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 Research & Giving News Article  Featuring a range of topics in mental illness research Below are edited summaries of talks by Amelia Gallitano-Mendel, M.D., Ph.D., on the interplay of genes and environment in the development of schizophrenia; John W. Newcomer, M.D., on the high incidence of diabetes and cardiovascular disease in people with severe mental illnesses; Joan L. Luby, M.D., on depression in young children; and Yvette I. Sheline, M.D., on new findings on depression and brain circuitry through neuroimaging studies. NARSAD President Constance E. Lieber opened the program by describing NARSAD’S mission and that of the Sidney Baer, Jr. Foundation, which channels support for mental health research through NARSAD and is named for its founder, a prominent St. Louis businessman who suffered from schizophrenia. Mrs. Lieber also paid tribute to Washington University’s pioneering research; in particular, the work of Drs. Eli Robins and Samuel B. Guze, early NARSAD Scientific Council members, who developed the Washington University diagnostic criteria, which led to the modern classification system for psychiatric diseases. Herbert Y. Meltzer, M.D., served as symposium moderator. A leader in the pharmacologic treatment of mental disorders, Dr. Meltzer is Bixler/May/Johnson Professor of Psychiatry, professor of pharmacology, and director of the Psychobiology Program for Translational Research at the Vanderbilt University School of Medicine. In the 1990s, he collaborated in the development of the antipsychotic drug clozapine. He chairs the NARSAD Scientific Council committee that each year selects NARSAD Young Investigators. In presenting the first speaker, Dr. Amelia Gallitano-Mendel, who this year received her second Young Investigator Award, Dr. Meltzer cited her gene studies as making important connections between basic research and clinical applications. As part of her research at Washington University, where she is an instructor in psychiatry, she is elucidating the mode action of clozapine. Dr. Gallitano-Mendel - The Interplay of Genes and Environment in the Development of Schizophrenia Dr. Gallitano-Mendel began by stating that the last five years have seen significant advances in the understanding of the role of genes in psychiatric illnesses. She explained that their role has been difficult to decipher because, as twin studies and other evidence suggest, these illnesses are not due solely to genetic mutations. In the case of schizophrenia, while many genes appear to be involved, none has yet been shown to play a definitive role. Nor has the contribution of nongenetic factors been explained. To examine the interplay between environmental factors such as stress and changes in gene expression in the brain, Dr. Gallitano-Mendel has been looking at a group of genes called the immediate early gene family (IEGs), so named because they become activated in brain cells within minutes following a stressful stimulus. Dr. Gallitano-Mendel reported that she and her colleagues, working with genetically altered mice, have found that mice engineered to be deficient in one of the IEGs, Egr3, are abnormally sensitive to stress. They react with greater than normal aggressive behavior toward their cage mates, fail to become habituated to a repeated stressor as normal animals do, and release abnormal amounts of stress hormone. Stressful events stimulate cells in the hippocampus, the brain region where memories form, which requires the participation of IEGs. The Egr3-deficient mice displayed abnormalities in brain pathways related to memory formation. To determine whether these findings have relevance for human disease, Dr. Gallitano-Mendel treated Egr3-deficient mice with clozapine. Their response was similar to that of patients with schizophrenia: the drug normalized their behavior, apparently reversing the effects of Egr3 deficiency. As apparently corroborating evidence of the involvement of Egr3 in schizophrenia, Dr. Gallitano-Mendel reported that recent research in another laboratory using brains of patients with schizophrenia who were examined postmortem showed much lower than normal levels of Egr3 expression. As her studies continue, Dr. Gallitano-Mendel hopes to be able to pinpoint new, more precise targets for antipsychotic treatment within the brain pathways of schizophrenia patients. Dr. John Newcomer - Mental Disorders, Metabolic Disturbances, and Cardiovascular Risk Dr. John Newcomer, the second speaker at the symposium, is a professor of psychiatry and medical director of the Center for Clinical Studies at the Washington University School of Medicine. He has received from NARSAD two Young Investigator Awards, an Independent Investigator Award, and the 2002 Klerman Award for Outstanding Clinical Research. The focus of his research, he explained, is to learn why people taking antipsychotic medications face greater than normal risks for obesity, unhealthy lipid levels, insulin resistance, and cardiovascular diseases; he cited a recent NIH-sponsored study that found the risk to be nearly twice normal for people with schizophrenia. There also is growing evidence that diabetes occurs at twice the average rate both for people with schizophrenia and for those with mood disorders. A key question Dr. Newcomer is addressing is whether this phenomenon is a side effect of medication or whether something intrinsic to the illness causes a metabolic disturbance. As Dr. Newcomer explained, the greatest risk factor for cardiovascular illness is excessive abdominal fat, which can lead to disturbances in glucose and lipid metabolism and insulin resistance. Some antipsychotic drugs raise weight levels. In studies tracking patients who are taking various antipsychotics, Dr. Newcomer ascertained that the weight changes were in fat mass and not muscle mass. However, in a comparable study of dogs administered different antipsychotics, all the dogs gained equal amounts of weight, but they did not all gain equal amounts of fat. Follow-up studies by Dr. Newcomer and others uncovered evidence that some antipsychotic drugs have a mechanism that causes problems of insulin resistance unrelated to changes in fat levels. For example, Dr. Newcomer found that rats injected with antipsychotic drugs showed reduced insulin sensitivity before showing any changes in fat. He is now trying to replicate these results in a human study. Different antipsychotics appear to differ in the risk they present of contributing to diabetes or dyslipidemia, Dr. Newcomer stated. Research to date indicates that clozapine and olanzapine present the greatest risk; results are mixed for risperidone and quetiapine; and there is no evidence of risk for aripiprazole or ziprasidone. The positive message, Dr. Newcomer said, is that even a small decrease in any risk factor can lead to significant decreases in coronary heart disease and stroke. The negative message is that people with mental disorders often do not get the level of medical care afforded the general population. He expressed hope that better understanding of the risk factors associated with antipsychotic drugs, and clearer understanding of the underlying mechanisms, will lead to greater vigilance by and collaboration between psychiatrists and primary care physicians who treat patients with mental disorders. Dr. Joan Luby - Depression in Young Children: Early Interventions and Long-Term Outcomes Dr. Meltzer characterized Dr. Joan Luby, the next speaker, as reflecting the Washington University tradition of identifying and describing psychiatric syndromes. An associate professor of child psychology and the founder and director of the university’s Early Emotional Development program, Dr. Luby has won NARSAD’s Young Investigator Award, Independent Investigator Award, and 2004 Klerman Award for Outstanding Clinical Research. Her goal, she explained, is to establish criteria for diagnosing and evaluating mood disorders in children and to explore whether early intervention can alter the trajectory of disease. When Dr. Luby began her research, her first hurdle, she said, was the widespread skepticism toward the idea that mental disorders could exist in very young children. Through studies begun in 1998 and recently completed, she reported that she and her colleagues have established the validity of a diagnosis of major depressive disorder in children as young as 3, who displayed symptoms comparable to those described in adults with depression. Sadness is the core symptom of depression, and 98 percent of the preschoolers Dr. Luby diagnosed as depressed reported sadness. They displayed other symptoms of depression such as sleep and appetite disturbances. The most severely affected exhibited anhedonia, the inability to experience pleasure typical of the most severely depressed adults, along with psychomotor retardation, weight loss, and inappropriate feelings of guilt. Looking for biological markers of depression, Dr. Luby found that stress-hormone levels rose significantly higher in depressed children in response to emotional stimuli than in normal controls or in children with behavioral problems such as ADHD (attention deficit hyperactivity disorder) and ODD (oppositional defiant disorder). This suggested to her that physiological changes in the brain were already occurring. Also, the children diagnosed as depressed came from families with a higher than average history of affective disorders. Dr. Luby is currently conducting larger, more comprehensive studies of mood disorders in children between the ages of 3 and 15, including a large-scale study of depression and a large-scale treatment study of mania. She also is developing means to identify bipolar disorder in children as young as 3. Based on evidence from a significant body of research on other mental disorders, Dr. Luby believes that early identification of illness and intervention during a period of rapid development and neurobiological change may offer a window of opportunity for more effective management of depression. She believes that the diagnostic criteria she is defining will give clinicians the tools to identify depression in young children, and she expressed the hope that early intervention might lessen deviations in development and ameliorate the course and severity of illness through a patient’s lifespan. Dr. Yvette Sheline - New Discoveries in Depression and Brain Circuitry The final speaker, Dr. Yvette Sheline, works in what Dr. Meltzer described as one of the fastest-growing areas of brain research: neuroimaging. He explained that recent advances in technology have given scientists unprecedented ability to observe brain activity noninvasively. Dr. Sheline is professor of psychiatry, radiology and neurology at Washington University and director of the Center for Depression and Neuroimaging. She has been the recipient of a NARSAD Young Investigator Award and two Independent Investigator Awards. The method she uses is called functional magnetic resonance imaging (fMRI), with which she is examining activity and changes in the brain that occur in major depression. The amygdala is part of the limbic system, the primitive brain region that reacts immediately to stress and fear. In earlier research, Dr. Sheline observed that the amygdala became far more activated in fearful or stressful situations in people with depression than it does in normal subjects. Antidepressants normalize amygdala response, but the mechanism is unclear. She then looked at the interplay between the amygdala and the frontal cortex, the part of the brain that in higher animals controls complex cognitive functions. She found that in people with depression the area of the frontal cortex that normally acts to control the limbic system did not do its job appropriately. Other imaging studies, she said, have shown that in depression the amygdala metabolizes at a higher than normal rate and the frontal regions at a lower than normal rate. While considerable research has continued on reactions in depression to negative stimuli, Dr. Sheline said that less attention has been given to the other side of the syndrome; namely, the lack of reaction to positive or pleasurable stimuli. She and her team have set up a trial to explore what happens in the reward area of the brain. In her trial, participants who succeed in a task win money. Dr. Sheline saw that when normal controls succeeded, the ventral striatum, the reward area, reacted strongly. But what was newly observed in the brains of depressed subjects was a weak reaction irrespective of whether they anticipated winning or losing. These results have led Dr. Sheline to the next question: do the same patients react to both negative and positive stimuli, or are there subsets of patients who have more difficulty with stress and others with reward? If so, does that suggest that they should be treated with different classes of antidepressants? Currently, she and her colleagues are gathering data from brain scans to see if antidepressant treatment reverses the lack of reward reaction in depression. |
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