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- Title
Randomized Multicenter Investigation of Folate Plus Vitamin B<sub>12</sub> Supplementation in Schizophrenia.
- Authors
Roffman, Joshua L.; Lamberti, J. Steven; Achtyes, Eric; Macklin, Eric A.; Galendez, Gail C.; Raeke, Lisa H.; Silverstein, Noah J.; Smoller, Jordan W.; Hill, Michele; Goff, Donald C.
- Abstract
Importance: More effective treatments are needed for negative symptoms of schizophrenia, which are typi-cally 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 vita-min B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response. Design: Parallel-group, randomized, double-blind, pla-cebo-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 affili-ated 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 pa-tients were 18 to 68 years old, were treated with an an-tipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Posi-tive and Negative Syndrome Scale. Intervention: One hundred forty subjects were ran-domized to receive daily oral folic acid plus vitamin B12 or placebo. Main Outcome Measures: Change in negative symp-toms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Posi-tive and Negative Syndrome Scale). Results: Folate plus vitamin Bn improved negative symp-toms significantly compared with placebo (group differ-ence, -- 0.33 change in SANS score per week; 95% CI, -- 0.62 to --0.05) when genotype was taken into ac-count but not when genotype was excluded. An inter-action of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P=.02), where only patients ho-mozygous for the 484T allele demonstrated signifi-cantly 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 al-lele load (P= .03), which persisted until 8 weeks of treat-ment. Change in positive and total symptoms did not dif-fer between treatment groups. Conclusions: Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treat-ment response is influenced by genetic variation in folate absorption. These findings support a personalized medi-cine approach for the treatment of negative symptoms.*****Trial Registration: clinicaltrials.gov Identifier: NCT00611806
- Subjects
VITAMIN B12; SCHIZOPHRENIA; SYMPTOMS; MEDICAL care costs; FOLIC acid; CLINICAL trials
- Publication
JAMA Psychiatry, 2013, Vol 70, Issue 5, p481
- ISSN
2168-622X
- Publication type
Article
- DOI
10.1001/jamapsychiatry.2013.900