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 Research & Giving News Article  by NARSAD-Funded Scientists Dozens of new studies were published by NARSAD scientists in peer-reviewed journals of psychiatry and neuroscience. These studies, in clinical and basic science, shed new light on the genetic and environmental contributions to psychiatric illnesses; unveiled the intricacies of brain structure and function; pointed to new molecular targets for pharmacological treatments; traced progress in the development of alternative, nonpharmacological approaches to treatment, such as brain stimulation techniques; and broke new ground in identifying biomarkers for various disorders that will make possible earlier diagnoses and more effective treatments. Highlighted below are just 10 of many noteworthy developments in NARSAD-supported research during 2008, with many more to come in 2009. (Click the headlines to learn more about each of these published studies.) SCHIZOPHRENIA Drug Candidate Effective in Targeting Cognitive Impairment in Schizophrenia University of Pittsburgh researchers led by NARSAD Scientific Council member and 2008 Distinguished Investigator David A. Lewis, M.D., have found an experimental agent with promise in addressing the working memory impairments seen in schizophrenia. Current drugs are often effective in treating symptoms of psychosis – delusions and hallucinations – but don’t address schizophrenia’s cognitive effects. One such effect is the impairment of working memory, which is critical because it’s needed to guide routine behavior. Dr. Lewis’ team followed up on the observation that a reduction of signaling by the neurotransmitter GABA in a part of the brain’s prefrontal cortex appeared to be linked with cognitive deficits. They were able to design a molecule whose action "turns up the volume" on GABA signaling and improved working memory in a small group of patients. Larger studies are planned to validate this promising drug candidate. SchizophreniaGene Database Homes in on 16 Genes With Credible Links to Disease Although schizophrenia’s genetic roots remain a scientific mystery, researchers are generating masses of new data with encouraging regularity. Every other day, a study is published linking genetic mutations with the illness. It’s hard for researchers to keep up, and even harder to know what to make of them. In 2008, a team led by NARSAD Investigator Lars Bertram, M.D., Ph.D., of Harvard Medical School and Massachusetts General Hospital, published a statistical assessment of 1,179 papers cumulatively reporting on 3,608 different gene variations with possible links to schizophrenia. These variations involved 516 different genes, which were winnowed by the team to only 118 variants appearing in 52 genes. “Meta-analysis” reduced this group to 24 variants residing in 16 genes showing risk effects that Bertram and colleagues deemed significant. After further reduction, four genes were judged to have the highest degree of “epidemiologic credibility” for relevance. These results will help researchers focus on the most promising gene candidates. Scientists Discover Role of Rare Gene Mutations in Schizophrenia NARSAD investigators and colleagues at several institutions identified multiple, individually rare gene mutations in people with schizophrenia. Many of the mutations affect early development of the brain and may help explain how schizophrenia is caused. Mary-Claire King, M.D., a NARSAD 2006 Distinguished Investigator at the University of Washington, and a member of her lab, Tom Walsh, Ph.D., a NARSAD 2007 Young Investigator, were among leaders of a team whose results were replicated by NARSAD Scientific Council member Judith Rapoport, M.D. at the National Institute of Mental Health. The scientists screened for novel deletions and duplications in the genome -- what are called gene copy-number variations, or CNVs. They found that deletions, disruptions and duplications of normal genes, most of them rare, were three to four times more frequent in people with schizophrenia than in healthy people. This suggests a previously unknown role for rare mutations in the causation of schizophrenia DEPRESSION AND BIPOLAR DISORDER FDA Approves Non-Invasive Treatment, TMS, for Treatment-Resistant Depression Patients suffering from treatment-resistant clinical depression now have access to a new, non-invasive method of treatment using a technique called Transcranial Magnetic Stimulation (TMS), developed by NARSAD investigator and Scientific Council member Mark S. George, M.D., director of the Brain Stimulation Laboratory at the Medical University of South Carolina. Approved on October 7 by the U.S. Food and Drug Administration (FDA), TMS involves the use of a magnetic source to stimulate the left prefrontal cortex, an area of the brain that previous imaging studies have shown to function abnormally in depression. TMS represents a new class of brain stimulation treatment. Patients don’t require anesthesia or sedation and remain awake and alert. It is administered in a 40-minute outpatient procedure prescribed by a psychiatrist and performed in a psychiatrist's office, with treatment typically administered daily for four to six weeks. In a randomized controlled trial for the FDA, TMS showed significant treatment effects without systemic side effects such as weight gain or sexual dysfunction. New Knowledge About How the Brain Processes Antidepressants Could Lead to Better Therapies A research team led by Jonathan Javitch, M.D., Ph.D., of Columbia University, a 2003 NARSAD Independent Investigator and a member of NARSAD’s Scientific Council, has described with unprecedented specificity how brain cells process antidepressant drugs, cocaine and amphetamines. The findings may prove useful in the development of more targeted medication therapies for a host of psychiatric diseases, most notably in the area of addiction. The Javitch team studied the neurotransmitter sodium symporter (NSS) molecule in several different activity states. They then observed how other molecules, such as drug molecules, affected the function of the NSSs, particularly their transition between different states. They found that two “docking ports” on the transporter molecule need to be filled simultaneously and cooperate in order for a nerve signal to be driven across the cell membrane. A potential application that would interfere with cocaine binding would represent an entirely new direction in addiction therapy. Toward a Blood Test for Mood Disorders A team led by Alexander B. Niculescu III, M.D., Ph.D., of Indiana University School of Medicine and a 2002 and 2005 NARSAD Young Investigator, reported that it has demonstrated how biomarkers in the blood might be able to measure the presence or absence, and even the intensity, of mood disorders, including bipolar disorder. This advance, while preliminary, was encouraging for those who eagerly await the development of reliable tests for rapid, positive diagnosis of mental illness. Such tests, if perfected, would be a boon to patients, permitting early diagnosis, and a powerful means of overcoming stigma. The biomarkers found by Dr. Niculescu are present in differing amounts in individuals suffering from high or low mood states. The blood concentration of the markers is postulated to vary depending on the severity of the depression or mania that an individual experiences. Although much research must be performed before such relationships can be quantified and validated, the results reported indicate a path forward for this important work. ANXIETY DISORDERS “Dry Cleaning Effect” Offers Insight on How to Modify Repetitive Behaviors Tasks performed over and over again are very hard to modify. For instance, once you get in your car and begin driving to work, you may well forget to interrupt the journey to make an important drop-off at the dry cleaners. This so-called “dry-cleaning effect,” according to Christopher J. Pittenger, M.D., a NARSAD Young Investigator, and Yale University colleagues including Ronald S. Duman, a member of NARSAD’s Scientific Council, provides an interesting bit of insight into how substance abusers and people with obsessive compulsive disorder might be taught to modify their behavior. The key is a tension between two brain areas: one, the striatum, implicated in routine tasks, and the other, the hippocampus, which is involved in a more flexible system called spatial learning. According to Dr. Pittenger, in cognitive-behavioral therapy, when we teach patients to recognize their destructive habits, to take a step back, and to learn to do things differently, what we're really asking them to do is to use one of these systems to overcome and, ultimately, re-train the other. High-Dose Corticosterone May Reduce PTSD Effects What is the best way of helping soldiers adjust to the stresses of war? One has to think both short-term and long-term, to help them adjust to combat, but also to help them return from combat to resume civilian life. Animal models of stress-related illness such as post-traumatic stress disorder (PTSD) are providing new knowledge about the brain that could help address the problem of flexible adjustments, such as those that would reach from the battlefield to the breakfast table. Hagit Cohen, Ph.D., of Ben-Gurion University in Israel, a NARSAD 2003 Young Investigator and 2006 Independent Investigator, has found in animal models of PTSD that high doses of corticosterone prevented the negative consequences of stress exposure, including increased “startle response” and “behavioral freezing,” when animals were exposed to reminders of stress. Low-dose corticosterone increased potential for these responses. The finding suggests corticosterone levels may influence both vulnerability and resilience in a dose-dependent manner through its involvement in memory processes. CHILDHOOD DISORDERS Gene Variation May Explain Key Mechanism of ADHD The change of a single “letter” in the 3-billion-letter human genome may help explain a key mechanism involved in attention-deficit hyperactivity disorder (ADHD) and how people with this and possibly other neuropsychiatric disorders respond to certain medications. Randy Blakely, Ph.D., a NARSAD Distinguished Investigator and Scientific Council member, and colleagues at Vanderbilt University studied a defect in a gene on human chromosome 5 that instructs certain cells to generate so-called dopamine transporter molecules. The gene variant, found in brothers with ADHD, produced transporters that appeared to “run backward.” They pushed dopamine into the space between neurons -- like normal transporters do when amphetamine is present -- altering dopamine signaling and contributing, the team hypothesizes, to the symptoms of ADHD. Overactive Transporters of Serotonin Are Linked to Autism Many children with autism have elevated blood levels of serotonin, a neurotransmitter that plays a central role in brain processes regulating mood and anxiety. New research led by a NARSAD investigator suggests that this condition, called “hyperserotonemia,” may play a role in the origins of certain autism-associated deficits. Ana Carneiro, Ph.D., a 2007 NARSAD Young Investigator, and colleagues at Vanderbilt University Medical Center, reported that protein in blood platelets called integrin beta3 physically associates with and regulates a protein called the serotonin transporter, or SERT, which controls serotonin availability. They found that cells lacking integrin beta3 took up less serotonin and that integrin beta3 activation or a human integrin beta3 mutation greatly enhances serotonin uptake. Dr. Carneiro is now hot on the trail of integrin interactions with brain SERT and is engaged in engineering mice that express human integrin beta3 mutations. |
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