Neuroimmune Mediators: Are Cytokines Mediators of Depression?

Beaurepaire, Renaud de; Świergiel, Artur H.; Dunn, Adrian J.

doi:10.1002/9783527619672.ch22

Cited by 6 publications

(4 citation statements)

References 144 publications

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“…Conceivably, depression has been induced in many of our patients by stress - and chronic, persistent pain is the big stressor for the patients. Exposure to stressful life events such as bereavement, divorce and academic stress is reported to cause depression and impairments of cellular immune function that may affect each other [ 46 - 51 ]. Chronic stress impaired at least T-helper type 1 responses, including the TNFα response [ 49 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of depression symptoms on serum tumor necrosis factor-α of patients with chronic low back pain

et al. 2010

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IntroductionPatients with chronic low back pain (cLBP) have high rates of comorbid psychiatric disorders, mainly depression. Recent evidence suggests that depressive symptoms and pain, as interacting factors, have an effect on the circulating levels of inflammatory markers relevant to coronary artery disease. Our previous work showed a higher serum level of an inflammatory marker tumour necrosis factor-alpha (TNFα) in patients with cLBP, which did not correlate with intensity of low back pain alone. In the present study we investigated the cross-sectional associations of depressive symptoms, low back pain and their interaction with circulating levels of TNFα.MethodsEach group of 29 patients with cLBP alone or with both cLBP and depression was age-matched and sex-matched with 29 healthy controls. All subjects underwent a blood draw for the assessment of serum TNFα and completed a standardised questionnaire regarding medication, depression scores according to the German version of Centre for Epidemiological Studies Depression Scale (CES-D), pain intensity from a visual analogue scale, and back function using the Roland and Morris questionnaire. The correlations between TNFα level and these clinical parameters were analysed.ResultsThere were no differences in TNFα level between cLBP patients with and without depression. Both cLBP patients with (median = 2.51 pg/ml, P = 0.002) and without (median = 2.58 pg/ml, P = 0.004) depression showed significantly higher TNFα serum levels than healthy controls (median = 0 pg/ml). The pain intensity reported by both patient groups was similar, while the patients with depression had higher CES-D scores (P < 0.001) and worse back function (P < 0.001). The variance analysis showed that the interaction between TNFα level and pain intensity, CES-D scores, sex, body mass index and medication was statistically significant.ConclusionsDepression as a comorbidity to cLBP did not influence the serum TNFα level. It seems that TNFα somehow acts as a mediator in both cLBP and depression, involving similar mechanisms that will be interesting to follow in further studies.

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Section: Discussionmentioning

confidence: 99%

Influence of depression symptoms on serum tumor necrosis factor-α of patients with chronic low back pain

et al. 2010

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“…The strongest association has been speculation of a role for cytokines in depression, Both schizophrenia [191] and depression [192] have often been associated with immune abnormalities, but the clinical data have been inconclusive and often conflicting [193]. The link to depression was proposed based on the apparent similarities between sickness behavior and depression [194][195][196][197].…”

Section: Implications Of Cytokine-induced Effects On Neuro-transmissimentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

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285

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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“…Evidence that altered immune system function may play a role in the pathophysiology of major depressive disorder (MDD) has been mounting for decades (Dunn et al, 2005; Enache et al, 2019; Miller & Raison, 2016) and led to the genesis of alternative and corollary hypotheses of depression such as the “cytokine hypothesis” (Smith, 1991). The cytokine hypothesis suggests that MDD is attributed to the chronic activity of proinflammatory cytokines, such as interleukin‐1α and ‐1β (IL‐1α, IL‐1β), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and others, many of which are consistently found to be elevated in MDD subjects both peripherally and centrally (de Beaurepaire et al, 2005; Dowlati et al, 2010; Enache et al, 2019; Miller et al, 2009). Increases in pro‐inflammatory cytokines in viral or bacterial infection result in characteristic sickness behaviors, such as a loss of appetite, anhedonia, physical and social withdrawal, fatigue, irritability, and sleep disruption that are common symptoms of MDD (Dantzer et al, 2008).…”

Section: Novel Targets and Radiotracersmentioning

confidence: 99%

“…Increases in pro‐inflammatory cytokines in viral or bacterial infection result in characteristic sickness behaviors, such as a loss of appetite, anhedonia, physical and social withdrawal, fatigue, irritability, and sleep disruption that are common symptoms of MDD (Dantzer et al, 2008). Administration of cytokines IL‐1β and TNF‐α in rats results in behaviors consistent with sickness (Dantzer, 2001), whereas depression is a common side effect seen in patients receiving cytokine therapy for the treatment of cancer and other conditions (de Beaurepaire et al, 2005; Trask et al, 2000; Valentine et al, 1998). Psychosocial stress is often associated with MDD (Gilman et al, 2013; Kendler et al, 1999) and stress paradigms are widely used in animals to model depressive behaviors (Ramirez et al, 2017).…”

Section: Novel Targets and Radiotracersmentioning

confidence: 99%

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders

Lopresti

Royse

Mathis

et al. 2022

Journal of Neurochemistry

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With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non‐invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [15O]H2O and [18F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders. The first neurochemical PET imaging probes targeted sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. Based on the centrality of monoamine dysfunction in psychiatric disorders and the measured success of monoamine‐enhancing drugs in treating them, the next 30 years witnessed the development of an armamentarium of PET radiopharmaceuticals and imaging methodologies for studying monoamines. Continued development of monoamine‐enhancing drugs over this time however was less successful, realizing only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely paralleled drug development priorities resulting in the development of new PET imaging agents for non‐monoamine targets. Part one of this review will briefly survey novel PET imaging targets with relevance to the field of psychiatry, which include the metabotropic glutamate receptor type 5 (mGluR5), purinergic P2X7 receptor, type 1 cannabinoid receptor (CB1), phosphodiesterase 10A (PDE10A), and describe radiotracers developed for these and other targets that have matured to human subject investigations. Current limitations of the targets and techniques will also be discussed.

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Neuroimmune Mediators: Are Cytokines Mediators of Depression?

Cited by 6 publications

References 144 publications

Influence of depression symptoms on serum tumor necrosis factor-α of patients with chronic low back pain

Influence of depression symptoms on serum tumor necrosis factor-α of patients with chronic low back pain

Effects of cytokines and infections on brain neurochemistry

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders

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