 |
|
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 RSSSchizophrenia gene's role may be broader, more potent, than thought
UCSF scientists studying nerve cells in fruit flies have uncovered a new function for a gene whose human equivalent may play a critical role in schizophrenia.
Full recovery now possible for an 'untreatable' mental illness
Patients coping with the chaos and misery of Borderline Personality Disorder now have reason for strong confidence in making major life changes through a new treatment, Schema Therapy.
Immune system activated in schizophrenia
Researchers at the Swedish medical university Karolinska Institutet have discovered that patients with recent-onset schizophrenia have higher levels of inflammatory substances in their brains. Their findings offer hope of being able to treat schizophrenia with drugs that affect the immune system.
Why can't chimps speak?
If humans are genetically related to chimps, why did our brains develop the innate ability for language and speech while theirs did not?
Developmental delay could stem from nicotinic receptor deletion
The loss of a gene through deletion of genetic material on chromosome 15 is associated with significant abnormalities in learning and behavior, said a consortium of researchers led by Baylor College of Medicine (www.bcm.edu) in a report that appears online today in the journal Nature Genetics.
Fighting Sleep, Penn Researchers Reverse the Cognitive Impairment Caused By Sleep Deprivation
A research collaboration led by biologists and neuroscientists at the University of Pennsylvania has found a molecular pathway in the brain that is the cause of cognitive impairment due to sleep deprivation.
Testicular tumors may explain why some diseases are more common in children of older fathers
A rare form of testicular tumour has provided scientists with new insights into how genetic changes (mutations) arise in our children.
CSHL-led team discovers rare mutation dramatically increasing schizophrenia risk
An international team of researchers led by geneticist Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory (CSHL), has identified a mutation on human chromosome 16 that substantially increases risk for schizophrenia.
Faulty 'wiring' in the brain triggers onset of schizophrenia
A new study by researchers at the Institute of Psychiatry (IoP), King's College London has discovered abnormalities in the white matter of the brain that seem to be critical for the timing of schizophrenia.
General anesthetics lead to learning disabilities in animal models
Studies by researchers at Wake Forest University School of Medicine have shown that blocking the NMDA receptor in immature rats leads to profound, rapid brain injury and disruption of auditory function as the animals mature.
More Schizophrenia Current Events and Schizophrenia News Articles
 |
Schizophrenia Revealed: From Neurons to Social Interactions by Michael Foster Green (Author) 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 Journal of Medicine |
 |
The Quiet Room: A Journey Out of the Torment of Madness by Lori Schiller (Author), Amanda Bennett (Author) Schiller's gripping, heart-rending and ultimately triumphant story of her journey into madness and back to reality is told through the voices of Lori and her family, friends and doctor, and captures a rare, astoundingly vivid view into the inner life of a schizophrenic. "A stunning story of courage, persistence, and hope."--Publishers Weekly. |
 |
Surviving Schizophrenia: A Manual for Families, Patients, and Providers by E. Fuller Torrey (Author) 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 family's point of view. This new, completely updated fifth edition includes the latest research findings on what causes the disease as well as information about the newest drugs for treatment and answers to the questions most often asked by families, consumers and providers. |
 |
ABC News 20/20 Schizophrenia It's all in their minds: visions, voices, taunting, never ending, driving them crazy or worse. It's hard to imagine, but now, an amazing device lets you feel their pain. The technology lets you go inside the mind of a schizophrenic. See what they see. Hear what they hear. Using the technique of virtual reality, Janssen Pharmaceuticals has developed a device to stimulate the visual and auditory hallucinations of a schizophrenic patient. Dr. Timothy Johnson explores the world of people struggling with the voices within. This "20/20" show contains the following additional stories: Victim's Comp Windsheilds |
 |
The Complete Family Guide to Schizophrenia: Helping Your Loved One Get the Most Out of Life by Kim T. Mueser PhD (Author), Susan Gingerich MSW (Author) Will the person you love ever get better? Chances are you've grappled with the question. With care and support from their families, people with schizophrenia can and do make vast improvements. Noted therapists Kim Mueser and Susan Gingerich deepen your understanding of the illness and cover a wide range of effective treatments. Based on decades of research and experience, they offer pragmatic suggestions for dealing with depression, psychosis, and other symptoms. They show you how to prioritize needs, resolve everyday problems, and encourage your loved one to set life goals. Plus, individual sections highlight special issues for parents, children, siblings, and partners. Whether you’re facing schizophrenia for the first time or you’ve dealt with its impact for years, you’ll discover... |
 |
Schizophrenia For Dummies (For Dummies (Health & Fitness)) by Jerome Levine (Author), Irene S. Levine (Author) Practical tools for leading a happy, productive life Schizophrenia is a chronic, severe, and disabling mental disorder that afflicts one percent of the population, an estimated 2.5 million people in America alone. The firsthand advice in this reassuring guide will empower the families and caregivers of schizophrenia patients to take charge, offering expert advice on identifying the warning signs, choosing the right health professional, understanding currently available drugs and those on the horizon (as well as their side effects), and evaluating traditional and alternative therapies. |
 |
Me, Myself, and Them: A Firsthand Account of One Young Person's Experience with Schizophrenia (Adolescent Mental Health Initiative) by Kurt Snyder (Author), Raquel E. Gur M.D. (Author), Linda Wasmer Andrews (Author) During his second semester at college, Kurt Snyder became convinced that he was about to discover a fabulously important mathematical principle, spending hours lost in daydreams about numbers and symbols. In time, his thoughts took a darker turn, and he became preoccupied with the idea that cars were following him, or that strangers wanted to harm him. Kurt's mind had been hijacked by schizophrenia, a severe mental disorder that typically strikes during the late teen or young adult years. In Me, Myself, and Them, Kurt, now an adult, looks back from the vantage point of recovery and eloquently describes the debilitating changes in thoughts and perceptions that took hold of his life during his teens and twenties. As a memoir, this book is remarkable for its unvarnished look at the... |
 |
Getting Your Life Back Together When You Have Schizophrenia by Roberta Temes (Author) |
 |
Understanding Mental Illness and Schizophrenia (Home Use) Part of the award winning public television series Healthy Body/Healthy Mind. Mental Illnesses are complex diseases of the brain affecting thoughts, moods, and coping ability. There are many diseases you can see, feel and understand, but there are others that aren't as easy to comprehend. Education and compassion are key. Untreated mental illness costs Americans more than 100 billion dollars each year. Fear of Mental Illness and the lack of understanding prevent millions of people from seeking much needed treatment. Meet some of these people in this program. This product is manufactured on demand using DVD-R recordable media. Amazon.com's standard return policy will apply. |
 |
Recovered, Not Cured: A Journey Through Schizophrenia by Richard McLean (Author) 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 step by step, issues of sexuality, identity, and drug abuse are discussed, along with the overarching issues relating to mental health and the medical profession. Messages from online posters who either have suffered from mental illness or have cared for the mentally ill are included throughout, adding more perspectives to the author's personal experiences. This powerful combination of words and... |
| © 2009 BrightSurf.com |