UNCOUPLING OF THE NORADRENERGIC-HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN PANIC DISORDER PATIENTS

In this paper the authors examine the interrelationship of both the no radrenergic (NA) system and the hypothalamic-pituitary-adrenal (HPA) a xis and its implications for panic disorder (PD). Seventeen PD patient s and 26 healthy volunteers were challenged orally 12 weeks apart with the an-agonist clonidine (13 healthy volunteers and 12 patients repea ted the challenge). Between challenges, PD patients were treated with fluoxetine, with 10 of 12 improving at least moderately. Both during t he acute phase of the illness and during the phase of pharmacological improvement, patients demonstrated a greater percentage of reductions of plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and plasma cortisol d uring clonidine challenge. We used correlational matrices to examine t he relationship between the NA system, as reflected by plasma MHPG, an d the HPA axis, as reflected by plasma cortisol measures. Healthy volu nteers exhibited multiple significant ''couplings'' between either bas eline or maximal decrease (Delta(max)) of plasma MHPG, with either bas eline or Delta(max) plasma cortisol measures both within the first and second challenges anti between the first and second challenges. In co ntrast, PD patients demonstrated ''uncoupling'' of the NA system and t he HPA axis, with no significant correlations observed between either baseline and/or maximal decrease (Delta(max)) measures of MHPG with th e same cortisol measures for either the first or second challenge. The same uncoupling was observed for NA/HPA correlations between the firs t and second challenges. These data suggest that the hyperresponsivity to clonidine in PD patients persists during fluoxetine treatment. The y also raise the possibility that an uncoupling of the NA system and t he HPA axis may be a feature of PD patients, even following clinically significant improvement. The authors suggest suboptimal NA regulation of the HPA axis in PD patients, with pathophysiological implications particularly prominent during periods of stress-induced activation of the two systems.