Reduction in basal afternoon plasma ACTH during early treatment of depression with fluoxetine

Rationale: Subjects with depression may exhibit activation of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the response of basal hormone levels to antidepressant therapy. Objectives: To determine whether treatment of depression with standard antidepressant medications resulted in reductions in basal activity of afternoon cortisol, ACTH and AVP. A secondary aim was to examine whether there was any difference in hormonal response between an SSRI (fluoxetine) and a tricyclic antidepressant (nortriptyline). Methods: Forty-three subjects with a DSM-IV diagnosis of depression (Hamilton score 18.9 +/-0.6 at baseline) had five basal venous blood samples drawn at 15-min intervals between 1400 and 1500 hours for cortisol, ACTH and AVP, before and 6 weeks after randomisation to treatment with fluoxetine (n=27) or nortriptyline (n=16). Results: Both medications resulted in a similar improvement in depression as determined by Hamilton score. In the group as a whole, ACTH levels showed a significant decrease over the 6 weeks (4.1 +/-0.4 pmol/l at baseline versus 3.3 +/-0.3 at 6 weeks, P <0.05), while cortisol and AVP levels were unchanged. Further analysis revealed that the fall in plasma ACTH occurred predominantly in the subgroup treated with fluoxetine (drug x time interaction by ANOVA, P=0.035). There was a significant relationship between cortisol and ACTH at baseline (r=0.48, P=0.002), that weakened considerably after treatment (r=0.22, P=0.16). The subgroup with baseline hypercortisolemia [mean cortisol > 276 nmol/l (10 mug/dl), n=18] demonstrated a reduction in both cortisol and ACTH following treatment, but also showed a loss of the relationship between the two. Conclusions: It is postulated that the initial recovery of the HPA axis during the treatment of depression with fluoxetine is mediated via restoration of glucocorticoid negative feedback on ACTH levels.