Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment

Biol Psychiatry. 2003 Nov 1;54(9):906-14. doi: 10.1016/s0006-3223(03)00173-2.


Background: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-alpha therapy.

Methods: Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-alpha treatment and continuing for the first 12 weeks of IFN-alpha therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-alpha treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity.

Results: Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-alpha therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients.

Conclusions: The results suggest that reduced TRP availability plays a role in IFN-alpha-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-alpha, attenuates the behavioral consequences of IFN-alpha-mediated TRP depletion.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Anxiety / chemically induced
  • Anxiety / drug therapy
  • Depression / chemically induced
  • Depression / drug therapy*
  • Double-Blind Method
  • Female
  • Humans
  • Interferon-alpha / adverse effects*
  • Interferon-alpha / therapeutic use
  • Kynurenine / drug effects
  • Kynurenine / metabolism
  • Male
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Middle Aged
  • Neopterin / metabolism
  • Paroxetine / therapeutic use*
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Time Factors
  • Tryptophan / drug effects*
  • Tryptophan / metabolism


  • Antidepressive Agents, Second-Generation
  • Interferon-alpha
  • Serotonin Uptake Inhibitors
  • Kynurenine
  • Paroxetine
  • Neopterin
  • Tryptophan