Preclinical evaluation of the putative antidepressant nefazodone

Michael J. Owens, Kenneth C. Dole, David L. Knight, Charles Nemeroff

Research output: Contribution to journalArticlepeer-review


The effects of the putative antidepressant, nefazodone, which possesses prominent 5‐HT2 antagonist properties and moderate 5‐HT uptake inhibition activity, on several neurochemical measures commonly observed in clinically efficacious antidepressants and serotonergic agents were evaluated. These include: (1) the number of β‐adrenergic and 5‐HT2 receptors and (2) measures of hypothalamic‐pituitary‐adrenal axis function. Chronic administration of nefazodone at clinically relevant doses resulted in small but significant decreases in the density of cortical 5‐HT2 and β‐adrenergic receptors. Moreover, chronic nefazodone administration resulted in an increase in cortical CRF receptor number. Acute administration of nefazodone (1‐100 mg/kg sc) did not alter plasma ACTH concentrations. Only the 100 mg/kg dose increased plasma corticosterone concentrations. Like nefazodone, acute administration of the selective 5‐HT2 antagonist ketanserin (1.5‐10 mg/kg) did not alter plasma ACTH or corticosterone concentrations. Neither acute (3.3 mg/kg sc) nor chronic (33.3 mg/kg/day × 28 days) administration of nefazodone altered the regional brain concentration of corticotropin‐releasing factor (CRF) in any of 10 brain regions examined. These data suggest that the 5‐HT2 antagonist properties of nefazodone are sufficient to inhibit any stimulation of HPA axis activity that may result from the drugs' inherent agonist activity (i.e., 5‐HT uptake inhibition and agonist activity of its metabolite m CPP). Moreover, chronic administration of nefazodone at a dose which produces down regulation of conical 5‐HT2 and β‐adrenergic receptors, an effect commonly observed after administration of other clinically effective antidepressants, increased cortical CRF receptor binding density, possibly the result of diminished extra‐hypothalamic CRF release. These data, taken together, provide further neurochemical evidence for the purported antidepressant effects of nefazodone. Depression 1:315‐323 (1993). © 1993 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)315-323
Number of pages9
Issue number6
StatePublished - 1993
Externally publishedYes


  • 5‐HT uptake
  • antidepressant
  • corticotropin‐releasing factor
  • hypothalamic‐pituitary‐adrenal axis
  • neuroendocrine

ASJC Scopus subject areas

  • Psychiatry and Mental health


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