Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

Abstract

Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood–brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Dantzer R, Wollman EE, Yirmiya R . Cytokines, Stress, and Depression Plenum, Kluwer Academic: New York 1999

    Book  Google Scholar 

  2. Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression J Affect Disord 1995 34: 301–309

    Article  CAS  Google Scholar 

  3. Anisman H, Ravindran AV, Griffiths J, Merali Z . Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features Mol Psychiatry 1999 4: 182–188

    Article  CAS  Google Scholar 

  4. Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells Ann Intern Med 1987 107: 293–300

    Article  CAS  Google Scholar 

  5. Fenner MH, Hanninen EL, Kirchner HH, Poliwoda H, Atzpodien J . Neuropsychiatric symptoms during treatment with interleukin-2 and interferon-alpha Lancet 1993 341: 372

    Article  CAS  Google Scholar 

  6. Miyaoka H, Otsubo T, Kamijima K, Ishii M, Onuki M, Mitamura K . Depression from interferon therapy in patients with hepatitis C Am J Psychiatry 1999 156: 1120

    CAS  PubMed  Google Scholar 

  7. Capuron L, Ravaud A, Dantzer R . Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy J Clin Oncol 2000 18: 2143–2151

    Article  CAS  Google Scholar 

  8. Licinio J, Kling MA, Hauser P . Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes Sem Oncol 1998 25 (suppl 1): 30–38

    Google Scholar 

  9. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH . Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684 J Clin Oncol 1996 14: 7–17

    Article  CAS  Google Scholar 

  10. Kammula US, White DE, Rosenberg SA . Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer Cancer 1998 83: 797–805

    Article  CAS  Google Scholar 

  11. Capuron L, Ravaud A . Prediction of the depressive effects of interferon alfa therapy by the patient's initial affective state New Engl J Med 1999 340: 1370

    Article  CAS  Google Scholar 

  12. Maes M, Meltzer HYM . The serotonin hypothesis of major depression. In: Bloom F, Kupher D (eds) Psychopharmacology: the Fourth Generation of Progress Raven Press: New York 1995 933–944

    Google Scholar 

  13. Meyers S . Use of neurotransmitter precursors for treatment of depression Altern Med Rev 2000 5: 64–71

    CAS  PubMed  Google Scholar 

  14. Curzon G, Sarna GS . Tryptophan transport to the brain: new findings and older ones reconsidered. In: Schlossberger HG, Kochen W, Linzen B, Steinhart H (eds) Progress in Tryptophan and Serotonin Research Walter de Gruyter: Berlin-New York 1984 145–157

    Google Scholar 

  15. 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 Neuropsychobiology 1994 29: 108–111

    Article  CAS  Google Scholar 

  16. DeMyer MK, Shea PA, Hendrie HC, Yoshimura NN . Plasma tryptophan and five other amino acids in depressed and normal subjects Arch Gen Psychiatry 1981 38: 642–646

    Article  CAS  Google Scholar 

  17. Dunn AJ, Wang J, Ando T . Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress Adv Exp Med Biol 1999 461: 117–127

    Article  CAS  Google Scholar 

  18. Song C, Merali Z, Anisman H . Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment Neuroscience 1999 88: 823–836

    Article  CAS  Google Scholar 

  19. Linthorst AC, Flachskamm C, Holsboer F, Reul JM . Local administration of recombinant human interleukin-1 beta in the rat hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity, and body temperature Endocrinology 1994 135: 520–532

    Article  CAS  Google Scholar 

  20. 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

    Article  CAS  Google Scholar 

  21. Brown RR, Lee MC, 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

    CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  Google Scholar 

  23. Maes M, Meltzer HY, Scharpe S, Bosmans E, Suy E, De Meester I et al. Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression Psychiatry Res 1993 49: 151–165

    Article  CAS  Google Scholar 

  24. Sleijfer DT, Janssen RA, Buter J, de Vries EG, Willemse PH, Mulder NH . Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis J Clin Oncol 1992 10: 1119–1123

    Article  CAS  Google Scholar 

  25. Négrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie N Engl J Med 1998 338: 1272–1278

    Article  Google Scholar 

  26. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10 J Clin Psychiatry 1998 59 (suppl 20): 22–33

    Google Scholar 

  27. Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change Br J Psychiatry 1979 134: 382–389

    Article  CAS  Google Scholar 

  28. Turnell DC, Cooper JD . Rapid assay for amino acids in serum or urine by pre-column derivatization and reversed-phase liquid chromatography Clin Chem 1982 28: 527–531

    CAS  Google Scholar 

  29. Maes M, Wauters A, Verkerk R, Demedts P, Neels H, Van Gastel A et al. Lower serum L-tryptophan availability in depression as a marker of a more generalized disorder in protein metabolism Neuropsychopharmacology 1996 15: 243–251

    Article  CAS  Google Scholar 

  30. Smith KA, Fairburn CG, Cowen PJ . Relapse of depression after rapid depletion of tryptophan Lancet 1997 349: 915–919

    Article  CAS  Google Scholar 

  31. Moore P, Landolt H, Seifritz E, Clark C, Bhatti T, Kelsoe J et al. Clinical and physiological consequences of rapid tryptophan depletion Neuropsychopharmacology 2000 23: 601–622

    Article  CAS  Google Scholar 

  32. Delgado PL, Price LH, Miller HL, Salomon RM, Aghajanian GK, Heninger GR et al. Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients Arch Gen Psychiatry 1994 51: 865–874

    Article  CAS  Google Scholar 

  33. Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, Robbins TW et al. Tryptophan depletion in normal volunteers produces selective impairments in learning and memory Neuropharmacology 1994 33: 575–588

    Article  CAS  Google Scholar 

  34. Smith KA, Morris JS, Friston KJ, Cowen PJ, Dolan RJ . Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion Br J Psychiatry 1999 174: 525–529

    Article  CAS  Google Scholar 

  35. Neumeister A, Praschak-Rieder N, Besselmann B, Rao ML, Gluck J, Kasper S . Effects of tryptophan depletion on drug-free patients with seasonal affective disorder during a stable response to bright light therapy Arch Gen Psychiatry 1997 54: 133–138

    Article  CAS  Google Scholar 

  36. Oquendo MA, Mann JJ . The biology of impulsivity and suicidality Psychiatr Clin North Am 2000 23: 11–25

    Article  CAS  Google Scholar 

  37. Plata-Salaman CR . Cytokines and anorexia: a brief overview Semin Oncol 1998 25 (1 Suppl 1): 64–72

    Google Scholar 

  38. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al. Cytokine-associated emotional and cognitive disturbances in humans Arch Gen Psychiatry 2001 58: 445–452

    Article  CAS  Google Scholar 

  39. Heyes MP, Saito K, Markey SP . Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid Biochem J 1992 283: 633–635

    Article  CAS  Google Scholar 

  40. Mellor AL, Munn DH . Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 1999 20: 469–473

    Article  CAS  Google Scholar 

  41. Saito K, Markey SP, Heyes MP . Chronic effects of gamma-interferon on quinolinic acid and indoleamine-2,3-dioxygenase in brain of C57BL6 mice Brain Res 1991 546: 151–154

    Article  CAS  Google Scholar 

  42. Daubener W, MacKenzie CR . IFN-gamma activated indoleamine 2,3-dioxygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism Adv Exp Med Biol 1999 467: 517–524

    Article  CAS  Google Scholar 

  43. Carlin JM, Borden EC, Sondel PM, Byrne GI . Biologic-response-modifier-induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures J Immunol 1987 139: 2414–2418

    CAS  PubMed  Google Scholar 

  44. Maes M, Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M et al. Treatment with interferon-alpha (IFNalpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFNalpha-induced depressive and anxiety symptoms and immune activation Mol Psychiatry 2001 6: 475–480

    Article  CAS  Google Scholar 

  45. Fuchs D, Moller AA, Reibnegger G, Werner ER, Werner-Felmayer G, Dierich MP et al. 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

    Article  CAS  Google Scholar 

  46. Fuchs D, Moller AA, Reibnegger G, Stockle E, Werner ER, Wachter H . 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

    CAS  PubMed  Google Scholar 

  47. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa New Engl J Med 2001 344: 961–966

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the patients for participating in the study, and Simon Scharpe, PhD, Robert Verkerk, PhD, and Norbert Gualde, MD, PhD, and their colleagues for their technical assistance. Supported by Ligue Nationale contre le Cancer, Fondation pour la Recherche Medicale, and Association pour la Recherche sur le Cancer.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L Capuron.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Capuron, L., Ravaud, A., Neveu, P. et al. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7, 468–473 (2002). https://doi.org/10.1038/sj.mp.4000995

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000995

Keywords

This article is cited by

Search

Quick links