The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders

doi:10.1016/J.NEUROSCIENCE.2015.05.018

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The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders

Journal Article•DOI•

The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders

Gislaine Z. Réus¹, Gislaine Z. Réus², Gabriel Rodrigo Fries³, Laura Stertz³, Marwa Badawy², Ives Cavalcante Passos³, Tatiana Barichello¹, Flávio Kapczinski³, João Quevedo¹ - Show less +5 more•Institutions (3)

Universidade do Extremo Sul Catarinense¹, University of Texas at Austin², Universidade Federal do Rio Grande do Sul³

06 Aug 2015-Neuroscience (Neuroscience)-Vol. 300, pp 141-154

TL;DR: The role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism will be highlighted and the role of microglial activation and associated molecular cascades will be discussed as a means by which these neuroinflammatory mechanisms take place.

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About: This article is published in Neuroscience.The article was published on 2015-08-06. It has received 467 citations till now. The article focuses on the topics: Schizophrenia & Neuroinflammation.

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Journal Article•DOI•

Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice

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Aurelijus Burokas¹, Silvia Arboleya¹, Rachel D. Moloney¹, Veronica L. Peterson¹, Kiera Murphy², Gerard Clarke¹, Catherine Stanton¹, Catherine Stanton², Timothy G. Dinan¹, John F. Cryan¹ - Show less +6 more•Institutions (2)

University College Cork¹, Teagasc²

24 Feb 2017-Biological Psychiatry

TL;DR: The findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology.

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593 citations

Cites background from "The role of inflammation and microg..."

...In fact, stress has been linked to the development of both depression and anxiety, with a key contribution of microglia activation as well as of recruitment of peripheral macrophages into the brain to such events (53)....
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Journal Article•DOI•

Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression

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Ives Cavalcante Passos¹, Ives Cavalcante Passos², Mirela Paiva Vasconcelos-Moreno¹, Leonardo Gazzi Costa³, Maurício Kunz¹, Elisa Brietzke³, João Quevedo², Giovanni Abrahão Salum¹, Pedro Vieira da Silva Magalhães¹, Flávio Kapczinski², Flávio Kapczinski¹, Márcia Kauer-Sant'Anna¹ - Show less +8 more•Institutions (3)

Universidade Federal do Rio Grande do Sul¹, University of Texas Health Science Center at Houston², Federal University of São Paulo³

01 Nov 2015-The Lancet Psychiatry

TL;DR: A meta-analysis and meta-regression of studies comparing inflammatory markers between patients with PTSD and healthy controls found that use of psychotropic medication and presence of comorbid major depressive disorder were important moderators that might explain the inconsistency between results of previous studies.

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504 citations

Journal Article•DOI•

Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial.

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Ghodarz Akkasheh¹, Zahra Kashani-Poor¹, Maryam Tajabadi-Ebrahimi², Parvaneh Jafari³, Hossein Akbari¹, Mohsen Taghizadeh¹, Mohammad Reza Memarzadeh, Zatollah Asemi¹, Ahmad Esmaillzadeh⁴ - Show less +5 more•Institutions (4)

Kashan University of Medical Sciences¹, Islamic Azad University², Islamic Azad University, Arak³, Isfahan University of Medical Sciences⁴

01 Mar 2016-Nutrition

TL;DR: Probiotic administration in patients with MDD for 8 wk had beneficial effects on Beck Depression Inventory, insulin, homeostasis model assessment of insulin resistance, hs-CRP concentrations, and glutathione concentrations, but did not influence fasting plasma glucose,Homeostatic model Assessment of beta cell function, quantitative insulin sensitivity check index, lipid profiles, and total antioxidant capacity levels.

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488 citations

Cites background from "The role of inflammation and microg..."

...Previous studies have shown a link between metabolic profiles, biomarkers of inflammation, oxidative stress, and MDD [1,3,4]....
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Journal Article•DOI•

Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness

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Marilia Calcia¹, David R. Bonsall², Peter S. Bloomfield², Sudhakar Selvaraj³, Tatiana Barichello³, Oliver D. Howes¹, Oliver D. Howes² - Show less +3 more•Institutions (3)

King's College London¹, Hammersmith Hospital², University of Texas at Austin³

05 Feb 2016-Psychopharmacology

TL;DR: There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions, which is considered in terms of the two-hit hypothesis.

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Abstract: Rationale Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before.

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433 citations

Cites background from "The role of inflammation and microg..."

...The importance of this finding and the impact of early-life stress exposure on subsequent later-life behaviours and health have only recently been explored (Réus et al. 2015)....
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...2008) and autism spectrum disorders (Réus et al. 2015; Morgan et al. 2012)....
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...Supporting this, changes in microglial markers have been reported in a number of mental disorders such as depression (Torres-Platas et al. 2014), anxiety (Frick et al. 2013), schizophrenia (van Berckel et al. 2008) and autism spectrum disorders (Réus et al. 2015; Morgan et al. 2012)....
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...Such cytokine elevations may induce changes to cortical microglia, which in turn may be associated with structural and functional changes in the brain that predispose individuals to mental illness (see review by Réus et al. 2015)....
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Journal Article•DOI•

Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation

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Dora Brites¹, Adelaide Fernandes¹•Institutions (1)

University of Lisbon¹

17 Dec 2015-Frontiers in Cellular Neuroscience

TL;DR: The role of neuroinflammation in the emergence of depression is discussed, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior.

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Abstract: Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines. Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis. Rapid advances in the understanding of microglial and astrocytic neurobiology were obtained in the past fifteen to twenty years. Indeed, recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions, besides their involvement in immune-response generating cytokines. The communication between microglia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), comprising ectosomes and exosomes with a size ranging from 0.1 to 1 μm, are key players in intercellular signaling. These EVs may carry specific proteins, mRNAs and microRNAs (miRNAs). Transfer of exosomes to neurons was shown to be mediated by oligodendrocytes, microglia and astrocytes that may either be supportive to neurons, or instead disseminate the disease. Interestingly, several recent reports have identified changes in miRNAs in depressed patients, which target not only crucial pathways associated with synaptic plasticity, learning and memory but also the production of neurotrophic factors and immune cell modulation. In this article, we discuss the role of neuroinflammation in the emergence of depression, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior. We will overview the involvement of miRNAs, exosomes, ectosomes and microglia in regulating critical pathways associated with depression and how they may contribute to other brain disorders including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson disease, which share several neuroinflammatory-associated processes. Specific reference will be made to EVs as potential biomarkers and disease monitoring approaches, focusing on their potentialities as drug delivery vehicles and on putative therapeutic strategies using autologous exosome-based delivery systems to treat neurodegenerative and psychiatric disorders.

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410 citations

Cites background from "The role of inflammation and microg..."

...In addition, minocycline, which is a suppressor of activated microglia, has been shown to exert protective effects by reducing microglial activation, oxidative stress and inflammation (Réus et al., 2015)....
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...In fact, stress has been linked to the development of both depression and anxiety, with a key contribution of microglia activation, as well as of recruitment of peripheral macrophages into the brain to such events (Phillips et al., 2015; Réus et al., 2015)....
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References

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Journal Article•DOI•

From inflammation to sickness and depression: when the immune system subjugates the brain

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Robert Dantzer¹, Jason C. O'Connor¹, Gregory G. Freund¹, Rodney W. Johnson¹, Keith W. Kelley¹ - Show less +1 more•Institutions (1)

University of Illinois at Urbana–Champaign¹

01 Jan 2008-Nature Reviews Neuroscience

TL;DR: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour, which can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals.

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Abstract: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

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5,665 citations

"The role of inflammation and microg..." refers background in this paper

...Moreover, peripheral immune modulators have been shown to induce psychiatric symptoms in humans and in animal models (Dantzer et al., 2008; Harrison et al., 2009; Eisenberger et al., 2010; Haroon et al., 2012)....
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Journal Article•DOI•

Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo

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Axel Nimmerjahn¹, Frank Kirchhoff¹, Fritjof Helmchen¹•Institutions (1)

Max Planck Society¹

27 May 2005-Science

TL;DR: Using in vivo two-photon imaging in neocortex, it is found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions.

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Abstract: Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.

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4,458 citations

Additional excerpts

...Non-activated microglia termed ‘‘quiescent’’ or ‘‘resting’’ microglia are constantly surveilling the surrounding environment in non-pathological conditions (Nimmerjahn et al., 2005; Marshall et al., 2013)....
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Journal Article•DOI•

Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression

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Andrew H. Miller¹, Vladimir Maletic², Charles L. Raison¹•Institutions (2)

Emory University¹, University of South Carolina²

01 May 2009-Biological Psychiatry

TL;DR: 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.

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3,084 citations

"The role of inflammation and microg..." refers background in this paper

...…also rouse vesicular release of glutamate from astrocytes, thereby activating presynaptic N-methyl-D-aspartate (NMDA) receptors (Santello and Volterra, 2012) and stimulating indoleamine 2,3 dioxygenase (IDO), which is a potent NMDA agonist and stimulator of glutamate release (Miller et al., 2009)....
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...Furthermore, cytokines also rouse vesicular release of glutamate from astrocytes, thereby activating presynaptic N-methyl-D-aspartate (NMDA) receptors (Santello and Volterra, 2012) and stimulating indoleamine 2,3 dioxygenase (IDO), which is a potent NMDA agonist and stimulator of glutamate release (Miller et al., 2009)....
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Journal Article•DOI•

Antidepressant effects of ketamine in depressed patients

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Robert M. Berman, Angela Cappiello¹, Amit Anand², Amit Anand¹, Dan A. Oren¹, Dan A. Oren², George R. Heninger¹, Dennis S. Charney², Dennis S. Charney¹, John H. Krystal², John H. Krystal¹ - Show less +7 more•Institutions (2)

Yale University¹, Veterans Health Administration²

15 Feb 2000-Biological Psychiatry

TL;DR: A first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression suggests a potential role for NMDA receptor-modulating drugs in the treatment of depression.

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3,039 citations

"The role of inflammation and microg..." refers background in this paper

...…and clinical studies have demonstrated that NMDA antagonists, such as ketamine, memantine, amantadine and others present antidepressant effects (Berman et al., 2000; Zarate et al., 2006; Ferguson and Shingleton, 2007; Garcia et al., 2008a,b, 2009; Roman et al., 2009; Réus et al., 2010)....
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Journal Article•DOI•

A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

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Carlos A. Zarate¹, Jaskaran Singh, Paul J. Carlson, Nancy E. Brutsche, Rezvan Ameli, David A. Luckenbaugh, Dennis S. Charney, Husseini K. Manji - Show less +4 more•Institutions (1)

National Institutes of Health¹

01 Aug 2006-Archives of General Psychiatry

TL;DR: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

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Abstract: Context Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Objective To determine whether a rapid antidepressant effect can be achieved with an antagonist at theN-methyl-D-aspartate receptor in subjects with major depression. Design A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Setting Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects withDSM-IVmajor depression (treatment resistant). Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Conclusions Robust and rapid antidepressant effects resulted from a single intravenous dose of anN-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Trial Registration clinicaltrials.gov Identifier:NCT00088699.

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2,965 citations

"The role of inflammation and microg..." refers background in this paper

...…and clinical studies have demonstrated that NMDA antagonists, such as ketamine, memantine, amantadine and others present antidepressant effects (Berman et al., 2000; Zarate et al., 2006; Ferguson and Shingleton, 2007; Garcia et al., 2008a,b, 2009; Roman et al., 2009; Réus et al., 2010)....
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