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

Psychopharmacology (Berl). 2001 Jun;156(1):73-8. doi: 10.1007/s002130100737.


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 microg/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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenocorticotropic Hormone / blood*
  • Adult
  • Analysis of Variance
  • Arginine Vasopressin / blood
  • Depression / blood
  • Depression / drug therapy*
  • Depression / psychology
  • Female
  • Fluoxetine / therapeutic use*
  • Humans
  • Hydrocortisone / blood
  • Male
  • Middle Aged
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Statistics, Nonparametric


  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Arginine Vasopressin
  • Adrenocorticotropic Hormone
  • Hydrocortisone