CHRONIC IMIPRAMINE IS ASSOCIATED WITH DIMINISHED HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY IN HEALTHY HUMANS

The hypercortisolism of melancholic depression is thought to reflect h ypothalamic hypersecretion of CRH and may be related to the hyperarous al associated with this syndrome. Although chronic administration of i mipramine to experimental animals significantly decreases CRH messenge r RNA levels in the paraventricular nucleus, it is generally thought t hat resolution of hypercortisolism following recovery from depression is related to the improvement in mood and decrease in anxiety that acc ompanies recovery rather than an intrinsic effect of imipramine. The p resent study was designed to explore whether chronic imipramine admini stration to healthy, nondepressed volunteers is associated with effect s on hypothalamic-pituitary-adrenal (HPA) axis function. We studied ba sal and provocative measures of HPA axis function in 14 healthy volunt eers before and after 6 weeks of imipramine treatment at therapeutic d oses. Imipramine was associated with decreased responses in peak ACTH and cortisol to ovine CRH and in peak ACTH to arginine vasopressin (P = 0.02, P = 0.003, and P = 0.02, respectively) without changes in indi ces of basal HPA axis function. These data are consistent with preclin ical findings and support the hypothesis that imipramine has an intrin sic effect on central components of HPA axis function, potentially rel ated to its therapeutic effects.