This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Post-traumatic stress disorder (PTSD) is a chronic and common anxiety disorder that follows exposure to an overwhelming traumatic event. The majority of patients with PTSD also meet criteria for other psychiatric disorders and many attempt suicide. Despite its impact on society, little is known about the etiology or pathophysiology of this disorder. PTSD is responsive to pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs), but response rates rarely exceed 60%, and even fewer patients (20-30%) achieve clinical remission. Thus, there is a clear need to develop novel and improved therapeutics for PTSD. A growing body of preclinical studies suggests that activation of substance P (SP) and its NK1 receptor is anxiogenic and that NK1 antagonists, with chronic administration, exert significant dampening effects on this system. SP is a neuropeptide belonging to the tachykinin family, and has been implicated in several neurological and psychiatric illnesses. Excess activity of the SP-NK1 system thus stands as a prime candidate for involvement in the pathophysiology of anxiety disorders such as PTSD.We propose to investigate the efficacy of the highly specific NK1 antagonist GW597599 in PTSD in a placebo-controlled clinical trial. Furthermore, we propose to longitudinally investigate whether certain biological surrogate markers (neuroendocrine, neuroimaging) are predictive of treatment response. If a patient is already taking medication for PTSD and has achieved therapeutic response, he/she will not be tapered off effective medication(s) to participate in this study, and will not be eligible for the study. Taper and discontinuation of medications in preparation for this study will only occur in those patients who are not responding to medication treatment for PTSD.Hypotheses: 1)PTSD patients randomized to the NK1 antagonist GW597599 will achieve higher response rates acutely compared to patients randomized to placebo. 2)Biological surrogate makers involving neuroendocrine (CSF SP and NE) and neuroimaging function will be predictive of treatment response.
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