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 Research & Giving News Article  Featuring research about schizophrenia and developmental brain disorders NARSAD Scientific Council member Francine M. Benes, M.D., Ph.D., served as symposium moderator. She is professor of psychiatry and an affiliate of the Program in Neuroscience at Harvard Medical School, director of the Program in Structural and Molecular Neuroscience at McLean Hospital, and director of the Harvard Brain Tissue Resource Center. Her studies of schizophrenia and bipolar disorder have earned her such honors as election to the National Academy of Science’s Institute of Medicine and the 2002 NARSAD Lieber Prize for Outstanding Achievement in Schizophrenia Research. In opening the program, she noted that all of the day’s presenters have been recipients of NARSAD support. Dr. Jonathan Picker - Development Events of Schizophrenia The first speaker, Jonathan Picker, M.D., Ph.D., won a NARSAD Young Investigator Award in 2004 and the first Sidney R. Baer, Jr. Prize, presented that same year. He is an attending physician in clinical genetics at Children’s Hospital, Boston, where he directs the Fragile X Center. Fragile X syndrome, the most common inherited cause of mental impairment, has been associated with developmental illnesses such as autism and schizophrenia. His current research focuses on developmental events in schizophrenia. As he explained, although full-blown symptoms of schizophrenia usually do not occur until adolescence or early adulthood, brain abnormalities presaging the disorder can appear as early as the fifth month of fetal development. While many genes have been implicated in schizophrenia, studies indicate that it does not result from gene defects alone, but from the interplay of predisposing genes and environmental factors. Dr. Picker is examining the role of maternal malnutrition during pregnancy as a risk factor; specifically, maternal folate deficiency. Folate, a B vitamin found in leafy vegetables and other foods, is essential to many biological functions, but under conditions such as war, famine or low socioeconomic status, or even winter pregnancies, folate-rich foods may be scarce or unavailable. In the brain, Dr. Picker said, folate is essential to the interaction of the amino acid homocysteine with the NMDA receptor, an important regulator of brain development. If there is a deficiency of folate, homocysteine can rise to abnormal, potentially dangerous levels. Among the effects Dr. Picker and his colleagues have noted, low folate in the presence of a gene called 677T produces an increase in fetal brain defects. 677T is a variant form of a gene that codes for the enzyme MTHFR, the function of which is to get rid of homocysteine. Homocystinuria is a rare disease caused by extremely high homocysteine levels. To further establish a connection between high homocysteine levels and schizophrenia, Dr. Picker has been reviewing records of homocystinuria patients treated at Children’s Hospital. Of 16 such patients, three who had the 677T gene also had schizophrenia. Dr. Picker found it particularly interesting that when those patients were treated for homocystinuria by decreasing their homocysteine level, their schizophrenia symptoms improved. Other studies have confirmed higher than average homocysteine levels in the presence of the 677T variant gene in people with schizophrenia. To test whether maternal plasma homocysteine may be a risk factor for schizophrenia, Dr. Picker is conducting a variety of human and animal studies. In one, homocysteine levels in pregnant mice were increased by adding homocysteine to their drinking water. Dr. Picker found that the offspring of those mice, compared with offspring of untreated mothers, showed higher than average levels of anxiety, which in humans is associated with schizophrenia, and they were somewhat less competent in activities requiring volition, motor function and learning. Dr. Picker also reported that a recent human study revealed higher than average homocysteine levels in stored plasma samples of mothers whose children went on to develop schizophrenia. Dr. Picker was drawn to this line of research in part, he said, by studies that showed maternal folate deficiency to be a causal factor in spina bifida. In recent years, folate treatment in early pregnancy has significantly reduced the incidence of neural tube defects, which lead to spina bifida. It is his hope that his research will help to identify comparable risk factors for schizophrenia which, if treated early, might help to forestall the development of the disease. Dr. Maurizio Fava - The STAR*D Study The second speaker, Maurizio Fava, M.D., a 1994 NARSAD Young Investigator, is professor of psychiatry at Harvard Medical School and director of the Depression Clinical and Research Program at Massachusetts General Hospital, where he is also associate chief of psychiatry for clinical research and a founding member of the Mood and Anxiety Disorders Institute. In his talk, he reviewed findings that have been emerging from the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, of which he is a co-principal investigator. Begun in 1999, STAR*D is the largest study of depression treatment ever conducted, involving 14 regional centers and a total of 41 clinical sites. Dr. Fava described the 2,876 participants as a real-world representation of depression patients in terms of sex, ethnicity, mean age, age of onset of illness, rate of recurrence and associated conditions, such as anxiety, hypertension and diabetes. In the first phase of the study, all the patients were given citalopram (Celexa), a selective serotonin reuptake inhibitor (SSRI). After 10 weeks of treatment, Dr. Fava stated, only 32 percent had achieved remission; the rest continued to show symptoms of depression ranging from mild to severe. In the second phase of the study, the nonresponders were either continued on citalopram for a longer period or switched to a different treatment. The STAR*D study was innovative, Dr. Fava said, in that patients and clinicians together participated in the treatment decision. The patients who chose to switch medication received either another SSRI, sertraline (Zoloft); a non-SSRI, bupropion (Wellbutrin); or a serotonin norepinephrine reuptake inhibitor, venlafaxine (Effexor). (Serotonin and norepinephrine are both neurotransmitters, chemical messengers in the brain.) Of the patients who participated in the second trial round, Dr. Fava reported that 26 percent experienced remission and that it occurred irrespective of which antidepressant they had taken. Overall success rates thus rose to above 50 percent. These results, recently published in The New England Journal of Medicine, represent the first systematic test of the degree of efficacy of antidepressant medications, Dr. Fava said, and he stressed that they underscore the value for patients of not giving up if treatments do not work initially. Further STAR*D trials are underway with other antidepressants for participants who did not achieve remission in either the first or second phase of the study. Dr. Fava reported that the STAR*D study also provided new insight into predictors of remission. Among patients less likely to remit, he said, were those with lower incomes or the unemployed, those with multiple medical conditions and those who had been lower functioning before treatment. In general, women did better than men, as did people with more education. As with Dr. Picker’s studies of schizophrenia, low folate level appeared to be a negative factor, a lead Dr. Fava said should be followed up. The biggest predictor, he stated, was ethnicity: African-American participants showed significantly lower rates of remission. Among ancillary STAR*D studies that Dr. Fava cited, one is examining the effects of maternal depression on children and another is seeking genetic predictors of response to antidepressant treatments. Dr. Gina Kuperberg - Brain Imaging of Schizophrenia Gina R. Kuperberg, M.D., Ph.D., who addressed the symposium next, is conducting imaging studies of thought processes in schizophrenia. Twice a NARSAD Young Investigator Award winner, in 2001 and 2003, she is an associate professor of psychology at Tufts University and a psychiatrist at Massachusetts General Hospital, where she works at the Martinos Center for Biomedical Imaging. Using remarkable new tools to peer inside the living brain, she is establishing links between abnormalities in brain structure and the clinical and cognitive symptoms of schizophrenia. Magnetic resonance imaging (MRI) is one of the most powerful technologies for observing and measuring changes in brain structure and function. With structural MRI, Dr. Kuperberg is measuring the gray matter, the tissue on the surface of the brain that includes the cerebral cortex, the site of higher thought processes, including human language. In actuality, the gray matter is tightly folded. Using computer algorithms to “unfold” it into a two-dimensional ribbon, Dr. Kuperberg and her colleagues have been comparing cortical thickness in schizophrenia patients and healthy controls. While the differences they found were subtle, measured in millimeters, Dr. Kuperberg said that schizophrenia patients showed thinning of the cortex in widespread areas in the brain. Other experiments are revealing correlations between structure and function in which inappropriate increases in brain activity appear to occur in brain regions in schizophrenia patients that show cortical thinning. A major clinical symptom of schizophrenia is the loosening of associations. As an example of semantic associations, Dr. Kuperberg explained that people normally recognize the word “stripes” more quickly after seeing the word “tiger” -- tigers have stripes -- than after seeing an unrelated word like “table.” In experiments using functional MRI (fMRI), in which increases in blood flow in a particular brain area indicate brain activity, Dr. Kuperberg and her team found that schizophrenia patients, as opposed to healthy controls, showed less activity in brain areas known to be involved in semantic memory and processing in reaction to semantically related words than they did to unrelated words, results that correlate with clinically observed behavior. The researchers next looked at sentence processing. They constructed sentences in which the words were related (breakfast, eggs, eat), but in some sentences were put together nonsensically (“At breakfast the eggs would eat.”) as opposed to other sentences that were logical (“At breakfast the boys would eat.”). Because fMRI is too slow to measure an activity this complex in real time, Dr. Kuperberg said, she turned to a technique called event-related potentials, which identifies abnormalities in electrophysiological response within milliseconds. She found that in schizophrenia patients semantic associations between individual words overrode sentence context. Experiments were then taken a step further to look at whole concepts, the relationships between ideas expressed in little stories. Dr. Kuperberg found that when the stories did not make sense, that is, when concepts within the stories did not relate, the brains of normal controls showed lessened activity, indicating, in effect, that they had recognized the disconnect and given up trying to make sense of the story. By contrast, Dr. Kuperberg said, the brains of the schizophrenia patients showed heightened activity, as if they were trying, inappropriately, to make sense of nonsense. The cerebral cortex connects to structures within the limbic system, the emotion center of the brain. When narratives have an emotional context, Dr. Kuperberg explained, negative scenarios will normally evince more activity than neutral ones. In experiments designed to better understand delusional thinking in schizophrenia, it was found that schizophrenia patients reacted more forcefully than controls to neutral or ambiguous scenarios. Dr. Kuperberg then reported on the work of a colleague who is trying to look beyond language, using short films in which the actions are incongruous or illogical; for example, a man shaving with a rolling pin. Here, too, Dr. Kuperberg said, schizophrenia patients attempt to process events that normal controls understand as unreal. Dr. Christopher Walsh - The Cerebral Cortex and Developmental Brain Disorders Dr. Benes described the work of the final speaker, Christopher A. Walsh, M.D., Ph.D., as an appropriate follow-up to Dr. Kuperberg’s: he is mapping the genes involved in the development of the cerebral cortex to try to understand the disruptions that underlie developmental brain disorders. Dr. Walsh is chief of the division of genetics at Children’s Hospital, Boston, chief of neurogenetics in the department of neurology at the Howard Hughes Medical Institute/Beth Israel Deaconess Medical Center, Bullard Professor of Neurology at Harvard Medical School, and director of its combined M.D.-Ph.D. program. His work has garnered widespread recognition, including a NARSAD Independent Investigator Award in 1998. Dr. Walsh began by stressing that disorders related to malfunction of the cerebral cortex, such as mental retardation, learning disorders, epilepsy, autism and schizophrenia, are all more or less genetically based and extremely complex. To get a handle on the problem, he and his colleagues started by studying simpler abnormalities of the cortex related to size or gray-matter folding, working mostly with patients in the Middle East, where populations tend to be more isolated, marriage between relatives is common and families large, thus providing a large and relatively homogeneous genetic pool. Through this research, Dr. Walsh stated, his team has identified many previously unknown syndromes and defined a number of them genetically. The findings from this research eventually led Dr. Walsh to contemplate the more complex challenge of autism. While twin studies and other evidence point to autism as a highly genetic disorder, Dr. Walsh explained that it has been very difficult to correlate its clinical symptoms with specific genes. Many genes are thought to be involved and different families with autistic members tend to show different genetic profiles. There are known chromosomal defects associated with the disorder, and probably complex multigenic interactions, none of which, he said, has been defined. Dr. Walsh’s laboratory recently joined forces with other groups from the major research institutions in the Boston area to form a consortium of some 80 researchers who are putting together a comprehensive “road plan” for attacking the problem of autism. They are working out standards for clinical and genetic diagnoses and a multifaceted approach to finding autism-associated genes. Dr. Walsh described one pilot study that is looking at missing or repeated pieces of the genome, the genetic package, in children with autism. The findings from such studies can help in assessing a family’s risk of having other autistic children and provide better diagnoses to guide treatments. Interestingly, in one of the children tested, the piece of missing DNA, containing a large number of genes, turned out to be one of the commonly missing DNA pieces in patients with schizophrenia. Through a multipronged approach involving both human and animal studies, the consortium is seeking to answer such questions as whether autism is genetically heterogeneous -- a bunch of different diseases -- or if there are common alleles (alternate forms of a gene) that can be traced to common loci (sites) on the genome. As in their earlier studies, Dr. Walsh’s group is focusing on families in the Middle East where there are many affected children, looking for genetic linkages and sequencing genes in search of specific mutations. Dr. Walsh closed his talk with a question now under consideration about whether the approach he and his colleagues are using to define autism might work for related illnesses like schizophrenia. Currently, he is looking for families that might help him answer this question. Meanwhile, he said, his laboratory has started a project to see if some of the genes the laboratory has discovered to be necessary for development of the cerebral cortex might play a role in schizophrenia. |
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