Panic disorder (PD) is a severe and debilitating anxiety disorder. Despite extensive research, the neurobiology of PD remains poorly understood. That PD is intimately linked to the phenomena of separation and attachment, and that separation anxious children display marked sensitivity to carbon dioxide (CO2), one of the most important biological markers of adult PD, suggests a common neurobiological substrate linking panic and attachment. The endogenous opioid system has remarkable specificity for the regulation of separation and attachment in preclinical models. The opioid system also modulates key neurotransmitter systems implicated in diverse anxiety states. Importantly, the opioid system is a critical regulator of CO2 sensitivity. Abnormalities in endogenous opioid function may therefore be integral to the neurobiology of PD. A powerful evaluation of endogenous opioid system activity is a single session administration of five doses of naloxone, an opioid receptor antagonist, and measurement of the hypothalamic-pituitary-adrenal (HPA) axis response. The five-dose naloxone/HPA axis methodology is a powerful marker of endogenous opioid activity that correlates with mu-opioid receptor activity. The central goal of this project is to determine if there is abnormal endogenous opioid system activity in PD with a rigorous and precise five-dose naloxone/HPA axis methodology in an adequate sample of PD patients, both before (baseline) and after SSRI treatment. The central hypothesis is that there will be decreased endogenous opioid activity at baseline in PD patients compared to normals. This proposal will also determine the effect of SSRI treatment on opioid function in PD by repeating the five-dose naloxone procedure after 8 weeks of SSRI treatment to determine if normalization of central opioid activity is associated with clinical improvement in PD.
There is a pressing need to elucidate the complex neurobiology of PD. This project's focus on the endogenous opioid system using a precise five-dose naloxone/HPA axis procedure can establish a novel biological marker of PD that is highly safe, feasible, and cost effective. The study will potentially establish opioid activity as a novel marker for treatment response that can develop as a screen for new antipanic agents, and aid development of novel therapeutics targeting the mu-opioid receptor.
