Schizophrenia Research Forum - A Catalyst for Creative Thinking

Keystone 2009—Insel Describes Challenges, Opportunities in Keynote Address

10 March 2009. From March 6 through 9, several hundred researchers climbed to the rarified air of Keystone, Colorado, for the meeting on “The Molecular Basis of Schizophrenia and Bipolar Disorder,” organized by Pamela Sklar of Harvard Medical School, David Porteous of University of Edinburgh, and Christopher Ross of Johns Hopkins University. Over the coming weeks, we will provide you with reports on some of the sessions and posters.

At the keynote session on Friday night, Sklar and Ross called the meeting to order and introduced keynote speaker Tom Insel, director of the U.S. National Institute of Mental Health, who spoke on “The Molecular Basis of Schizophrenia and Bipolar Disorder: What Do We Know? What Do We Need?”

Before turning to science, Insel had the pleasant task of announcing that as part of the stimulus bill that the U.S. Government hopes will stave off economic disaster, he and his fellow institute directors will be pumping more than $7 billion into research, a large increase for a budget currently at about $30 billion. The tricky part will be to spend it responsibly in a short time—the directive is to pump it into the economy by the summer of 2010, and many funds will go out the door long before that. For example, among the first announcements have been Challenge grants, which must be awarded by April 27 (more information at the NIMH website). And this is just the beginning. U.S. researchers should keep an eye on the NIMH’s website over the next couple of weeks as other programs are rolled out.

What do we know?
Insel’s synopsis of the fundamental facts of schizophrenia and bipolar disorder are that they 1) have early onset and a chronic course in ~90 percent of cases; 2) cause high disability and mortality; 3) have high heritability with complex genetics; and 4) are developmental brain disorders with complex circuitry abnormalities.

He also noted that the cognitive and behavioral symptoms of these disorders really represent the end stage, much as a heart attack is the end stage of ischemic heart disease. What is needed, he argued is to move to defining the disorder by earlier manifestations—aspects of the prodrome such as family history and subclinical symptoms, but also perhaps genetics, imaging, and subtle dysfunctions in cognition.

What do we need?
What is needed, Insel said, is a better understanding of pathophysiology, better interventions (rational, preemptive, personalized, based on pathophysiology, recovery-based), and better delivery of current interventions.

Translational research is an important priority, and it is not limited to the familiar bench-to-bedside stage. There is also bedside-to-practice, which focuses on optimizing current treatments. But Insel was clear that he does not support the view that we have all the necessary therapeutic tools at our disposal and just need to optimize them.

Genetics of developmental disorders is the major focus in giving the clinic more tools. Insel argues that the point of genetic research is not diagnosis, as commonly presented to the public; rather, the goal is mainly to gain insight into the disorders. He discussed a cycle of research that has been dubbed reverse translation that follows this cycle: developmental disorder > gene discovery > animal models > cellular pathology > discovering molecular targets > identifying small molecule therapeutics > bringing this back to the clinic.

Tools are already available for each of these, Insel said, and he pointed to the success, with Fragile X syndrome, of Mark Bear and colleagues, where they are already working at the small molecule therapeutic stage (see Bear, 2008).

What about genomewide association studies (GWASs), highly touted as sure bets just a few years ago for psychiatric genetics, but now vulnerable to charges of impotency against the complexity of these diseases? Insel noted that disappointments in the psychiatric community notwithstanding, many others consider them a success, with ~140 significant findings from GWASs in different diseases. While we are not there yet for schizophrenia or bipolar, Insel believes that large samples will yet bring home solid susceptibility genes—the “portal to pathophysiology.”—Hakon Heimer.