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Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial

Molecular Psychiatry volume 23, pages 316–322 (2018)Cite this article

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Abstract

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.

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Acknowledgements

We are grateful to the study participants and their families. We also thank Lisa Raeke, Leah Briggs, and Claire Oppenheim for administrative support and Franklin Huntington for assistance with the manuscript. The study was funded by Pamlab and NIMH (R01MH101425, S10RR023043, S10RR023401, K24MH094614). The funders of the study had no role in study design, patient recruitment, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. Data were presented in part at the American College of Neuropsychopharmacology Annual Meeting, Phoenix, AZ, December 2014; and the American Society of Clinical Psychopharmacology Annual Meeting, Miami Beach, FL, June 2015.

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Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    J L Roffman, L J Petruzzi, A S Tanner, H E Brown, H Eryilmaz, N F Ho, M Giegold, N J Silverstein, D S Manoach, J W Smoller & D C Henderson

  2. Center of Metabolomics, Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA

    T Bottiglieri

  3. Department of Psychiatry, New York University School of Medicine and Nathan Kline Institute, New York, NY, USA

    D C Goff

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  1. J L Roffman
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Correspondence to J L Roffman.

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Competing interests

JLR reports receiving grant support for this study from Pamlab, and has served as a consultant for Pamlab. TB reports receiving grant support for this study from Pamlab. JWS is an unpaid member of the Scientific Advisory Board of PsyBrain. DCH reports personal fees from Otsuka Phamaceutical, McLean Hospital and Global CME; and grants from Novartis, Forum and Reckitt Benckiser; all outside the submitted work. DCG reports receiving grant support for this study from Pamlab. The remaining authors report no biomedical financial interests or potential conflicts of interest.

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Roffman, J., Petruzzi, L., Tanner, A. et al. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry 23, 316–322 (2018). https://doi.org/10.1038/mp.2017.41

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