Extinction of Fear Memories With Glucocorticoids in Veterans With PTSD

Background information and related research: Post-traumatic stress disorder (PTSD) is characterized, among other things, by intrusive memories in the form of unwanted images, nightmares, and flashbacks. These memories are associated with intense distress and involve excessive physiological and psychological responses to fear associated stimuli. Prevalence rates of combat-related PTSD are increasing due to Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployments, with the estimated risk for PTSD from service in the Iraq War at 18%, and 11% for Afghanistan. According to the Pentagon's own mental health taskforce, 38% of soldiers, 31% of marines, 49% of National Guard members, and 43% of marine reservists have shown symptoms of post-traumatic stress disorder or other psychological problems within three months of returning from active duty. Estimates from the National Center on PTSD suggest that 40% of OEF/OIF troops may have or will acquire PTSD. The Department of Defense (DoD) reports that 22% of OEF/OIF troops have been flagged for PTSD and referred for follow-up care, and records indicate that over 39,000 OEF/OIF vets had been treated for PTSD as of December, 2006. Current research efforts are exploring the underlying neurochemical changes associated with PTSD. Recently, these efforts have focused on the prevention of PTSD in persons exposed to trauma by administration of medication to affect the underlying neurochemical processes. For example, preliminary evidence suggests that interference with consolidation of trauma-related memories using the beta-antagonist, propranalol, may prevent PTSD in humans with recent traumas. However, given that as much as 90% of the US population is exposed to at least one traumatic event during their lifetime, the utility of this treatment is limited by the logistical problems of treating everyone at risk for developing PTSD after a trauma. To date, there are very few systematic studies on humans that focus on changing the underlying traumatic memory once PTSD has been established. The trauma experience is initially stored in short-term memory, then consolidated into long-term memory. However, the long-term stability conferred by the consolidation process undergoes a period of labiality as follows. Each time a consolidated memory is activated, the memory trace becomes newly labile and must be consolidated again to remain in long-term memory. This process is called reconsolidation. Reconsolidation therefore offers a biologic window during which long-term memories can be disrupted. Preclinical studies have begun to unravel the biological changes that underlie these processes. Both pharmacological agents, including glucocorticoids, and protein synthesis inhibitors can interfere with memory consolidation and reconsolidation. Endogenously produced stress-hormones, or glucocorticoids, enhance consolidation for emotionally-arousing experiences, but these effects are dependent on dose, aversiveness of task, and timing of hormone administration. Conversely, glucocorticoids appear to impair the retrieval of memories of aversive experiences.10 Recent data also suggest that glucocorticoids enhance extinction of traumatic memories. Preclinical work in our laboratory at the UT Southwestern Medical Center has established that corticosterone can dose-dependently reduce an established fear memory in rodents. In this study, mice were trained to associate foot-shock with a specific training context to induce fear memory. When this fear memory was reactivated by the contextual stimulus and then followed by glucocorticoid administration, subsequent reactivation of the fear memory produced significantly less fear responses relative to mice administered saline after memory reactivation. After only one pairing of reactivation and glucocorticoid, this effect was reversible with a subthreshold reminder shock and was transient, indicating that the effect of glucocorticoids was on the extinction process. These results strongly suggested glucocorticoid treatment paired with therapeutic traumatic memory reactivation as a specific therapy for PTSD in humans and directly informed our pilot studies in PTSD patients.