Antioxidants and amino acids could play role in mental illness

Antioxidants and amino acids could play role in mental illness

The systematic review involved eight independent clinical trials of nutrient supplementation in 457 young people. The review primarily covered ‘first-episode psychosis’ (FEP) as well as schizophrenia and a myriad of other ailments associated with the two.

Adjunctive nutrients in first-episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms. Early Intervention in Psychiatry, 2018; DOI: 10.1111/eip.12544

Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients

Contact: Kristen Stanton kstanton3@partners.org 617-643-3907 Massachusetts General Hospital

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

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.”

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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.”

Link between creativity and mental illness confirmed

Simon Kyaga

[PRESS RELEASE 16 October 2012]

People in creative professions are treated more often for mental illness than the general population, there being a particularly salient connection between writing and schizophrenia. This according to researchers at Karolinska Institutet, whose large-scale Swedish registry study is the most comprehensive ever in its field.

Last year, the team showed that artists and scientists were more common amongst families where  bipolar disorder and schizophrenia is present, compared to the population at large. They subsequently expanded their study to many more psychiatric diagnoses – such as schizoaffective disorder, depression, anxiety syndrome, alcohol abuse, drug abuse, autism, ADHD, anorexia nervosa and suicide – and to include people in outpatient care rather than exclusively hospital patients.

 

The present study tracked almost 1.2 million patients and their relatives, identified down to second-cousin level. Since all were matched with healthy controls, the study incorporated much of the Swedish population from the most recent decades. All data was anonymized and cannot be linked to any individuals.

 

The results confirmed those of their previous study: certain mental illness – bipolar disorder – is more prevalent in the entire group of people with artistic or scientific professions, such as dancers, researchers, photographers and authors. Authors specifically also were more common among most of the other psychiatric diseases (including schizophrenia, depression, anxiety syndrome and substance abuse) and were almost 50 per cent more likely to commit suicide than the general population.

 

The researchers also observed that creative professions were more common in the relatives of patients with schizophrenia, bipolar disorder, anorexia nervosa and, to some extent, autism. According to Simon Kyaga, consultant in psychiatry and doctoral student at the Department of Medical Epidemiology and Biostatistics, the results give cause to reconsider approaches to mental illness.

 

“If one takes the view that certain phenomena associated with the patients illness are beneficial, it opens the way for a new approach to treatment,” he says. “In that case, the doctor and patient must come to an agreement on what is to be treated, and at what cost. In psychiatry and medicine generally there has been a tradition to see the disease in black-and-white terms and to endeavour to treat the patient by removing everything regarded as morbid.”

 

The study was financed with grants from the Swedish Research Council, the Swedish Psychiatry Foundation, the Bror Gadelius Foundation, the Stockholm Centre for Psychiatric Research and the Swedish Council for Working Life and Social Research

http://ki.se/ki/jsp/polopoly.jsp?l=en&d=130&a=151722&newsdep=130

 

With a little training, signs of schizophrenia are averted

Contact: Mary Beth O’Leary moleary@cell.com 617-397-2802 Cell Press

Animals that literally have holes in their brains can go on to behave as normal adults if they’ve had the benefit of a little cognitive training in adolescence. That’s according to new work in the August 23 Neuron, a Cell Press publication, featuring an animal model of schizophrenia, where rats with particular neonatal brain injuries   develop schizophrenia-like symptoms.

“The brain can be loaded with all sorts of problems,” said André Fenton of New York University. “What this work shows is that experience can overcome those disabilities.”

Fenton’s team made the discovery completely by accident. His team was interested in what Fenton considers a core problem in schizophrenia: the inability to sift through confusing or conflicting information and focus on what’s relevant.

“As you walk through the world, you might be focused on a phone conversation, but there are also kids in the park and cars and other distractions,” he explained. “These information streams are all competing for our brain to process them. That’s a really challenging situation for someone with schizophrenia.”

Fenton and his colleagues developed a laboratory test of cognitive control needed for that kind of focus. In the test, rats had to learn to avoid a foot shock while they were presented with conflicting information. Normal rats can manage that task quickly. Rats with brain lesions can also manage this task, but only up until they become young adults—the equivalent of an 18- or 20-year-old person—when signs of schizophrenia typically set in.

While that was good to see, Fenton says, it wasn’t really all that surprising. But then some unexpected circumstances in the lab led them to test animals with adolescent experience in the cognitive control test again, once they had grown into adults.

These rats should have shown cognitive control deficits, similar to those that had not received prior cognitive training, or so the researchers thought. Instead, they were just fine. Their schizophrenic symptoms had somehow been averted.

Fenton believes their early training for focus forged some critical neural connections, allowing the animals to compensate for the injury still present in their brains in adulthood. Not only were the animals’ behaviors normalized with training, but the patterns of activity in their brains were also.

The finding is consistent with the notion that mental disorders are the consequence of problems in brain development that might have gotten started years before. They raise the optimistic hope that the right kinds of experiences at the right time could change the future by enabling people to better manage their diseases and better function in society. Adolescence, when the brain undergoes significant change and maturation, might be a prime time for such training.

“You may have a damaged brain, but the consequences of that damage might be overcome without changing the damage itself,” Fenton says. “You could target schizophrenia, but other disorders aren’t very different,” take autism or depression, for example.

And really, in this world of infinite distraction, couldn’t we all use a little more cognitive control?

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Lee et al.: “Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model.