The coexistence of immune-mediated inflammatory diseases with depression has long been recognised. Data that illustrate the intimate associations between peripheral and brain immune responses raise ...the possibility of shared pathophysiological mechanisms. These associations include the negative effects of proinflammatory cytokines on monoaminergic neurotransmission, neurotrophic factors, and measures of synaptic plasticity. The evidence supporting this association is accumulating and includes findings from clinical trials of immunomodulatory therapy, indicating that these interventions can provide benefits to mental health independent of improvements in physical disease scores. In this Review, we assess this evidence in relation to rheumatoid arthritis and depression, with a focus on innate immune and molecular responses to inflammation, and discuss the challenges of assessing causation in this population, acknowledging the difficulty of assessing the confounding and contributory effects of pain and fatigue. We also discuss how future clinical and preclinical research might improve diagnosis of depression in people with rheumatoid arthritis and shed light on mechanisms that could be substrates for therapeutic interventions.
Topical application of Aldara cream, containing the Toll-like receptor 7/8 agonist Imiquimod, is a widely used mouse model for investigating the pathogenesis of psoriasis. We have previously used ...this model to study the effects of peripheral inflammation on the brain, and reported a brain-specific response characterised by increased transcription, infiltration of immune cells and anhedonic-like behavior. Here, we perform a more robust characterisation of the systemic response to Aldara application and find a potent but transient response in the periphery, followed by a prolonged response in the brain. Mass spectrometry analysis of plasma and brain samples identified significant levels of Imiquimod in both compartments at molar concentrations likely to evoke a biological response. Indeed, the association of Imiquimod with the brain correlated with increased Iba1 and GFAP staining, indicative of microglia and astrocyte reactivity. These results highlight the potency of this model and raise the question of how useful it is for interpreting the systemic response in psoriasis-like skin inflammation. In addition, the potential impact on the brain should be considered with regards to human use and may explain why fatigue, headaches and nervousness have been reported as side effects following prolonged Aldara use.
Abstract Proton magnetic resonance spectroscopy (1 H MRS) measures glutamatergic metabolites namely glutamate and glutamine located in neurons and astrocytes respectively. In this meta-analysis the ...contribution of glutamatergic neurotransmission to depressive symptoms was evaluated together with other putative prefrontal metabolites described in the pathogenesis of mood disorders, and in relation to treatment effects. A comprehensive literature search up to 2014 identified 17 reports which measured absolute concentrations of neurometabolites in the prefrontal cortex with1 H MRS meeting criteria for inclusion in this meta-analysis. Excess of heterogeneity was investigated with meta-regressions. The analyses showed an exclusive reduction in absolute values of the composite measure of Glutamine and Glutamate (Glx) in the prefrontal cortex in depression, correlating in meta-regression analyses with treatment severity. Glutamate measurements in isolation did not differ vs. healthy controls or in relation to treatment and/or clinical improvement. Similarly there were no significant changes in other neurometabolites at baseline and following treatment. The analysis supports a role for glutamatergic dysfunction in the pathogeneses of mood dysregulation. The reduction in the absolute Glx values in the absence of changes in glutamate levels, suggests a possible modulatory role of astrocytes in the pathophysiology of depression.
Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering ...mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.
Recent years have seen an explosion of research pertaining to biological psychiatry, yet despite subsequent advances in our understanding of neuroimmune communication pathways, how the brain senses ...and responds to peripheral inflammation remains poorly understood. A better understanding of these pathways may be important for generating novel therapeutics to treat many patients with chronic inflammatory diseases who also suffer from neuropsychiatric comorbidities. Here we have systematically assessed the leukocyte infiltrate to the brain following systemic endotoxin exposure to better understand this novel route of neuroimmune communication.
Mice were injected intraperitoneally with LPS daily for 2, 5 or 7 consecutive days. We systematically interrogated the subsequent induction of chemokine transcription in the brain using TaqMan low-density arrays. A combination of flow cytometry and immunohistochemistry was then used to characterise the accompanying leukocyte infiltrate.
Repeated LPS challenges resulted in prolonged activation of brain-resident microglia, coupled with an increased local transcription of numerous chemokines. After 2 days of administering LPS, there was a marked increase in the expression of the neutrophil chemoattractants CXCL1 and CXCL2; the monocyte chemoattractants CCL2, CCL5, CCL7 and CCL8; and the lymphocyte chemoattractants CXCL9, CXCL10 and CXCL16. In a number of cases, this response was sustained for several days. Chemokine induction was associated with a transient recruitment of neutrophils and monocytes to the brain, coupled with a sustained accumulation of macrophages, CD8+ T cells, NK cells and NKT cells. Strikingly, neutrophils, monocytes and T cells appeared to extravasate from the vasculature and/or CSF to infiltrate the brain parenchyma.
Prolonged exposure to a peripheral inflammatory stimulus triggers the recruitment of myeloid cells and lymphocytes to the brain. By altering the inflammatory or metabolic milieu of the brain, this novel method of immune-to-brain communication may have profound implications for patients with chronic inflammatory diseases, potentially leading to neuropsychiatric comorbidities.
Depression: an inflammatory illness? Krishnadas, Rajeev; Cavanagh, Jonathan
Journal of neurology, neurosurgery and psychiatry,
05/2012, Letnik:
83, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Major depressive disorder (MDD) is associated with significant morbidity and mortality. Findings from preclinical and clinical studies suggest that psychiatric illnesses, particularly MDD, are ...associated with inflammatory processes. While it is unlikely that MDD is a primary 'inflammatory' disorder, there is now evidence to suggest that inflammation may play a subtle role in the pathophysiology of MDD. Most of the evidence that links inflammation to MDD comes from three observations: (a) one-third of those with major depression show elevated peripheral inflammatory biomarkers, even in the absence of a medical illness; (b) inflammatory illnesses are associated with greater rates of MDD; and (c) patients treated with cytokines are at greater risk of developing major depressive illness. We now know that the brain is not an immune privileged organ. Inflammatory mediators have been found to affect various substrates thought to be important in the aetiopathogenesis of MDD, including altered monoamine and glutamate neurotransmission, glucocorticoid receptor resistance and adult hippocampal neurogenesis. At a higher level, inflammation is thought to affect brain signalling patterns, cognition and the production of a constellation of symptoms, termed 'sickness behaviour'. Inflammation may therefore play a role in the aetiology of depression, at least in a 'cohort' of vulnerable individuals. Inflammation may not only act as a precipitating factor that pushes a person into depression but also a perpetuating factor that may pose an obstacle to recovery. More importantly, inflammatory markers may aid in the diagnosis and prediction of treatment response, leading to the possibility of tailored treatments, thereby allowing stratification of what remains a heterogenous disorder.
Background: This paper explores whether individuals with a mood disorder can identify the nature and duration of depressive and manic prodromes.
Methods: Seventy-three publications of prodromal ...symptoms in bipolar and unipolar disorders were identified by computer searches of seven databases (including
medline and Psyc
lit) supplemented by hand searches of journals. Seventeen studies (total sample=1191 subjects) met criteria for inclusion in a systematic review.
Results: At least 80% of individuals with a mood disorder can identify one or more prodromal symptoms. There are limited data about unipolar disorders. In bipolar disorders, early symptoms of mania are identified more frequently than early symptoms of depression. The most robust early symptom of mania is sleep disturbance (median prevalence 77%). Early symptoms of depression are inconsistent. The mean length of manic prodromes (>20 days) was consistently reported to be longer than depressive prodromes (<19 days). However, depressive prodromes showed greater inter-individual variation (ranging from 2 to 365 days) in duration than manic prodromes (1–120 days).
Limitations: Few prospective studies of bipolar, and particularly unipolar disorders have been reported.
Conclusions: Early symptoms of relapse in affective disorders can be identified. Explanations of the apparent differences in the recognition and length of prodromes between mania and bipolar depression are explored. Further research on duration, sequence of symptom appearance and characteristics of prodromes is warranted to clarify the clinical usefulness of early symptom monitoring.
Abstract Background Workplace-related musculoskeletal pain has been studied in various occupations, but it is rarely reported in the surgical literature. Objective The aim of this study was to ...examine work-related discomfort and injury among pediatric otolaryngologists and to assess their knowledge of workplace ergonomic principles. Methods We surveyed current North American members of the American Society of Pediatric Otolaryngology. Our main outcomes were whether the physician had ever experienced discomfort or physical symptoms that they attributed to their surgical practice. Results Response rate of 43.7% was attained, and 62.0% of respondents reported experiencing pain or discomfort that they attributed to their surgical practice. Women were significantly more likely to report experiencing pain or discomfort that they associated with their surgical practice ( P = .033). There were no significant differences found among length of time in practice, academic vs community setting, or number of surgeries completed by the surgeon. Some of the surgeons (31.0%) were aware of ergonomic principles, and of those who were aware, 83.9% had implemented ergonomic principles into their surgical practice. Conclusion Almost two thirds of surgeons who responded to the survey reported experiencing pain or discomfort that they attributed to their surgical practice. Only a minority of respondents were aware of ergonomic principles. These findings may confirm that most physicians believe that their physical health is affected by their operative environment. Increased knowledge of surgical ergonomics may lead to strategies that improve workplace health and safety.
The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, ...are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.
Early illness course correlates with long-term outcome in psychosis. Accurate prediction could allow more focused intervention. Earlier intervention corresponds to significantly better symptomatic ...and functional outcomes. Our study objective is to use routinely collected baseline demographic and clinical characteristics to predict employment, education or training (EET) status, and symptom remission in patients with first episode psychosis (FEP) at one-year.
83 FEP patients were recruited from National Health Service (NHS) Glasgow between 2011 and 2014 to a 24-month prospective cohort study with regular assessment of demographic and psychometric measures. An external independent cohort of 79 FEP patients were recruited from NHS Glasgow and Edinburgh during a 12-month study between 2006 and 2009. Elastic net regularised logistic regression models were built to predict binary EET status, period and point remission outcomes at one-year on 83 Glasgow patients (training dataset). Models were externally validated on an independent dataset of 79 patients from Glasgow and Edinburgh (validation dataset). Only baseline predictors shared across both cohorts were made available for model training and validation. After excluding participants with missing outcomes, models were built on the training dataset for EET status, period and point remission outcomes and externally validated on the validation dataset. Models predicted EET status, period and point remission with receiver operating curve (ROC) area under the curve (AUC) performances of 0.876 (95%CI: 0.864, 0.887), 0.630 (95%CI: 0.612, 0.647) and 0.652 (95%CI: 0.635, 0.670) respectively. Positive predictors of EET included baseline EET and living with spouse/children. Negative predictors included higher PANSS suspiciousness, hostility and delusions scores. Positive predictors for symptom remission included living with spouse/children, and affective symptoms on the Positive and Negative Syndrome Scale (PANSS). Negative predictors of remission included passive social withdrawal symptoms on PANSS. A key limitation of this study is the small sample size (n) relative to the number of predictors (p), whereby p approaches n. The use of elastic net regularised regression rather than ordinary least squares regression helped circumvent this difficulty. Further, we did not have information for biological and additional social variables, such as nicotine dependence, which observational studies have linked to outcomes in psychosis.
Using advanced statistical machine learning techniques, we provide the first externally validated evidence, in a temporally and geographically independent cohort, for the ability to predict one-year EET status and symptom remission in individual FEP patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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