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Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia.

Abstract

IMPORTANCE

More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation.

OBJECTIVES

To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response.

DESIGN

Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12.

SETTING

Three community mental health centers affiliated with academic medical centers in the United States.

PARTICIPANTS

Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale.

INTERVENTION

One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo.

MAIN OUTCOME MEASURES

Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale).

RESULTS

Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups.

CONCLUSIONS

Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT00611806.

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  • Authors+Show Affiliations

    ,

    Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA 02129, USA. jroffman@partners.org

    , , , , , , , ,

    Source

    JAMA psychiatry 70:5 2013 May pg 481-9

    MeSH

    Adolescent
    Adult
    Aged
    Double-Blind Method
    Drug Therapy, Combination
    Female
    Folic Acid
    Glutamate Carboxypeptidase II
    Humans
    Male
    Middle Aged
    Schizophrenia
    Treatment Outcome
    Vitamin B 12
    Young Adult

    Pub Type(s)

    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23467813

    Citation

    Roffman, Joshua L., et al. "Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia." JAMA Psychiatry, vol. 70, no. 5, 2013, pp. 481-9.
    Roffman JL, Lamberti JS, Achtyes E, et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013;70(5):481-9.
    Roffman, J. L., Lamberti, J. S., Achtyes, E., Macklin, E. A., Galendez, G. C., Raeke, L. H., ... Goff, D. C. (2013). Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry, 70(5), pp. 481-9. doi:10.1001/jamapsychiatry.2013.900.
    Roffman JL, et al. Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA Psychiatry. 2013;70(5):481-9. PubMed PMID: 23467813.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. AU - Roffman,Joshua L, AU - Lamberti,J Steven, AU - Achtyes,Eric, AU - Macklin,Eric A, AU - Galendez,Gail C, AU - Raeke,Lisa H, AU - Silverstein,Noah J, AU - Smoller,Jordan W, AU - Hill,Michele, AU - Goff,Donald C, PY - 2013/3/8/entrez PY - 2013/3/8/pubmed PY - 2013/6/29/medline SP - 481 EP - 9 JF - JAMA psychiatry JO - JAMA Psychiatry VL - 70 IS - 5 N2 - IMPORTANCE: More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation. OBJECTIVES: To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response. DESIGN: Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12. SETTING: Three community mental health centers affiliated with academic medical centers in the United States. PARTICIPANTS: Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale. INTERVENTION: One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo. MAIN OUTCOME MEASURES: Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale). RESULTS: Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups. CONCLUSIONS: Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00611806. SN - 2168-6238 UR - https://www.unboundmedicine.com/medline/citation/23467813/full_citation L2 - https://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/jamapsychiatry.2013.900 DB - PRIME DP - Unbound Medicine ER -