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Interferon, tryptophan and depression

Published online by Cambridge University Press:  24 June 2014

D. Fekkes and
A. R. Van Gool
D. Fekkes*
Affiliation:
Department of Psychiatry, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
A. R. Van Gool
Affiliation:
Department of Psychiatry, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
*
Durk Fekkes PhD, Erasmus Medical Center Rotterdam, Laboratory of Psychiatry, Room Ee 1438, PO Box 1738, 3000 DR Rotterdam, the Netherlands. Tel: + 31 10 4087529; Fax: + 31 10 4089495, E-mail: fekkes@pathg.fgg.eur.nl
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Abstract

Depression is a frequent comorbid disorder of many inflammatory diseases and it is suggested that brain inflammatory processes have a pathogenic role in mood dysregulation. Several immunocompromised patients have been treated with cytokines and long-term treatments have resulted in a variety of neuropsychiatric side-effects. The objective of the study was to present evidence for an association between the induction of neuropsychiatric side-effects during treatment with interferon-α (IFN-α) and changes in serotonergic and immunological parameters. Moreover, the use of IFN-α-induced depression as a paradigm for research into the pathophysiology of depressive disorders in general will be discussed. This literature review focused on the relationships between tryptophan, serotonin, cytokines and depression associated with interferon treatment. Immunotherapy with IFN-α influences several immunological and serotonergic parameters, and induces in most patients neurovegetative, somatic and depressive symptoms. Literature findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy are secondary to cytokine induction and could be mediated by a reduced availability of tryptophan to the brain, resulting ultimately in decreased serotonergic activity. Changes in the metabolism of tryptophan and consequently of serotonin may play a role in the pathophysiology of interferon-induced depression. Studies on interferon-induced neuropsychiatric side-effects may be a promising research paradigm and shed light on the role of immunological and serotonergic factors in the pathogenesis of depressive disorders in general. However, first the appropriate symptomatology of the interferon-induced depressive states has to be documented.

Keywords

cytokinesdepressioninterferonserotoninsymptom dimensionstryptophan

Information

Type
Review Article
Information
Acta Neuropsychiatrica , Volume 15 , Issue 1 , February 2003, pp. 8 - 14
Copyright
Copyright © 2003 Blackwell Munksgaard

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References

Sargent, PA, Kjaer, KH, Bench, CJet al. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57: 174–180.CrossRefGoogle ScholarPubMed
Menkes, DB, MacDonald, JA. Interferons, serotonin and neurotoxicity. Psychol Med 2000;30: 259–268.CrossRefGoogle ScholarPubMed
Maes, M, Meltzer, HY, Scharpe, Set al. Relationships between lower plasma l-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Res 1993;49: 151–165.CrossRefGoogle ScholarPubMed
Weidenfeld, J, Yirmiya, R. Effects of bacterial endotoxine on the glucocorticoid feedback regulation of adrenocorticol response to stress. Neuroimmunomodulation 1996;3: 352–357.CrossRefGoogle Scholar
Yirmiya, R. Endotoxin produces a depressive-like episode in rats. Brain Res 1996;711: 163–174.CrossRefGoogle ScholarPubMed
Korf, J, Klein, HC, Versijpt, J, Den Boer, JA, Ter Horst, GJ. Considering depression as a consequence of the inflammatory response system. Acta Neuropsychiatrica 2002;14: 1–10. CrossRefGoogle ScholarPubMed
Kronfol, Z, Remick, DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000;157: 683–694.CrossRefGoogle ScholarPubMed
Maes, M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19: 11–38.CrossRefGoogle ScholarPubMed
Van Gool, AR, Kruit, WHJ, Cornelissen, JJ, Berk, L, Eggermont, AMM, Bannink, M. Management of psychiatric adverse events with immunotherapy with inteferon-alfa. Acta Neuropsychiatrica 1999;11: 120–124. CrossRefGoogle Scholar
Maes, M, Capuron, L, Ravaud, Aet al. Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy. Neuropsychopharmacology 2001;24: 130–140.CrossRefGoogle ScholarPubMed
Maes, M, Bonaccorso, S, Marino, Vet al. Treatment with interferon-alpha (IFN alpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN alpha-induced depressive and anxiety symptoms and immune activation. Mol Psychiatry 2001;6: 475–480.CrossRefGoogle ScholarPubMed
Capuron, L, Ravaud, A, Gualde, Net al. Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy. Psychoneuroendocrinology 2001;26: 797–808.CrossRefGoogle ScholarPubMed
Bonaccorso, S, Puzella, A, Marino, Vet al. Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatr Res 2001;105: 45–55. CrossRefGoogle Scholar
Bonaccorso, S, Marino, V, Puzella, Aet al. 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.CrossRefGoogle ScholarPubMed
Capuron, L, Ravaud, A, Neveu, PJ, Miller, AH, Maes, M, Dantzer, R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002;7: 468–473.CrossRefGoogle ScholarPubMed
Heninger, GR. The role of serotonin in clinical disorders. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: the fourth generation of progress. New York: Raven Press, 1994: 461–469. Google Scholar
Fernstrom, JD & Wurtman, RJ. Brain serotonin content. Physiological dependence on plasma tryptophan levels. Science 1971;173: 149–152.CrossRefGoogle ScholarPubMed
Quintana, J. Platelet serotonin and plasma tryptophan decreases in endogenous depression. Clinical, therapeutic and biological correlations. J Affect Disord 1992;24: 55–62.CrossRefGoogle ScholarPubMed
Demyer, MK, Shea, P, Hendrie, HC, Yoshimura, NY. Plasma tryptophan and five other amino acids in depressed and normal subjects. Arch Gen Psychiatry 1981;38: 642–646.CrossRefGoogle ScholarPubMed
Joseph, MS, Brewerton, TD, Reus, VI, Stebbins, GT. Plasma l-tryptophan/neutral amino acid ratio and dexamethason suppression in depression. Psychiatr Res 1984;11: 185–192. CrossRefGoogle ScholarPubMed
Maes, M, De Ruyter, M, Hobbin, P, Suy, E. Relationship between the dexamethason suppression test and the l-tryptophan/competing amino acids ratio in depression. Psychiatr Res 1987;21: 323–335. CrossRefGoogle ScholarPubMed
Cowen, PJ, Parry-Billings, M, Newsholme, EA. Decreased plasma tryptophan levels in major depression. J Affect Disord 1989;16: 27–31.CrossRefGoogle ScholarPubMed
Lucca, A, Lucini, V, Piatti, E, Ronchi, P, Smeraldi, E. Plasma tryptophan levels and plasma tryptophan/neutral amino acids ratio in patients with mood disorder, patients with obsessive-compulsive disorder, and normal subjects. Psychiatr Res 1992;44: 85–91. CrossRefGoogle ScholarPubMed
Fekkes, D, Timmerman, L, Pepplinkhuizen, L. Effects of clomipramine on plasma amino acids and serotonergic parameters in panic disorder and depression. Eur Neuropsychopharmacol 1997;7: 235–339.CrossRefGoogle ScholarPubMed
Riley, CJ, Shaw, DM. Total and nonbound tryptophan in unipolar ilness. Lancet 1976;ii: 1249. CrossRefGoogle Scholar
Møller, SE, Kirk, L, Honore, P. Free and total plasma tryptophan in endogenous depression. J Affect Disord 1979;1: 69–76.CrossRefGoogle ScholarPubMed
Sarrias, MJ, Artigas, F, Martinez, Eet al. Decreased plasma serotonin in melancholic patients: a study with clomipramine. Biol Psychiatry 1987;22: 1429–1438.CrossRefGoogle ScholarPubMed
Lucca, A, Lucini, V, Catalano, M, Alfano, M, Smeraldi, E. Plasma tryptophan to large neutral amino acids ratio and therapeutic response to a selective serotonin uptake inhibitor. Neuropsychobiol 1994;29: 108–111. CrossRefGoogle ScholarPubMed
Lucini, V, Lucca, A, Catalano, M, Smeraldi, E. Predictive value of tryptophan/large neutral amino acids ratio to antidepressant response. J Affect Disord 1996;36: 129–133.CrossRefGoogle ScholarPubMed
Blier, P, Montigny, C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994;15: 220–225.CrossRefGoogle ScholarPubMed
Delgado, P, Price, L, Miller, Het al. Rapid serotonin depletion as a provocative challenge test for patients with major depression. Psychopharmacol Bull 1991;27: 321–330.Google ScholarPubMed
Smith, K, Fairburn, C, Cowen, P. Relapse of depression after rapid depletion of tryptophan. Lancet 1997;349: 915–919.CrossRefGoogle ScholarPubMed
Anderson, IM, Parry-Billings, M, Newsholme, E, Poortmans, J, Cowen, PJ. Decreased plasma tryptophan concentration in major depression: relationship melancholia and weight loss. J Affect Disord 1990;20: 185–191.CrossRefGoogle ScholarPubMed
Deakin, JF. 5HT2 receptors, depression and anxiety. Pharmacol Biochem Behav 1988;29: 819–820.CrossRefGoogle ScholarPubMed
Deakin, JF, Graeff, FG. 5-HT and mechanisms of defence. J Psychopharmacol 1991;5: 305–315. CrossRefGoogle ScholarPubMed
Goodall, EM, Cowen, PJ, Franklin, M, Silverstone, T. Ritanserin attenuates anorectic, endocrine and thermic responses to d-fenfluramine in human volunteers. Psychopharmacology 1993;112: 461–466.CrossRefGoogle ScholarPubMed
O'Keane, V, Dinan, TG. Prolactin and cortisol responses to d-fenfluramine in major depression. evidence for diminished responsivity of central serotonergic function. Am J Psychiatry 1991;148: 1009–1015.Google ScholarPubMed
Lichtenberg, P, Shapira, B, Gillon, Det al. Hormone responses to fenfluramine and placebo challenge in endogenous depression. Psychiatr Res 1992;43: 137–146. CrossRefGoogle ScholarPubMed
Siever, LJ, Murphy, DL, Slater, S, De La Vega, E, Lipper, S. Plasma prolactin changes following fenfluramine in depressed patients compared to controls: an evaluation of central serotonergic responsivity in depression. Life Sci 1984;34: 1029–1039.CrossRefGoogle ScholarPubMed
Trask, PC, Esper, P, Riba, M, Redman, B. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms and future directions. J Clin Oncol 2000;18: 2316–2326.CrossRefGoogle ScholarPubMed
Musselman, DL, Lawson, DH, Gumnick, JFet al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344: 961–966.CrossRefGoogle ScholarPubMed
Dieperink, E, Willenbring, M, Ho, SB. Neuropsychiatric symptoms associated with hepatitis C and interferon-alfa: a review. Am J Psychiatry 2000;157: 867–876.CrossRefGoogle ScholarPubMed
Capuron, L, Gumnick, JF, Musselman, DLet al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002;26: 643–652.CrossRefGoogle ScholarPubMed
Brown, RR, Lee, CM, Kohler, PC, Hank, JA, Storer, BE, Sondel, PM. Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2. Cancer Res 1989;49: 4941–4944.Google ScholarPubMed
Brown, RR, Ozaki, Y, Datta, SP, Borden, EC, Sondel, PM, Malone, DG. Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS. Adv Exp Med Biol 1991;294: 425–435.CrossRefGoogle ScholarPubMed
MacKenzie, CR, Gonzalez, RG, Kniep, E, Och, S, Daubener, W. Cytokine mediated regulation of interferon-gamma-induced IDO activation. Adv Exp Med 1999;567: 533–539. CrossRefGoogle Scholar
Recht, M, Borden, EC, Knight, E JrA human 15-kDa IFN-induced protein induces the secretion of IFN-gamma. J Immunol 1991;147: 2617–2623.CrossRefGoogle ScholarPubMed
Liberati, AM, Horisberger, MA, Garofani, Pet al. Interferon-alpha-induced biologic modifications in patients with chronic myelogenous leukemia. J Interferon Res 1994;14: 349–355.CrossRefGoogle ScholarPubMed
Taylor, M, Feng, G. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase and tryptophan catabolism. FASEB J 1991;5: 2516–2522.CrossRefGoogle ScholarPubMed
Kamata, M, Higuchi, H, Yoshimoto, M, Yoshida, K, Shimizu, T. Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain. Eur Neuropsychopharmacol 2000;10: 129–132.CrossRefGoogle ScholarPubMed
Morikawa, O, Sakai, N, Obara, H, Saito, N. Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 1998;349: 317–324.CrossRefGoogle ScholarPubMed
Benkelfat, C, Ellenbogen, MA, Dean, P, Palmour, RM, Young, SN. Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry 1994;51: 687–697.CrossRefGoogle ScholarPubMed
McAllister-Williams, RH, Young, AH, Menkes, DB. Antidepressant response reversed by interferon. Br J Psychiatry 2000;176: 93.CrossRefGoogle ScholarPubMed