Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients

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

2013-03-07

(Press-News.org) 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 variant in a folate-pathway gene called MTHFR that reduced the 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.

Among all 140 participants in the study protocol, those receiving folate and vitamin B12 showed improvement in negative symptoms, but the degree of improvement was not statistically significant compared with the placebo group. But when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, chiefly reflecting the effects of specific variants in MTHFR and in a gene called FOLH1. Variants in the other two genes studied did not appear to have an effect on treatment outcome.

While a low-functioning variant in FOLH1 had been associated with more severe negative symptoms in previous research, in this study it was the high-functioning FOLH1 variant that predicted a better treatment outcome. Measurement of participants' blood folate levels throughout the study provided an explanation for this unexpected finding. Those with the low-functioning FOLH1 variant started the trial with substantially lower folate levels, suggesting a problem with folate absorption. 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."

He adds that, 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 supplementation 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 variants in conditions such as dementia and cardiovascular disease, in which low folate appears to increase risk but supplementation 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." END

ELSE PRESS RELEASES FROM THIS DATE:

Feinstein Institute researcher discovers new protein regulator of taste

2013-03-07

MANHASSET, NY – In collaboration with other research institutions, a Feinstein Institute for Medical Research investigator discovered a new protein that controls the sense of taste. The findings are published in the March issue of Nature. In a search for new proteins involved in the progression of Alzheimer's disease, Philippe Marambaud, PhD, an investigator in the Litwin-Zucker Research Center for the Study of Alzheimer's Disease at the Feinstein Institute, discovered the protein calcium homeostasis modulator 1 (CALHM1) in 2008. CALHM1 represents a new family of pore-forming ...

Circuitry of cells involved in immunity, autoimmune diseases exposed

2013-03-07

Cambridge and Boston, MA. Wed. March 6, 2013 – New work from the Broad Institute's Klarman Cell Observatory, Brigham and Women's Hospital, Harvard University, MIT, and Yale University expands the understanding of how one type of immune cell – known as a T helper 17 or Th17 cell – develops, and how its growth influences the development of immune responses. By figuring out how these cells are "wired," the researchers make a surprising connection between autoimmunity and salt consumption, highlighting the interplay of genetics and environmental factors in disease susceptibility. ...

Monell scientists help identify a missing link in taste perception

2013-03-07

PHILADELPHIA (March 6, 2013) -- Working with a multidisciplinary consortium of 19 researchers from nine institutions, Monell scientists have provided critical information to identify CALHM1, a channel in the walls of taste receptor cells, as a necessary component in the process of sweet, bitter, and umami (savory) taste perception. When sweet, bitter and umami molecules reach the tongue, they activate taste receptors in specialized cells called Type II taste cells. "The question that the consortium wanted to answer is, 'how do these taste cells tell the brain that they ...

How the body's energy molecule transmits 3 types of taste to the brain

2013-03-07

PHILADELPHIA – Saying that the sense of taste is complicated is an understatement, that it is little understood, even more so. Exactly how cells transmit taste information to the brain for three out of the five primary taste types was pretty much a mystery, until now. A team of investigators from nine institutions discovered how ATP – the body's main fuel source– is released as the neurotransmitter from sweet, bitter, and umami, or savory, taste bud cells. The CALHM1 channel protein, which spans a taste bud cell's outer membrane to allow ions and molecules in and out, ...

Study identifies new risk factor for heart disease among kidney dialysis patients

2013-03-07

BOSTON– Kidney failure affects 25 million individuals in the U.S. and many more throughout the world. Loss of kidney function means the majority of these patients must undergo dialysis treatments to remove excess fluids and waste products. Although dialysis therapy coupled with medication has improved the life expectancy for people with kidney failure, for unknown reasons, patients' risk of sudden heart failure and death remains 10 to 20 times greater than average. Now, a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Massachusetts General ...

Bats not bothered by forest fires, study finds

2013-03-07

A survey of bat activity in burned and unburned areas after a major wildfire in the southern Sierra Nevada mountains found no evidence of detrimental effects on bats one year after the fire. The findings suggest that bats are resilient to high-severity fire, and some species may even benefit from the effects of fire on the landscape. The study, led by bat ecologist Winifred Frick of the University of California, Santa Cruz, will be published in the journal PLOS ONE on March 6. The findings are important because current understanding of how wildlife responds to fire is ...

Hidden layer of genome unveils how plants may adapt to environments throughout the world

2013-03-07

LA JOLLA, CA – Scientists at the Salk Institute for Biological Studies have identified patterns of epigenomic diversity that not only allow plants to adapt to various environments, but could also benefit crop production and the study of human diseases. Published March 6 in Nature, the findings show that in addition to genetic diversity found in plants throughout the world, their epigenomic makeup is as varied as the environments in which they are found. Epigenomics is the study of the pattern of chemical markers that serve as a regulatory layer on top of the DNA sequence. ...

Processed meat linked to premature death

2013-03-07

In a huge study of half a million men and women, research in Biomed Central's open access journal BMC Medicine demonstrates an association between processed meat and cardiovascular disease and cancer. One of the difficulties in measuring the effect of eating meat on health is the confounding effect of lifestyle on health. Often vegetarians have healthier lifestyles than the general population, they are less likely to smoke, are less fat, and are more likely to be physically active. Only within a very large study can the consequences of eating meat and processed meat ...

International study: Excess dietary salt may drive the development of autoimmune diseases

2013-03-07

Increased dietary salt intake can induce a group of aggressive immune cells that are involved in triggering and sustaining autoimmune diseases. This is the result of a study conducted by Dr. Markus Kleinewietfeld, Prof. David Hafler (both Yale University, New Haven and the Broad Institute of the Massachusetts Institute of Technology, MIT, and Harvard University, USA), PD Dr. Ralf Linker (Dept. of Neurology, University Hospital Erlangen), Professor Jens Titze (Vanderbilt University and Friedrich-Alexander-Universität Erlangen-Nürnberg, FAU, University of Erlangen-Nuremberg) ...

Short bouts of exercise boost self control

2013-03-07

The resulting increased blood and oxygen flow to the pre-frontal cortex may explain the effects, suggest the researchers. They trawled medical research databases for studies looking at the impact of physical exercise on higher brain functions, such as memory, concentration, planning, and decision-making, in three groups: 6 to 12 year olds; 13 to 17 year olds; and 18 to 35 year olds. They found 24 relevant studies published up to April 2012. Nineteen of these, involving 586 participants, addressed the impact of short bouts of exercise, and five, involving 358 participants, ...

Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients

ELSE PRESS RELEASES FROM THIS DATE:

LAST 30 PRESS RELEASES: