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Original Article |

Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia

Joshua L. Roffman, MD, MMSc; J. Steven Lamberti, MD; Eric Achtyes, MD, MS; Eric A. Macklin, PhD; Gail C. Galendez, BS; Lisa H. Raeke, MA; Noah J. Silverstein, BA; Jordan W. Smoller, MD, ScD; Michele Hill, MD; Donald C. Goff, MD
JAMA Psychiatry. 2013;70(5):481-489. doi:10.1001/jamapsychiatry.2013.900.
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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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Figures

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Figure 1. Consolidated Standards of Reporting Trials flow diagram. To convert folate to nanomoles per liter, multiply by 2.266.

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Figure 2. Change in red blood cell (RBC) folate level over time. A, Change in the active and placebo groups. B, Change among patients receiving active treatment, grouped by FOLH1 484T>C genotype. Error bars indicate standard error. * P < .05. † P < .01. To convert folate to nanomoles per liter, multiply by 2.266.

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Figure 3. Change from baseline negative symptoms (Scale for the Assessment of Negative Symptoms [SANS] total score) among FOLH1 484T/T (A) and 484C carrier (B) patients, assessed throughout the course of treatment. For T/T patients, change over time was significant among those who received active treatment (P = .003) but not placebo (P = .16), with a significant difference between groups (P = .005). For C carrier patients, change over time was not significant in either the active (P = .93) or placebo (P = .60) groups, with no significant difference between groups (P = .64). Error bars indicate standard error.

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