 |
|
NARSAD Researchers Identify Specific Genes and Family Traits Linked to Schizophrenia, Bipolar Disorder and Depression
June 04, 2008New findings from research supported by NARSAD, the world's leading charity dedicated to mental health research, and conducted by Harvard-affiliated scientists are providing important clues into how genes work to impair various aspects of attention, memory and perception -- the behaviors associated with many psychiatric illnesses, such as schizophrenia, bipolar disorder and depression.
Presented at NARSAD's 3rd annual Boston Mental Health Research Symposium on May 30 at the Harvard Medical School, the studies shed new light on how specific genes contribute to the susceptibility to and pathology of schizophrenia, bipolar disorder and depression, some of the most severe, chronic and disabling mental illnesses that collectively affect an estimated 40 million Americans. Coming at a time when some treatments for mental illnesses are a matter of trial and error, these findings have relevance in the development of novel therapies targeted to specific patients and to specific genes.
Donald C. Goff, M.D., director of the Schizophrenia Clinical and Research Program at Massachusetts General Hospital and a leading researcher on the role of genetics in the development of new treatments for schizophrenia, moderated the discussion.
Folate as a Cause and Treatment for Schizophrenia: Who Will Benefit?
Do genes explain why some people with schizophrenia are helped when they take supplements of the common B vitamin, folate? The answer is yes and now, new NARSAD funded research is examining the reasons why.
According to Dr. Goff, whose pioneering research identified a link between low blood levels of folate and negative schizophrenia symptoms, folate is involved in many different chemical pathways in the brain, including keeping levels of the amino acid homocysteine low. When homocysteine levels are too high, this interferes with the functioning of receptors located all over the brain -- called NMDA ( N-methyl-D-aspartate) receptors -- that are critical to learning, memory, brain development, and general neural processing.
However, what causes low folate in people with schizophrenia is still open to question. One reason, confirmed by epidemiological studies, is poor dietary intake. Based on examining two major famines in the 20th century -- the Dutch Hunger Winter of 1944-45 brought about by the Nazi occupation in World War II and the Chinese famine in 1959-61 -- scientists found that the incidence of schizophrenia among children born to women who were pregnant during these famines increased two-fold.
But in most cases, starvation is not the problem. That is why Dr. Goff's team looked for other causes, including two genes: GCPII (glutamate carboxypeptidase II), which controls the absorption of folate and may be deficient in people with schizophrenia, and MTHFR (methylenetetrahydrofolate reductase), which activates folate for use in the brain. Using this information, Dr. Goff and his colleagues are recruiting patients for a large trial to determine whether folate supplementation will help individuals affected by these genes, many of whom have treatment-resistant psychotic symptoms. Funded by the National Institute of Mental Health, this double-blind study will follow 150 patients with schizophrenia at three sites over a 16-week period.
"Schizophrenia is a prevalent and costly disorder and can be very difficult to treat. This is especially true for the estimated 30 percent of patients with treatment-resistant psychotic symptoms, who may also experience social withdrawal, apathy, and depression," Dr. Goff
said. "Having these new data will validate whether folate, which is known to be very safe, is
an effective way to improve outcomes for people with schizophrenia who now suffer from treatment-resistant psychotic symptoms."
Building on this landmark research, scientist and colleague, Joshua Roffman, M.D., is using NARSAD funds to go the next step -- identifying people with schizophrenia who are most likely to benefit from folate supplementation. Here, Dr. Roffman and his colleagues started with the MTHFR gene and found that one variant increases the severity of schizophrenia symptoms. Moreover, in patients with this variant, low folate intake was associated with symptoms that were especially severe.
Now, Dr. Roffman's team is looking at the combination of MTHFR and another gene -- COMT (catechol-O-methyltransferase) -- that affects dopamine levels in the brain. Although the two genes have separately been associated with schizophrenia, Dr. Roffman's just completed study finds that when these genes interact, a specific subset of patients is at greater risk for cognitive impairment. In individuals who carry the risk variants of both MTHFR and COMT, lower-than-normal levels of dopamine in the part of the brain called the prefrontal cortex may cause problems with information processing and working memory. Using functional neuroimaging, Dr. Roffman and his colleagues also found that the same combination of MTHFR and COMT variants were associated with abnormally low activity in the prefrontal cortex.
"We now have the techniques to determine how genes combine to produce schizophrenia symptoms," Dr. Roffman explained. "As we gain a better understanding of individual biogenetic pathways, we can identify high-risk groups and those most likely to benefit from specific treatments."
Genes and Depression
If a better understanding of genes may lead to customized therapies for schizophrenia, can the same be true for new depression treatments? Answering this question is especially important now that a 2006 government study found that a significant number of people with clinical depression - more than half - are not helped by their initial course of antidepressant treatment, whether medication or talk therapy. In addition, antidepressant medications often come with troubling side effects, such as sleep changes, sexual problems, headaches and gastrointestinal problems, and an analysis by the Food and Drug Administration has shown that antidepressants may cause suicidal thinking and behavior in children, adolescents and adults ages 18 to 24.
According to Roy Perlis, M.D., M.Sc., the director of pharmacogenomics research at Massachusetts General Hospital's Department of Psychiatry, specific genes may influence how individual patients respond to antidepressant therapies, which is why his research team is using NARSAD funds to try to find these genes.
After studies in mice identified variations of four genes that may affect how individuals respond to antidepressant treatment, Dr. Perlis and his colleagues examined these four genes in DNA samples provided by 1,554 people participating in a large government study called the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. What the team found was a link between a variation in the gene TREK1 and poorer response to antidepressant treatment. This is especially significant because people with depression often require more than one treatment before they find one that "works" for them. If individuals with more "treatment-resistant" depression can be identified early in their illness, they may be treated more effectively. Further, Dr. Perlis believes that studying how variations in genes affect response to medications will also lead to a completely new class of more targeted antidepressant therapies.
"Our hope is that one day, we will be able to match patients to those treatments that are most likely to be effective," Dr. Perlis noted. "When we understand how people respond to different treatments and why, we will be able to design more targeted therapies for depression."
Family Traits Provide Clues to Genes for Schizophrenia, Bipolar Disorder
It is also important to identify the endophenotypes -- traits associated with a clinical disorder -- that can serve as a roadmap for detecting disease-related genes. That is why Deborah L.
Levy, Ph.D., associate professor of psychology in the Department of Psychiatry at Harvard Medical School and director of the Psychology Research Laboratory at McLean Hospital, is studying families to detect relatives who are carriers of the genes for schizophrenia and bipolar disorder, even though these individuals don't have the diseases themselves.
"One of the key issues in any genetic study is to distinguish individuals who are gene carriers from individuals who are not gene carriers," explained Dr. Levy. In single gene disorders, such as cystic fibrosis and Huntington's disease, 25 percent and 50 percent of family members, respectively, have the same illness. In contrast, only 6.5 percent of family members of people with schizophrenia actually have the illness, which means most relatives don't have symptoms of the illness but may still be gene carriers.
To find the relatives who are likely carriers of genes for schizophrenia and bipolar disorder, Dr. Levy and her colleagues have zeroed in on four discernable schizophrenia-related traits that occur in well family members at a much higher rate than schizophrenia itself: difficulty following a slow moving target with one's eyes, syntax errors or idiosyncratic use of language, subtle anomalies involving the midline of the face , and difficulty filtering out noises and other irrelevant stimuli (a condition known as sensory gating).
These traits, according to Dr. Levy, are much more common in families with schizophrenia. For example, idiosyncratic use of language (a trait similar to the thought disorder observed in schizophrenia) occurs in 37 percent of clinically unaffected first-degree relatives of individuals with schizophrenia, a rate that is almost six times higher than schizophrenia in the same families. When the rates for thought disorder and schizophrenia and related clinical conditions are combined, the proportion of potential gene-carrying relatives is close to 50 percent, consistent with a dominant gene, and much higher than the 6.5 percent rate of schizophrenia in the same families.
"With diseases like schizophrenia and bipolar disorder, identifying the genes is just the starting point," noted Dr. Levy. "The ultimate goal is to discover the biological processes these genes initiate in the brain, ultimately leading to better treatments in the future."
NARSAD
Folate as a Cause and Treatment for Schizophrenia: Who Will Benefit?
Do genes explain why some people with schizophrenia are helped when they take supplements of the common B vitamin, folate? The answer is yes and now, new NARSAD funded research is examining the reasons why.
According to Dr. Goff, whose pioneering research identified a link between low blood levels of folate and negative schizophrenia symptoms, folate is involved in many different chemical pathways in the brain, including keeping levels of the amino acid homocysteine low. When homocysteine levels are too high, this interferes with the functioning of receptors located all over the brain -- called NMDA ( N-methyl-D-aspartate) receptors -- that are critical to learning, memory, brain development, and general neural processing.
However, what causes low folate in people with schizophrenia is still open to question. One reason, confirmed by epidemiological studies, is poor dietary intake. Based on examining two major famines in the 20th century -- the Dutch Hunger Winter of 1944-45 brought about by the Nazi occupation in World War II and the Chinese famine in 1959-61 -- scientists found that the incidence of schizophrenia among children born to women who were pregnant during these famines increased two-fold.
But in most cases, starvation is not the problem. That is why Dr. Goff's team looked for other causes, including two genes: GCPII (glutamate carboxypeptidase II), which controls the absorption of folate and may be deficient in people with schizophrenia, and MTHFR (methylenetetrahydrofolate reductase), which activates folate for use in the brain. Using this information, Dr. Goff and his colleagues are recruiting patients for a large trial to determine whether folate supplementation will help individuals affected by these genes, many of whom have treatment-resistant psychotic symptoms. Funded by the National Institute of Mental Health, this double-blind study will follow 150 patients with schizophrenia at three sites over a 16-week period.
"Schizophrenia is a prevalent and costly disorder and can be very difficult to treat. This is especially true for the estimated 30 percent of patients with treatment-resistant psychotic symptoms, who may also experience social withdrawal, apathy, and depression," Dr. Goff
said. "Having these new data will validate whether folate, which is known to be very safe, is
an effective way to improve outcomes for people with schizophrenia who now suffer from treatment-resistant psychotic symptoms."
Building on this landmark research, scientist and colleague, Joshua Roffman, M.D., is using NARSAD funds to go the next step -- identifying people with schizophrenia who are most likely to benefit from folate supplementation. Here, Dr. Roffman and his colleagues started with the MTHFR gene and found that one variant increases the severity of schizophrenia symptoms. Moreover, in patients with this variant, low folate intake was associated with symptoms that were especially severe.
Now, Dr. Roffman's team is looking at the combination of MTHFR and another gene -- COMT (catechol-O-methyltransferase) -- that affects dopamine levels in the brain. Although the two genes have separately been associated with schizophrenia, Dr. Roffman's just completed study finds that when these genes interact, a specific subset of patients is at greater risk for cognitive impairment. In individuals who carry the risk variants of both MTHFR and COMT, lower-than-normal levels of dopamine in the part of the brain called the prefrontal cortex may cause problems with information processing and working memory. Using functional neuroimaging, Dr. Roffman and his colleagues also found that the same combination of MTHFR and COMT variants were associated with abnormally low activity in the prefrontal cortex.
"We now have the techniques to determine how genes combine to produce schizophrenia symptoms," Dr. Roffman explained. "As we gain a better understanding of individual biogenetic pathways, we can identify high-risk groups and those most likely to benefit from specific treatments."
Genes and Depression
If a better understanding of genes may lead to customized therapies for schizophrenia, can the same be true for new depression treatments? Answering this question is especially important now that a 2006 government study found that a significant number of people with clinical depression - more than half - are not helped by their initial course of antidepressant treatment, whether medication or talk therapy. In addition, antidepressant medications often come with troubling side effects, such as sleep changes, sexual problems, headaches and gastrointestinal problems, and an analysis by the Food and Drug Administration has shown that antidepressants may cause suicidal thinking and behavior in children, adolescents and adults ages 18 to 24.
According to Roy Perlis, M.D., M.Sc., the director of pharmacogenomics research at Massachusetts General Hospital's Department of Psychiatry, specific genes may influence how individual patients respond to antidepressant therapies, which is why his research team is using NARSAD funds to try to find these genes.
After studies in mice identified variations of four genes that may affect how individuals respond to antidepressant treatment, Dr. Perlis and his colleagues examined these four genes in DNA samples provided by 1,554 people participating in a large government study called the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. What the team found was a link between a variation in the gene TREK1 and poorer response to antidepressant treatment. This is especially significant because people with depression often require more than one treatment before they find one that "works" for them. If individuals with more "treatment-resistant" depression can be identified early in their illness, they may be treated more effectively. Further, Dr. Perlis believes that studying how variations in genes affect response to medications will also lead to a completely new class of more targeted antidepressant therapies.
"Our hope is that one day, we will be able to match patients to those treatments that are most likely to be effective," Dr. Perlis noted. "When we understand how people respond to different treatments and why, we will be able to design more targeted therapies for depression."
Family Traits Provide Clues to Genes for Schizophrenia, Bipolar Disorder
It is also important to identify the endophenotypes -- traits associated with a clinical disorder -- that can serve as a roadmap for detecting disease-related genes. That is why Deborah L.
Levy, Ph.D., associate professor of psychology in the Department of Psychiatry at Harvard Medical School and director of the Psychology Research Laboratory at McLean Hospital, is studying families to detect relatives who are carriers of the genes for schizophrenia and bipolar disorder, even though these individuals don't have the diseases themselves.
"One of the key issues in any genetic study is to distinguish individuals who are gene carriers from individuals who are not gene carriers," explained Dr. Levy. In single gene disorders, such as cystic fibrosis and Huntington's disease, 25 percent and 50 percent of family members, respectively, have the same illness. In contrast, only 6.5 percent of family members of people with schizophrenia actually have the illness, which means most relatives don't have symptoms of the illness but may still be gene carriers.
To find the relatives who are likely carriers of genes for schizophrenia and bipolar disorder, Dr. Levy and her colleagues have zeroed in on four discernable schizophrenia-related traits that occur in well family members at a much higher rate than schizophrenia itself: difficulty following a slow moving target with one's eyes, syntax errors or idiosyncratic use of language, subtle anomalies involving the midline of the face , and difficulty filtering out noises and other irrelevant stimuli (a condition known as sensory gating).
These traits, according to Dr. Levy, are much more common in families with schizophrenia. For example, idiosyncratic use of language (a trait similar to the thought disorder observed in schizophrenia) occurs in 37 percent of clinically unaffected first-degree relatives of individuals with schizophrenia, a rate that is almost six times higher than schizophrenia in the same families. When the rates for thought disorder and schizophrenia and related clinical conditions are combined, the proportion of potential gene-carrying relatives is close to 50 percent, consistent with a dominant gene, and much higher than the 6.5 percent rate of schizophrenia in the same families.
"With diseases like schizophrenia and bipolar disorder, identifying the genes is just the starting point," noted Dr. Levy. "The ultimate goal is to discover the biological processes these genes initiate in the brain, ultimately leading to better treatments in the future."
NARSAD
Schizophrenia Current Events and Schizophrenia News RSSNewer antipsychotics no better than older drug in treating child and adolescent schizophrenia
Two newer atypical antipsychotic medications were no more effective than an older conventional antipsychotic in treating child and adolescent schizophrenia and may lead to more metabolic side effects, according to a new study funded by the National Institutes of Health's National Institute of Mental Health (NIMH).
First generation antipsychotic drugs as effective as newer ones in some children
Nearly every child who receives an antipsychotic medicine is first prescribed one of the second-generation, or "atypical" drugs, such as olanzapine and risperidone. However, there has never been evidence that these drugs are more effective than the older, first-generation medications.
Immaturity of the brain may cause schizophrenia
The underdevelopment of a specific region in the brain may lead to schizophrenia in individuals. According to research published today in BioMed Central's open access journal Molecular Brain, dentate gyrus, which is located in the hippocampus in the brain and thought to be responsible for working memory and mood regulation, remained immature in an animal model of schizophrenia.
Aberrations in region of chromosome 1q21.1 associated with broad range of disorders in children
Researchers have discovered a submicroscopic aberration in a particular region of human chromosome 1q21.1 that appears to be associated with a variety of developmental disorders in children.
Protein found that regulates gene critical to dopamine-releasing brain cells
Researchers have identified a protein they say appears to be a primary player in maintaining normal functioning of an important class of neurons - those brain cells that produce, excrete and then reabsorb dopamine neurotransmitters.
New way to help schizophrenia sufferers' social skills
Researchers from the University of Newcastle are investigating a new way to help schizophrenia patients develop their communication and social skills.
Hopkins researchers piece together gene 'network' linked to schizophrenia
Reporting this week in the Archives of General Psychiatry, researchers at the Johns Hopkins University School of Medicine have uncovered for the first time molecular circuitry associated with schizophrenia that links three previously known, yet unrelated proteins.
Risks and benefits of antipsychotics in children and adolescents
Many of the psychiatric disorders observed in adults have their onset in childhood or adolescence. In fact some studies show that at least 20% of children and adolescents will fulfil a diagnostic criterion for a mental disorder before reaching adulthood.
Children of older fathers more likely to have bipolar disorder
Older age among fathers may be associated with an increased risk for bipolar disorder in their offspring, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals.
Anti-psychotic drug use in the elderly increases despite drug safety warnings
Three regulatory warnings of serious adverse events slowed the growth of use of atypical antipsychotic drugs among elderly patients with dementia, but they did not reduce the overall prescription rate of these drugs.
More Schizophrenia Current Events and Schizophrenia News Articles
 | Surviving Schizophrenia: A Manual for Families, Consumers, and Providers (4th Edition) by E. Fuller Torrey Since its first publication in 1983, Surviving Schizophrenia has become the standard reference book on the disease and has helped thousands of patients, their families and mental health professionals. In clear language, this much–praised and important book describes the nature, causes, symptoms, treatment and course of schizophrenia and also explores living with it from both the patient and the... |
 | The Complete Family Guide to Schizophrenia: Helping Your Loved One Get the Most Out of Life by Kim T. Mueser, Susan Gingerich Do people with schizophrenia ever get better? With the vast majority of those with the disorder dependent on their families for care, close relatives often grapple with that question. The Complete Family Guide to Schizophrenia inspires hope. Authors Kim T. Mueser, PhD, and Susan Gingerich, MSW, walk readers through a range of treatment and support options that can lead to a better life for the... |
 | Getting Your Life Back Together When You Have Schizophrenia by Roberta Temes |
 | Social Skills Training for Schizophrenia, Second Edition: A Step-by-Step Guide (TREATMENT MANUALS FOR PRACTITIONERS) by Alan S. Bellack, Kim T. Mueser, Susan Gingerich, Julie Agresta This popular manual presents an empirically tested format and ready-made curricula for skills training groups in a range of settings. Part I takes therapists and counselors step by step through assessing clients' existing skills, teaching new skills, and managing common treatment challenges. Part II comprises over 60 ready-to-photocopy skill sheets. Each sheet--essentially a complete lesson... |
 | Cognitive Therapy of Schizophrenia (Guides to Individualized Evidence-Based Treatment) by David G. Kingdon, Douglas Turkington Drawing on the authors' decades of influential work in the field, this highly practical volume presents an evidence-based cognitive therapy approach for clients with schizophrenia. Guidelines are provided for collaborative assessment and case formulation that enable the clinician to build a strong therapeutic relationship, establish reasonable goals, and tailor treatment to each client's needs.... |
 | Divided Minds: Twin Sisters and Their Journey Through Schizophrenia by Pamela Spiro Wagner, Carolyn Spiro Growing up in the fifties, Carolyn Spiro was always in the shadow of her more intellectually dominant and social outgoing twin, Pamela. But as the twins approached adolescence, Pamela began to succumb to schizophrenia, hearing disembodied voices and eventually suffering many breakdowns and hospitalizations. Divided Minds is a dual memoir of identical twins, one of whom faces a life sentence of... |
 | Schizophrenia Revealed: From Neurons to Social Interactions by Michael Foster Green A modern view of schizophrenia based on neuroscience that goes far beyond the symptoms of the illness. "Green has lifted the bar in this realm of explanatory neuroscience-based psychiatry. If you wish to read an enjoyable and instructive primer on what we know about schizophrenia at the beginning of the 21st century, you could do no better than to choose Schizophrenia Revealed." —New England... |
 | Schizophrenia Genesis: The Origins of Madness (Series of Books in Psychology) by Irving I. Gottesman Sorting out fact from fiction, one of the world's leading experts presents an absorbing account of what is actually know about the complex subject of... |
 | Diagnosis: Schizophrenia by Rachel Miller, Susan Mason The disease is not fatal but few diagnoses have the capacity to instill as much fear in the hearts of patients and families. Here is a profoundly reassuring book that shows there can be life after a diagnosis of schizophrenia. The book includes thirty-five first-person accounts, along with chapters by professionals on a wide range of issues from hospitalization to rehabilitation. Jargon-free... |
 | Recovered, Not Cured: A Journey Through Schizophrenia by Richard McLean This very personal exploration of schizophrenia explores each stage, from the early signs and reactions from friends and family to seeking help and the challenges of recovery. McLean bravely shares his paranoid delusions and offers both a verbal and a visual experience by including digital artwork he created to help objectify and control his impulses and fears. As McLean relates his experiences... |
| © 2008 BrightSurf.com |