Abstract
Rationale
This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment.
Objective
We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia.
Methods
The primary outcome was an improvement in total symptoms. Other outcomes were psychopathology subscales (positive, negative, general, and depressive symptoms), discontinuation due to all-cause and adverse events, and individual adverse events. The meta-analysis evaluated the effect size based on a random-effects model.
Results
Although we included ten RCTs with 925 patients in total (seven folic acid RCTs (n = 789), two methylfolate RCTs (n = 96), and one folinic acid RCT (n = 40)) in the systematic review, only seven RCTs were included in the meta-analysis. Pooled FA + AP treatments were not superior to placebo + AP in the improvement of total (N = 7, n = 340; standardized mean difference (SMD) = − 0.20, 95% confidence interval (CI) = − 0.41, 0.02, p = 0.08, I2 = 0%), positive, general, or depressive symptoms. Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = −0.25, 95% CI = −0.49, −0.01, p = 0.04, I2 = 0%). Although pooled FA + AP treatments were associated with a lower incidence of serious adverse events than placebo treatments (N = 4, n = 241; risk ratio = 0.32, 95% CI = 0.12–0.82, p = 0.02, I2 = 0%; number needed to harm = not significant), there were no significant differences in other safety outcomes between both treatments.
Conclusions
Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients. Moreover, this treatment was well tolerated. However, because our results might exhibit a small-study effect, future studies with a larger sample should be conducted to obtain more robust results.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andreasen NC (1982) Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry 39:784–788
Arroll MA, Wilder L, Neil J (2014) Nutritional interventions for the adjunctive treatment of schizophrenia: a brief review. Nutr J 13:91
Brown HE, Roffman JL (2014) Vitamin supplementation in the treatment of schizophrenia. CNS Drugs 28:611–622
Cao B, Wang DF, Xu MY, Liu YQ, Yan LL, Wang JY, Lu QB (2016) Lower folate levels in schizophrenia: a meta-analysis. Psychiatry Res 245:1–7
Carney MW, Sheffield BF (1970) Associations of subnormal serum folate and vitamin B12 values and effects of replacement therapy. J Nerv Ment Dis 150:404–412
Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S (2017) Efficacy of 42 pharmacologic Cotreatment strategies added to antipsychotic Monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatr 74:675–684
Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, Yung AR (2017) The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychol Med 47:1515–1527
Fleischhacker WW, Kemmler G (2007) The clinical relevance of percentage improvements on the PANSS score. Neuropsychopharmacology 32:2435–2436
Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH (1990) Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336:392–395
Goff DC, Bottiglieri T, Arning E, Shih V, Freudenreich O, Evins AE, Henderson DC, Baer L, Coyle J (2004) Folate, homocysteine, and negative symptoms in schizophrenia. Am J Psychiatry 161:1705–1708
Higgins J, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). In: Collaboration TC (ed). http://handbookcochrane.org
Hill M, Shannahan K, Jasinski S, Macklin EA, Raeke L, Roffman JL, Goff DC (2011) Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res 127:41–45
ISRCTN32434568 (2009) OCTUMI-4: evaluation of mirtazapine and folic acid for schizophrenia
Kane JM (2012) Treatment options for refractory positive and negative symptoms in schizophrenia. Schizophrenia research 136, S21
Kay SR, Opler LA, Lindenmayer JP (1989) The Positive And Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl:59–67
Krawiecka M, Goldberg D, Vaughan M (1977) A standardized psychiatric assessment scale for rating chronic psychotic patients. Acta Psychiatr Scand 55:299–308
Lang FU, Kosters M, Lang S, Becker T, Jager M (2013) Psychopathological long-term outcome of schizophrenia -- a review. Acta Psychiatr Scand 127:173–182
Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, Samara M, Rabaioli M, Bacher S, Cipriani A, Geddes JR, Salanti G, Davis JM (2017) Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 174:927–942
Levine J, Stahl Z, Sela BA, Ruderman V, Shumaico O, Babushkin I, Osher Y, Bersudsky Y, Belmaker RH (2006) Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry 60:265–269
Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, Arnelle DR, Stamler JS (1997) Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 94:5923–5928
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535
Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M (2006) Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry 11:143–149
NCT00202280 (2005) Efficacy of treating first episode psychosis with folic acid, B12 and B6 in addition to antipsychotic medication (Principal Investigator: Dr Colin P O'Donnel)
NCT00300404 (2006) Effect of specific anti-toxoplasmatic add-on medcation in toxoplasma gondii seropositive individuals with schizophrenia or major depression. (Principal Investigator: Dunja Hinze-Selch)
NCT00403247 (2006) Effect of high-dose B-complex vitamins on the symptoms of schizophrenia. (Principal Investigator: William M Greenberg)
NCT01263080 (2010) Evaluation of mirtazapine and folic acid for schizophrenia: (RECOVERY2). (Principal Investigator: Gang Wang)
Nielsen RE, Levander S, Kjaersdam Telleus G, Jensen SO, Ostergaard Christensen T, Leucht S (2015) Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials. Acta Psychiatr Scand 131:185–196
Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, Shimodera S, Tomotake M, Ohi K, Hashimoto R, Imoto I, Takeda M, Ohmori T (2014) Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull 40:1154–1163
Numata S, Kinoshita M, Tajima A, Nishi A, Imoto I, Ohmori T (2015) Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Med Genet 16:54
Rai V, Yadav U, Kumar P, Yadav SK, Gupta S (2017) Methylenetetrahydrofolate reductase A1298C genetic variant & risk of schizophrenia: A meta-analysis. Indian J Med Res 145(4): 437–447
Roffman JL, Gollub RL, Calhoun VD, Wassink TH, Weiss AP, Ho BC, White T, Clark VP, Fries J, Andreasen NC, Goff DC, Manoach DS (2008a) MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met. Proc Natl Acad Sci U S A 105:17573–17578
Roffman JL, Weiss AP, Purcell S, Caffalette CA, Freudenreich O, Henderson DC, Bottiglieri T, Wong DH, Halsted CH, Goff DC (2008b) Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia. Biol Psychiatry 63:42–48
Roffman JL,Lamberti JS, Achtyes E, Macklin EA,GalendezGC, Raeke LH, Silverstein NJ, Tuinstra D, Hill M, Goff DC (2011) A multicenter investigation of folate plus B12 supplementation in schizophrenia. Neuropsychopharmacology 36, S198–S323
Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, Goff DC (2013) Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry 70:481–489
Roffman JL,Lamberti JS, Achtyes E, Macklin EA,Galendez GC, Raeke LH, Tanner AS, Silverstein NJ, Ho NF, Smoller JW, Hill M, Goff DC (2014a) Effects of (6S)-5-methyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid supplementation on cortical thickness in schizophrenia. Neuropsychopharmacology 39, S6
Roffman JL,Lamberti JS, Achtyes E, Macklin EA,GalendezGC, Raeke LH, Tanner AS, Silverstein NJ, Ho NF, Smoller JW, Hill M, Goff DC (2014b) Effects of folic acid and vitamin b12 supplementation on negative symptoms and related MRI indices. Schizophrenia Research 153, S80
Roffman JL, Petruzzi LJ, Tanner AS, Brown HE, Eryilmaz H, Ho NF, Giegold M, Silverstein NJ, Bottiglieri T, Manoach DS, Smoller JW, Henderson DC, Goff DC (2017) Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry 23(2):316–322
Rucklidge JJ, Kaplan BJ (2013) Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: a systematic review. Expert Rev Neurother 13:49–73
Sterne JA, Gavaghan D, Egger M (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53:1119–1129
van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645
Wang WW, Wang XS, Zhang ZR, He JC, Xie CL (2017) A meta-analysis of folic acid in combination with anti-hypertension drugs in patients with hypertension and Hyperhomocysteinemia. Front Pharmacol 8:585
Acknowledgments
We thank Dr. Donald C. Goff (Marvin Stern Professor, Vice Chair for Research, Department of Psychiatry, NYU Langone Medical Center, NY, USA), Dr. Eric A. Macklin (MGH Biostatistics Center, Boston, MA, USA), and Dr. William M. Greenberg (St. George’s University School of Medicine, True Blue, Grenada, Mental Health Association of Rockland County, Valley Cottage, NY, USA) for providing information for this study.
Author information
Authors and Affiliations
Contributions
Dr. Sakuma had complete access to all the data used in the study and takes responsibility for the integrity of the data (with Drs. Matsunaga, Nomura, and Okuya) and accuracy of the data analysis (with Dr. Matsunaga and Dr. Kishi). The study concept and design were performed by Dr. Kishi. The manuscript was written by all authors. Dr. Iwata supervised the review.
Corresponding author
Ethics declarations
Competing interests
Drs. Sakuma, Matsunaga, Nomura and Okuya, Kishi, and Iwata declare that they have no direct conflicts of interest relevant to this study. No grant support or other sources of funding were used to conduct this study or prepare this manuscript. Dr. Sakuma has nothing to disclose. Dr. Nomura has received speaker’s honoraria from Meiji, MSD, and Otsuka. Dr. Okuya has received speaker’s honoraria from Meiji. Dr. Matsunaga has received speaker’s honoraria from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Meiji, MSD, Novartis, Otsuka, and Tanabe-Mitsubishi and has received a Fujita Health University School of Medicine research grant and a grant-in-aid for Young Scientists (B). Dr. Kishi has received speaker’s honoraria from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Otsuka, Meiji, MSD, and Tanabe-Mitsubishi (Yoshitomi) and has received a Health Labour Sciences Research Grant and a Fujita Health University School of Medicine research grant. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and Pfizer and has had research grants from GlaxoSmithKline, Meiji, and Otsuka.
Electronic supplementary material
ESM 1
(DOC 359 kb)
Rights and permissions
About this article
Cite this article
Sakuma, K., Matsunaga, S., Nomura, I. et al. Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis. Psychopharmacology 235, 2303–2314 (2018). https://doi.org/10.1007/s00213-018-4926-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-018-4926-4