A critical review of human endotoxin administration as an experimental paradigm of depression.

DellaGioia, Nicole; Hannestad, Jonas

doi:10.1016/j.neubiorev.2009.07.014

Cited by 175Tryptophan and brain disordersStress Responses and CortisolTreatment of Major Depression

A critical review of human endotoxin administration as an experimental paradigm of depression.

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DellaGioia, Nicole, Hannestad, Jonas·2010·Neuroscience & Biobehavioral Reviews

DOI 10.1016/j.neubiorev.2009.07.014PMC PMC2795398

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Abstract

The syndrome called depression may represent the common final pathway at which different aetiopathogenic processes converge. One such aetiopathogenic process is innate immune system activation. Some depressed patients have increased levels of inflammatory cytokines and other immunologic abnormalities. It is not known whether immune system activation contributes to the pathogenesis of depressive symptoms. Supporting this possibility is the observation that in both rodents and humans, exogenous immune stimuli such as endotoxin can produce symptoms that resemble depression. A new approach to depression research would be to use immune stimuli to elicit depressive symptoms in humans. Here we review each of the symptoms elicited in humans by endotoxin administration, and compare this model to two other immune depression paradigms: interferon-alpha treatment and typhoid vaccine administration, to assess to what degree endotoxin administration represents a valid model of immune depression. We also review corresponding behavioral changes in rodents and the potential molecular pathways through which immune system activation produces each symptom.

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Endotoxin administration induces feelings of social disconnection and a desire to be alone, which are hallmarks of some depressive episodes.
“endotoxin administration induces feelings of social disconnection and a desire to be alone, which are hallmarks of some depressive episodes”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as DellaGioia & Hannestad, 2010
Section 5.1 (page unavailable) reports that endotoxin reduced participants’ desire for social interaction on a scale asking whether they wanted to be alone or with others. It does not report that participants felt socially disconnected; that feeling is distinct from wanting less social contact. (LLM, conf=0.85)
Experimental — accuracy not yet measured
A large data set has documented mechanistic links between somatic symptoms of depression and increased inflammation in animals and humans.
“a large data set has documented mechanistic links between somatic symptoms of depression and increased inflammation in animals and humans (DellaGioia and Hannestad, 2010)”
From The interplay between stress, inflammation, and emotional attention: relevance for depression (2019) · cites this paper as DellaGioia and Hannestad, 2010
Endotoxin administration to healthy individuals leads to depressive symptoms including negative mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep, social withdrawal, and anxiety.
“These studies have shown that endotoxin administration leads to symptoms of depression including negative mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep, and social withdrawal, as well as anxiety symptoms (DellaGioia and Hannestad, 2010; Eisenberger et al., 2010a; Reichenberg et al., 2001).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as DellaGioia and Hannestad, 2010
Pro-inflammatory cytokines released during infection and inflammation can affect behavior, mood, and functioning of the central nervous system.
“The release of pro-inflammatory cytokines during infection and inflammation can affect behavior, mood, and functioning of the central nervous system (CNS) [1], [2], [3].”
From Dose-dependent effects of endotoxin on neurobehavioral functions in humans (2011) · cites this paper as [2]
IL-6 frequently has been discussed as a potential modulator of mood during sickness behavior and even depression and other neuropsychological diseases.
“Associations between circulating IL-6 levels and negative mood have been reported previously [28], [62] and IL-6 frequently has been discussed as a potential modulator of mood during sickness behavior and even depression and other neuropsychological diseases [2], [3], [9].”
From Dose-dependent effects of endotoxin on neurobehavioral functions in humans (2011) · cites this paper as [2]

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Untitled work
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Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study
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Coincidental Changes in Behavior and Plasma Cortisol in Unrestrained Pigs after Intracerebroventricular Injection of Tumor Necrosis Factor-α*
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Infection-induced proinflammatory cytokines are associated with decreases in positive affect, but not increases in negative affect
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Selective effects of upper respiratory tract infection on cognition, mood and emotion processing: A prospective study
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Cytokines and Sleep
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Background
Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases
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TNF α: A Trigger of Autonomic Dysfunction
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Cognition as predictor of current and follow-up depressive symptoms in the general population
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Antidepressant reversal of interferon-α-induced anhedonia
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Overexpression of IL-1β by adenoviral-mediated gene transfer in the rat brain causes a prolonged hepatic chemokine response, axonal injury and the suppression of spontaneous behaviour
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Lipopolysaccharide and TNF-α Produce Very Similar Changes in Gene Expression in Human Endothelial Cells
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Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence
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Endotoxin Enhances EEG Alpha and Beta Power in Human Sleep
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Recombinant human interferon-α does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats
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Depressive Behavior in Mice Due to Immune Stimulation is Accompanied by Reduced Neural Activity in Brain Regions Involved in Positively Motivated Behavior
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Acute interferon-α administration modulates sucrose consumption in the rat
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Endotoxin-induced changes in sleep and sleepiness during the day
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The widely-used anti-viral drug interferon-alpha induces depressive- and anxiogenic-like effects in healthy rats
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“Sucrose preference is inhibited by endotoxin, IL-1 and TNF (Brebner et al., 2000; De La Garza et al., 2005a,b; Weil et al., 2006), while the data regarding the effects of IFN-a are inconclusive (Sammut et al., 2001; De La Garza et al., 2005a,b; Loftis et al., 2006a,b; Fahey et al., 2007).”
Background
Effects of inflammation produced by chronic lipopolysaccharide administration on the survival of hypocretin neurons and sleep
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“…and social-cognitive aspects of depression are limited, there is some evidence that endotoxin administration induces feelings of social disconnection and a desire to be alone, which are hallmarks of some depressive episodes (DellaGioia & Hannestad, 2010; Eisenberger, Inagaki, et al., 2010).”
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Authors: DellaGioia, N., & Hannestad, J.
Affiliations: Yale University (US)
Corresponding author: Hannestad, Jonas
ORCID: DellaGioia, Nicole
Hannestad, Jonas
Venue: Neuroscience & Biobehavioral Reviews
Publisher: Elsevier BV
Published: 2010-01
Volume: 34
Issue: 1
Pages: 130-143
ISSN: 0149-7634 (ISSN-L)
DOI: 10.1016/j.neubiorev.2009.07.014
PMC: PMC2795398
OpenAlex: W2043189848
Cited by: 175
References: 185
Citations by year: 2026: 5 · 2025: 8 · 2024: 14 · 2023: 12 · 2022: 9 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 15 · 2017: 12 · 2016: 11 · 2015: 8 · 2014: 8 · 2013: 11 · 2012: 16
FWCI: 0.40
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Neuroscience & Biobehavioral Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Center for Research Resources
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: depression, innate immune activation, inflammatory cytokines, interferon-alpha, typhoid vaccine, depressive symptoms, neuroinflammation
MeSH terms: Animals, Brain, Depression, Depressive Disorder, Endotoxins, Humans, Inflammation, Models, Neurological

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A critical review of human endotoxin administration as an experimental paradigm of depression.

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