Cytokines and major depression.
01 Feb 2005-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 29, Iss: 2, pp 201-217
TL;DR: Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.
Abstract: In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.
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TL;DR: A biologically plausible, multilevel theory is proposed that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis and may shed light on several important questions including how depression develops, why it frequently recurs, and why it is strongly predicted by early life stress.
Abstract: Major life stressors, especially those involving interpersonal stress and social rejection, are among the strongest proximal risk factors for depression. In this review, we propose a biologically plausible, multilevel theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis. Central to this social signal transduction theory of depression is the hypothesis that experiences of social threat and adversity up-regulate components of the immune system involved in inflammation. The key mediators of this response, called proinflammatory cytokines, can in turn elicit profound changes in behavior, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. This highly conserved biological response to adversity is critical for survival during times of actual physical threat or injury. However, this response can also be activated by modern-day social, symbolic, or imagined threats, leading to an increasingly proinflammatory phenotype that may be a key phenomenon driving depression pathogenesis and recurrence, as well as the overlap of depression with several somatic conditions including asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, obesity, and neurodegeneration. Insights from this theory may thus shed light on several important questions including how depression develops, why it frequently recurs, why it is strongly predicted by early life stress, and why it often co-occurs with symptoms of anxiety and with certain physical disease conditions. This work may also suggest new opportunities for preventing and treating depression by targeting inflammation.
1,361 citations
Cites methods from "Cytokines and major depression."
...Adapted from Schiepers, Wichers, and Maes (2005), Dantzer, O’Connor, Freund, Johnson, and Kelley (2008), and DellaGioia and Hannestad (2010)....
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TL;DR: It is concluded that aberrations in O&NS pathways are--together with the inflammatory processes--key components of depression, and the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.
Abstract: This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (ION and increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage. There is also evidence in major depression, that ON and increased IgM-mediated immune responses against membrane fatty acids, like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and NO-arginine; and NO-albumin. There is a significant association between depression and polymorphisms in O&NS genes, like manganese superoxide dismutase, catalase, and myeloperoxidase. Animal models of depression very consistently show lowered antioxidant defences and activated O&NS pathways in the peripheral blood and the brain. In animal models of depression, antidepressants consistently increase lowered antioxidant levels and normalize the damage caused by O&NS processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic GPX activity, and zinc exhibit antidepressive effects. This paper reviews the pathways by which lowered antioxidants and O&NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&NS pathways are--together with the inflammatory processes--key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.
982 citations
Cites methods from "Cytokines and major depression."
...Thus, we called this theory the monocyte-T-lymphocyte hypothesis of depression, the cytokine hypothesis of depression, and the inflammatory hypothesis of depression (Maes, 1993, 1995, 1999, 2002; Schiepers et al., 2005)....
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TL;DR: Screening for inflammatory and neurodegenerative processes in depression will allow to discover new I&ND biomarkers, both at the level of gene expression and the phenotype, and elucidate the underlying molecular I &ND pathways causing depression; identify new therapeutic targets in the I& ND pathways; develop new anti-I&ND drugs for these targets; and select existingAnti-I &ND drugs or substances that could augment the efficacy of antidepressants.
Abstract: Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (IN established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new IN and elucidate the underlying molecular IN and 2) identify new therapeutic targets in the IN develop new anti-IN select existing anti-IN and predict therapeutic response by genetic I&ND profiles.
794 citations
Cites background or methods from "Cytokines and major depression."
...Since then there have been many consistent findings over the years of increased levels of proinflammatory cytokines in patients with depression, e.g. interleukin-1 (IL-1), IL-2, IL-6, IL-8, IL-12, interferon-γ (IFNγ and tumor necrosis factor-α (TNFα) (review: Schiepers et al. 2005)....
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...This hypothesis was termed the monocyte-T-lymphocyte or cytokine hypothesis of depression (Maes 1993, 1995, 1999; Maes et al. 1995b; Schiepers et al. 2005)....
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TL;DR: GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.
Abstract: Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.
709 citations
Cites background from "Cytokines and major depression."
...tion may contribute to therapy based on both the (a) depressive effects that cytokines can produce, as well as (b) on much evidence that classical anti-depressants have anti-inflammatory effects [59, 63]....
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TL;DR: The human and animal results related to immune involvement suggest novel therapeutic avenues based on immune interventions, which could help to explain some of the heterogeneity of schizophrenia.
692 citations
References
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01 Jan 2001
4,346 citations
Book•
01 Sep 1994
TL;DR: Introductory immunology textbook for medical students, advanced undergraduates, and graduate students.
Abstract: Introductory immunology textbook for medical students, advanced undergraduates, and graduate students.
3,751 citations
TL;DR: The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded understanding of how the nervous system modulates immune responses, and the opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.
Abstract: Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.
3,146 citations
"Cytokines and major depression." refers background in this paper
...studied by Yirmiya (1996). The effects of the bacterial endotoxin LPS, which is a potent activator of the immune system, on affective and cognitive functions were investigated in healthy human volunteers....
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...The parasympathetic vagal nucleus, located in the brain stem, may downregulate immune function and cytokine production through ACh signalling by the vagus nerve (cranial nerve X; Tracey, 2002)....
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TL;DR: The "catecholamine hypothesis of affective disorders" as discussed by the authors suggests that depression is associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites.
Abstract: The "catecholamine hypothesis of affective disorders" proposes that some, if not all, depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines. Evidence supporting this hypothesis was reviewed. Data from pharmacological studies, mainly in animals, suggest that the actions of both major classes of antidepressant drugs are mediated through the catecholamines. The monoamine oxidase inhibitors increase brain concentrations of norepinephrine while imipramine-like agents potentiate the physiological effects of norepinephrine. Reserpine, a drug which can cause clinical depression, depletes catecholamines, but other amines may also be involved in its mechanism of action. A rigorous extrapolation from pharmacological studies to pathophysiology clearly cannot be made. Clinical studies relevant to the catecholamime hypothesis are limited and the ...
3,012 citations
TL;DR: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than metotrexate alone.
Abstract: Background Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate. Methods In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks. Results The addition of eta...
2,090 citations
"Cytokines and major depression." refers background in this paper
...TNF-a blockers, such as etanercept (EnbrelR) and infliximab (RemicadeR) have been administered to patients suffering from RA and IBD, respectively (Rogler and Andus, 1998; Weinblatt et al., 1999)....
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