The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans
Open accessAbstract
Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.
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Cytokine-related tryptophan depletion may represent a key event in the pathogenesis of depression.
“cytokine-related tryptophan depletion may well represent a key event in the pathogenesis of depression”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Wichers & Maes, 2002
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- Authors
- Wichers, M., & Maes, M.
- Affiliations
- Maastricht University (NL)
- Corresponding author
- Maes, Michael
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-12
- Volume
- 5
- Issue
- 4
- Pages
- 375-388
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2119526257
- Cited by
- 329
- References
- 10
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 4 · 2020: 5 · 2019: 11 · 2018: 14 · 2017: 11 · 2016: 21 · 2015: 17 · 2014: 16 · 2013: 18 · 2012: 16
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- interferon-alpha, interleukin-2, inflammatory cytokines, sickness behavior, serotonin, tryptophan depletion, indoleamine 2,3-dioxygenase, noradrenergic system, hypothalamic-pituitary-adrenal axis, blood-brain barrier, depression pathophysiology
- MeSH terms
- Mental Disorders, Blood-Brain Barrier, Depressive Disorder, Humans, Hypothalamo-Hypophyseal System, Interleukin-2, Norepinephrine, Serotonin, Cytokines, Interferon-alpha
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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