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      Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase , and Interferon-Gamma

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          Abstract

          Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.

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          Most cited references189

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          Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study

          The Lancet, 349(9064), 1498-1504
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            A neurotrophic model for stress-related mood disorders.

            There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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              Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

              This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of or=11 (HRSD(17)>or=14) defined relapse. The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.
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                Author and article information

                Contributors
                antonio.inserra@sahmri.com
                LicinioJ@upstate.edu
                WongMa@upstate.edu
                Journal
                Mol Neurobiol
                Mol. Neurobiol
                Molecular Neurobiology
                Springer US (New York )
                0893-7648
                1559-1182
                10 October 2018
                10 October 2018
                2019
                : 56
                : 6
                : 4288-4305
                Affiliations
                [1 ]GRID grid.430453.5, Mind and Brain Theme, , South Australian Health and Medical Research Institute, ; Adelaide, Australia
                [2 ]ISNI 0000 0004 0367 2697, GRID grid.1014.4, Department of Psychiatry, College of Medicine and Public Health, , Flinders University, ; Bedford Park, Australia
                [3 ]ISNI 0000 0004 0367 2697, GRID grid.1014.4, Centre for Neuroscience, , Flinders University, ; Bedford Park, Australia
                [4 ]ISNI 0000 0001 2205 5940, GRID grid.412191.e, School of Medicine and Health Sciences, , Universidad Del Rosario, ; Bogota, Colombia
                [5 ]ISNI 0000 0001 2205 5940, GRID grid.412191.e, Neuroscience (NEUROS) Research Group, , Universidad del Rosario, ; Bogota, Colombia
                [6 ]Infection and Immunity Theme, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA Australia
                [7 ]ISNI 0000 0004 0367 2697, GRID grid.1014.4, SAHMRI Microbiome Research Laboratory, , Flinders University College of Medicine and Public Health, ; Bedford Park, SA Australia
                [8 ]ISNI 0000 0000 9159 4457, GRID grid.411023.5, College of Medicine, , State University of New York Upstate Medical University, ; Syracuse, NY USA
                [9 ]ISNI 0000 0000 9159 4457, GRID grid.411023.5, Department of Psychiatry, , State University of New York Upstate Medical University, ; Syracuse, NY USA
                Author information
                http://orcid.org/0000-0002-7261-5659
                Article
                1359
                10.1007/s12035-018-1359-3
                6505498
                30306457
                d2f47461-2603-402c-9863-0d0620b47b38
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 29 April 2018
                : 19 September 2018
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                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Neurosciences
                major depressive disorder,mdd,inflammation,neuroinflammation,caspase 1,inflammasome,t-helper 1 (th1),interleukin 1,inducible nitric oxide synthase,interferon gamma,gut microbiome

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