Patients with depression frequently have symptom clusters which point strongly to
involvement of the hypothala-mic-pituitary-adrenal (HPA) system as a relay station
between neurocircuitries in the brain and peripheral hormone and autonomic nervous
function. It has been proposed that this increased, state-dependent hyperactivity
of the HPA-system in depression is probably initiated and/or maintained by the combination
of enhanced central production of CRH and desensitization of the binary, glucocorticoid
receptor binding system in the hippocampus, which is the central regulator of HPA
system activity. In a first series of studies a refined neuroendocrine test to probe
the integrity of HPA system status - the combined dexamethasone suppression/CRH challenge
(DEX/CRH) test -was developed and the differential effects of aging and depressed
psychopathology on DEX/CRH test outcome were described. In a second set of studies,
the chronological relationship between improvement of psychopathology in depressed
patients treated with antidepressants and normalization of the disturbed HPA system
function in these patients was further elucidated. Given the evidence from animal
studies, we conclude that antidepressants induce an up-regulation of hippocampal glucocorticoid
receptor mRNA concentration, thus amplifying the negative feedback effect of glucocorticoids.
This then results in the normalization of DEX/CRH test results observed in the depressed
patients in our study. We further conclude that dampening of HPA system hyperactivity
in depression by means of antidepressants is a conditio sine qua non for successful
improvement of psychopathology.
