Randomized Multicenter Investigation of Folate Plus Vitamin B 12 Supplementation in Schizophrenia Folate and Vitamin B 12 in Schizophrenia

Roffman JL, Lamberti J, Achtyes E, et al. — Wed, 01 May 2013 00:00:00 GMT

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

JAMA Psychiatry: Nutrition/Metabolic Disorders Topic Collection

Randomized Multicenter Investigation of Folate Plus Vitamin B 12 Supplementation in Schizophrenia Folate and Vitamin B 12 in Schizophrenia