More than five million Americans suffer from post-traumatic stress disorder each year. But not everyone who lives through a terrifying ordeal will experience the chronic anxiety, flashbacks, and other symptoms that are its hallmarks; the factors that influence individuals' susceptibility to the disorder are poorly understood. To prevent or treat the disease, says Kerry Ressler, scientists need to understand the genetics and neurobiology that control emotion and emotional learning.
Researchers have made considerable progress in uncovering the biological mechanisms that underlie fear, and Ressler says he sees a tremendous opportunity to build on that knowledge with research that can have a real impact on patients' lives. His studies of the molecular neurobiology of fear have already led to the discovery that a drug used to treat tuberculosis may help people overcome anxiety disorders.
“The neural basis of fear is similar across all mammals, and the translational insights offered by studying fear neurobiology in animal models are just tremendous,” says Ressler, who is the first psychiatrist to be appointed an HHMI investigator. He estimates that genetics account for 30 to 40 percent of an individual's susceptibility to post-traumatic stress disorder, similar to the contribution genetics makes to depression. “But we know it's not all genetic, and we need to know much more about how emotional learning takes place in the brain and how we can treat, even prevent, the fear response.”
As a graduate student at Harvard in the early 1990s, Ressler studied the molecular basis of olfaction in the laboratory of Linda Buck—part of the body of work for which Buck was awarded a Nobel Prize in 2004. He earned an M.D./Ph.D. from Harvard and went on to do a residency in psychiatry at the Emory University School of Medicine. Since then, Ressler has made major strides in understanding the genes and neural systems involved in fear, largely through laboratory studies of mice and rats.
His research has helped elucidate the molecules that influence the learning of fear as well as the extinction of fear. Fear extinction is a process in which fear is “unlearned” or inhibited through repeated exposure to a fearful memory, without adverse consequences. Information gleaned from animal studies of fear extinction has helped Ressler develop a promising therapy for humans with anxiety and other fear-based disorders such as post-traumatic stress disorder.
Among his findings in rodents is that enhancing the activity of the neurotransmitter receptor for NMDA (N-methyl-D-aspartate) enhances this extinction process. Other researchers had shown that a tuberculosis drug called D-cycloserine (DCS) partially enhances NMDA receptor functioning. On the basis of these findings, Ressler, along with Michael Davis and colleagues, decided to administer the drug to rats that had undergone fear conditioning. These studies showed that DCS enhanced the fear extinction process.
With these animal results, Ressler then led a clinical study along with Davis, Barbara Rothbaum, and colleagues demonstrating that DCS, combined with psychotherapy, can help people overcome acrophobia, the abnormal fear of heights. Their findings were so encouraging that more than 10 additional clinical trials are now under way to examine the effect of DCS on other anxiety and fear-based disorders. One of these is investigating whether DCS can help patients with post-traumatic stress disorder, including soldiers who have returned from Iraq.
“I always knew I wanted to do translational research to combine the molecular genetic research from the lab with novel interventions in the clinic,” says Ressler, who is also codirector of the post-traumatic stress disorder program at Grady Memorial Hospital in Atlanta. In a proposed clinical trial, Ressler hopes to determine whether early drug and psychotherapy interventions can prevent post-traumatic stress disorder in civilian patients who visit Grady's emergency department after a trauma. Like the studies of DCS, the trial is designed to follow up on findings from Ressler's lab. It can take hours to days for emotional memories to be stored in the brain, so Ressler tested whether that process could be interrupted by targeting the molecules shown to be required for this “consolidation” of fear. Their studies in rodents suggest that drugs and possibly psychotherapy provided within hours of exposure to a trauma may be able to interrupt the formation of long-term fear memory, thus preventing the development of post-traumatic stress disorder.
Ressler also plans to expand clinical trials based on these laboratory findings to post-traumatic stress disorder patients, including war veterans and inner city residents in Atlanta who have been traumatized by exposure to violence.
The data Ressler collects from these trials will also help him decide on the next steps in his laboratory research on the molecular and genetic basis of fear and fear disorders. “This unique interchange of preclinical and clinical data is the most exciting aspect of my work,” says Ressler.
