Abstract
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)-α 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-α treatment
and continuing for the first 12 weeks of IFN-α therapy. At treatment initiation and
at 2, 4, and 12 weeks of IFN-α 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-α 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-α–induced depressive
symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-α,
attenuates the behavioral consequences of IFN-α–mediated TRP depletion.
Keywords
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References
- Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Press, Washington, DC1994
- Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat.Br J Pharmacol. 1991; 102: 429-433
- Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system.J Clin Psychopharmacol. 2002; 22: 86-90
- Induction of tryptophan degradation in vitro and in vivo.J Interferon Res. 1986; 6: 389-396
- Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions.Neuropsychopharmacology. 2002; 26: 643-652
- Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy.Mol Psychiatry. 2002; 7: 468-473
- A neuroendocrine study of 5HT function in depression.Psychopharmacology (Berl). 1990; 101: 85-92
- Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients.Arch Gen Psychiatry. 1994; 51: 865-874
- Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms.J Acquir Immune Defic Syndr. 1990; 3: 873-876
- Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection.Immunol Lett. 1991; 28: 207-211
- Changes of serum neopterin, beta 2-microglobulin and interferon-gamma in patients with chronic hepatitis C treated with interferon-alpha 2b.Eur J Med. 1992; 1: 196-200
Gilmor ML, Owens MJ, Nemeroff (2002): Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine. Am J Psychiatry 159:1702–1710
- A rating scale for depression.J Neurol Neurosurg Psychiatry. 1960; 23: 52-62
- Prolonged desipramine treatment increases the production of interleukin-10, an anti-inflammatory cytokine, in C57BL/6 mice subjected to the chronic mild stress model of depression.J Affect Disord. 2001; 63: 171-178
- Plasma tryptophan levels and plasma tryptophan/neutral amino acids ratio in patients with mood disorder, patients with obsessive-compulsive disorder, and normal subjects.Psychiatry Res. 1992; 44: 85-91
- Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression.Psychiatry Res. 1994; 54: 143-160
- The Hamilton Anxiety Scale.J Affect Disord. 1988; 14: 61-68
- Serotonin and major depression.in: Mann J.J. Kupfe D.J. Biology of Depressive Disorders, vol 3, part A A System Perspective. Plenum Press, New York1993: 29-49
- Tryptophan catabolism and T-cell tolerance.Immunol Today. 1999; 20: 469-473
- Clinical and physiological consequences of rapid tryptophan depletion.Neuropsychopharmacology. 2000; 23: 601-622
- Tryptophan depletion and risk of depression relapse.Biol Psychiatry. 2000; 48: 327-329
- The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.Psychopharmacol (Berl). 2002; 163: 42-53
- Immune reaction links disease progression in cancer patients with depression.Med Hypotheses. 2000; 55: 137-140
- Neopterin as a marker for immune system activation.Curr Drug Metab. 2002; 3: 175-187
- Paroxetine for the prevention of depression induced by high-dose interferon alfa.N Engl J Med. 2001; 344: 961-966
- The biology of impulsivity and suicidality.Psychiatr Clin North Am. 2000; 23: 11-25
- Role of serotonin in the pathophysiology of depression.Clin Chem. 1994; 40: 288-295
- Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release.Neuroimmunomodulation. 2000; 8: 179-187
- Influence of acute tryptophan depletion on mood and immune measures in healthy males.Psychoneuroendocrinology. 1999; 24: 99-113
- Role of serotoninergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders.Depress Anxiety. 2000; 12: 2-19
- Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation.Psychopharmacology (Berl). 1999; 141: 362-369
- The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression.J Affect Disord. 1998; 49: 211-219
- Selective serotonin reuptake inhibitors.in: Schatzberg A.F. Nemeroff C.B. Textbook of Psychopharmacology. 2nd ed. American Psychiatric Press, Washington, DC1998: 219-237
- Treatment of neurotoxic side effects of interferon-alpha with naltrexone.Cancer Invest. 1995; 13: 561-566
- Interferon-gamma-induced tryptophan degradation.Curr Drug Metab. 2000; 1: 193-204
- Simultaneous measurement of serum tryptophan and kynurenine by HPLC.Clin Chem. 1997; 43: 2424-2426
- The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels.Pharmacol Biochem Behav. 2002; 71: 857-865
Article info
Publication history
Accepted:
January 24,
2003
Received in revised form:
January 17,
2003
Received:
October 16,
2002
Identification
Copyright
© 2003 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
