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Journal ArticleDOI

Inflammation and Schizophrenia

01 Nov 2013-Schizophrenia Bulletin (Oxford University Press)-Vol. 39, Iss: 6, pp 1174-1179
TL;DR: The purposes of this special feature are to clarify the key findings on inflammation in schizophrenia, identify major gaps in the literature, and suggest priorities for research in this area.
Abstract: An association between inflammatory abnormalities and schizophrenia has been found repeatedly. The purposes of this special feature are to clarify the key findings on inflammation in schizophrenia, identify major gaps in the literature, and suggest priorities for research in this area. What is inflammation? Inflammation is one of the body’s first lines of defense in response to injury or infection, and increased inflammation is found in many diseases. Acute inflammation is a nonspecific response characterized by warmth, pain, and swelling. Leukocytes migrate to the area of injury and become activated, the blood supply to the area increases, and blood vessels become more permeable, allowing cells and molecules to leave blood vessels and enter the injured tissue. The inflammatory response also involves the complement system, a group of proteins that, when activated, combine to form a complex molecular structure that kills cells, usually bacteria and parasites. Cytokines are key molecules that regulate inflammation; they also have important roles in the immune system. They are produced by a wide variety of immune cells and cells outside of the immune system. The term cytokine derives from their ability to influence the movement of inflammatory cells, but they also have other functions. Chronic inflammation is usually a lower grade response, lacks the grossly visible signs of acute inflammation, and may be systemic rather than localized. Chronic inflammation plays a role in the pathophysiology of many chronic diseases, including cardiovascular and cerebrovascular disease, diabetes, Alzheimer’s disease, and some cancers. The characteristics of chronic inflammation differ somewhat in the brain from what occurs in other tissues. An important component of neuroinflammation is the microglial activation. The brain contains relatively few of the inflammatory cells that are found outside the brain. Microglia, which are related to the peripheral inflammatory cells, serve some of the protective functions such cells play in the rest of the body. Microglia are involved in other brain functions, including the pruning and maintenance of synapses, trafficking of neurotransmitters, and devouring—phagocytosis—of cell fragments and damaged cells. Activated microglia produce inflammatory cytokines and the phagocytose cells or proteins that provoke the inflammatory response. Microglial activation and subsequent proinflammatory cytokine production may disrupt the blood-brain barrier (BBB). An intact BBB usually tightly controls the entry of cytokines and leukocytes into brain tissue. Damage to the BBB impairs its ability to control which inflammatory cells and molecules enter the brain; other substances leak into brain tissue, and the brain is unable to function normally.

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Citations
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Journal ArticleDOI
TL;DR: It is shown how ecosystem service assessments can be expanded to include mental health, and a heuristic, conceptual model for doing so is provided.
Abstract: A growing body of empirical evidence is revealing the value of nature experience for mental health. With rapid urbanization and declines in human contact with nature globally, crucial decisions must be made about how to preserve and enhance opportunities for nature experience. Here, we first provide points of consensus across the natural, social, and health sciences on the impacts of nature experience on cognitive functioning, emotional well-being, and other dimensions of mental health. We then show how ecosystem service assessments can be expanded to include mental health, and provide a heuristic, conceptual model for doing so.

736 citations

Journal ArticleDOI
TL;DR: Roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness are examined; how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies is discussed.
Abstract: The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

607 citations

Journal ArticleDOI
TL;DR: This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with multiple physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders.
Abstract: The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.

288 citations

Journal ArticleDOI
TL;DR: Longitudinal studies in animal models indicate that infection-induced developmental neuroinflammation may be pathologically relevant beyond the antenatal and neonatal periods, and may contribute to disease progression associated with the gradual development of full-blown schizophrenic disease.
Abstract: There is increasing interest in and evidence for altered immune factors in the etiology and pathophysiology of schizophrenia. Stimulated by various epidemiological findings reporting elevated risk of schizophrenia following prenatal exposure to infection, one line of current research aims to explore the potential contribution of immune-mediated disruption of early brain development in the precipitation of long-term psychotic disease. Since the initial formulation of the “prenatal cytokine hypothesis” more than a decade ago, extensive epidemiological research and remarkable advances in modeling prenatal immune activation effects in animal models have provided strong support for this hypothesis by underscoring the critical role of cytokine-associated inflammatory events, together with downstream pathophysiological processes such as oxidative stress, hypoferremia and zinc deficiency, in mediating the short- and long-term neurodevelopmental effects of prenatal infection. Longitudinal studies in animal models further indicate that infection-induced developmental neuroinflammation may be pathologically relevant beyond the antenatal and neonatal periods, and may contribute to disease progression associated with the gradual development of full-blown schizophrenic disease. According to this scenario, exposure to prenatal immune challenge primes early pre- and postnatal alterations in peripheral and central inflammatory response systems, which in turn may disrupt the normal development and maturation of neuronal systems from juvenile to adult stages of life. Such developmental neuroinflammation may adversely affect processes that are pivotal for normal brain maturation, including myelination, synaptic pruning, and neuronal remodeling, all of which occur to a great extent during postnatal brain maturation. Undoubtedly, our understanding of the role of developmental neuroinflammation in progressive brain changes relevant to schizophrenia is still in infancy. Identification of these mechanisms would be highly warranted because they may represent a valuable target to attenuate or even prevent the emergence of full-blown brain and behavioral pathology, especially in individuals with a history of prenatal complications such as in-utero exposure to infection and/or inflammation.

268 citations


Cites background or methods from "Inflammation and Schizophrenia"

  • ...…Müller and Schwarz, 2006, 2010; Müller et al., 2000; Steiner et al., 2010), including peripheral low-grade inflammation (Altamura et al., 1999; Fan et al., 2007; Miller et al., 2011; Potvin et al., 2008) and signs of microglia and astrocyte over-activation (Bernstein et al., 2009; Doorduin et…...

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  • ...The author receives support from the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679....

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Journal ArticleDOI
TL;DR: The anatomical and molecular basis of the neural interface with immunity is reviewed, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus.
Abstract: The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.

260 citations


Cites background from "Inflammation and Schizophrenia"

  • ...There is evidence that chronic peripheral immune activation and inflammation exacerbate neuroinflammation in neurodegenerative diseases, including Alzheimer disease (157) and schizophrenia (158, 159)....

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References
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Journal ArticleDOI
TL;DR: A meta-analysis of studies measuring cytokine concentration in patients with major depression reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects, strengthening evidence that depression is accompanied by activation of the IRS.

3,800 citations

Journal ArticleDOI
TL;DR: Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications.

1,426 citations

Journal ArticleDOI
TL;DR: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.
Abstract: Context Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants. Objectives To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. Design Double-blind, placebo-controlled, randomized clinical trial. Setting Outpatient infusion center at Emory University in Atlanta, Georgia. Participants A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Interventions Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial. Main Outcome Measures The 17-item Hamilton Scale for Depression (HAM-D) scores. Results No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P Conclusions This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. Trial Registration clinicaltrials.gov Identifier: NCT00463580.

1,282 citations

Journal ArticleDOI
TL;DR: The promise of this work for facilitating the identification of susceptibility loci in genetic studies of schizophrenia is illustrated by examples of interaction between in utero exposure to infection and genetic variants.
Abstract: An emerging literature from epidemiologic, clinical, and preclinical investigations has provided evidence that gestational exposure to infection contributes to the etiology of schizophrenia. In recent years, these studies have moved from ecologic designs, which ascertain infection based on epidemics in populations, to investigations that have capitalized on reliable biomarkers in individual pregnancies. These studies have documented specific candidate infections that appear to be associated with an elevated risk of schizophrenia. Animal models of maternal immune activation inspired by this work have revealed intriguing findings indicating behavioral, neurochemical, and neurophysiologic abnormalities consistent with observations in schizophrenia. In parallel studies in humans and animals, investigators are working to uncover the cellular and molecular mechanisms by which in utero exposure to infection contributes to schizophrenia risk. In this review, the authors discuss and critically evaluate the...

1,103 citations

Journal ArticleDOI
TL;DR: Long-chain omega-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states.
Abstract: Context: The use of antipsychotic medication for the prevention of psychotic disorders is controversial. Longchain-3 (omega-3) polyunsaturated fatty acids (PUFAs) may be beneficial in a range of psychiatric conditions, including schizophrenia. Given that-3 PUFAs are generally beneficial to health and without clinically relevant adverse effects, their preventive use in psychosis merits investigation. Objective: To determine whether -3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis. Design: Randomized, d ouble-blind, p lacebocontrolled trial conducted between 2004 and 2007. Setting: Psychosis detection unit of a large public hospital in Vienna, Austria. Participants: Eighty-one individuals at ultra-high risk of psychotic disorder. Interventions: A 12-week intervention period of 1.2g/d -3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months. Main Outcome Measures: The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of -6 to -3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition. Results: Seventy-six of 81 participants (93.8%) completed the intervention. By study’s end (12 months), 2 of 41 individuals (4.9%) in the -3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to fullthreshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). -3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P=.01), negative symptoms (P=.02), and general symptoms (P=.01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups. Conclusions: Long-chain-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states. Trial Registration: clinicaltrials.gov Identifier: NCT00396643

835 citations

Trending Questions (1)
What is the relationship between inflammation and hallucinations?

The provided paper does not specifically mention the relationship between inflammation and hallucinations.