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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.
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“Immunotherapy alters the clinical biochemistry of patients; the most revealing sign is a pronounced reduction in plasma levels of tryptophan56, which correlates with the patients’ depression scores 3 weeks into the treatment.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [56]
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“Moreover, cytokine therapies, used for treatment of hepatitis C and cancer, have been repeatedly associated with an enhanced incidence of depressive symptoms (Bonaccorso et al., 2001; Musselman et al., 2001b; Capuron et al., 2002; Schaefer et al., 2003; Capuron et al., 2003a).”
BackgroundInfluentialCorona, A. W., Huang, Y., O’Connor, J. C., Dantzer, R., Kelley, K. W., Popovich, P. G., & Godbout, J. P. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-93 · Cited by 206
“For instance, in clinical studies, depression is significantly higher in patients undergoing therapy with IFNa and this is associated with increased TRP and KYN levels in the plasma [59,60] and increased QUIN in the cerebrospinal fluid [46].”
BackgroundSelf-citationPeripheral Markers of Depression
Nobis, A., Zalewski, D., & Waszkiewicz, N. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123793 · Cited by 197
“The intensity of depressive symptoms correlates with the level of TRP depletion during antidepressant treatment [344].”
BackgroundImmune activation and degradation of tryptophan in coronary heart disease
Wirleitner, B., Rudzite, V., Neurauter, G., Murr, C., Kalnins, U., Ērglis, A., Trušinskis, K., & Fuchs, D. (2003) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2003.01186.x · Cited by 194
“A relationship between lower tryptophan levels and depression was reported recently [ 30 ].”
BackgroundCommon Biological Pathways Underlying the Psychoneurological Symptom Cluster in Cancer Patients
Kim, H., Barsevick, A. M., Fang, C. Y., & Miaskowski, C. A. (2012) · Cancer Nursing · doi:10.1097/ncc.0b013e318233a811 · Cited by 181
“…symptoms Alesci et al (2005)44; Dinan et al (2009)45 Patients with depression showed elevated cytokine levels and shift of their circadian rhythms Capuron et al (2002)46; Yirmiya et al (2001)47 Antidepressants had anti-inflammatory properties and reversed cytokine-induced depressive symptoms…”
BackgroundThe biology of depression in cancer and the relationship between depression and cancer progression
Sotelo, J. L., Musselman, D. L., & Nemeroff, C. B. (2014) · International Review of Psychiatry · doi:10.3109/09540261.2013.875891 · Cited by 188
“Two types of sickness behaviour have been identifi ed in humans: a depressive type, which responds to treatment with antidepressants, and a neurovegetative type, which does not (Capuron et al., 2002a).”
BackgroundInfluentialBermejo, P., Martín-Aragón, S., Benedí, J., Susín, C., Felici, E., Gil, P., Ribera, J. M., & Villar, Á. M. (2008) · Immunology Letters · doi:10.1016/j.imlet.2008.02.002 · Cited by 178
Schaefer, M., Schwaiger, M., Garkisch, A. S., Pich, M. G. L., Hinzpeter, A., Uebelhack, R., Heinz, A., van Bömmel, F., & Berg, T. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.01.020 · Cited by 176
Lestage, J., Verrier, D., Palin, K., & Dantzer, R. (2002) · Brain, Behavior, and Immunity · doi:10.1016/s0889-1591(02)00014-4 · Cited by 170
“This is not the case, however, for symptoms of depressed mood that coincide with decreased circulating levels of tryptophan (Capuron et al., 2002).”
BackgroundSelf-citationAsnis, G. M., & Garza, R. D. L. (2006) · Journal of Clinical Gastroenterology · doi:10.1097/01.mcg.0000210099.36500.fe · Cited by 169
“2).(77) In addition, although all IFN-treated melanoma patients exhibited significant increases in plasma kynurenine and neopterin and in the kynurenine/tryptophan ratio, individuals who developed MDD exhibited significantly greater increases in kynurenine and neopterin and more prolonged decreases in tryptophan than…”
BackgroundMoreau, M. M., André, C., O’Connor, J. C., Dumich, S. A., Woods, J. A., Kelley, K. W., Dantzer, R., Lestage, J., & Castanon, N. (2008) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2008.04.001 · Cited by 180
“These results are consistent with clinical data reporting that the delayed development of depressive symptoms observed in patients undergoing cytokine immunotherapy is associated with a drastic decrease in circulating levels of TRP (Capuron et al., 2002b).”
BackgroundResultInfluentialSelf-citationSu, K., Huang, S., Peng, C., Lai, H., Huang, C., Chen, Y.-C., Aitchison, K. J., & Pariante, C. M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.11.005 · Cited by 170
“Interestingly, the link between serotonergic genes and IFN-α–induced depression is consistent with biomarker studies showing that depression in these patients is driven, at least in part, by changes in tryptophan and serotonin metabolism (17,18).”
ResultInflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery
Remus, J. L., & Dantzer, R. (2016) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw028 · Cited by 170
“Specifically, the greater the fall in tryptophan levels, the more severe the symptoms of depression as measured by the Montgomery and Asberg depression rating scale (Capuron et al., 2002).”
BackgroundInfluentialSelf-citationSavitz, J., Frank, M. B., Victor, T., Bebak, M., Marino, J. H., Bellgowan, P. S. F., McKinney, B. A., Bodurka, J., Kent Teague, T., & Drevets, W. C. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.10.007 · Cited by 146
The role of inflammatory cytokines in suicidal behavior: A systematic review
Serafini, G., Pompili, M., Elena Seretti, M., Stefani, H., Palermo, M., Coryell, W., & Girardi, P. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.06.002 · Cited by 151
“A link between inflammation, major depression and suicide has also been demonstrated by the fact that the treatment of patients with hepatitis C increases risks for both depression and suicidal attempts (Dieperink et al., 2004; Kraus et al., 2003; Capuron et al., 2002).”
BackgroundAppetite and Cancer-Associated Anorexia: A Review
Davis, M. P., Dreicer, R., Walsh, D., Lagman, R. L., & LeGrand, S. B. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.03.103 · Cited by 152
Liu, W., Sheng, H., Xu, Y., Liu, Y., Lu, J., & Ni, X. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.12.041 · Cited by 151
Alcoholism and inflammation: Neuroimmunology of behavioral and mood disorders
Kelley, K. W., & Dantzer, R. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.12.013 · Cited by 147
Self-citationFidalgo, S., Ivanov, D. K., & Wood, S. H. (2012) · Biogerontology · doi:10.1007/s10522-012-9406-3 · Cited by 154
Lotrich, F. E., Ferrell, R. E., Rabinovitz, M., & Pollock, B. G. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.08.009 · Cited by 135
“In humans, IFN-α also decreases peripheral tryptophan levels, an effect correlated with depression (51).”
BackgroundIs there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?
Dantzer, R., & Walker, A. K. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1187-1 · Cited by 146
Self-citationD’Mello, C., & Swain, M. G. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00184.2011 · Cited by 136
“Cancer patients who were treated with IFN- showed reduced levels of tryptophan within 1 mo of therapy, and the decrease in serum tryptophan correlated positively with the severity of depressive symptoms (15).”
BackgroundThe skin as a mirror of the soul: exploring the possible roles of serotonin
Nordlind, K., Azmitia, E. C., & Slominski, A. T. (2007) · Experimental Dermatology · doi:10.1111/j.1600-0625.2007.00670.x · Cited by 132
Treatment of cytokine-induced depression
Capuron, L., Hauser, P., Hinze-Selch, D., Miller, A. H., & Neveu, P. J. (2002) · Brain Behavior and Immunity · doi:10.1016/s0889-1591(02)00007-7 · Cited by 132
Self-citationLeonard, B. E. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.10.018 · Cited by 129
“These cytokines initiate a severe depressive episode in a substantialminority of the patients, effects which are largely attenuated by appropriate treatment with SSRI antidepressants (Capuron et al., 2002a,b, 2004).”
Fu, X., Zunich, S. M., O’Connor, J. C., Kavelaars, A., Dantzer, R., & Kelley, K. W. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-43 · Cited by 137
“ratio increases in the plasma and brain of patients and animals following both acute and chronic stimulation of the immune system [12-17].”
BackgroundSelf-citationOuakinin, S. R. S., Barreira, D. P., & Gois, C. J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00431 · Cited by 125
Liver–brain interactions in inflammatory liver diseases: Implications for fatigue and mood disorders
D’Mello, C., & Swain, M. G. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.10.009 · Cited by 133
“Cancer patients that were treated with IFN-a showed reduced serum levels of tryptophan within one month of therapy, and the decrease in serum tryptophan correlated positively with the severity of depressive symptoms (Capuron et al., 2002).”
Reichenberg, A., Gorman, J. M., & Dieterich, D. T. (2005) · AIDS · doi:10.1097/01.aids.0000192087.64432.ae · Cited by 129
“It has also been suggested that in cancer patients cognitive dysfunction is only secondary to depressive symptomatology [9].”
BackgroundDiet, Obesity, and Depression: A Systematic Review
Patsalos, O., Keeler, J. L., Schmidt, U. H., Penninx, B. W. J. H., Young, A. H., & Himmerich, H. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11030176 · Cited by 136
“For example, IL-2 reduces tryptophan plasma levels [81], possibly by activating tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO).”
BackgroundAiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications
Lucido, M. J., Bekhbat, M., Goldsmith, D. R., Treadway, M. T., Haroon, E., Felger, J. C., & Miller, A. H. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000043 · Cited by 133
“…with early appearance of neurovegetative symptoms including anhedonia, psychomotor slowing, and fatigue and later appearance of more cognitive symptoms including depressed mood and cognitive dysfunction (Capuron et al., 2002a; Capuron and Miller, 2004; Wichers et al., 2005; Su et al., 2019a).”
BackgroundSelf-citation
Metadata
- 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
- Venue
- Molecular Psychiatry
- Published
- 2002-06-01
- Volume
- 7
- Issue
- 5
- Pages
- 468-473
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- 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
- 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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