Clinical efficacy and safety of folic acid and vitamin B12 for the adjuvant treatment of schizophrenia: a systematic review and meta-analysis.:

Kai  Niu; Ximin  Zhao; Ying  Wei; Yuefeng  Wang

doi:10.54817/IC.v64n3a12

Kai Niu Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China. https://orcid.org/0000-0003-0314-9735
Ximin Zhao Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China. https://orcid.org/0000-0001-5924-0058
Ying Wei Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China. https://orcid.org/0000-0001-7642-3614
Yuefeng Wang Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China. https://orcid.org/0000-0001-9064-3525

DOI: https://doi.org/10.54817/IC.v64n3a12

Keywords: folic acid, meta-analysis, schizophrenia, vitamin B 12

Abstract

Given the different effects of folate and vitamin B 12 on the adjuvant treatment of schizophrenia (SCH), their efficacy and safety as adjuvant therapies for SCH were systematically evaluated by evidence-based medicine. Publication retrieval was performed using authoritative databases such as the Cochrane Library, PubMed, and Web of Science to screen randomized controlled trials (RCTs). After the quality evaluation and data extraction of included studies, eligible RCTs were systematically reviewed using Review Manager 5.2 software. In total, 14 RCTs were included. The results of the meta-analysis revealed that as the adjuvant therapy for SCH, vitamin B 12 differed significantly from folate in terms of anxiety relief rate [odds ratio (OR)=1.28, 95% confidence interval (CI) (1.02, 1.61), p=0.03, I2 =0%, Z=2.13]. However, there were no significant differences in the incidence rate of mania [OR=1.13, 95% CI (0.78,1.65), p=0.65, I2=36%, Z=0.65], total efficacy [OR=1.06, 95% CI (0.72, 1.56), p=0.77, I2=0%, Z=0.30] and incidence rate of adverse reactions [OR=1.15, 95% CI (0.88, 1.49), p=0.31, I2=0%, Z=1.03]. Although folate and vitamin B12 exhibit no significant differences in the adjuvant treatment of SCH, vitamin B 12 exerts markedly fewer side effects than folate drugs, and it is of determinant significance for the clinical adjuvant medication of SCH.

Downloads

Download data is not yet available.

Author Biographies

Kai Niu, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Department of Psychiatry, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Ximin Zhao, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Medical Record Statistics Office, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Ying Wei, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Medical Record Statistics Office, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Yuefeng Wang, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

Department of Psychiatry, Zhoushan Second People’s Hospital, Zhoushan, Zhejiang Province, China.

References

Ma F, Zhou X, Li Q, Zhao J, Song A, An P, Du Y, Xu W, Huang G. Effects of folic acid and vitamin B12, alone and in combination on cognitive function and inflammatory factors in the elderly with mild cognitive impairment: a single-blind experimental design. Curr Alzheimer Res 2019; 16(7): 622-632. https://doi.org/10.2174/156720 5016666190725144629.

van de Leemput J, Hess JL, Glatt SJ, Tsuang MT. Genetics of schizophrenia: historical insights and prevailing evidence. Adv Genet 2016; 96: 99-141. https://doi. org/10.1016/bs.adgen.2016.08.001.

Satapathy S, Bandyopadhyay D, Patro BK, Khan S, Naik S. Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: A multiarm randomized controlled clinical trial. Complement Ther Med 2020; 53: 102526. https://doi.org/10.1016/j.ctim.2020.102526.

Richetto J, Meyer U. Epigenetic modifications in schizophrenia and related disorders: molecular scars of environmental exposures and source of phenotypic variability. Biol Psychiatry 2021; 89(3): 215-226. https://doi.org/10.1016/j.biopsych.2020.03.008.

Almeida OP, Ford AH, Flicker L. Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. Int Psychogeriatr 2015; 27(5): 727-737. https://doi. org/10.1017/S1041610215000046.

Bortolon C, Macgregor A, Capdevielle D, Raffard S. Apathy in schizophrenia: A review of neuropsychological and neuroanatomical studies. Neuropsychologia 2018; 118(Pt B): 22-33. https:// doi.org/10.1016/j.neuropsychologia. 2017.09.033.

Guéant JL, Guéant-Rodriguez RM, Alpers DH. Vitamin B12 absorption and malabsorption. Vitam Horm 2022; 119: 241-274. https://doi.org/10.1016/bs.vh. 2022.01.016.

Izawa J, Asai T, Imamizu H. Computational motor control as a window to understanding schizophrenia. Neurosci Res 2016; 104: 44-51. https://doi.org/10.1016/j.neures.2015.11.004.

Shen L, Ji HF. Associations between homocysteine, folic acid, vitamin B12 and Alzheimer’s Disease: iInsights from metaanalyses. J Alzheimers Dis 2015; 46(3): 777-790. https://doi.org/10.3233/JAD150140.

Hosák L, Silhan P, Hosáková J. Genomewide association studies in schizophrenia, and potential etiological and functional implications of their results. Acta Medica 2012; 55(1): 3-11. https://doi. org/10.14712/18059694.2015.67.

Hsu YC, Ye Z, Dai L, Jing Y, Tsui KL, Yip PS, Li W, Zhang Q. Understanding MMPI-2 response structure between schizophrenia and healthy individuals. Front Psychiatry 2022; 13: 918999. https://doi. org/10.3389/fpsyt.2022.918999.

Yazici AB, Akcay Ciner O, Yazici E, Cilli AS, Dogan B, Erol A. Comparison of vitamin B12, vitamin D and folic acid blood levels in patients with schizophrenia, drug addiction and controls. J Clin Neurosci 2019; 65: 11-16. https://doi. org/10.1016/j.jocn.2019.04.031.

Yazici E, Mutu Pek T, Guzel D, Yazici AB, Akcay Ciner O, Erol A. Klotho, vitamin D and homocysteine levels during acute episode and remission periods in schizophrenia patients. Nord J Psychiatry 2019; 73(3): 178-184. https://doi.org/10.1080/08039488.2019.1582697.

Altun H, Sahin N, Belge Kurutas E, Güngör O. Homocysteine, pyridoxine, folate and vitamin B12 levels in children with attention deficit hyperactivity disorder. Psychiatr Danub 2018; 30(3): 310-316. https://doi.org/10.24869/psyd.2018.310.

Hope S, Naerland T, Høiland AL, Torske T, Malt E, Abrahamsen T, Nerhus M, Wedervang-Resell K, Lonning V, Johannessen J, Steen NE, Agartz I, Stenberg N, Hundhausen T, Mørkrid L, Andreassen OA. Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia: A comparison among participants between 2 and 53 years. FASEB J 2020; 34(6): 8114-8124. https://doi.org/10.1096/fj.201900855RRR.

Allott K, McGorry PD, Yuen HP, Firth J, Proffitt TM, Berger G, Maruff P, O’Regan MK, Papas A, Stephens TCB, O’Donnell CP. The vitamins in psychosis study: a randomized, double-blind, placebo-controlled trial of the effects of vitamins B12, B6, and folic acid on symptoms and neurocognition in first-episode psychosis. Biol Psychiatry 2019; 86(1): 35-44. https://doi. org/10.1016/j.biopsych.2018.12.018.

Topal Z, Tufan AE, Karadag M, Gokcen C, Akkaya C, Sarp AS, Bahsi I, KilincM. Evaluation of peripheral inflammatory markers, serum B12, folate, ferritin levels and clinical correlations in children with autism spectrum disorder (ASD) and atention deficit hyperactivity disorder (ADHD). Nord J Psychiatry 2022; 76(2): 150-157. https://doi.org/10.1080/080394 88.2021.1946712.

Ramaekers VT, Thöny B, Sequeira JM, Ansseau M, Philippe P, Boemer F, Bours V, Quadros EV. Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Mol Genet Metab 2014; 113(4): 307-314. https://doi. org/10.1016/j.ymgme.2014.10.002.

Chen CH, Chen PY, Chen CY, Chiu CC, Lu ML, Huang MC, Lin YK, Chen YH. Associations of genetic variants of methylenetetrahydrofolate reductase and serum folate levels with metabolic parameters in patients with schizophrenia. Int J Environ Res Public Health 2021; 18(21): 11333. https:// doi.org/10.3390/ijerph182111333.

Misiak B, Frydecka D, Kiejna A. Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients. Eur J Clin Pharmacol 2014; 70(12): 1433-1441. https://doi.org/10.1007/s00228-0141762-2.

Kale A, Naphade N, Sapkale S, Kamaraju M, Pillai A, Joshi S, Mahadik S. Reduced folic acid, vitamin B12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: implications for altered one-carbon metabolism. Psychiatry Res 2010; 175(12): 47-53. https://doi.org/10.1016/j.psy chres.2009.01.013.

Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, Goff DC. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry 2013; 70(5): 481-489. https://doi.org/10.1001/ jamapsychiatry.2013.900.

Saedisomeolia A, Djalali M, Moghadam AM, Ramezankhani O, Najmi L. Folate and vitamin B12 status in schizophrenic patients. J Res Med Sci 2011; 16 Suppl 1: S437-S441. PMID: 22247731.

Misiak B, Laczmanski L, Sloka NK, Szmida E, Piotrowski P, Loska O, Slezak R, Kiejna A, Frydecka D. Metabolic dysregulation in first-episode schizophrenia patients with respect to genetic variation in one-carbon metabolism. Psychiatry Res 2016; 238: 60-67. https://doi.org/ 10.1016/j.psychres.2016.01.077.

Misiak B, Kiejna A, Frydecka D. The history of childhood trauma is associated with lipid disturbances and blood pressure in adult first-episode schizophrenia patients. Gen Hosp Psychiatry 2015; 37(4): 365-367. https://doi.org/10.1016/j.genhosppsych.2015.03.017.

Gadgil M, Joshi K, Pandit A, Otiv S, Joshi R, Brenna JT, Patwardhan B. Imbalance of folic acid and vitamin B12 is associated with birth outcome: An Indian pregnant women study. Eur J Clin Nutr 2014; 68(6): 726-729. https://doi.org/10.1038/ ejcn.2013.289.

Möller HJ. Is schizophrenia still one entity with similar symptomatic patterns, neurobiological characteristics, and treatment perspectives? Eur Arch Psychiatry Clin Neurosci 2018; 268(6): 525-527. https:// doi.org/10.1007/s00406-018-0926-y.

Lawrie SM, Hall J, McIntosh AM, Cunningham-Owens DG, Johnstone EC. Neuroimaging and molecular genetics of schizophrenia: pathophysiological advances and therapeutic potential. Br J Pharmacol 2008; 153 Suppl 1: S120-S124. https:// doi.org/10.1038/sj.bjp.0707655.

Rothenberg SP. Application of competitive ligand binding for the radioassay of vitamin and folic acid. Metabolism 1973; 22(8):B12 1075-1082. https://doi.org10.1016/00260495(73)90226-6./

Roberts MT, Shokraneh F, Sun Y, Groom M, Adams CE. Classification of psychotherapy interventions for people with schizophrenia: development of the Nottingham Classification of Psychotherapies. Evid Based Ment Health 2021; 24(2): 62-69. https://doi.org/10.1136/ebmental-2020300151.

Lin CH, Yang S, Huang YJ, Lane HY. Polymorphism in the LASP1 gene promoter region alters cognitive functions of patients with schizophrenia. Sci Rep 2019; 9(1): 18840. https://doi.org/10.1038/s41598019-55414-1.

Dang S, Yan H, Zeng L, Wang Q, Li Q, Xiao S, Fan X. The status of vitamin B12 and folate among Chinese women: a population-based cross-sectional study in northwest China. PLoS One 2014; 9(11): e112586. https://doi.org/10.1371/journal.pone.0112586.

Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev 2003; (4): CD004514. https:// doi.org/10.1002/14651858.CD004514

Pomarol-Clotet E, Salvador R, Murray G, Tandon S, McKenna PJ. Are there va-lid subtypes of schizophrenia? A grade of membership analysis. Psychopathology 2010; 43(1): 53-62. https://doi. org/10.1159/000260044.

Satoskar RS, Kulkarni BS, Mehta BM. Serum vitamin B12 and folic acid (P.G.A.) levels in hypoproteinaemia and marasmus in Indian children. Arch Dis Child 1962; 37(191): 9-16. https://doi.org/10.1136/ adc.37.191.9.

McIntosh AM, Gow A, Luciano M, Davies G, Liewald DC, Harris SE, Corley J, Hall J, Starr JM, Porteous DJ, Tenesa A, Visscher PM, Deary IJ. Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biol Psychiatry 2013; 73(10): 938943. https://doi.org/10.1016/j.biopsych. 2013.01.011.

Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M. Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother 2009; 9(9): 1393-1412. https://doi.org/10.1586/ern.0 9.75.

Cocchi E, Drago A, Serretti A. Hippocampal pruning as a new theory of schizophrenia Etiopathogenesis. Mol Neurobiol 2016; 53(3): 2065-2081. https://doi. org/10.1007/s12035-015-9174-6.

Girdwood RH. Abnormalities of vitamin B12 and folic acid metabolism--their influence on the nervous system. Proc Nutr Soc 1968; 27(1): 101-107. https://doi. org/10.1079/pns19680021.

Yang QX, Wang YX, Li FC, Zhang S, Luo YC, Li Y, Tang J, Li B, Chen YZ, Xue WW, Zhu F. Identification of the gene signature reflecting schizophrenia’s etiology by constructing artificial intelligence-based method of enhanced reproducibility. CNS Neurosci Ther 2019; 25(9): 1054-1063. https://doi.org/10.1111/cns.13196.

Williams JN. Some metabolic interrelationships of folic acid, vitamin B12, and ascorbic acid. Am J Clin Nutr 1955; 3(1): 2029. https://doi.org/10.1093/ajcn/3.1.20.

Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, Goff DC. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry 2013; 70(5): 481-489. https://doi.org/10.1001/ jamapsychiatry.2013.900.

Clinical efficacy and safety of folic acid and vitamin B12 for the adjuvant treatment of schizophrenia: a systematic review and meta-analysis.

Eficacia clínica y seguridad del ácido fólico y la vitamina B12 como tratamiento adyuvante de la esquizofrenia: una revisión sistemática y metanálisis.

Abstract

Downloads

Author Biographies

References