Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance (original) (raw)
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Recent Advances in Psychoneuroimmunology: Inflammation in Psychiatric Disorders
Translational Neuroscience, 2011
Psychiatric disorders are common and complex and their precise biological underpinnings remain elusive. Multiple epidemiological, molecular, genetic and gene expression studies suggest that immune system dysfunction may contribute to the risk for developing psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder. However, the precise mechanisms by which inflammationrelated events confer such risk are unclear. In this review, we examine the peripheral and central evidence for inflammation in psychiatric disorders and the potential molecular mechanisms implicated including inhibition of neurogenesis, apoptosis, the HPA-axis, the role of brain-derived neurotrophic factor and the interplay between the glutamatergic, dopaminergic and serotonergic neurotransmitter systems.
Interaction Between Inflammatory State and Neurochemical Changes in Major Psychiatric Disorders
In 1975, Ader and Cohen reported that immune suppression could be induced by behavioural condition (Ader and Cohen, 1975). That was the clear demonstration that peripheral immune system could be influenced by emotion or behavioural manipulation. In the following years, the body and brain crosstalk through immune system became of interest in pathophysiology of psychiatric disorders. In 1987, the low natural killer cell activity in patients with depression was reported (Irwin et al., 1987). In early 1990s "sickness behaviour" was proposed as peripheral immune activation induced depressive like behaviour based on the fact that injection of bacterial toxin, lipopolysaccharide, peripherally could induce depressive like behaviour (Bluthe et al., 1992). They also reported that sickness behaviour induced by peripheral immune activation was reversed by administering the antagonist of interleukin-1 (IL1) receptor. While sickness behaviour is, unlike major depressive disorders, a short term syndrome, the symptoms of sickness behaviour such as lack of interest, inability to concentrate, loss of appetite, disturbance of sleep and social anhedonia are the similar symptoms as in depression. Thus, immune activation in the periphery was considered as part of the pathophysiological mechanisms of major depression and anti inflammatory medication or manipulation of immune system became of new therapeutic interest. The first theory on the immune activation in psychiatric disorders proposed was "macrophage theory of depression" (Smith, 1991) in which the association between cytokine secreted from macrophage and hypothalamus activity were proposed as pathophysiological mechanism of major depressive disorder. This theory has highlighted the interaction between immune system and endocrine system which could influence the emotion and higher function of the human brain. Based on the finding related to the connection between lymphocyte function, hypothalamo-hypophysial-adrenal axis and depression which indicated the impaired lymphocyte response to mitogen stimulation (Maes et al., 1989), the macrophage theory of depression was extended to monocyte-lymphocyte hypothesis of depression (Maes et al., 1995). The same authors have also extended the hypothesis to another major psychiatric disorder, schizophrenia (Smith and Maes, 1995). It was discussed that the cytokines, such as, IL1 and IL2 in low concentration could enhance the dopaminergic neurotransmission whereas high IL2 could suppress it. Around this period, the impairment of neutrophil and macrophage phagocytoses in depressed patients was also reported (McAdams and Leonard, 1993). Changes in immunoglobulin, complement and acute phase protein levels were also reported in patients with depression (Song et al., 1994). Also in late 1080s, Nishino and colleagues has first demonstrated the prostaglandin E2 (PGE2), an enzyme involved in inflammatory process is increased in the saliva of depressed patients (Nishino et al., 1989). Based on the different subtypes of immune cells, some studies explore the ratios between different subsets of T-lymphocytes and demonstrated the higher T-helper/T-suppressor cytotoxic cell ratio in depressed patients (Maes et al., 1992). The enhanced T-helper type 1 immune response which is associated with development of inflammation was proposed in major depressive disorders. Similar development in research related to inflammatory response and schizophrenia also occur around this later 20 th Century and the beginning of 21 st Century. The increased T-helper type 2 cells in the blood of patients with schizophrenia were reported and the dominance of T-helper type 2 reaction was suggested (Spernerwww.intechopen.com Interaction Between Inflammatory State and Neurochemical Changes in Major Psychiatric Disorders 167 Unterweger et al., 1999). Based on this finding "Th-2 hypothesis of schizophrenia" was proposed (Schwarz et al., 2001). Around the same period in the beginning of 21 st Century, the tryptophan degradation induced by the indoleamine 2,3-dioxygenase (IDO) enzyme in the presence of inflammatory state became of interest as a link between immune function and serotonergic abnormalities due to reduced tryptophan availability (Capuron et al., 2002; Maes et al., 2002). A year later, the possible involvement of downstream tryptophan metabolites in terms of neurotoxic changes in major depressive disorders and further immune system and NMDA-glutermatergic neurotransmission interaction were proposed in "neurodegeneration hypothesis of depression" (Myint and Kim, 2003). Several therapeutic strategies have been studied in the area of immune activation and psychiatric disorders. The antagonist of pro-inflammatory cytokine such as tumour necrosis factor- (TNF), eternacept, and n3 fatty acids are those studied and given some promising results. Recently, add-on therapy with inhibitor of cyclooxygenase-2 (COX-2) enzyme, celecoxib which was originally an anti-inflammatory medication was reported to enhance the response to both anti-depressant therapy and anti-psychotic therapy. Moreover, the possible use of inflammatory based biomarkers in diagnosis and choice of medication in major psychiatric disorders are considered. In this chapter, brief basic immunology on inflammation, findings and mechanisms related to inflammatory state in psychiatric disorders, the immune-endocrine interaction, immuneendocrine-tryptophan metabolism interaction and inflammation-tryptophan metabolismneurochemicals interaction network were explained and discussed. 2. Inflammatory state 2.1 A short survey of the body's defence system The body's defense system is a complex arrangement of physical, chemical, biochemical, and cellular barriers. Here we will focus on immunity, which is the result of the interplay between two "immune" systems: the innate immune system, which is phylogenetically older, and the adaptive immune system of T and B cells (Medzhitov and Janeway-CA, 1998). The innate immune system functions in an antigen-nonspecific way, while antigen-specific mechanisms are mediated by the adaptive one. Characteristic cells of the innate immune system are e.g. granulocytes, natural killer (NK) cells, monocytes/macrophages, or dendritic cells. The innate immune system is the first line of defense against infection and it provides signals for the activation of the adaptive immune system. Innate responses serve to regulate the onset, duration, magnitude, and character of the antibody-and cell-mediated adaptive response. In contrast to the adaptive immune system, the innate immune system is not able to confer long-lasting memory, i.e. immunity against a specific pathogen. In the late 1980s, Janeway proposed the model of the antigen-presenting cells, which are able to recognize and differentiate distinct groups of microbes by special receptors, the socalled pattern-recognition receptors (Janeway, Jr., 1989). The identification of pathogenassociated molecular patterns or microbe-associated molecular patterns by the innate immune system allows the body's defense system to discriminate between "infectious nonself" and "non-infectious self". This concept was expanded by Matzinger's hypothesis of danger signals as inducers of the body's defense system (Matzinger, 1994). According to this new concept, immunological phenomena like autoimmunity, sterile inflammation, or the acceptance of the fetus, who is immunologically 50% non-self, by the mother's immune system can be explained. Matzinger proposed that antigen presenting cells are not activated
Bipolar Disorders, 2014
Research evidence has shown that bipolar disorder (BD) and unipolar depression (UD) are both related to inflammatory dysregulation, but few studies have compared the levels of cytokines between these two disorders. Methods: Study subjects were age-and gender-matched outpatients with BD or UD and normal controls (NC). Severities of depression and mania symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Pro-inflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1), soluble p-selectin receptor (sP-selectin), and monocyte chemotactic protein-1 (MCP-1), were assessed in all subjects by enzyme-linked immunosorbent assays. Results: In all, 130 patients with BD, 149 patients with UD, and 130 NC were enrolled in the study; 67.6% were female and the average age was mean AE standard deviation (SD) 43.5 AE 11.8 years. The BD group had a significantly higher smoking rate, more medical comorbidity, higher body mass index (BMI), and higher levels of sIL-2R, sIL-6R, CRP, sTNF-R1, and MCP-1 (all p < 0.01) than the UD and NC groups. When the remitted patients with BD (YMRS scores ≤ 12) were compared with the patients with UD, controlling for age, MADRS score, smoking, medical comorbidity, and BMI in the regression model, the results showed that the BD group had significantly higher levels of sIL-6R (p < 0.001), CRP (p = 0.045), sTNF-R1 (p = 0.036), and MCP-1 (p = 0.001) than the UD group. Conclusions: Higher levels of sIL-6R, CRP, sTNF-R1, and MCP-1 were noted in BD than in UD. These results may suggest a more severe inflammatory dysregulation in BD. Further studies are required to investigate whether these cytokines could be biomarkers for affective disorders.
Journal of Psychiatric Research, 2011
Soluble tumor necrosis factor receptor 1 Interleukin-1Ra Interleukin 6 von Willebrand factor Osteoprotegerin CRP a b s t r a c t Objective: Elevated levels of inflammation are reported in bipolar disorders (BP), but how this relates to affective symptoms is unclear. We aimed to determine if immune markers that consistently have been reported elevated in BP were associated with depressive and manic symptoms, and if this was specific for BP. Methods: From a catchment area, 112 BP patients were included together with 153 schizophrenia (SCZ) patients and 239 healthy controls. Depression and mania were assessed and the patients were grouped into depressed, neutral, and elevated mood. We measured the immune markers tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), interleukin 6 (IL-6), high sensitive Creactive protein (hsCRP), osteoprotegerin (OPG) and von Willebrand factor (vWf) which have been found increased in severe mental disorders. Results: In BP all inflammatory markers were lowest in depressed state, with significant group differences after control for confounders with respect to TNF-R1 (p ¼ 0.04), IL-1Ra (p ¼ 0.02), OPG (p ¼ 0.004) and IL-6 (p ¼ 0.005). STNF-R1 was positively correlated with the item elevated mood (p ¼ 0.02) whereas sad mood was negatively correlated with OPG (p ¼ 0.0003), IL-1Ra (p ¼ 0.001) and IL-6 (p ¼ 0.006). Compared to controls the neutral mood group had significantly higher levels of OPG (p ¼ 0.0003) and IL-6 (p ¼ 0.005), and the elevated mood group had higher levels of TNF-R1 (p ¼ 0.000005) and vWf (p ¼ 0.002). There were no significant associations between affective states orsymptoms in SCZ. Conclusions: The current associations between inflammatory markers and affective symptomatology in BP and not SCZ suggest that immune related mechanisms are associated with core psychopathology of BP.
Inflammation and Its Discontents: the Role of Cytokines In the Pathophysiology of Major Depression
Biological psychiatry, 2009
Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.
Inflammation and Mood Disorders: Proinflammatory Cytokines and the Pathogenesis of Depression
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2010
Increasing evidence suggests that activation of the innate immune system may play a seminal role in the pathophysiology of depression. Several lines of evidence support the association of inflammation and depression. Peripheral administration of cytokines, such as interferon-alpha, can induce many of the symptoms of the depressive syndrome. In addition, medically healthy patients with major depression exhibit elevated plasma levels of proinflammatory cytokines. Moreover, cytokines produce effects on a variety of neurobiological substrates previously implicated in the pathogenesis of depression. Thus, proinflammatory cytokines alter neuroendocrine function, several neurotransmitter systems including dopamine and glutamate, neural plasticity, and neuronal activity in limbic regions. The burgeoning evidence that depression is an inflammatory disease is reviewed.
Inflammatory Process and Immune System in Major Depressive Disorder
The International Journal of Neuropsychopharmacology, 2021
Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the general population. In mental disorders, the activation of inflammatory pathways in the brain is a major producer of excitotoxicity and an inducer of oxidative stress. The occurrence of these 2 events is partly responsible for the neuronal damage inherent in patients with mental disorders. In the case of MDD, the release of hormone and increase in pro-inflammatory cytokines in plasma and indicators of oxidative stress have been identified as consequences of this event. The most important affectations in patients with MDD are changes in their cognitive and executive functions due to brain inflammation. Hence, these biomarkers can serve as diagnostic and severity classification tools and treatment. In this work, we described the communication pathway between the immune and neuroendocrine systems in MDD and suggested possible therapeutic options for the disease.