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

Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine Dependence Evidence From a 4-Decade Longitudinal Study Developmental Progression of Smoking Behavior

Belsky DW, Moffitt TE, Baker TB, et al. — Wed, 01 May 2013 00:00:00 GMT

Importance

Genome-wide hypothesis-free discovery methods have identified loci that are associated with heavy smoking in adulthood. Research is needed to understand developmental processes that link newly discovered genetic risks with adult heavy smoking.

Objective

To test how genetic risks discovered in genome-wide association studies of adult smoking influence the developmental progression of smoking behavior from initiation through conversion to daily smoking, progression to heavy smoking, nicotine dependence, and struggles with cessation.

Design

A 38-year, prospective, longitudinal study of a representative birth cohort.

Setting

The Dunedin Multidisciplinary Health and Development Study of New Zealand.

Participants

The study included 1037 male and female participants.

Exposure

We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in 3 meta-analyses of genome-wide association studies of smoking quantity phenotypes.

Main Outcomes and Measures

Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerström Test of Nicotine Dependence), and cessation difficulties were evaluated at 8 assessments spanning the ages of 11 to 38 years.

Results

Genetic risk score was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that 2 adolescent developmental phenotypes—early conversion to daily smoking and rapid progression to heavy smoking—mediated associations between the genetic risk score and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The genetic risk score predicted smoking risk over and above family history.

Conclusions and Relevance

Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers.

JAMA Psychiatry: Genetics Topic Collection

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

Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine Dependence Evidence From a 4-Decade Longitudinal Study Developmental Progression of Smoking Behavior