schizophr Bull. 2024;50 (1):14-21.
2. Remington G, Foussias G, Fervaha G, Agid O, Takeuchi H, Lee J, et al. Treating Negative Symptoms in Schizophrenia: an Update. Curr Treat Options Psychiatry. 2016;3:133-50.
3. Onaolapo OJ, Onaolapo AY. Nutrition, nutritional deficiencies, and schizophrenia: An association worthy of constant reassessment. World J Clin Cases. 2021;9 (28):8295-311.
4. Bansal V, Chatterjee I. Association of vitamins and neurotransmitters: understanding the effect on schizophrenia. Neurochemical Journal. 2022;16(1):39-45.
5. Helaly AMN, Ghorab D. Schizophrenia as metabolic disease. What are the causes? Metab Brain Dis. 2023;38 (3):795-804.
6. Cao B, Sun XY, Zhang CB, Yan JJ, Zhao QQ, Yang SY, et al. Association between B vitamins and schizophrenia: A population-based case-control study. Psychiatry Res. 2018;259:501-5.
7. Zhilyaeva T, Sergeeva A, Blagonravova A, Mazo G, Kibitov A. One-carbon metabolism disorders in schizophrenia: genetic and therapeutic aspects. Neurochemical Journal. 2019;13(2):113-20.
8. Alachkar A, Wang L, Yoshimura R, Hamzeh AR, Wang Z, Sanathara N, et al. Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits. Mol Psychiatry. 2018;23 (2):282-94.
9. Yan Y, Zhou D, Chen J. Navigating Nutritional Inequality in Schizophrenia: A Comprehensive Exploration of Diet, Genetics, and Holistic Management Across the Life Cycle. Nutrients. 2024;16 (21) :3738.
10. Łoboś P, Regulska-Ilow B. Link between methyl nutrients and the DNA methylation process in the course of selected diseases in adults. Rocz Panstw Zakl Hig. 2021;72 (2):123-36.
11. Kulaksızoglu B, Kulaksızoglu S, Ellidag HY, Cinemre B, Baykal A, Yılmaz N. Increased ratios of homocysteine/vitamin B12, homocysteine/folate and methionine/vitamin B12 in schizophrenic patients. Neurochemical Journal. 2016;10(2):166-71.
12. Pana A. Homocysteine and neuropsychiatric disease. Psychiatric Annals. 2015;45(9):463-8.
13. Yang Y, Wang J, Xiong Z, Yao X, Zhang Y, Ning X, et al. Prevalence and clinical demography of hyperhomocysteinemia in Han Chinese patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2021;271 (4):759-65.
14. Chen CH, Chiu CC, Chiu YH, Chang CH, Chang YH, Huang MC, et al. Folate and vitamin B12 supplementation in patients with schizophrenia and low serum folate level: A 24-week randomized, double-blind, placebo-controlled study. J Formos Med Assoc. 2026;125 (1):66-71.
15. Bekdash RA. Epigenetics, Nutrition, and the Brain: Improving Mental Health through Diet. Int J Mol Sci. 2024;25 (7):4036.
16. Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, et al. The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychol Med. 2017;47 (9):1515-27.
17. Simamora RH, Loebis B, Husada MS, Effendy E. Folic Acid and Vitamin B12 Supplementation on Male Patients with Schizophrenia Predominant Negative Symptoms. Current Nutrition & Food Science. 2020;16(1):98-104.
18. Sakuma K, Matsunaga S, Nomura I, Okuya M, Kishi T, Iwata N. Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis. Psychopharmacology (Berl). 2018;235 (8):2303-14.
19. Wan L, Wei J. Early-Onset Schizophrenia: A Special Phenotype of the Disease Characterized by Increased MTHFR Polymorphisms and Aggravating Symptoms. Neuropsychiatr Dis Treat. 2021;17:2511-25.
20. Cheng BF, Liang Y, Wu Q. Unraveling the mysteries of schizophrenia: Insights into prefrontal cortex dysfunction and therapeutic implications. World J Psychiatry. 2025;15 (11):107604.
21. Marazziti D, Mucci F, Avella MT, Palagini L, Simoncini M, Dell'Osso L. The increasing challenge of the possible impact of ethnicity on psychopharmacology. CNS Spectr. 2021;26 (3):222-31.
22. Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013;70 (5):481-9.
23. Hill M, Shannahan K, Jasinski S, Macklin EA, Raeke L, Roffman JL, et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011;127 (1-3):41-5.
24. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl. 1989 (7):49-58.
25. Ghamari Givi H, Moulavi P, Heshmati R. Exploration of the factor structure of positive and negative syndrome scale in schizophernia spectrum disorder. Clinical Psychology: Research and Practice Innovations. 2010;2(2):1-10.
26. Kay SR, Opler LA, Lindenmayer JP. The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl. 1989 (7):59-67.
27. Gharaeipour M, Andrew MK. Examining Cognitive Status of Elderly Iranians: Farsi Version of the Modified Mini-Mental State Examination. Appl Neuropsychol Adult. 2013;20 (3):215-20.
28. Mitchell AJ. The Mini-Mental State Examination (MMSE): an update on its diagnostic validity for cognitive disorders. Cognitive screening instruments: A practical approach: Springer; 2012. p. 15-46.
29. Agmashe S, Sadighi G, Radman N, Mazinani R. Effects of B Vitamins on Symptoms and Cognitive Functions in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Iran J Psychiatry. 2025;20 (1):3-11.
30. Aucoin M, LaChance L. Vitamin B12, vitamin B6, folic acid and psychosis: a review. J Orthomol Med. 2018;35.
31. Ye M, Yang X, Yan J, Yao Y, Lv H, Yue Z, et al. Causal relationship between B vitamins and neuropsychiatric disorders: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2025;170:106068.
32. Peedicayil J. Role of epigenetics in pharmacotherapy, psychotherapy and nutritional management of mental disorders. J Clin Pharm Ther. 2012;37 (5):499-501.
33. Amenyah SD, Hughes CF, Ward M, Rosborough S, Deane J, Thursby SJ, et al. Influence of nutrients involved in one-carbon metabolism on DNA methylation in adults-a systematic review and meta-analysis. Nutr Rev. 2020;78 (8):647-66.
34. Frajerman A, Urban M, Rivollier F, Plaze M, Chaumette B, Krebs MO, et al. Abnormalities in one-carbon metabolism in young patients with psychosis. Front Psychiatry. 2023;14:1128890.
35. Holloway JB. The role of herbal and nutraceutical supplementation in the amelioration of schizophrenia and schizoaffective symptomology. Scientia et Humanitas. 2016;6:95-114.
36. Allott K, McGorry PD, Yuen HP, Firth J, Proffitt TM, Berger G, et al. The Vitamins in Psychosis Study: A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Vitamins B (12), B (6), and Folic Acid on Symptoms and Neurocognition in First-Episode Psychosis. Biol Psychiatry. 2019;86 (1):35-44.
37. Ayesa-Arriola R, Pérez-Iglesias R, Rodríguez-Sánchez JM, Mata I, Gómez-Ruiz E, García-Unzueta M, et al. Homocysteine and cognition in first-episode psychosis patients. Eur Arch Psychiatry Clin Neurosci. 2012;262 (7):557-64.
38. dos Reis FP, Duarte L, Cartaxo T, Santos V. Folic acid, vitamin B12, and psychotic symptoms among young psychiatric inpatients. BIRTH AND GROWTH MEDICAL JOURNAL. 2021;30(2):85-91.
39. Roffman JL. B Vitamin Supplements in First-Episode Psychosis: Some Neurodevelopmental and Physiologic Context. Biol Psychiatry. 2019;86 (1):4-6.
40. Firth J, Carney R, Stubbs B, Teasdale SB, Vancampfort D, Ward PB, et al. Nutritional Deficiencies and Clinical Correlates in First-Episode Psychosis: A Systematic Review and Meta-analysis. Schizophr Bull. 2018;44 (6):1275-92.
41. Goff DC. Future perspectives on the treatment of cognitive deficits and negative symptoms in schizophrenia. World Psychiatry. 2013;12 (2):99-107.
42. Arroll MA, Wilder L, Neil J. Nutritional interventions for the adjunctive treatment of schizophrenia: a brief review. Nutr J. 2014;13:91.
43. Abd El Mawella S, Hussein H, Ahmed T. Folate, vitamin B [sub] 12, and negative symptoms in schizophrenia. Egyptian Journal of Psychiatry. 2018;39(2):89-..
44. Levine J, Stahl Z, Sela BA, Ruderman V, Shumaico O, Babushkin I, et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry. 2006;60 (3):265-9.
2. Remington G, Foussias G, Fervaha G, Agid O, Takeuchi H, Lee J, et al. Treating Negative Symptoms in Schizophrenia: an Update. Curr Treat Options Psychiatry. 2016;3:133-50.
3. Onaolapo OJ, Onaolapo AY. Nutrition, nutritional deficiencies, and schizophrenia: An association worthy of constant reassessment. World J Clin Cases. 2021;9 (28):8295-311.
4. Bansal V, Chatterjee I. Association of vitamins and neurotransmitters: understanding the effect on schizophrenia. Neurochemical Journal. 2022;16(1):39-45.
5. Helaly AMN, Ghorab D. Schizophrenia as metabolic disease. What are the causes? Metab Brain Dis. 2023;38 (3):795-804.
6. Cao B, Sun XY, Zhang CB, Yan JJ, Zhao QQ, Yang SY, et al. Association between B vitamins and schizophrenia: A population-based case-control study. Psychiatry Res. 2018;259:501-5.
7. Zhilyaeva T, Sergeeva A, Blagonravova A, Mazo G, Kibitov A. One-carbon metabolism disorders in schizophrenia: genetic and therapeutic aspects. Neurochemical Journal. 2019;13(2):113-20.
8. Alachkar A, Wang L, Yoshimura R, Hamzeh AR, Wang Z, Sanathara N, et al. Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits. Mol Psychiatry. 2018;23 (2):282-94.
9. Yan Y, Zhou D, Chen J. Navigating Nutritional Inequality in Schizophrenia: A Comprehensive Exploration of Diet, Genetics, and Holistic Management Across the Life Cycle. Nutrients. 2024;16 (21) :3738.
10. Łoboś P, Regulska-Ilow B. Link between methyl nutrients and the DNA methylation process in the course of selected diseases in adults. Rocz Panstw Zakl Hig. 2021;72 (2):123-36.
11. Kulaksızoglu B, Kulaksızoglu S, Ellidag HY, Cinemre B, Baykal A, Yılmaz N. Increased ratios of homocysteine/vitamin B12, homocysteine/folate and methionine/vitamin B12 in schizophrenic patients. Neurochemical Journal. 2016;10(2):166-71.
12. Pana A. Homocysteine and neuropsychiatric disease. Psychiatric Annals. 2015;45(9):463-8.
13. Yang Y, Wang J, Xiong Z, Yao X, Zhang Y, Ning X, et al. Prevalence and clinical demography of hyperhomocysteinemia in Han Chinese patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2021;271 (4):759-65.
14. Chen CH, Chiu CC, Chiu YH, Chang CH, Chang YH, Huang MC, et al. Folate and vitamin B12 supplementation in patients with schizophrenia and low serum folate level: A 24-week randomized, double-blind, placebo-controlled study. J Formos Med Assoc. 2026;125 (1):66-71.
15. Bekdash RA. Epigenetics, Nutrition, and the Brain: Improving Mental Health through Diet. Int J Mol Sci. 2024;25 (7):4036.
16. Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, et al. The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychol Med. 2017;47 (9):1515-27.
17. Simamora RH, Loebis B, Husada MS, Effendy E. Folic Acid and Vitamin B12 Supplementation on Male Patients with Schizophrenia Predominant Negative Symptoms. Current Nutrition & Food Science. 2020;16(1):98-104.
18. Sakuma K, Matsunaga S, Nomura I, Okuya M, Kishi T, Iwata N. Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis. Psychopharmacology (Berl). 2018;235 (8):2303-14.
19. Wan L, Wei J. Early-Onset Schizophrenia: A Special Phenotype of the Disease Characterized by Increased MTHFR Polymorphisms and Aggravating Symptoms. Neuropsychiatr Dis Treat. 2021;17:2511-25.
20. Cheng BF, Liang Y, Wu Q. Unraveling the mysteries of schizophrenia: Insights into prefrontal cortex dysfunction and therapeutic implications. World J Psychiatry. 2025;15 (11):107604.
21. Marazziti D, Mucci F, Avella MT, Palagini L, Simoncini M, Dell'Osso L. The increasing challenge of the possible impact of ethnicity on psychopharmacology. CNS Spectr. 2021;26 (3):222-31.
22. Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013;70 (5):481-9.
23. Hill M, Shannahan K, Jasinski S, Macklin EA, Raeke L, Roffman JL, et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011;127 (1-3):41-5.
24. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl. 1989 (7):49-58.
25. Ghamari Givi H, Moulavi P, Heshmati R. Exploration of the factor structure of positive and negative syndrome scale in schizophernia spectrum disorder. Clinical Psychology: Research and Practice Innovations. 2010;2(2):1-10.
26. Kay SR, Opler LA, Lindenmayer JP. The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl. 1989 (7):59-67.
27. Gharaeipour M, Andrew MK. Examining Cognitive Status of Elderly Iranians: Farsi Version of the Modified Mini-Mental State Examination. Appl Neuropsychol Adult. 2013;20 (3):215-20.
28. Mitchell AJ. The Mini-Mental State Examination (MMSE): an update on its diagnostic validity for cognitive disorders. Cognitive screening instruments: A practical approach: Springer; 2012. p. 15-46.
29. Agmashe S, Sadighi G, Radman N, Mazinani R. Effects of B Vitamins on Symptoms and Cognitive Functions in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Iran J Psychiatry. 2025;20 (1):3-11.
30. Aucoin M, LaChance L. Vitamin B12, vitamin B6, folic acid and psychosis: a review. J Orthomol Med. 2018;35.
31. Ye M, Yang X, Yan J, Yao Y, Lv H, Yue Z, et al. Causal relationship between B vitamins and neuropsychiatric disorders: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2025;170:106068.
32. Peedicayil J. Role of epigenetics in pharmacotherapy, psychotherapy and nutritional management of mental disorders. J Clin Pharm Ther. 2012;37 (5):499-501.
33. Amenyah SD, Hughes CF, Ward M, Rosborough S, Deane J, Thursby SJ, et al. Influence of nutrients involved in one-carbon metabolism on DNA methylation in adults-a systematic review and meta-analysis. Nutr Rev. 2020;78 (8):647-66.
34. Frajerman A, Urban M, Rivollier F, Plaze M, Chaumette B, Krebs MO, et al. Abnormalities in one-carbon metabolism in young patients with psychosis. Front Psychiatry. 2023;14:1128890.
35. Holloway JB. The role of herbal and nutraceutical supplementation in the amelioration of schizophrenia and schizoaffective symptomology. Scientia et Humanitas. 2016;6:95-114.
36. Allott K, McGorry PD, Yuen HP, Firth J, Proffitt TM, Berger G, et al. The Vitamins in Psychosis Study: A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Vitamins B (12), B (6), and Folic Acid on Symptoms and Neurocognition in First-Episode Psychosis. Biol Psychiatry. 2019;86 (1):35-44.
37. Ayesa-Arriola R, Pérez-Iglesias R, Rodríguez-Sánchez JM, Mata I, Gómez-Ruiz E, García-Unzueta M, et al. Homocysteine and cognition in first-episode psychosis patients. Eur Arch Psychiatry Clin Neurosci. 2012;262 (7):557-64.
38. dos Reis FP, Duarte L, Cartaxo T, Santos V. Folic acid, vitamin B12, and psychotic symptoms among young psychiatric inpatients. BIRTH AND GROWTH MEDICAL JOURNAL. 2021;30(2):85-91.
39. Roffman JL. B Vitamin Supplements in First-Episode Psychosis: Some Neurodevelopmental and Physiologic Context. Biol Psychiatry. 2019;86 (1):4-6.
40. Firth J, Carney R, Stubbs B, Teasdale SB, Vancampfort D, Ward PB, et al. Nutritional Deficiencies and Clinical Correlates in First-Episode Psychosis: A Systematic Review and Meta-analysis. Schizophr Bull. 2018;44 (6):1275-92.
41. Goff DC. Future perspectives on the treatment of cognitive deficits and negative symptoms in schizophrenia. World Psychiatry. 2013;12 (2):99-107.
42. Arroll MA, Wilder L, Neil J. Nutritional interventions for the adjunctive treatment of schizophrenia: a brief review. Nutr J. 2014;13:91.
43. Abd El Mawella S, Hussein H, Ahmed T. Folate, vitamin B [sub] 12, and negative symptoms in schizophrenia. Egyptian Journal of Psychiatry. 2018;39(2):89-..
44. Levine J, Stahl Z, Sela BA, Ruderman V, Shumaico O, Babushkin I, et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry. 2006;60 (3):265-9.
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How to Cite
1.
Shah Ali M, Rezaei O, Momeni Shideh R, Sadighi G. Effects of Vitamin B12 and Folic Acid Supplementation on Negative Symptoms as the Primary Outcome and Positive and Cognitive Symptoms as Secondary Outcomes in Schizophrenia: A Randomized Controlled Trial. Iran J Psychiatry. 2026;:1-12.
