Schizophrenia is a serious mental illness that generally affects people in early adulthood and is one of the leading causes of disability worldwide, often resulting in premature death. Individuals experience psychosis, or altered perceptions of reality, which interferes with their abilities to take part in everyday activities. Approximately one million children and adolescents in the United States display forms of thinking and social functioning that can be indicative of the eventual onset of psychosis, but the underlying cause of psychosis is still not well understood.
Martha Shenton, PhD, of the Department of Psychiatry and Department of Radiology, is co-leading one of three major research projects on psychosis as part of the National Institutes of Health’s new schizophrenia initiative for its Accelerating Medicine Partnership (AMP), a partnership with the U.S. Food and Drug Administration, biotechnology companies, pharmaceutical companies, and non-profit organizations. Shenton is serving as principal investigator with co-leader Rene Kahn, MD, of Mount Sinai Hospital in New York. Ongoing AMP projects are focused on improving the productivity of therapeutic development for Parkinson’s disease, Alzheimer’s disease, type 2 diabetes, and the autoimmune disorders rheumatoid arthritis and systemic lupus erythematosus. The schizophrenia AMP marks the first AMP initiative focused on a neuropsychiatric disorder. Its aim is to improve identification of psychosis risk-states to help researchers develop targeted therapeutic interventions more quickly and ultimately produce preventions and cure.
Shenton spoke with CRN about her decades-long involvement with neuropsychiatric research, developments in the field, and her part in the new AMP schizophrenia initiative.
What has been the major focus of your research over the years?
MS: Years ago, people thought that schizophrenia was the result of how a child was raised. Today, we have a better understanding of the importance of biological vulnerability. A broad goal of my research and that of research done by members of our laboratory has been to develop tools to help us characterize areas of the brain that are affected in neuropsychiatric disorders like schizophrenia.
In the early 1990s we studied individuals who were experiencing their first psychosis. We found that the first 18 months following a first episode of psychosis was really important as the brain showed changes over this very short period of time. Others in the field reported similar findings and there was interest in studying the period just prior to illness, or psychosis onset, called the prodromal period. This is a period of time when those who are at clinical high risk for developing psychosis have not yet been diagnosed with a disease. We thought that if we could intervene early, maybe we could prevent people from becoming psychotic.
Your lab is particularly well-known for its work in neuroimaging. Can you speak further about its role in your study of psychosis?
MS: When I was a graduate student, I’d been looking at clinical features of schizophrenia, such as how individuals’ language was different. They often experienced delusions, and their perceptions were also altered, with some hearing voices. An interesting finding was that those with a diagnosis of schizophrenia experience difficulties in smoothly tracking an object with their eyes. Here, I was struck by how something so subtle, a far less noticeable behavior than hearing unusual ideas expressed or hearing voices, might be more important in understanding the possible etiology of this disorder. I was really surprised and wanted to know more about brain and behavior associations. What was the connection? As I became more knowledgeable about the brain and behavior, I also realized how important it was to work with computer scientists to develop tools that could help us probe the brain using imaging techniques that would provide a more fine-grained analysis.
Back in the 1980s, you could look at a one-centimeter slice of the brain. Today, you’re able to examine millimeter slices, and the resolution has improved dramatically. Now we understand it’s not just an isolated area of the brain that’s affected in neuropsychiatric disorders; that isolated area is connected to networks in the brain. Neuroimaging can help to reveal these connections.
How does the new AMP study of clinical high-risk participants expand on the research you’ve done?
MS: I think this is really an exciting and important opportunity because the focus is not on a small sample of people. There will instead be clinical sites around the world where those who are at clinical high risk for psychosis will be studied and experts across institutions will come together to assess a wide range of clinical symptoms, as well as measures of cognition, psychophysiology measures such as EEG, neuroimaging measures, and potential blood and fluid biomarkers that will be standardized within and across sites. This large effort, which includes scientists, pharmaceutical companies, non-profit organizations, and biotech firms, is directed towards compressing the time between developing treatments and applying them. Today this time is too long and often hampered by the inability to identify subgroups of patients that are more homogeneous and where new treatments will likely be more efficacious than in more heterogeneous groups. Thus the goal of the new AMP is to identify and validate subtypes of individuals by studying a range of variables to develop more homogeneous groupings of those at clinical high risk for psychosis in order to more quickly bring new and targeted to groups that are better characterized.
What do you hope to learn from the data?
MS: Out of all clinical high-risk individuals, not all will experience psychosis. In fact, more individuals who are at risk for psychosis do not develop psychosis. What happens with this latter group? Do these individuals have mood and anxiety disorders? How can we characterize them? The idea of having a large sample where one can investigate subgroups that are similar can help us to answer some of these questions. This project, the AMP project, gives us a lot more statistical power to be able to really look at subgroups which are more likely to respond to different targeted treatments.
What will the Brigham’s role be in such a large endeavor?
MS: Our role in this is to be the coordinating center. All of the data acquired at the sites will come to the coordinating center at the Brigham and Women’s Hospital and we will monitor the data, perform quality control and analyses, and provide feedback. It’s like having a dashboard of all the variables for each of the sites. We’re also working with IBM on developing algorithms to help us better delineate subgroups of individuals who may respond differently to different treatments. IBM is very well known for their work with machine learning and we can use that to stratify groups into distinct categories.
What advantages does your lab have in tackling a project like this?
MS: Our lab is very international and very interdisciplinary. We have psychiatrists, computer scientists, psychologists, radiologists, and physicists. It’s a wide group of people and being able to talk to people who are doing something different than you matches up well with a project like this.