, Volume 235, Issue 8, pp 2303–2314 | Cite as

Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis

  • Kenji Sakuma
  • Shinji Matsunaga
  • Ikuo Nomura
  • Makoto Okuya
  • Taro KishiEmail author
  • Nakao Iwata
Original Investigation



This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment.


We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia.


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.


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.


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.


Folic acid Methylfolate Schizophrenia Systematic review Meta-analysis Negative symptoms 



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 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.

Compliance with ethical standards

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.

Supplementary material

213_2018_4926_MOESM1_ESM.doc (360 kb)
ESM 1 (DOC 359 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychiatryFujita Health University School of MedicineToyoakeJapan
  2. 2.Department of Department of Geriatrics and Cognitive DisordersFujita Health University School of MedicineToyoakeJapan

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