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The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo in 1993 as a first generation internet teaching tool consolidating human embryology teaching for first year medical students.

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Folate and Vitamin B12 Reduce Schizophrenia Symptoms in Some with Specifc Genes Variants

Adding supplements to antipsychotic medication alleviated negative symptoms in patients with specific genes

Adding the dietary supplements folate and vitamin B12 to treatment with antipsychotic medication improved a core symptom component of schizophrenia in a study of more than 100 patients.

The study focused on negative symptoms of schizophrenia – which include apathy, social withdrawal, and a lack of emotional expressiveness. While the level of improvement across all participants was modest, results were more significant in individuals carrying specific variants in genes involved with folate metabolism. The report from a team based at Massachusetts General Hospital (MGH) will appear in the journal JAMA Psychiatry (formerly Archives of General Psychiatry) and has been issued online.

"The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness. These include negative symptoms, which can be particularly devastating," says Joshua Roffman, MD, MMSc, of the MGH Department of Psychiatry, corresponding author of the JAMA Psychiatry paper. "Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia. Because treatment effects differed based on which genetic variants were present in each participant, the results also support a personalized medical approach to treating schizophrenia."

An essential nutrient, folate (or folic acid) is required for
the synthesis of DNA and neurotransmitters and plays
a role in the control of gene expression.

Adequate folate intake during pregnancy can reduce the risk
of birth defects – in particular neural tube defects –
and studies have suggested that folate deficiency during
pregnancy significantly increases the risk
of schizophrenia among offspring.

Earlier research by members of the MGH-based team
associated low blood folate levels with more severe
negative symptoms among patients with schizophrenia.

The current study was designed specifically to investigate whether supplementation with folate and B12 – which can magnify the effects of folate – reduced negative symptoms of schizophrenia.

A 2011 pilot study found symptom improvement only among
patients carrying a variation in a folate-pathway gene
called MTHFR that reduced that gene's activity.

To get a clearer picture of folate's effect on negative symptoms, the current study enrolled 140 patients with schizophrenia at community mental health centers in Boston, Rochester, N.Y., and Grand Rapids, Mich.

Participants were all taking antipsychotic medications – which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms – and were randomized to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks.

Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine, an amino acid that tends to rise when folate levels drop.

Nutritional information was compiled to account for differences in dietary intake of the nutrients. Participants' blood samples were analyzed to determine the variants they carried of MTHFR and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia.

Although supplementation enabled their blood folate levels to eventually catch up with those of participants with the high-functioning variant, it was probably too late to produce symptom improvement during the 16-week trial period.

"For participants who did show a benefit, it took the full 16 weeks of treatment for that benefit to appear," Roffman explains. "While we don't know why this is the case, changes in gene expression – which take time – are a likely explanation. Folate plays a critical role in DNA methylation, which regulates gene expression, so it's plausible that its effects on negative symptoms act through gene expression changes. Participants with the low-functioning FOLH1 variant might eventually show a benefit of folate supplementation if treated for a longer period of time, but that needs to be investigated in future studies."

While the benefits of supplementation for the overall group
were modest, the lack of effective treatment for negative
symptoms and the safety of folate and vitamin B12
supplements support the need for larger-scale trials.

In addition, the impact of genotype on this study's results
suggests the need to investigate the role of folate pathway
variations in conditions such as dementia and cardiovascular
disease, in which low folate appears to increase risk but
supplement trials have had inconclusive results.

"We are now conducting a clinical trial of 1-methylfolate, which bypasses some of these folate-pathway enzymes and might have greater efficiency among individuals with low-functioning variants," explains Roffman, an assistant professor of Psychiatry at Harvard Medical School. "Understanding more about the basic neural mechanisms of folate in patients with schizophrenia could help us generate more targeted and effective interventions to reduce and possibly even prevent symptoms."

The senior author of the JAMA Psychiatry report is Donald Goff, MD, formerly of MGH Psychiatry and now at the Nathan Kline Institute and New York University School of Medicine. Additional co-authors are Gail Galendez, Lisa Raeke, Noah Silverstein, Jordan Smoller, MD, ScD, and Michelle Hill, MD, MGH Psychiatry; Eric Macklin, PhD, MGH Biostatistics Center; Steven Lamberti, MD, University of Rochester Medical Center; and Eric Achtyes, MD, MS, Michigan State University College of Human Medicine. The study was supported primarily by National Institute of Mental Health grant R01MH070831.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."

Original article: http://www.massgeneral.org/about/pressrelease.aspx?id=1559