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

Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH
Interferon-Alpha-Induced Changes in Tryptophan Metabolism: Relationship to Depression and Paroxetine Treatment.
Biological Psychiatry 2003;54:906-914.

Summary

Emory University Department of Psychiatry and Behavioral Sciences faculty who are also members of the CDC/Emory University Collaborative CFS Research Program published this article under partial support of the CFS research program.

Studies examining the pathophysiology of CFS have been complicated by patient heterogeneity with respect to chronicity and co-morbid illnesses. "Model" systems in which symptom-free subjects develop CFS-like illness following exposure to a known immune system stimulus obviate these problems and permit controlled studies of the pathophysiology of fatigue and associated symptoms as they relate to immune and endocrine activation. Interferon-alpha (IFN-alpha), a cytokine widely used in the treatment of hepatitis C and malignant melanoma, represents a model system of great promise, given that IFN-alpha activates the immune system and produces a high rate of symptoms commonly observed in CFS, including fatigue, cognitive complaints, pain, sleep disturbance and depression. Thus, the CDC/Emory University Collaborative Group has undertaken a series of integrated studies using INF-alpha-associated fatigue to model CFS.

Previous studies by the group have shown that the antidepressant paroxetine was effective in preventing the development of major depression in patients receiving INF-alpha therapy for malignant melanoma but had a minimal effect on fatigue and pain. This suggests that the core symptoms of CFS (in the context of immune activation) have a different natural history and treatment response than do core symptoms of major depression. This study investigated physiologic parameters that might explain the differences. Similar to the findings with neuroendocrine responses, alterations in the metabolism of the neurotransmitter, serotonin, also appear to be involved in the development of mood/anxiety symptoms but not fatigue. Indeed, IFN-alpha-induced decreases in tryptophan (the primary precursor of serotonin) and increases in the tryptophan metabolite, kynurenine, reflecting activation of the enzyme, indolamine 2,3, dioxygenase, were associated with the development of depressive symptoms but not neurovegetative symptoms (e.g. fatigue and psychomotor slowing) in patients with malignant melanoma. These findings suggest that immune activation may produce fatigue via effects of cytokines on dopamine neurotransmission in the basal ganglia, while major depression develops as a function of IFN-alpha-induced effects on the neuroendocrine (CRH) system and monoamine (serotonin) metabolism. These potential neurobiological differences between immune-mediated fatigue and depression in patients receiving IFN-alpha are especially intriguing in light of data demonstrating that while major depression and CFS are frequently comorbid, the two conditions are also clearly separable and need not occur together.

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)- a 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-a treatment and continuing for the first 12 weeks of IFN-a therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-a 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-a 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-a-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-a , attenuates the behavioral consequences of IFN-a-mediated TRP depletion.

Page last modified on May 8, 2006

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