Peer-Review Research Studies
Peer-Reviewed Research Studies on the Connection between
Inflammation in the Brain, Stress and Depression
Miller, A and Raison, C. Immune System Contributions to the Pathophysiology of Depression. Journal of the American Psychiatric Association 2008; Focus 6:36-45.
Major depression is a devastating disorder that represents a major public health concern. Of special relevance is the high percentage of patients whose depression does not respond to or who are unable to tolerate conventional antidepressant medications, which primarily target monoamine neurotransmission. Recent data indicate that the immune system may play a role in the pathophysiology of depression, representing a novel pathway for therapeutic development. Patients with major depression have been found to exhibit evidence of an activated innate immune response as reflected by increased biomarkers of inflammation, including innate immune cytokines, acute-phase proteins, chemokines, and adhesion molecules. In addition, administration of innate immune cytokines to laboratory animals and humans has been shown to induce behavioral changes that significantly overlap with the symptom criteria of major depression. Treatment of patients with inflammatory disorders using anticytokine therapies has also been found to reduce depressive symptoms. Interestingly, psychosocial stress, a well-known precipitant of depressive disorders, has been shown to activate the innate immune response. Finally, innate immune cytokines have been shown to influence virtually every pathophysiological domain relevant to depression including monoamine neurotransmission, neuroendocrine function, synaptic plasticity, and regional brain metabolism. Of note, a response to conventional antidepressant medications is associated with a decrease in inflammatory biomarkers, whereas patients with treatment-resistant depression are more likely to exhibit evidence of increased inflammation. Taken together, these data provide the foundation for considering an activated innate immune response as a potential target for further study and therapeutic development in mood disorders, especially in the context of treatment resistance.
Illman et al. Are inflammatory cytokines the common link between cancer-associated cachexia and depression? J Support Oncol 2005;3:37-50.
The prevalence of depression among patients diagnosed with cancer is higher than among the general medical population and is associated with faster tumor progression and shortened survival time. Cancer-related depression often occurs in association with anorexia and cachexia, although until recently the relationship between these conditions has not been well understood. Cachexia is associated with poorer quality of life and survival outcomes and is the eventual cause of death in approximately 30% of all patients with cancer. Recent evidence has linked elevated levels of inflammatory cytokines with both depression and cachexia, and experiments have shown that introducing cytokines induces depression and cachectic symptoms in both humans and rodents, suggesting that there may be a common etiology at the molecular level. Therapeutic agents targeting specific cytokine molecules, such as interleukin-6 or tumor necrosis factor-alpha, are currently being evaluated for their potential to simultaneously treat both depression and cachexia pharmacologically. This review summarizes the available data suggesting a dual role for cytokines in the development of cancer-related depression and cachexia and describes how biologic therapies targeting specific cytokines may improve outcomes beyond depression and cachexia, such as survival and quality of life.
PMID: 15724944 [PubMed - indexed for MEDLINE]
Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol. 2004 Oct 1;500(1-3):399-411.
Sufficient evidence is now available to accept the concept that the brain recognizes cytokines as molecular signals of sickness. Clarifying the way the brain processes information generated by the innate immune system is accompanied by a progressive elucidation of the cellular and molecular components of the intricate system that mediates cytokine-induced sickness behavior. We are still far, however, from understanding the whole. Among the hundreds of genes that proinflammatory cytokines can induce in their cellular targets, only a handful has been examined functionally. In addition, a dynamic view of the cellular interactions that occur at the brain sites of cytokine production and action is missing, together with a clarification of the mechanisms that favor the transition toward pathology.
PMID: 16877117 [PubMed - indexed for MEDLINE]
Borovikova LV, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62.
Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.
PMID: 10839541 [PubMed - indexed for MEDLINE]
Brydon L, Edwards S, Mohamed-Ali V, Steptoe A: Socioeconomic status and stress-induced increases in interleukin-6. Brain, Behavior, & Immunity 2004; 18:281–290), as well as activation of nuclear factor (NF)-.B.
Coronary artery disease (CAD) is more prevalent in people from a low socioeconomic background, and low socioeconomic status (SES) is associated with an increased exposure to psychological stress. The pro-inflammatory cytokine interleukin-6 (IL-6) plays a central role in CAD development. IL-6 is responsive to psychological stress and could potentially mediate the effect of psychosocial factors on CAD risk. Accordingly, we predicted that people of low SES would have greater and/or more sustained IL-6 responses to acute psychological stress. Based on previous findings, we also predicted that these people would have delayed post-stress cardiovascular recovery. Thirty-eight male civil servants were tested, with participants divided into high and low SES groups according to employment grade. There were no differences between the groups at baseline. However there were significant differences in IL-6 and heart rate responses to stress. Stress induced increases in plasma IL-6 in all participants. However, in the low SES group, IL-6 continued to increase between 75 min and 2h post-stress, whereas IL-6 levels stabilised at 75 min in the high SES group. Heart rate increased to the same extent following stress in both groups, however by 2h post-stress, it had returned to baseline in 75% of the high SES group compared with only 38.1% of the low SES group. These results suggest that low SES people are less able to adapt to stress than their high SES counterparts. Prolonged stress-induced increases in IL-6 in low SES groups represents a novel mechanism potentially linking socioeconomic position and heart disease.
PMID: 15050655 [PubMed - indexed for MEDLINE]
Glaser JK, Glaser R. Depression and immune function: central pathways to morbidity and mortality. J Psychosom Res 2002;53:873–876.
OBJECTIVE: The increased morbidity and mortality associated with depression is substantial. In this paper, we review evidence suggesting that depression contributes to disease and death through immune dysregulation. METHOD: This review focuses on recent human studies addressing the impact of depression on immune function, and the health consequences of those changes. RESULTS: There is growing evidence that depression can directly stimulate the production of proinflammatory cytokines that influence a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. Additionally, depression can down-regulate the cellular immune response; as a consequence, processes such as prolonged infection and delayed wound healing that fuel sustained proinflammatory cytokine production may be promoted by depression. CONCLUSIONS: These direct and indirect processes pose the greatest health risks for older adults who already show age-related increases in proinflammatory cytokine production. Thus, aging interacts with depression to enhance risks for morbidity and mortality.
PMID: 12377296 [PubMed - indexed for MEDLINE]
Song C, Lin A, Bonaccorso S, et al. The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 1998;49:211–219.
BACKGROUND: It is now well established that major depression is accompanied by an immune-inflammatory system response and that indicators of the latter are inversely correlated with lower availability of plasma tryptophan in depression. Inflammation and infection can alter sleep architecture, whereas sleep disturbances can impair immune functions. AIMS AND METHODS: The aims of the present study were to examine: (i) immune-inflammatory markers, i.e. serum interleukin-6 (IL-6), IL-8, IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA), gp130, and prostaglandin E2 (PGE2) production by mitogen-stimulated whole blood and the availability of plasma tryptophan in patients with primary sleep disorders, major depression and healthy volunteers; and (ii) the relationships between the availability of tryptophan and indicators of the immune-inflammatory response system. RESULTS: Mitogen-stimulated release of PGE2, and serum IL-6 and IL-8, were significantly increased in both depressed and sleep disordered patients compared to normal controls. Serum IL-1RA was significantly higher in depressed patients than in normal controls. Patients with depression and sleep disorders had a significantly lower availability of tryptophan than normal controls. There were significant and inverse relationships between the availability of plasma tryptophan and serum IL-1RA, IL-6 and IL-8. CONCLUSIONS: The results suggest that (i) there is an activation of the immune-inflammatory response system in primary sleep disorders and depression; and (ii) the decreased availability of plasma tryptophan may be related to the inflammatory system response.
PMID: 9629951 [PubMed - indexed for MEDLINE]
Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, et al. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A 2003;100:9090–9095.
Overproduction of IL-6, a proinflammatory cytokine, is associated with a spectrum of age-related conditions including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. To describe the pattern of change in IL-6 over 6 years among older adults undergoing a chronic stressor, this longitudinal community study assessed the relationship between chronic stress and IL-6 production in 119 men and women who were caregiving for a spouse with dementia and 106 noncaregivers, with a mean age at study entry of 70.58 (SD = 8.03) for the full sample. On entry into this portion of the longitudinal study, 28 of the caregivers' spouses had already died, and an additional 50 of the 119 spouses died during the 6 years of this study. Levels of IL-6 and health behaviors associated with IL-6 were measured across 6 years. Caregivers' average rate of increase in IL-6 was about four times as large as that of noncaregivers. Moreover, the mean annual changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse. There were no systematic group differences in chronic health problems, medications, or health-relevant behaviors that might have accounted for caregivers' steeper IL-6 slope. These data provide evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response.
PMID: 12840146 [PubMed - indexed for MEDLINE]
Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007 Feb;21(2):153-60. Epub 2006 Nov 7.
Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.
PMID: 17088043 [PubMed - indexed for MEDLINE]
Bierhaus A, et al.. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Nat Acad Sci U S A 2003; 100:1920–1925.
Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.
PMID: 12578963 [PubMed - indexed for MEDLINE]
Bluthé RM, et al. Effects of insulin-like growth factor-I on cytokine-induced sickness behavior in mice. Brain, Behavior, and Immunity 2006; 57–63.
Central administration of insulin-like growth factor-I (IGF-I) attenuates sickness behavior in response to the cytokine inducer lipopolysaccharide. The present study was designed to determine the respective roles of the two main proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), in these effects. Male CD1 mice were injected into the lateral ventricle (i.c.v.) of the brain with optimal amounts of either TNFalpha (50 ng) or IL-1beta (2 ng) that induce sickness behavior. Behavioral responses to IGF-I (0, .1, and 1 microg) also given i.c.v. were measured at various time intervals before and after treatment with the two proinflammatory cytokines. Mice treated with TNFalpha and IL-1beta lost body weight and displayed equivalent reductions in social exploration and instances of immobility. At the dose of .1 microg, IGF-I attenuated these signs of sickness in TNFalpha-but not in IL-1beta-treated mice. At the dose of 1 microg, IGF-I attenuated IL-1beta-induced immobility and the reduction in social exploration but had no effect on loss of body weight. These findings indicate that IGF-I is more potent in attenuating sickness behavior induced by TNFalpha than that caused by IL-1beta, which is consistent with the relative specificity of the TNFalpha/IGF-I interactions in the brain.
PMID: 16364817 [PubMed - indexed for MEDLINE]
Caro AA, Cederbaum AI. Role of cytochrome P450 in phospholipase A2- and arachidonic acid-mediated cytotoxicity. Free Radic Biol Med. 2006 Feb 1;40(3):364-75.
Phospholipases A2 (PLA2) comprise a set of extracellular and intracellular enzymes that catalyze the hydrolysis of the sn-2 fatty acyl bond of phospholipids to yield fatty acids and lysophospholipids. The PLA2 reaction is the primary pathway through which arachidonic acid (AA) is released from phospholipids. PLA2s have an important role in cellular death that occurs via necrosis or apoptosis. Several reports support the hypothesis that unesterified arachidonic acid in cells is a signal for the induction of apoptosis. However, most of the biological effects of arachidonic acid are attributable to its metabolism by mainly three different groups of enzymes: cytochromes P450, cyclooxygenases, and lipoxygenases. In this review we will focus on the role of cytochrome P450 in AA metabolism and toxicity. The major pathways of arachidonic acid metabolism catalyzed by cytochrome P450 generate metabolites that are subdivided into two groups: the epoxyeicosatrienoic acids, formed by CYP epoxygenases, and the arachidonic acid derivatives that are hydroxylated at or near the omega-terminus by CYP omega-oxidases. In addition, oxidation of AA by cytochrome P450-derived reactive oxygen species produces lipid hydroperoxides as primary oxidation products. In some cellular models of toxicity, cytochrome P450 activity exacerbates PLA2- and AA-dependent injury, mainly through the production of oxygen radicals that promote lipid peroxidation or production of metabolites that alter Ca2+ homeostasis. In contrast, in other situations, cytochrome P450 metabolism of AA is protective, mainly by lowering levels of unesterified AA and by production of metabolites that activate antiapoptotic pathways. Several lines of evidence point to the combined action of phospholipase A2 and cytochrome P450 as central in the mechanism of cellular injury in several human diseases, such as alcoholic liver disease and myocardial reperfusion injury. Inhibition of specific PLA2 and cytochrome P450 isoforms may represent novel therapeutic strategies against these diseases.
PMID: 16443151 [PubMed - indexed for MEDLINE]
Carr D, Goudas L, Lawrence D, et al. Management of cancer symptoms: pain depression and fatigue. Evidence Report/Technology Assessment No. 61. AHRQ Publication No. 02-E032. Agency for Healthcare Research and Quality. July 2002.
PMID: 12187571 [PubMed - indexed for MEDLINE]
Cleeland et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokineimmunologic model of cancer symptoms. Cancer 2003. 97:2919–2925.
BACKGROUND: Cancers and cancer treatments produce multiple symptoms that collectively cause a symptom burden for patients. These symptoms include pain, wasting, fatigue, cognitive impairment, anxiety, and depression, many of which co-occur. There is growing recognition that at least some of these symptoms may share common biologic mechanisms. METHODS: In November 2001, basic and clinical scientists met to consider evidence for a cytokine-immunologic model of symptom expression along with directions for future research. RESULTS: The characteristics of cytokine-induced sickness behavior in animal models have much in common with those of symptomatic cancer patients. Sickness behavior refers to a set of physiologic and behavioral responses observed in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines. In some cases, these responses can be prevented by cytokine antagonists. A combination of animal and human research suggests that several cancer-related symptoms may involve the actions of proinflammatory cytokines. CONCLUSIONS: Based on the similarities between cancer symptoms and sickness behavior, the authors discussed approaches to further test the implications of the relationship between inflammatory cytokines and symptoms for both symptom treatment and symptom prevention. Copyright 2003 American Cancer Society.
PMID: 12767108 [PubMed - indexed for MEDLINE]
Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I. Gender differences in neurological disease: role of estrogens and cytokines. Endocrine 2006 Apr;29(2):243-56.
Increasing evidence suggests that inflammatory response may be a critical component of different brain pathologies. However, the role played by this reaction is not fully understood. The present findings suggest that neuroinflammtory mediators such as cytokines may be involved in a number of key steps in the pathological cascade of events leading to neuronal injury. This hypothesis is strongly supported by experimental and clinical observations indicating that inhibition of the inflammatory reaction correlates with less neuronal damage. Estrogens are thought to play a role in the sex difference observed in many neurological diseases with inflammatory components including stroke, Alzheimer's and Parkinson's diseases, multiple sclerosis, or amyotrophic lateral sclerosis. Clinical and experimental studies have established estrogen as a neuroprotective hormone in these diseases. However, the exact mechanisms involved in the neuroprotective effects of estrogens are still unclear. It is possible that the beneficial effects of these hormones may be dependent on their inhibitory activity on the inflammatory reaction associated with the above-mentioned brain pathologies. Here, we review the current clinical and experimental evidence with respect to the inflammation-modulating effects of estrogens as one potential explanatory factor for sexual dimorzphism in the prevalence of numerous neurological diseases.
PMID: 16785600 [PubMed - indexed for MEDLINE]
Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I. Estrogen and cytokines production - the possible cause of gender differences in neurological diseases. Curr Pharm Des. 2005;11(8):1017-30.
Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogen's wide range of effects within the mammalian central nervous system (CNS), with it's neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of it's anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.
PMID: 15777251 [PubMed - indexed for MEDLINE]
Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav. Immun. 2001;15: 7–24.
Sickness behavior refers to the coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the effects of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), in the brain. Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the body site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens. There is clinical and experimental evidence that activation of the brain cytokine system is associated with depression, although the exact relationship between sickness behavior and depression is still elusive.
PMID: 11259077 [PubMed - indexed for MEDLINE]
Dantzer R. Innate immunity at the forefront of psychoneuroimmunology. Brain Behav Immun. 2004 Jan;18(1):1-6.
The last 15 years of research in psychoneuroimmunology have been marked by a renewed interest in the mechanisms of inflammation and participation of the brain in these mechanisms. Peripheral proinflammatory cytokines produced by activated accessory immune cells act in the brain to trigger sickness, in the form of fever, pituitary-adrenal axis activation, and sickness behavior. Communication between the periphery and brain takes place via both neural and humoral pathways. Recognition of the role of local production of cytokines and their downstream messengers in the central nervous system opens important new vistas for understanding and treating non-specific neurovegetative and psychiatric symptoms of diseases. In this presidential address, I present the main methodological and conceptual developments that have allowed such progress.
PMID: 14651940 [PubMed - indexed for MEDLINE]
Darmon P, et al. Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity. Am J Physiol Endocrinol Metab. 2006 Jun 13.
Glucocorticoids hypersensitivity may be involved in the development of abdominal obesity and insulin resistance. Eight normal weight and eight obese women received on two occasions a 3-h intravenous infusion of saline or hydrocortisone (HC) (1.5 microg x kg(-1) x min(-1)). Plasma cortisol, insulin, and glucose levels were measured every 30 min from time(-30) (min) (time(-30)) to time(240). Free fatty acids, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were measured at time(-30), time(180), and time(240). At time(240), subjects underwent an insulin tolerance test to obtain an index of insulin sensitivity (K(ITT)). Mean(30-240) cortisol level was similar in control and obese women after saline (74 +/- 16 vs. 75 +/- 20 microg/l) and HC (235 +/- 17 vs. 245 +/- 47 microg/l). The effect of HC on mean(180-240) insulin, mean(180-240) insulin resistance obtained by homeostasis model assessment (HOMA-IR), and K(ITT) was significant in obese (11.4 +/- 2.0 vs. 8.2 +/- 1.3 mU/l, P < 0.05; 2.37 +/- 0.5 vs. 1.64 +/- 0.3, P < 0.05; 2.81 +/- 0.9 vs. 3.32 +/- 1.02%/min, P < 0.05) but not in control women (3.9 +/- 0.6 vs. 2.8 +/- 0.5 mU/l; 0.78 +/- 0.1 vs. 0.49 +/- 0.1; 4.36 +/- 1.1 vs. 4.37 +/- 1.2%/min). In the whole population, the quantity of visceral fat, estimated by computerized tomography scan, was correlated with the increment of plasma insulin and HOMA-IR during HC infusion [Delta mean(30-240) insulin (r = 0.61, P < 0.05), Delta mean(30-240) HOMA-IR (r = 0.66, P < 0.01)]. The increase of PAI-1 between time(180) and time(240) after HC was higher in obese women (+25%) than in controls (+12%) (P < 0.05), whereas no differential effect between groups was observed for free fatty acids or adiponectin. A moderate hypercortisolism, equivalent to that induced by a mild stress, has more pronounced consequences on insulin sensitivity in abdominally obese women than in controls. These deleterious effects are correlated with the amount of visceral fat.
PMID: 16772320 [PubMed - indexed for MEDLINE]
Gidron Y, Gilutz H, Berger R, Huleihel M. Molecular and cellular interface between behavior and acute coronary syndromes. Cardiovasc Res. 2002 Oct;56(1):15-21.
This review article integrates empirical findings from various scientific disciplines into a proposed psychoneuroimmunological (PNI) model of the acute coronary syndrome (ACS). Our starting point is an existing, mild, atherosclerotic plaque and a dysfunctional endothelium. The ACS is triggered by three stages. (1) Plaque instability: Pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha) and chemoattractants (MCP-1, IL-8) induce leukocyte chemoattraction to the endothelium, and together with other triggers such as the CD40L-CD40 co-stimulation system activate plaque monocytes (macrophages). The macrophages then produce matrix metalloproteinases that disintegrate extra-cellular plaque matrix, causing coronary plaque instability. Acute stress, hostility, depression and vital exhaustion (VE) have been associated with elevated pro-inflammatory cytokines and leukocyte levels and their recruitment. (2) Extra-plaque factors promoting rupture: Neuro-endocrinological factors (norepinephrine) and cytokines induce vasoconstriction and elevated blood pressure (BP), both provoking a vulnerable plaque to rupture. Hostility/anger and acute stress can lead to vasoconstriction and elevated BP via catecholamines. (3) Superimposed thrombosis at a ruptured site: Increases in coagulation factors and reductions in anticoagulation factors (e.g. protein C) induced by inflammatory factors enhance platelet aggregation, a key stage in thrombosis. Hostility, depression and VE have been positively correlated with platelet aggregation. Thrombosis can lead to severe coronary occlusion, clinically manifested as an ACS. Thus, PNI processes might, at least in part, contribute to the pathogenesis of the ACS. This chain of events may endure due to lack of neuroendocrine-to-immune negative feedback stemming from cortisol resistance. This model has implications for the use of psychological interventions in ACS patients.
PMID: 12237162 [PubMed - indexed for MEDLINE]
Hellhammer J, Schlotz W, Stone AA, Pirke KM, Hellhammer D. Allostatic load, perceived stress, and health: a prospective study in two age groups. Ann N Y Acad Sci. 2004 Dec;1032:8-13.
Overactivity of the hypothalamus-pituitary-adrenal axis (HPAA) has been observed in the presence of acute stress and, under chronic conditions, in disorders such as depression and anorexia nervosa as well as in cardiovascular and metabolic disorders. However, there may be other stress-related disorders (fatigue, pain, etc) that seem to be associated with mild hypocortisolism. This suggests that two major subtypes of the HPAA response to stress need to be discriminated. In this study, we investigated 76 subjects with and without hypocortisolism, respectively, over a 1-year period. Surprisingly, hypocortisolemic subjects had a lower allostatic load but they scored higher on measures of depression, perceived stress, and physical complaints. We propose a protective role of the hypocortisolemic stress response on cardiovascular and metabolic disorders, particularly in the elderly.
PMID: 15677392 [PubMed - indexed for MEDLINE]
Kelley KW, et al. Cytokine-induced sickness behavior. Brain Behav Immune. 2003 Feb;17 Suppl 1:S112-8.
The behavioral repertoire of humans and animals changes dramatically following infection. Sick individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They display an inability to experience pleasure, have exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines acting in the brain cause sickness behaviors. These nearly universal behavioral changes are a manifestation of a central motivational state that is designed to promote recovery. Exaggerated symptoms of sickness in cancer patients, such as cachexia, can be life-threatening. However, quality of life is often drastically impaired before the cancer becomes totally debilitating. Although basic studies in psychoneuroimmunology have defined proinflammatory cytokines as the central mediators of sickness behavior, a much better understanding of how cytokine and neurotransmitter receptors communicate with each other is needed. Advances that have been made during the past decade should now be extended to clinical studies in an attempt to alleviate sickness symptoms and improve quality of life for cancer patients.
PMID: 12615196 [PubMed - indexed for MEDLINE]
Kiecolt-Glaser JK, Glaser R. Depression and immune function: central pathways to morbidity and mortality. J Psychosom Res. 2002 Oct;53(4):873-6.
OBJECTIVE: The increased morbidity and mortality associated with depression is substantial. In this paper, we review evidence suggesting that depression contributes to disease and death through immune dysregulation. METHOD: This review focuses on recent human studies addressing the impact of depression on immune function, and the health consequences of those changes. RESULTS: There is growing evidence that depression can directly stimulate the production of proinflammatory cytokines that influence a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. Additionally, depression can down-regulate the cellular immune response; as a consequence, processes such as prolonged infection and delayed wound healing that fuel sustained proinflammatory cytokine production may be promoted by depression. CONCLUSIONS: These direct and indirect processes pose the greatest health risks for older adults who already show age-related increases in proinflammatory cytokine production. Thus, aging interacts with depression to enhance risks for morbidity and mortality.
PMID: 12377296 [PubMed - indexed for MEDLINE]
Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome.Curr Diab Rep. 2005 Feb;5(1):70-5.
Advances in adipose tissue biology over the past 10 years have led to an improved understanding of the mechanisms linking obesity with the metabolic syndrome and other complications. Obesity is characterized by a chronic, systemic low-grade state of inflammation. Biomarkers of inflammation, such as the leukocyte count, tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and C-reactive protein, are increased in obesity, associated with insulin resistance, and predict the development of type 2 diabetes and cardiovascular disease. It is now clear that the adipocyte is an active participant in the generation of the inflammatory state in obesity. Adipocytes secrete a variety of cytokines, including IL-6 and TNF-alpha, that promote inflammation. Moreover, recent studies suggest that obesity is associated with an increase in adipose tissue macrophages, which also participate in the inflammatory process through the elaboration of cytokines. An improved understanding of the role of adipose tissue in the activation of inflammatory pathways may suggest novel treatment and prevention strategies aimed at reducing obesity-associated morbidities and mortality.
PMID: 15663921 [PubMed - indexed for MEDLINE]
Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA: Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiology 2002; 90:1279–1283
Despite mounting evidence that psychiatric depression heightens risk for cardiac morbidity and mortality, little is known about the mechanisms responsible for this association. The present study examined the relation between depression and the expression of inflammatory risk markers implicated in the pathogenesis of coronary heart disease (CHD). One hundred adults were enrolled (68% women, 48% Caucasian, 48% African-American, mean age 30 +/- 2 years). Fifty subjects met the diagnostic criteria for clinical depression; the remaining 50 were demographically matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or regular medication regimen aside from oral contraceptives. The depressed subjects exhibited significantly higher levels of the inflammatory markers C-reactive protein (3.5 +/- 0.5 vs 2.5 +/- 5 mg/L, p = 0.04) and interleukin-6 (3.0 +/- 0.3 vs 1.9 +/- 0.2 pg/ml, p = 0.007) compared with control subjects. Mediational analyses aimed at identifying the pathways contributing to this association revealed that neither cigarette smoking nor subclinical infection with cytomegalovirus or Chlamydia pneumoniae had been responsible. However, depressed subjects exhibited greater body mass than control subjects, and analyses were consistent with adiposity accounting for a portion of the relation between clinical depression and increased expression of inflammatory markers. These findings indicate that in otherwise healthy adults, depression is associated with heightened expression of inflammatory markers implicated in the pathogenesis of CHD. Increased body mass appears to be partially, although not completely, responsible for this relation.
PMID: 12480034 [PubMed - indexed for MEDLINE]
Pace TW, et al. Increased Stress-Induced Inflammatory Responses in Male Patients With Major Depression and Increased Early Life Stress. Am J Psychiatry. 2006 Sep;163(9):1630-1633.
OBJECTIVE: The authors sought to determine innate immune system activation following psychosocial stress in patients with major depression and increased early life stress. METHOD: Plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells were compared in medically healthy male subjects with current major depression and increased early life stress (N=14) versus nondepressed male comparison subjects (N=14) before and after completion of the Trier Social Stress Test. RESULTS: Trier Social Stress Test-induced increases in IL-6 and NF-kappaB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity, but not early life stress. Natural killer (NK) cell percentages also increased following stress. However, there were no differences between groups and no correlation between NK cell percentage and stress-induced NF-kappaB DNA-binding or IL-6. CONCLUSIONS: Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.
PMID: 16946190 [PubMed - indexed for MEDLINE]
Raz Yirmiya. Depression in medical illness: The role of the immune system. West J Med. 2000 November; 173(5): 333–336.
Many interactions occur between the immune, neural, and psychological systems. These interactions include communication pathways from the brain to the immune system, particularly the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, that mediate the influence of psychological variables, such as stress and emotions, on immunity and resistance to disease.1
In addition, when the body is confronted by pathogens, the immune system serves as a sensory organ, alerting the brain to the presence of infection-induced immune activation.2 The communication from the immune system to the brain is mediated by cytokines, which are peptides that orchestrate the immune response with a wide range of other biologic activities. During immune stimulation, cytokines such as interleukins and interferons are produced both in the periphery and in the brain, where they can affect neural, neuroendocrine, and behavioral functions through specific receptors.2,3
In addition to physiologic responses, such as fever, and hormonal responses, such as activation of the HPA axis, brain cytokines also produce behavioral changes. A person with a physical illness may show depressed mood, anorexia, weight loss, sleepiness and altered sleep patterns, fatigue and retardation of motor activity, reduced interest in the physical and social environment, and impaired cognitive abilities.3,4 During an acute infection, these behavioral symptoms, collectively termed “sickness behavior,” are considered to be an adaptive response, rather than due to the disease process itself and the fever that accompanies it. However, during chronic infections and other chronic medical conditions associated with intense immune activation, the sickness behavior syndrome can develop into a depressive episode. Illness-associated depression can cause high levels of distress in a sick person and may further complicate the existing physical symptoms and compliance with therapy.
In this review, I present the current knowledge on the role of cytokines in mediating the depressive symptoms that accompany various medical conditions. I also consider the possible use of antidepressant drugs—and their mechanism of action—in the treatment of illness-associated depression.
PMID: 11069873 [PubMed - indexed for MEDLINE]
Romanovsky AA. Signaling the brain in the early sickness syndrome: are sensory nerves involved? Front Biosci. 2004 Jan 1;9:494-504.
Nonspecific manifestations (sickness symptoms) of inflammation and infection occur as two sequential syndromes, the early and late. This review deals with the early sickness syndrome, which occurs at the onset of the inflammatory process and manifests itself with a high deep body temperature, hyperalgesia/allodynia, arousal, motor agitation, and arterial hypertension. Two rat models of intravenous lipopolysaccharide (LPS)-induced fever are used to study the early syndrome: 1) a monophasic response to low, just suprathreshold doses of LPS and 2) the first rise in body temperature (Phase I) of the polyphasic response to higher doses. Experiments in the first model reveal a blockade of monophasic fever by total subdiaphragmatic or selective hepatic vagotomy, thus suggesting mediation of this response by the hepatic vagal fibers, presumably afferent. Experiments in the second model show that Phase I of polyphasic fever is insensitive to surgical vagotomy but does not occur in animals desensitized with low intraperitoneal doses of capsaicin (an agonist of the vanilloid receptor VR1). These findings suggest that Phase I is mediated by intra-abdominal, VR1-receptor-bearing afferents, either splanchnic or possibly splanchnic and vagal. The involvement of the splanchnic nerve and VR1 receptor in Phase I of LPS fever is currently under investigation in our laboratory. Based on studies completed so far, neural signaling mechanisms are involved in both monophasic fever and Phase I of polyphasic fever. We speculate that these mechanisms are triggered by peripherally originated, blood-borne prostaglandin E2.
PMID: 14766385 [PubMed - indexed for MEDLINE]
Sharpe M, Strong V, Allen K, et al. Major depression in outpatients attending a regional cancer centre: screening and unmet treatment needs. Br J Cancer 2004;90:314–320.
A screening programme designed to identify cases of Major Depressive Disorder (MDD) in patients attending a Regional Cancer Centre outpatient department was established. It comprised two stages: (1) The Hospital Anxiety and Depression Scale (HADS) self-rating questionnaire administered by a touch-screen computer; (2) we interviewed patients with high scores on the HADS (15 or more total score) over the telephone using the depression section of the Structured Clinical Interview for DSMIV (SCID). A large consecutive sample (5613) of oncology clinic attenders was screened, and practical difficulties in the screening process were identified. The estimated prevalence of major depressive disorder (MDD) in the sample surveyed was approximately 8% (7.8%; 95% confidence intervals 6.9-8.5%). We assessed a consecutive series of 150 patients identified as having MDD to determine how many had received evidence-based treatment for MDD. Only half had discussed their low mood with their general practitioner, only one-third had been prescribed any antidepressant medication, and very few had taken a therapeutic dose for an adequate period. Very few had received psychological treatment or had been referred to mental health services. Most were receiving no potentially effective therapy.
PMID: 14735170 [PubMed - indexed for MEDLINE]
Suarez EC, et al. Increases in stimulated secretion of proinflammatory cytokines by blood monocytes following arousal of negative affect: the role of insulin resistance as moderator. Brain Behav Immun. 2006 Jul;20(4):331-8.
We examined the effect of negative affect on changes in stimulated secretion of cytokines by blood monocytes and determined whether insulin resistance (IR), as indexed by the Homeostasis Model Assessment (HOMA), moderated these associations in 58 healthy men (aged 18-65 years). Blood samples and ratings of negative affect were collected at rest and 15min following subjects' participation in the Anger Recall Interview (ARI). Assessment of lipopolysaccharide (LPS)-stimulated secretion of IL-1beta, IL-6, and TNF-alpha was accomplished by ELISA of supernatant. Regression models controlling for age, body mass index, and race/ethnicity revealed that higher HOMA-IR values were associated with larger stress-induced increases in IL-1beta and TNF-alpha (p<.05). Furthermore, arousal of negative affect during the ARI was differentially associated with stress-induced changes in stimulated secretion of TNF-alpha and IL-6 as a function of HOMA-IR (p<.05). Increases in stimulated cytokine secretion were associated with arousal of negative affect, but only among men with higher HOMA-IR values. Among men with lower HOMA-IR values, arousal of negative affect was associated with diminished cytokine secretion. Collectively, these data suggest that the HOMA-IR moderates the impact that arousal of negative affect has on the ability of blood monocytes to secrete inflammatory cytokines in response to LPS. Stress-induced increases in cytokine secretion among high HOMA-IR men are consistent with the role of inflammation in cardiovascular disease, hypertension, type 2 diabetes as well as the metabolic syndrome and underscore the relevance of negative affect in the etiology of these inflammatory conditions.
PMID: 16288846 [PubMed - indexed for MEDLINE]
Tchekmedyian NS, Kallich J, McDermott A, Fayers P, Erder MH. The relationship between psychologic distress and cancer-related fatigue. Cancer 2003;98:198–203.
BACKGROUND: The authors examined the relationship between changes in depression and anxiety levels with changes in fatigue levels among anemic patients with lung cancer who participated in a randomized, double-blind, placebo-controlled clinical trial of darbepoetin alfa for the treatment of anemia. METHODS: Patients completed the Brief Symptom Inventory (BSI) Depression and Anxiety subscales and the Functional Assessment of Cancer Therapy (FACT) Fatigue subscale during the trial. Pearson correlation coefficients were used to compare changes in the BSI scores with changes in the FACT Fatigue scores. Multiple regression models were used to explore sociodemographic and clinical explanatory variables. RESULTS: At baseline, 25% and 35% of 250 patients reported high levels (normed BSI scores >or= 65) of anxiety and depression, respectively. Correlations of changes in normed BSI Anxiety and Depression subscale scores with changes in FACT Fatigue scores had coefficients of -0.45 (P < 0.001) and -0.44 (P < 0.001), respectively. In the multiple regression models, change in the FACT Fatigue score was the only significant explanatory variable (P < 0.001). For every unit improvement in FACT Fatigue score, there was a corresponding improvement of 0.7 points and 0.8 points in anxiety and depression levels, respectively. CONCLUSIONS: Improvements in fatigue were associated significantly with reductions in anxiety and depression. For patients with anemia, fatigue can be improved or reversed with darbepoetin alfa therapy. Thus, less fatigued patients also may benefit from reduced levels of anxiety and depression. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11463
PMID: 12833472 [PubMed - indexed for MEDLINE]
Thaker, P.H., et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nature Medicine. 2006; 12:939 - 944 (2006)
Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.
PMID: 16862152 [PubMed - indexed for MEDLINE]
Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on depression, anxiety, and oncology. J Clin Psychiatry 2001;62(suppl 8):64–67.
PMID: 12108825 [PubMed - indexed for MEDLINE]
Treatment of Sickness Syndrome
Coulman KD,et al. Nutr Cancer. 2005;52(2):156-65.
The mammalian lignans enterolactone and enterodiol, which are produced by the microflora in the colon of humans and animals from precursors in foods, have been suggested to have potential anticancer effects. This study determined the production of mammalian lignans from precursors in food bars containing 25 g unground whole flaxseed (FB), sesame seed (SB), or their combination (FSB; 12.5 g each). In a randomized crossover study, healthy postmenopausal women supplemented their diets with the bars for 4 wk each separated by 4-wk washout periods, and urinary mammalian lignan excretion was measured at baseline and after 4 wk as a marker of mammalian lignan production. Results showed an increase with all treatments (65.1-81.0 mumol/day; P < 0.0001), which did not differ among treatments. Lignan excretion with the whole flaxseed was similar to results of other studies using ground flaxseed. An unidentified lignan metabolite was detected after consumption of SB and FSB but not of FB. Thus, we demonstrated for the first time that 1) precursors from unground whole flaxseed and sesame seed are converted by the bacterial flora in the colon to mammalian lignans and 2) sesame seed, alone and in combination with flaxseed, produces mammalian lignans equivalent to those obtained from flaxseed alone.
PMID: 16201847 [PubMed - indexed for MEDLINE]
Ammon HP. Boswellic acids (components of frankincense) as the active principle in treatment of chronic inflammatory diseases Wien Med Wochenschr. 2002;152(15-16):373-8.
Arora S, Dhillon S, Rani G, Nagpal A. The in vitro antibacterial/synergistic activities of Withania somnifera extracts. Fitoterapia. 2004 Jun;75(3-4):385-8.
Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003 Feb;9(1):161-8.
Chen PR, et al. Lipids. 2005 Sep;40(9):955-61.
Chiu PY et al. In vivo antioxidant action of a lignan-enriched extract of Schisandra fruit and an anthraquinone-containing extract of Polygonum root in comparison with schisandrin B and emodin. Planta Med. 2002 Nov;68(11):951-6.
Chochinov HM. Depression in cancer patients. Lancet Oncol 2001;2:499–505.
Leipner J, Saller R. Systemic enzyme therapy in oncology: effect and mode of action. Drugs. 2000 Apr;59(4):769-80.
Davidson, R, et al. Alterations in brain and immune function produced by mindfulness meditation. Psychosomatic Medicine. 2003 Jul-Aug;65(4):564-70.
Dharmananda S. Amino Acid Supplements IV: Theanine. Institute for Traditional Medicine, Portland, Oregon Available at: http://www.itmonline.org/arts/theanine.htm.
Ivanhoe Newswire —SOURCE: American Journal of Psychiatry, published online Sept. 1, 2006: “Major depression is considered the leading cause of disability in countries all over the world. Costs associated with the condition in the United States come in at around $70 billion a year.”
Roy S, et al. Human genome screen to identify the genetic basis of the anti-inflammatory effects of Boswellia in microvascular endothelial cells. DNA Cell Biol. 2005 Apr;24(4):244-55.
Hougee S, Faber J, Sanders A, Berg WB, Garssen J, Smit HF, Hoijer MA. Planta Med. 2006 Feb;72(3):228-33.