Cited by 473Tryptophan and brain disordersTreatment of Major DepressionCancer survivorship and care

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

Capuron, L, Ravaud, A, Neveu, P J, Miller, A H, Maes, M, Dantzer, R·2002·Molecular Psychiatry

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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.

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“Finding that cytokine therapy induces depression may indicate that the severity of depressive symptoms would be correlated with a serum TRP decrease and/or KYN increase (Bonaccorso et al. 2002; Capuron et al. 2002, 2003), and, as mentioned above, IDO activity may play a role in these changes.”
Background
Exploration for biomarkers of postpartum depression based on metabolomics: A systematic review
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Molecular and Cellular Aspects of Major Depressive Disorder
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Acute Psychological Stress Modulates the Expression of Enzymes Involved in the Kynurenine Pathway throughout Corticolimbic Circuits in Adult Male Rats
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“Consistent with this, kynurenine levels are elevated in diseases that have elevated glucocorticoid output and inflammatory mediators, such as major depression and coronary heart disease [1, 2].”
Background
Immunologic influences on emotion regulation
Miller, A. H., Capuron, L., & Raison, C. L. (2005) · Clinical Neuroscience Research · doi:10.1016/j.cnr.2005.03.010 · Cited by 22
Self-citation
Alterations in the metabolism of tryptophan in patients with chronic hepatitis C six months after pegylated interferon-α 2a treatment
Pawłowski, T., Małyszczak, K., Inglot, M., Zalewska, M., Radkowski, M., Laskus, T., & Pawlak, D. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.06.004 · Cited by 21
“The increase in IDO activity was related to a marked fall in TRP concentration, as well as an increased KYNA and AA concentration, which finds corroboration in the studies carried out by other authors (Bonaccorso et al., 2002; Capuron et al., 2002; Cozzi et al. 2006; Wichers et al., 2005).”
Genetically engineered bacterium-modified magnetic particles assisted chiral recognition and colorimetric determination of D/L-tryptophan in millets
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Self-citation
Interferon- α induces negative biases in emotional processing in patients with hepatitis C virus infection: a preliminary study
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“For example, it has been proposed that IFN-α-induced changes in tryptophan metabolism may lead to lowered brain serotonin levels and increased production of neurotoxic metabolites, such as quinolinic acid (Capuron et al. 2002; Miller, 2009).”
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Depression has a Strong Relationship to Alterations in the Immune, Endocrine and Neural System
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“In fact, a landmark paper by Capuron et al. (2002b) demonstrated that immune activation through repeated IL-2 and IFN-α immunotherapy in cancer patients induced a drastic fall in plasma tryptophan levels, which was positively correlated with depression scores.”
Background
Not all depression is created equal: sex interacts with disease to precipitate depression
Nemeth, C. L., Harrell, C. S., Beck, K. D., & Neigh, G. N. (2013) · Biology of Sex Differences · doi:10.1186/2042-6410-4-8 · Cited by 19
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A quantitative assessment of depression and thyroid dysfunction secondary to interferon- α therapy in patients with hepatitis C
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Depressive Störungen bei körperlich Kranken
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Natural Killer Cells may Exert Antidepressant-like Effects in Mice by Controlling the Release of Inflammatory Factors
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“The chronic inflammation observed in MDD leads to overactivity of IDO, resulting in elevated KYN levels in the brain (Capuron et al., 2002; Parrott et al., 2016; Walker et al., 2013).”
BackgroundInfluential
13C-tryptophan breath test detects increased catabolic turnover of tryptophan along the kynurenine pathway in patients with major depressive disorder
Teraishi, T., Hori, H., Sasayama, D., Matsuo, J., Ogawa, S., Ota, M., Hattori, K., Kajiwara, M., Higuchi, T., & Kunugi, H. (2015) · Scientific Reports · doi:10.1038/srep15994 · Cited by 18
Conceptualising the neurobiology of fatigue
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“In vulnerable subjects, tryptophan depletion can induce depression (Neumeister, 2003) and in cancer patients treated with cytokines a drastic decrease of plasma tryptophan has been shown to occur that is associated with high depression scores at 4 weeks of treatment (Capuron et al., 2002).”
Background
Comparative effects of two type I interferons, human IFN‐α and ovine IFN‐τ on indoleamine‐2,3‐dioxygenase in primary cultures of human macrophages
Manéglier, B., Rogez‐Kreuz, C., Spreux‐Varoquaux, O., Malleret, B., Thérond, P., Samah, B., Drouet, I., Dormont, D., Advenier, C., & Clayette, P. (2007) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2006.00460.x · Cited by 18
Psychiatric Implications of Hepatitis-C Infection
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Sex Specific Changes in Tryptophan Breakdown Over a 6 Week Treatment Period
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“A number of studies have proven the role of IDO in cytokineinduced depression by demonstrating correlations between cytokine-induced depression and lower Trp and raised Kyn concentrations as well as an increase in the Kyn/Trp-ratio (2, 3).”
Background
Interferon-α Influences Tryptophan Metabolism without Inducing Psychiatric Side Effects
Bannink, M., Fekkes, D., Gool, A. R. V., Kruit, W. H. J., Sleijfer, S., van der Holt, B., Eggermont, A. M. M., Stoter, G., & Hengeveld, M. W. (2007) · Neuropsychobiology · doi:10.1159/000108382 · Cited by 18
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Background
Moxibustion alleviates depression-like behavior in rats with Crohn’s disease by inhibiting the kynurenine pathway metabolism in the gut-brain axis
Bao, C., Huang, J., Wu, H., Ma, Y., Zhou, H., Chen, L., Yang, D., Liu, H., Shi, Y., & Lu, Y. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1019590 · Cited by 17
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Cytokines, neurophysiology, neuropsychology, and psychiatric symptoms.
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Authors: Capuron, L., Ravaud, A., Neveu, P. J., Miller, A. H., Maes, M., & Dantzer, R.
Affiliations: Inserm (FR)
Institut Bergonié (FR)
Emory University (US)
Maastricht University (NL)
Corresponding author: Capuron, L
ORCID: Capuron, L
Ravaud, A
Miller, A H
Maes, M
Dantzer, R
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2002-06-01
Volume: 7
Issue: 5
Pages: 468-473
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/sj.mp.4000995
OpenAlex: W2137877753
Cited by: 473
References: 49
Citations by year: 2026: 3 · 2025: 3 · 2024: 11 · 2023: 13 · 2022: 15 · 2021: 17 · 2020: 20 · 2019: 19 · 2018: 22 · 2017: 28 · 2016: 26 · 2015: 25 · 2014: 16 · 2013: 32 · 2012: 23
FWCI: 8.78
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Funders: Association pour la Recherche sur le Cancer
Ligue Contre le Cancer
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Health Sciences › Medicine › Oncology › Cancer survivorship and care
Keywords: tryptophan, depressive symptoms, cytokine therapy, cancer patients, interleukin-2, interferon-alpha, large neutral amino acids, serotonin precursor, anorexia, suicidal ideation, mood disorders
MeSH terms: Adult, Aged, Blood-Brain Barrier, Depressive Disorder, Female, Humans, Interleukin-2, Male, Middle Aged, Neoplasms, Regression Analysis, Time Factors, Tryptophan, Biomarkers, Cytokines, Interferon-alpha

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

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