Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment.
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.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Lucile
L
Capuron
Gabriele
G
Neurauter
Dominique L
DL
Musselman
David H
DH
Lawson
Charles B
CB
Nemeroff
Dietmar
D
Fuchs
Andrew H
AH
Miller
D000328:Adult; D000368:Aged; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D007737:Kynurenine / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D019798:Neopterin / Q000378:metabolism; D017374:Paroxetine / Q000627:therapeutic use*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013997:Time Factors; D014364:Tryptophan / Q000187:drug effects* / Q000378:metabolism
D018687:Antidepressive Agents, Second-Generation; D016898:Interferon-alpha; D007737:Kynurenine; D019798:Neopterin; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D014364:Tryptophan