Aging and gene expression -- possible links to autism and schizophrenia in offspring

Advanced paternal age has been associated with greater risk for psychiatric disorders, such as schizophrenia and autism. With an increase in paternal age, there is a greater frequency of certain types of mutations that contribute to these disorders in offspring. Mutations are changes in the genetic code. Recent research, however, looks beyond the genetic code to "epigenetic effects", which do not involve changes in the genes themselves, but rather in how they are expressed to determine one's characteristics. Such epigenetic changes in sperm, related to ageing, have been linked with psychiatric disorders in offspring. Maria Milekic, PhD, reported today, at the American College of Neuropsychopharmacology annual meeting in Hollywood Florida, that old mice have an epigenetic change ‒ a loss of DNA methylation at the locations where the genetic code starts being transcribed. DNA methylation is a biochemical process that plays an important regulatory role in development and disease. The work was done by a research team in the Department of Psychiatry at Columbia University. Offspring of old fathers showed the same deficit in DNA methylation, and they differed in their behavior from the offspring of the young fathers. They showed less exploratory activity and differed in the startle response and in habituation. Two groups, with 10 breeder mice per group, were tested. The breeders were either old (12 month) or young (3 month) males, each bred with two young (3 month) female mice. Then the behavior of the offspring was tested when they were 3 months old. DNA methylation also was tested in the young and old fathers' sperm, and brains of the offspring were tested for DNA methylation as well as gene expression. "We were interested in understanding the mechanism of the paternal age effect", said Dr. Milekic."The risk for schizophrenia increases 2-fold when a father is over 45 years of age, and the risk for autism increases 2-5-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism." Not only did the offspring of the old fathers differ from their counterparts with young fathers in DNA methylation, they also showed significant differences in the expression of genes that have been implicated in autism spectrum disorders and that are known to regulate the development and function of the brain. These findings point to possible factors that can lead to autism spectrum disorders and schizophrenia, and ultimately may lead to more effective therapeutic interventions. With respect to studies in the immediate future, Dr. Milekic said,"We are trying to evaluate changes in different brain regions. Our studies before did not compare brain regions. Most of the genes that have altered expression are in the cerebellum. We are interested in how DNA methylation in the cerebellum is affected by paternal age." Social Worker CEUs ### The work was supported by grants from NIMH and the Simon Foundation to Jay Gingrich, MD, PhD, and a NARSAD Young Investigator Awa rd from the Brain and Behavior Research Foundation to Dr. Milekic.

National Institute of Mental Health (NIMH) Grantees To Receive 2013 Lasker Award

A current and a former National Institute of Mental Health (NIMH) grantee recently collected the prestigious 2013 Albert Lasker Basic Medical Research Award for their meticulous mapping of the molecular mechanisms involved in neurotransmitter release, the process by which the brain sends and receives chemical messages. Richard H. Scheller, Ph.D. Richard H. Scheller, Ph.D Genentech Thomas C. Südhof, M.D., at Stanford University School of Medicine, and Richard H. Scheller, Ph.D., at Genentech, parsed the proteins that enable one neuron to speak to another. This communication occurs across the synapse, a gap that separates the two neurons. Collectively called the “SNARE complex,” these proteins include vesicle-associated membrane protein (VAMP/synaptobrevin), synaptogamin, syntaxin, and SNAP-25. The complex allows for the preparation and release of the neurotransmitters into the synapse. Defects in this process contribute to mental disorders such as schizophrenia, depression, bipolar disorder, epilepsy, and many other pathological conditions. Thomas C. Südhof, M.D. Thomas C. Südhof, M.D. Stanford University School of Medicine Dr. Südhof is a current NIMH grantee and has served on several study sections at the NIH Center for Scientific Review, in addition to the Molecular, Cellular, and Developmental Neuroscience study section at NIMH. Dr. Scheller received research support from NIMH, and served on both the NIMH Molecular, Cellular, and Developmental Neuroscience study section, and the National Advisory Mental Health Council. Both have received the NIMH MERIT Award. Known as “America’s Nobels” because many recipients go on to win the Nobel Prize, the Lasker Awards are among the most respected science prizes in the world. Congratulations, Drs. Südof and Scheller Aspira Continuing Education Online Courses

New Data Reveal Extent of Genetic Overlap Between Major Mental Disorders

Schizophrenia, Bipolar Disorder Share the Most Common Genetic Variation Press Release • August 12, 2013 The largest genome-wide study of its kind has determined how much five major mental illnesses are traceable to the same common inherited genetic variations. Researchers funded in part by the National Institutes of Health found that the overlap was highest between schizophrenia and bipolar disorder; moderate for bipolar disorder and depression and for ADHD and depression; and low between schizophrenia and autism. Overall, common genetic variation accounted for 17-28 percent of risk for the illnesses. “Since our study only looked at common gene variants, the total genetic overlap between the disorders is likely higher,” explained Naomi Wray, Ph.D., University of Queensland, Brisbane, Australia, who co-led the multi-site study by the Cross Disorders Group of the Psychiatric Genomics Consortium (PGC), which is supported by the NIH’s National Institute of Mental Health (NIMH). “Shared variants with smaller effects, rare variants, mutations, duplications, deletions, and gene-environment interactions also contribute to these illnesses.” Dr. Wray, Kenneth Kendler, M.D., of Virginia Commonwealth University, Richmond, Jordan Smoller, M.D., of Massachusetts General Hospital, Boston, and other members of the PGC group report on their findings August 11, 2013, in the journal Nature Genetics. “Such evidence quantifying shared genetic risk factors among traditional psychiatric diagnoses will help us move toward classification that will be more faithful to nature,” said Bruce Cuthbert, Ph.D., director of the NIMH Division of Adult Translational Research and Treatment Development and coordinator of the Institute’s Research Domain Criteria (RDoC) project, which is developing a mental disorders classification system for research based more on underlying causes. Earlier this year, PGC researchers – more than 300 scientists at 80 research centers in 20 countries – reported the first evidence of overlap between all five disorders. People with the disorders were more likely to have suspect variation at the same four chromosomal sites. But the extent of the overlap remained unclear. In the new study, they used the same genome-wide information and the largest data sets currently available to estimate the risk for the illnesses attributable to any of hundreds of thousands of sites of common variability in the genetic code across chromosomes. They looked for similarities in such genetic variation among several thousand people with each illness and compared them to controls – calculating the extent to which pairs of disorders are linked to the same genetic variants. The overlap in heritability attributable to common genetic variation was about 15 percent between schizophrenia and bipolar disorder, about 10 percent between bipolar disorder and depression, about 9 percent between schizophrenia and depression, and about 3 percent between schizophrenia and autism. The newfound molecular genetic evidence linking schizophrenia and depression, if replicated, could have important implications for diagnostics and research, say the researchers. They expected to see more overlap between ADHD and autism, but the modest schizophrenia-autism connection is consistent with other emerging evidence. The study results also attach numbers to molecular evidence documenting the importance of heritability traceable to common genetic variation in causing these five major mental illnesses. Yet this still leaves much of the likely inherited genetic contribution to the disorders unexplained – not to mention non-inherited genetic factors. For example, common genetic variation accounted for 23 percent of schizophrenia, but evidence from twin and family studies estimate its total heritability at 81 percent. Similarly, the gaps are 25 percent vs. 75 percent for bipolar disorder, 28 percent vs. 75 percent for ADHD, 14 percent vs. 80 percent for autism, and 21 percent vs. 37 percent for depression. Among other types of genetic inheritance known to affect risk and not detected in this study are contributions from rare variants not associated with common sites of genetic variation. However, the researchers say that their results show clearly that more illness-linked common variants with small effects will be discovered with the greater statistical power that comes with larger sample sizes. “It is encouraging that the estimates of genetic contributions to mental disorders trace those from more traditional family and twin studies. The study points to a future of active gene discovery for mental disorders” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funds the project.

Common inherited genetic variation (single nucleotide polymorphisms, or SNPs) accounted for up to about 28 percent of the risk for some disorders, such as ADHD (dark green). Among pairs of disorders (light green), schizophrenia and bipolar disorder (SCZ-BPD) shared about 16 percent of the same common genetic variation (coheritabilities). Source: Cross-Disorder Group of the Psychiatric Genomics Consortium Professional Counselor Continuing Education Reference Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics, August 11, 2013 Grants R01MH065562, R01MH43518, R01MH065554, R01MH65707, R01MH065571, R01MH65588, R01MH65578, R01MH65558 ### The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website. Press Contact(s) Jules Asher NIMH Press Office 301-443-4536 NIMHPress@nih.gov More Science News about: Attention Deficit Hyperactivity Disorder (ADHD) Autism Bipolar Disorder Depression Schizophrenia Contact the Press Office Phone: 301-443-4536 Email: NIMHpress@mail.nih.gov Press Resources Mental Health Information Statistics on Mental Disorders Summaries of Scientific Meetings Information about NIMH RePORTER: Research Portfolio Online Reporting Tool Expenditures and Results PubMed Central: An Archive of Life Sciences Journals Recommendations for Reporting on Suicide News from the Field News from the Field NIMH-Funded Science on EurekAlert Teen Eating Disorders Increase Suicide Risk The Love Hormone is 2-Faced Fear Factor: Missing Brain Enzyme Leads to Abnormal Levels of Fear in Mice, Reveals New Research More news from the field... Bookmark & Share Newsletters RSS Feeds Facebook

5 Most Common Mental Illnesses Share the Same Genes

From Autism to Depression: Largest Genetic Study Shows Mental Disorders Share Genetic Kinks --Associated Press Mental Illnesses Share Common DNA Roots, Study Finds --nbcnews.com An NIMH-funded study published online today in Lancet reveals that the five most common disorders—autism, attention deficit hyperactivity disorder, bipolar disease, schizophrenia, and major depression—all share similar genetic components. “These disorders that we thought of as quite different may not have such sharp boundaries,” said Dr. Jordan W. Smoller of Massachusetts General Hospital, one of the lead study authors. The results suggest that a rethink in how these disorders are defined might be in order. Rather than focusing on symptoms, which can be attributed to one or more disorder, physicians could one day start to rely on specific gene mutations or biologic pathways to make a formal diagnosis Aspira Continuing Education Online Courses And it also could lead to better treatments, said Dr. Bruce Cuthbert, director of the NIMH’s Division of Adult Translational Research and Treatment Development. “We are finally starting to make inroads where we have actual physiological mechanisms that we can target,” he said. “We can really start to understand the biology instead of having to guess at it.” Reference Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: A Genome-wide Analysis. Lancet, published online February 28, 2013.

Mapping Brain Circuits Provides Clues to Schizophrenia, Earlier Detection of Psychosis

Two regions in the brain have been linked to schizophrenia and psychosis, which may lead to earlier detection of this disorder and symptom, reported an imaging study funded by the National Institute of Mental Health (NIMH) that was published online last month in Biological Psychiatry. Background Patients with schizophrenia experience decreased activity in the prefrontal cortex ( blue, top figure) and excess activity in the basal ganglia (red, bottom figure). The greater the disconnect between these two regions, the higher the level of psychosis seen in these patients. Psychosis is a loss of contact with reality that usually includes false beliefs about what is taking place or who one is (delusions) and seeing or hearing things that aren’t there (hallucinations). Numerous medical problems can cause psychosis such as substance abuse, brain tumors, and certain mental disorders such as schizophrenia and bipolar disorder. Treatment approaches include hospitalization, antipsychotic drugs, and various psychosocial treatments. Too often, psychosis is not diagnosed or treated early enough. The longer this duration of untreated psychosis, the poorer the patient’s long-term functioning and response to treatment. In the United States, the average time between the first onset of psychotic symptoms and the initiation of treatment is about 110 weeks, or over 2 years. Disordered thinking and psychosis often go hand-in-hand in patients with the chronic brain disorder schizophrenia. A popular and long-standing theory in the field implicates the prefrontal cortex, the brain area just behind the forehead that normally supports higher-order capabilities such as prioritizing, categorizing, and strategizing. Damage to this area causes not only disordered thinking but also leads to psychosis from the excess release of the neurotransmitter dopamine into regions deep inside the brain. While this theory offers a compelling explanation for the co-occurrence of these two symptoms in schizophrenia, there have been only a small handful of studies that have directly supported this theory. Identification of the exact circuit(s) involved has so far remained elusive Professional Counselor Continuing Education “Schizophrenia is a very complex condition, involving a constellation of diverse symptoms. This diversity presents both a challenge and a constraint for figuring out the neurobiological root causes of schizophrenia. There is likely not just one lesion but a number of lesions that are present across different brain regions that are the proximal causes for these symptoms.” explained Jong H. Yoon, M.D., at the University of California, Davis, and lead author of the study. Yoon’s study focused on the prefrontal cortex and the basal ganglia. The basal ganglia is a subcortical collection of neuron clusters, including the ventral tegmental area and substantia nigra, which produce the majority of the brain’s dopamine, and the striatum, an important site of action of dopamine. Using functional magnetic resonance imaging (fMRI), the researchers examined the brain activity within the prefrontal cortex and basal ganglia of 18 individuals with schizophrenia and 19 healthy controls. The subjects completed a memory task in which they had to remember images of faces across a brief delay period to determine if subsequently presented faces were the same faces; it was hypothesized that patients with schizophrenia would have more difficulty performing this task. Results of the Study Patients with schizophrenia experienced excess activity in the substantia nigra, decreased activity in the prefrontal cortex, and diminished functional connectivity between these regions, suggesting that communication among these regions was out of sync. Additionally, the higher the level of connectivity between the substantia nigra and the striatum, the higher the level of psychosis seen in the patients with schizophrenia. Significance These findings suggest that the prefrontal cortex-basal ganglia circuit may be a common pathway linking cognitive deficits and psychosis in schizophrenia. It also points to a more widespread use of fMRI in diagnosis and treatment. Compared to other neuroimaging techniques such as positron emission tomography (PET), fMRI yields more detailed images, does not use radiation, and is relatively widely available since most university-based brain imaging centers have this technology. These findings could also lead to the creation of a better animal model of psychosis, of which there currently are few. Biomedical research has shown that early detection and intervention could preempt later stages of diseases. This concept of “treatment as prevention” is seen in the NIMH-supported North American Prodrome Longitudinal Study (NAPLS), which is using biological assessments, such as neuroimaging, to predict who will convert to psychosis and to develop new treatment and prevention approaches. Another NIMH study, Recovery After an Initial Schizophrenia Episode (RAISE), supports the development and testing of two complementary models for early intervention in schizophrenia. Research is also underway to identify genes and environmental elements associated with schizophrenia. What’s Next Because the study involved patients with established illness who are already on antipsychotic medications, it needs replication in patients with schizophrenia who are not medicated and/or in the early phases of illness. The study should also be performed in individuals at high risk of developing psychosis to see if these findings could help identify individuals in the earliest stages of illness when interventions to prevent or significantly ameliorate schizophrenia can be instituted. To obtain greater precision in localizing brain regions, the study also warrants replication with high-resolution fMRI. Furthermore, the techniques in this study could also be applied to other disorders that can have psychosis as one of its symptoms, such as mood disorders, and post-traumatic stress disorder. Reference Yoon JH, Minzenberg MJ, Raouf S, D’Esposito M, Carter CS. Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia. Biological Psychiatry, published online January 14, 2013.

Study: Use of antipsychotic drugs improves life expectancy for individuals with schizophrenia

Results of a Johns Hopkins study suggest that individuals with schizophrenia are significantly more likely to live longer if they take their antipsychotic drugs on schedule, avoid extremely high doses and also regularly see a mental health professional. Psychiatrists have long known that people with schizophrenia who stick to a drug regimen have fewer of the debilitating delusions and hallucinations that are hallmarks of this illness. But there have been concerns about whether some of the known side effects of the medications — increased risk of cardiovascular disease and diabetes, for example — carry higher mortality risks, the researchers say. "We know that antipsychotic medications reduce symptoms, and our study shows that staying on reasonable, recommended doses is associated with longer life," says Bernadette A. Cullen, M.B., B.Ch., B.A.O., MRCPsych, an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, and leader of the study published in Schizophrenia Bulletin. "The same is true for going to see a psychiatrist or therapist," she says, noting that regular visits to a mental health professional are one way to monitor and encourage drug-use compliance, but also in and of themselves increased survival in this vulnerable population. Cullen and her colleagues analyzed data collected between 1994 through 2004 on 2,132 adult Maryland Medicaid beneficiaries with schizophrenia. The researchers reviewed how much medication the patients took, how regularly they took it and how often they visited a mental health professional. The goal of the study was to review how adherence to the 2009 pharmacological Schizophrenia Patient Outcomes Research Team (PORT) guidelines was associated with mortality in this population. Comparing data from year to year, the researchers found that among those patients who had 90 percent or better compliance with their medication schedules, the risk of death was 25 percent lower compared to those who were less than 10 percent compliant. Over the decade-long study period, taking medication did not increase the risk of death and there was a trend towards reducing the mortality rate. In addition, the researchers found that each additional visit per year to a mental health professional was linked to a 5 percent reduction in risk of death overall LSW Continuing Education Cullen's study did not rule out all links between increased mortality and antipsychotic drugs. For example, her team found that people who took high doses of first-generation antipsychotic medication daily (1500 mg or greater chlorpromazine equivalents) were 88 percent more likely to die. She says mortality rates possibly increased in this group because first-generation antipsychotics have been associated with cardiac disease risks, and among those who died while taking the larger doses, 53 percent died of cardiovascular disease. "These drugs work very well, but there is clearly a point of diminishing returns," she says. "You rarely need to be on extremely high doses." Among those whose information was reviewed, the most common cause of death was cardiovascular disease (28 percent); unintended harm, including suicide, was responsible for 8 percent. "If people are taking their medications, they usually have fewer symptoms and are able to be more organized in other areas of their lives," says Cullen, director of community psychiatry at The Johns Hopkins Hospital. "We believe they are then more likely to make appointments with their primary care doctors, to stay on top of other illnesses they may have and to regularly take diabetes, blood pressure or cholesterol medication that they may require to stay healthy. We also believe that they are more likely to be socially engaged and have a healthier lifestyle." "If your illness is under control, you can do a lot more," she adds. Cullen says the study clearly lays out the value of mental health providers to individuals with schizophrenia. Those who saw therapists or psychiatrists were more likely to survive, regardless of whether the individual also took his or her antipsychotic medication on a regular basis, she says. This finding is crucial, she says, given that Maryland Medicaid officials are considering capping the number of mental health visits allowed each year, something the data now suggest is potentially detrimental to survival. Cullen notes that adherence to a medication regimen and moderate first-generation antipsychotic dosing are both part of the 2009 PORT recommendations designed to guide treatment. ### The study was supported by a grant from the National Institutes of Health's National Institute of Mental Health (R01MH074070). Other Johns Hopkins researchers involved in the study include Emma E. McGinty, M.S.; Yiyi Zhang, Ph.D.; Susan dos Reis, Ph.D.; Donald M. Steinwachs, Ph.D.; Eliseo Guallar, M.D., Dr.PH.; and Gail L. Daumit, M.D., M.H.S. For more information: http://www.hopkinsmedicine.org/psychiatry/specialty_areas/community_psych/

Researchers identify dozens of new de novo genetic mutations in schizophrenia

Many newly discovered genes most active during fetal development New York, NY (October 3, 2012) — Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease. The study, the largest and most comprehensive of its kind, was published today in the online edition of the journal Nature Genetics. Although schizophrenia typically onsets during adolescence and early adulthood, many of the mutations were found to affect genes with higher expression during early-to-mid fetal development. Together, the findings show that both the function of the mutated gene and when the gene is expressed are critically important in determining the risk for schizophrenia. The findings inform epidemiologic studies showing that environmental factors, such as malnutrition or infections during pregnancy, can contribute to the development of schizophrenia. "Our findings provide a mechanism that could explain how prenatal environmental insults during the first and second trimester of pregnancy increase one's risk for schizophrenia," said study leader Maria Karayiorgou, MD, professor of psychiatry at CUMC, and acting chief, division of Psychiatric and Medical Genetics, New York State Psychiatric Institute. "Patients with these mutations were much more likely to have had behavioral abnormalities, such as phobias and anxiety in childhood, as well as worse disease outcome." In an earlier study of 53 families, the team of investigators found that spontaneous, or de novo, mutations — genetic errors that are present in patients but not in their parents — play a role in a substantial portion of sporadic cases of schizophrenia. The mutations were found in the part of the genome that codes for proteins, known as the exome. In the larger, current study, the researchers performed whole-exome sequencing on 231 patient "trios" from the United States and South Africa. Each trio consisted of a patient and both of his or her parents, who were unaffected by the disease. By comparing the exomes of the patients with those of their parents, the researchers were able to identify de novo rather than heritable, mutations that may contribute to schizophrenia. This is the first study of this scale to search for single nucleotide variations in the exomes of schizophrenia patients. Previous studies from the Columbia group and others searched for much larger genetic variations, such as gene deletions or duplications. The researchers identified many mutated genes with diverse functions. They also identified four new genes (LAMA2, DPYD, TRRAP, and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance. The researchers estimate that several hundred loci (genetic locations) can contribute to the development of schizophrenia. "The chance that two patients have exactly the same mutation or combination of mutations is rather small" said Dr. Karayiorgou. "What is intriguing is that despite this variability, people with schizophrenia tend to have, more or less, the same phenotype—that is, the same clinical presentation. Our hypothesis is that many neural circuits are extremely important in schizophrenia and that these circuits are vulnerable to a number of influences. So, when any of the genes involved in these circuits are mutated, the end result is the same." According to the researchers, the challenge remains to identify the affected biological processes and neural circuits, and to determine how they are affected. "Although the genetics of schizophrenia are extremely complex, a coherent picture of the disease is beginning to emerge," said co-director of the study Dr. Joseph Gogos, MD, PhD, and associate professor of physiology and neuroscience at Columbia University Medical Center. "Our studies show that dozens, and perhaps hundreds, of different spontaneous mutations can raise one's risk for schizophrenia. On the surface, this is daunting, but using these new findings to understand how these mutations affect the same neural circuits, including during early fetal development, raises hopes that it may be possible to develop effective prevention and treatment strategies for the disease." Social Worker CEUs The paper is titled, "De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia." The other contributors are Bin Xu (CUMC), Iuliana Ionita-Laza (CUMC), J. Louw Roos (University of Pretoria, Pretoria, South Africa), Braden Boone (Hudson Alpha Institute for Biotechnology, Huntsville, Ala.), Scarlet Woodrick (CUMC), Yan Sun (CUMC) and Shawn Levy (Hudson Alpha Institute for Biotechnology). The research was partially supported by National Institute of Mental Health grants MH061399 and MH077235 and the Lieber Center for Schizophrenia Research at Columbia University. The authors declare no financial conflict of interest. About Schizophrenia Contrary to popular belief, schizophrenia is not a split personality; it is a chronic, severe, and disabling brain disorder that affects just over one percent of the adult population and is characterized by loss of contact with reality (psychosis), hallucinations (usually, hearing voices), firmly held false beliefs (delusions), abnormal thinking, a restricted range of emotions (flattened affect) or inappropriate and disorganized behavior, social withdrawal, and diminished motivation. The disease often strikes in the early adult years, and although many individuals experience some recovery, many others experience substantial and lifelong disability. People with schizophrenia often have problems functioning in society and in relationships and are over-represented on disability rolls and among the homeless and imprisoned. The precise causes of schizophrenia are not known, but current research suggests a combination of hereditary and environmental factors. Fundamentally, however, it is a biologic problem (involving changes in the brain), not one caused by poor parenting or a mentally unhealthy environment. Since the causes of schizophrenia are not clear, treatments focus on eliminating disease symptoms. Treatments include antipsychotic medications and various psychosocial treatments. ### Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States. www.cumc.columbia.edu Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the Nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University's College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders. http://columbiapsychiatry.org/

Simple tool may help evaluate risk for violence among patients with mental illness

Mental health professionals, who often are tasked with evaluating and managing the risk of violence by their patients, may benefit from a simple tool to more accurately make a risk assessment, according to a recent study conducted at the University of California, San Francisco. The research, led by psychiatrist Alan Teo, MD, when he was a UCSF medical resident, examined how accurate psychiatrists were at evaluating risk of violence by acutely ill patients admitted to psychiatric units. The first part of the study showed that inexperienced psychiatric residents performed no better than they would have by chance, whereas veteran psychiatrists were moderately successful in evaluating their patients' risk of violence. However, the second part of the study showed that when researchers applied the information from the "Historical, Clinical, Risk Management󈞀–Clinical" (HRC-20-C) scale – a brief, structured risk assessment tool – to the patients evaluated by residents, accuracy in identifying their potential for violence increased to a level nearly as high as the faculty psychiatrists', who had an average of 15 years more experience. "Similar to a checklist a pilot might use before takeoff, the HRC-20-C has just five items that any trained mental health professional can use to assess their patients," Teo said. "To improve the safety for staff and patients in high-risk settings, it is critical to teach budding psychiatrists and other mental health professionals how to use a practical tool such as this one." The study was published Aug. 31 in the journal Psychiatric Services. The HCR-20-C was developed several years ago by researchers in Canada, where it is used in a number of settings such as prisons and hospitals. However, in the United States, structured tools such as the HCR-20-C are only beginning to be used in hospitals. "This is the first study to compare the accuracy of risk assessments by senior psychiatrists to those completed by psychiatric residents," said senior author Dale McNiel, PhD, UCSF professor of clinical psychology. "It shows that clinicians with limited training and experience tend to be inaccurate in their risk assessments, and that structured methods such as HCR-20-C hold promise for improving training in risk assessment for violence." "The UCSF study was unusual," Teo added, "in applying a shorter version of the tool that could be more easily incorporated into clinical practice." Teo and his team assessed the doctors' accuracy by comparing the risk assessments that they made at the time patients were admitted to the hospital, to whether or not patients later became physically aggressive toward hospital staff members, such as by hitting, kicking or biting. The study included 151 patients who became violent and 150 patients who did not become violent mhc continuing education The patients in the study had severe mental illnesses, often schizophrenia, and had been involuntarily admitted to the hospital. ### The study was partly supported by the National Institute of Mental Health, a Minority Fellowship sponsored by the American Psychiatric Association and the Clinical and Translational Science Award from the National Institute of Health (NIH). When this study was conducted, all of the authors were affiliated with the UCSF Department of Psychiatry. Teo now is with the Department of Psychiatry, University of Michigan, Ann Arbor, and Sarah Holley, PhD, a co-author, now is with the Department of Psychology, San Francisco State University. Mark Leary, MD, of the UCSF Department of Psychiatry, also is a co-author. UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Researchers pursue red flag for schizophrenia relapse

AUGUSTA, Ga. – Blood levels of a protein that helps regulate inflammation may also serve as a red flag for relapse in some schizophrenia patients, researchers said. "There are no good, objective measures of treatment efficacy or indicators for relapse," said Dr. Brian Miller, a psychiatrist specializing in schizophrenia at the Medical College of Georgia at Georgia Health Sciences University. Researchers hope monitoring levels of interleukin-6 can fill that gap for a population in which more than half of patients don't take their medications as prescribed, often because of side effects. The relapse rate is about 80 percent within two years in patients who don't take their medication properly and about half that in those who do, according to the National Institute of Mental Health LSW Continuing Education "We hope the upshot of our studies will lead to new treatment approaches and strategies for care," Miller said, including the kind of personalized, multi-drug therapies that are becoming the standard for controlling other chronic conditions such as diabetes and hypertension. "We want to attack the disease from as many directions as possible." To get a better handle on how IL-6 levels correspond to disease status, they are looking at levels in blood samples taken multiple times over several years in 305 patients enrolled in a study comparing injectable to oral medication. They also are taking one-time measurements in 80 healthy controls and comparing those to levels in 240 patients who are acutely ill, stable outpatients or stable outpatients who smoke marijuana, a drug commonly abused by patients. While many previous studies have excluded drug abusers, marijuana may increase inflammation, so they want to explore the relationship between IL-6 levels and its use, Miller said. Miller received a five-year, $920,000 National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award to measure IL-6 levels as a potential indicator of how well treatment is working to control disease in these vulnerable patients and whether they are headed to relapse. Amazingly the contributions of "immune disturbances" to schizophrenia have been debated for about 100 years yet anti-inflammatory drugs aren't routinely given to patients in addition to their antipsychotic medication, Miller said. Part of the problem is physicians still have no idea what percentage of patients with this very heterogeneous disease have evidence of increased inflammation. In fact, no two patients have the exact constellation of symptoms considered disease hallmarks, such as hallucinations, delusions, disorganized speech and thinking, he said. But mounting evidence suggests inflammation's impact in schizophrenia. A British study of 50 patients experiencing their first episode of schizophrenic behavior found a handful had indicators of an immune response to their brains, called autoantibodies, and no other conditions, such as a brain infection, to explain them. What amounts to a chronic low-grade flu has been found in some patients and rare immune system disorders such as Sjögren's syndrome, which attacks moisture-producing glands resulting in dry eyes and mouth, also tend to be more common in schizophrenics. Additionally, a handful of clinical trials has shown – not surprisingly – that patients with the highest levels of pro-inflammatory factors had the best response to anti-inflammatory drugs. "It's likely we are talking about a subset of people with this illness who would be most likely to respond to anti-inflammatory therapy – in addition to standard anti-psychotics – so part of our work is to begin to piece out who those people are (and whether) they have a particular clinical picture," Miller said. "Even being able to predict relapse or improve therapy in 25 percent of patients would be a tremendous advance," he said, noting that the vast majority of schizophrenia drugs work essentially by the same mechanism. Once patients can be identified, ideally with a blood test of their IL-6 levels, the next questions are which drugs to use and for how long. Miller's primary mentor for the studies is Dr. Andrew Mellor, a molecular geneticist and immunologist who leads the Cancer Immunology, Inflammation Tolerance Program at the GHSU Cancer Center. Mellor also is Bradley-Turner & Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics. Co-secondary mentors are schizophrenia experts Dr. Peter F. Buckley, Dean of the Medical College of Georgia at GHSU, and Dr. Mark Rapaport, Chair of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. Schizophrenia affects about 1 percent of the population, or some 2.4 million American adults. Hallucinations are a disease hallmark: patients hear voices and can even see, touch and taste things that are not real. They can become depressed, reclusive and suicidal and have an increased risk of cardiovascular and other health conditions. Patients die on average15-20 years younger than the general population. Miller, a recipient of the 2011 National Alliance on Mental Illness Exemplary Psychiatrist Award, said he felt a calling to psychiatry and specifically schizophrenia as a medical student at The Ohio State University. "The patients are wonderful and their stories are fascinating," he said, noting that the field is "wide open" to improve their care. ###

Using biomarkers to identify and treat schizophrenia

Researchers say lab-based tests may be boon to both clinicians and researchers In the current online issue of PLoS ONE, researchers at the University of California, San Diego School of Medicine say they have identified a set of laboratory-based biomarkers that can be useful for understanding brain-based abnormalities in schizophrenia. The measurements, known as endophenotypes, could ultimately be a boon to clinicians who sometimes struggle to recognize and treat the complex and confounding mental disorder. "A major problem in psychiatry is that there are currently no laboratory tests that aid in diagnosis, guide treatment decisions or help predict treatment response or outcomes," said Gregory A. Light, PhD, associate professor of psychiatry and the study's first author. "Diagnoses are currently based on a clinician's ability to make inferences about patients' inner experiences." continuing education for counselors Diagnosing and treating schizophrenia is a particularly troubling challenge. The disorder, which affects about 1 percent of the U.S. population or roughly 3 million people, is characterized by a breakdown of normal thought processes and erratic, sometimes dangerous or harmful, behaviors. "Schizophrenia is among the most severe and disabling conditions across all categories of medicine," said Light, who also directs the Mental Illness, Research, Education and Clinical Center at the San Diego VA Healthcare System. The precise cause or causes of schizophrenia are not known, though there is a clear genetic component, with the disorder more common in some families. Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient's inner experiences. That is, their ability to describe what's happening inside their minds. "But even the best clinicians struggle with diagnostic complexities based on sometimes fuzzy clinical phenomenology," said Light. The clinical challenge is compounded by the fact that "many schizophrenia patients have cognitive and functional impairments," said Light. They may not be able to reasonably explain how or what they think. Light and colleagues investigated whether a select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable, accurate, long-term indicators of brain dysfunction, even when overt symptoms of the disorder were not apparent. These markers ranged from tests of attention and memory to physiological assessments of basic perceptual processes using scalp sensors to measure brain responses to simple sounds. The researchers measured the biomarkers in 550 schizophrenia patients, and then re-tested 200 of the patients one year later. They found that most of the markers were significantly abnormal in schizophrenia patients, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient. Light said further research is required, including whether the endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions or even be used to predict which subjects are at high risk of developing a psychotic illness. "We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia," Light said. ### Co-authors are Neal R. Swerdlow, Anthony J. Rissling and Marlena Pela, Department of Psychiatry, UCSD; Allen Radant, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; Catherine A. Sugar, Departments of Psychiatry and Biostatistics, UCLA; Joyce Sprock, Mark A. Geyer and David L. Braff, Mental Illness, Research, Education and Clinical Center, San Diego VA Healthcare System and Department of Psychiatry, UCSD. Funding for this research came, in part, from National Institute of Mental Health grants MH042228, MH079777 and MH065571 and the Department of Veterans Affairs.