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Sirkis DW, Oddi AP, Jonson C, Bonham LW, Hoang PT, Yokoyama JS. The role of interferon signaling in neurodegeneration and neuropsychiatric disorders. Front Psychiatry 2024; 15:1480438. [PMID: 39421070 PMCID: PMC11484020 DOI: 10.3389/fpsyt.2024.1480438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/09/2024] [Indexed: 10/19/2024] Open
Abstract
Recent advances in transcriptomics research have uncovered heightened interferon (IFN) responses in neurodegenerative diseases including Alzheimer's disease, primary tauopathy, Parkinson's disease, TDP-43 proteinopathy, and related mouse models. Augmented IFN signaling is now relatively well established for microglia in these contexts, but emerging work has highlighted a novel role for IFN-responsive T cells in the brain and peripheral blood in some types of neurodegeneration. These findings complement a body of literature implicating dysregulated IFN signaling in neuropsychiatric disorders including major depression and post-traumatic stress disorder. In this review, we will characterize and integrate advances in our understanding of IFN responses in neurodegenerative and neuropsychiatric disease, discuss how sex and ancestry modulate the IFN response, and examine potential mechanistic explanations for the upregulation of antiviral-like IFN signaling pathways in these seemingly non-viral neurological and psychiatric disorders.
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Affiliation(s)
- Daniel W. Sirkis
- Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Alexis P. Oddi
- Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Caroline Jonson
- Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
- Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, United States
- DataTecnica LLC, Washington, DC, United States
| | - Luke W. Bonham
- Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
| | - Phuong T. Hoang
- Movement Disorders and Neuromodulation Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Jennifer S. Yokoyama
- Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
- Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States
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2
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Takahashi A. Associations of the immune system in aggression traits and the role of microglia as mediators. Neuropharmacology 2024; 256:110021. [PMID: 38825308 DOI: 10.1016/j.neuropharm.2024.110021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 05/23/2024] [Accepted: 05/30/2024] [Indexed: 06/04/2024]
Abstract
There is an important relationship between the immune system and aggressive behavior. Aggressive encounters acutely increase the levels of proinflammatory cytokines, and there are positive correlations between aggressive traits and peripheral proinflammatory cytokines. Endotoxin lipopolysaccharide (LPS) treatment, which results in peripheral immune activation, decreases aggressive behavior as one of the sickness behavioral symptoms. In contrast, certain brain infections and chronic interferon treatment are associated with increased aggression. Indeed, the effects of proinflammatory cytokines on the brain in aggressive behavior are bidirectional, depending on the type and dose of cytokine, target brain region, and type of aggression. Some studies have suggested that microglial activation and neuroinflammation influence intermale aggression in rodent models. In addition, pathological conditions as well as physiological levels of cytokines produced by microglia play an important role in social and aggressive behavior in adult animals. Furthermore, microglial function in early development is necessary for the establishment of the social brain and the expression of juvenile social behaviors, including play fighting. Overall, this review discusses the important link between the immune system and aggressive traits and the role of microglia as mediators of this link.
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Affiliation(s)
- Aki Takahashi
- Laboratory of Behavioral Neurobiology, Institute of Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
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3
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Steffen J, Focken N, Çalışkan G. Recognizing depression as an inflammatory disease: the search for endotypes. Am J Physiol Cell Physiol 2024; 327:C205-C212. [PMID: 38826138 DOI: 10.1152/ajpcell.00246.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/04/2024]
Abstract
Major depressive disorder (MDD) affects millions of individuals worldwide, leading to considerable social and economic costs. Despite advancements in pharmacological treatments, achieving remission remains a key challenge, with a substantial number of patients showing resistance to existing therapies. This resistance is often associated with elevated levels of proinflammatory cytokines, suggesting a connection between inflammation, MDD pathophysiology, and treatment efficacy. The observation of increased immune activation in about a quarter of patients with MDD resulted in the distinction between inflammatory and noninflammatory endotypes. Although anti-inflammatory treatments show promise in alleviating depression-like symptoms, responses are heterogeneous, thus highlighting the importance of identifying distinct inflammatory endotypes to tailor effective therapeutic strategies. The intestinal microbiome emerges as a crucial modulator of mental health, mediating its effects partially through different immune pathways. Microbiota-derived short-chain fatty acids (SCFAs) significantly impact innate and adaptive immune cells, regulating their differentiation, function, and cellular response. Furthermore, gut-educated immune cells reach the border regions of the central nervous system (CNS), regulating glial cell functions. Although the CNS modulates immune responses via efferent parts of the vagus nerve, afferent tracts concurrently transport information on peripheral inflammation back to the brain. This bidirectional communication is particularly relevant in depression, allowing for therapeutic stimulation of the vagus nerve in the context of inflammatory depression endotypes. In this review, we explore the intricate relationship between inflammation and depression, discuss how inflammatory signals are translated into depressive-like symptoms, and highlight immune-modulating therapeutic avenues.
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Affiliation(s)
- Johannes Steffen
- Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany
| | - Nis Focken
- Research Group "Synapto-Oscillopathies," Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University, Magdeburg, Germany
| | - Gürsel Çalışkan
- Research Group "Synapto-Oscillopathies," Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University, Magdeburg, Germany
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Dinkelborg K, Kahlhöfer J, Dörge P, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, Akarca US, Gürel S, Zeuzem S, Erhardt A, Lüth S, Papatheodoridis GV, Keskin O, Port K, Radu M, Celen MK, Idilman R, Weber K, Stift J, Wittkop U, Heidrich B, Mederacke I, von der Leyen H, Dienes HP, Cornberg M, Koch A, Manns MP, Wedemeyer H, Deterding K. Quality-of-life scores improve after 96 weeks of PEG-IFNa-2a treatment of hepatitis D: An analysis of the HIDIT-II trial. Liver Int 2023; 43:1663-1676. [PMID: 37183524 DOI: 10.1111/liv.15602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/28/2023] [Accepted: 04/23/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND & AIMS Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient-reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta. METHODS Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF-36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG-IFNa-2a)-based treatment in the HIDIT-II trial. HIDIT-II was a randomized prospective trial exploring PEG-IFNa-2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available. RESULTS Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG-IFNa-2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV-RNA clearance was not associated with relevant changes in physical or social SF-36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co-treatment had no influence on QOL. CONCLUSIONS Overall, our findings suggest that PEG-IFNa-2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF-36 questionnaires. Of note, several patients may benefit from PEG-IFNa-2a-based therapies with off-treatment improvements in quality of life.
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Affiliation(s)
- Katja Dinkelborg
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Julia Kahlhöfer
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
| | - Petra Dörge
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
| | - Cihan Yurdaydin
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
- Department of Internal Medicine, Koc University Medical School, Istanbul, Turkey
| | - Svenja Hardtke
- German Center for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- Institute for Infection Research and Vaccine Development, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - Kendal Yalcin
- Dicle University Medical Faculty, Diyarbakir, Turkey
| | | | - Selim Gürel
- Uludağ University Medical Faculty, Bursa, Turkey
| | - Stefan Zeuzem
- Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany
| | | | - Stefan Lüth
- Institute for Infection Research and Vaccine Development, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | | | - Onur Keskin
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | - Kerstin Port
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Monica Radu
- Institutul de Boli Infectioase, Bucharest, Romania
| | | | - Ramazan Idilman
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | - Kristina Weber
- Institute for Biometry, Hannover Medical School, Hannover, Germany
| | - Judith Stift
- Department of Pahology, Institute for Infection Research and Vaccine Development, Medical University of Vienna, Vienna, Austria
| | | | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Excellence Cluster Resist, Hannover Medical School, Hannover, Germany
| | - Ingmar Mederacke
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Hans Peter Dienes
- Department of Pahology, Institute for Infection Research and Vaccine Development, Medical University of Vienna, Vienna, Austria
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Center for Individualized Infection Medicine (CIIM), Hannover, Germany
| | - Armin Koch
- Institute for Biometry, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Excellence Cluster Resist, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
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5
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Fang Y, Chen CY, Yu HC, Lin PC. Neuropsychiatric disorders in chronic hepatitis C patients after receiving interferon or direct-acting antivirals: a nationwide cohort study. Front Pharmacol 2023; 14:1191843. [PMID: 37538181 PMCID: PMC10394649 DOI: 10.3389/fphar.2023.1191843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/03/2023] [Indexed: 08/05/2023] Open
Abstract
Background: Data on the neuropsychological outcomes after receiving direct-acting antivirals (DAAs) among chronic hepatitis C (CHC) patients have not been well-documented. Aim: This study aimed to evaluate the difference in incidence of neuropsychological disorders (NPDs) after treatment completion between CHC patients receiving interferon (IFN) therapy and DAA therapy. Methods: A nationwide retrospective cohort study was performed using Taiwan's National Health Insurance Research Database (NHIRD) between 2010 and 2018. CHC patients without pre-existing mental disorders were included and divided into the treatment (Tx)-naïve DAA group, retreatment (re-Tx) DAA group, and Tx-naïve IFN group based on their HCV therapy. Propensity score matching was used to balance baseline differences between groups. The primary outcome was the incidence of NPDs during 6 months after completion of therapy. Results: After one-to-one matching, there were 6,461 pairs of patients selected from the Tx-naïve DAA group and Tx-naïve IFN group and 3,792 pairs from the re-Tx DAA group and Tx-naïve IFN group. A lower incidence of NPDs was observed in the Tx-naïve DAA group than in the Tx-naïve IFN group (HR = 0.72, 95% CI = 0.55-0.94, and p = 0.017). The risk of NPDs did not differ between the re-Tx DAA group and the Tx-naïve IFN group (HR = 0.74, 95% CI: 0.52-1.05, and p = 0.092). Conclusion: DAA therapy was associated with lower risk of NPDs when compared with IFN therapy among Tx-naïve CHC patients in a 6-month period after treatment completion, especially among the patients less than 65 years, male gender, and cirrhosis.
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Affiliation(s)
- Yu Fang
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Pingtung Veterans General Hospital, Pingtung, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hsien-Chung Yu
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Business Management, Institute of Health Care Management, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Nursing, Meiho Institute of Technology, Ping-Tung, Taiwan
| | - Pei-Chin Lin
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
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6
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Gonda X, Serafini G, Dome P. Fight the Fire: Association of Cytokine Genomic Markers and Suicidal Behavior May Pave the Way for Future Therapies. J Pers Med 2023; 13:1078. [PMID: 37511694 PMCID: PMC10381806 DOI: 10.3390/jpm13071078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
The fight against suicide is highly challenging as it may be one of the most complex and, at the same time, most threatening among all psychiatric phenomena. In spite of its huge impact, and despite advances in neurobiology research, understanding and predicting suicide remains a major challenge for both researchers and clinicians. To be able to identify those patients who are likely to engage in suicidal behaviors and identify suicide risk in a reliable and timely manner, we need more specific, novel biological and genetic markers/indicators to develop better screening and diagnostic methods, and in the next step to utilize these molecules as intervention targets. One such potential novel approach is offered by our increasing understanding of the involvement of neuroinflammation based on multiple observations of increased proinflammatory states underlying various psychiatric disorders, including suicidal behavior. The present paper overviews our existing understanding of the association between suicide and inflammation, including peripheral and central biomarkers, genetic and genomic markers, and our current knowledge of intervention in suicide risk using treatments influencing inflammation; also overviewing the next steps to be taken and obstacles to be overcome before we can utilize cytokines in the treatment of suicidal behavior.
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Affiliation(s)
- Xenia Gonda
- Department of Psychiatry and Psychotherapy, Semmelweis University, 1085 Budapest, Hungary
- NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, 1085 Budapest, Hungary
- International Centre for Education and Research in Neuropsychiatry (ICERN), Samara State Medical University, 443079 Samara, Russia
| | - Gianluca Serafini
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, 16126 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Peter Dome
- Department of Psychiatry and Psychotherapy, Semmelweis University, 1085 Budapest, Hungary
- National Institute of Mental Health, Neurology and Neurosurgery, 1135 Budapest, Hungary
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7
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Coccaro EF, Lee R, Breen EC, Irwin MR. Plasma and cerebrospinal fluid inflammatory markers and human aggression. Neuropsychopharmacology 2023; 48:1060-1066. [PMID: 36804488 PMCID: PMC10209212 DOI: 10.1038/s41386-023-01541-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/05/2023] [Accepted: 01/24/2023] [Indexed: 02/19/2023]
Abstract
A growing body of work suggests that individuals with aggressive behavior and/or aggressive tendencies have evidence of chronic, low level, inflammation as manifested by elevated circulating levels of acute phase reactant proteins and pro-inflammatory cytokines. While animal studies report that direct application of pro-inflammatory proteins in brain increase aggressive behavior, there is no data on the relationship of central levels of these proteins and aggression in human subjects. We simultaneously measured levels of both plasma and lumbar cerebrospinal fluid (CSF) C-Reactive Protein (CRP) and IL-6, IL-8, and TNF-α in 77 medically healthy, drug-free, individuals with varying degrees of aggression including 22 individuals with DSM-5 Intermittent Explosive Disorder (IED). Aggression was assessed using the Life History of Aggression (LHA) and the Buss-Perry Aggression Questionnaire (BPAQ). Plasma and CSF levels of CRP, IL-8, and TNF-α, but not IL-6, correlated significantly with each other. Aggressive individuals with IED displayed elevated plasma, but not CSF, levels of proinflammatory markers and this relationship was specific to IED. Similarly, composite aggression scores correlated significantly with plasma, but not CSF, pro-inflammatory markers. Aggressive behavior in humans is correlated with Plasma, but not CSF, proinflammatory markers despite the observation that these two sets of markers are significantly correlated. Since the direct application of proinflammatory proteins in brains of animals increase aggressive behavior, proinflammatory proteins likely influence brain-based behavior in a manner not reflected in lumbar CSF.
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Affiliation(s)
- Emil F Coccaro
- Clinical Neuroscience and Psychotherapeutics Research Unit, Department of Psychiatry and Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Royce Lee
- Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA
| | - Elizabeth C Breen
- Department of Psychiatry & Biobehavioral Sciences and Medicine, Norman Cousins Center, and Semel Institute, UCLA School of Medicine, Los Angeles, CA, USA
| | - Michael R Irwin
- Department of Psychiatry & Biobehavioral Sciences and Medicine, Norman Cousins Center, and Semel Institute, UCLA School of Medicine, Los Angeles, CA, USA
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8
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Lai JY, Ho JX, Kow ASF, Liang G, Tham CL, Ho YC, Lee MT. Interferon therapy and its association with depressive disorders - A review. Front Immunol 2023; 14:1048592. [PMID: 36911685 PMCID: PMC9992192 DOI: 10.3389/fimmu.2023.1048592] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/13/2023] [Indexed: 02/24/2023] Open
Abstract
Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body's inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates memory and emotional response, damage of neurons in this region is correlated with mood disorders. Due to the drawbacks of the treatment, often patients will not complete the treatment sessions, and this affects their recovery process. However, with proper management, this could be avoided. This review briefly describes the different types of IFNs and its pharmacological and clinical usages and a focus on IFN-α and its implications on depression.
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Affiliation(s)
- Jing Yung Lai
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Jian Xiang Ho
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
| | | | - Gengfan Liang
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Chau Ling Tham
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Yu-Cheng Ho
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - Ming Tatt Lee
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
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9
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Bisgaard TH, Allin KH, Keefer L, Ananthakrishnan AN, Jess T. Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment. Nat Rev Gastroenterol Hepatol 2022; 19:717-726. [PMID: 35732730 DOI: 10.1038/s41575-022-00634-6] [Citation(s) in RCA: 239] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2022] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity.
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Affiliation(s)
- Tania H Bisgaard
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Kristine H Allin
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark.,Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Laurie Keefer
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Tine Jess
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark. .,Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.
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10
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Hu J, Johnson TA, Zhang H, Cheng HW. The Microbiota-Gut-Brain Axis: Gut Microbiota Modulates Conspecific Aggression in Diversely Selected Laying Hens. Microorganisms 2022; 10:microorganisms10061081. [PMID: 35744601 PMCID: PMC9230770 DOI: 10.3390/microorganisms10061081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/22/2022] Open
Abstract
The gut microbiota plays an important role in regulating brain function, influencing psychological and emotional stability. The correlations between conspecific aggression, gut microbiota, and physiological homeostasis were further studied in inbred laying chicken lines, 63 and 72, which were diversely selected for Marek’s disease, and they also behave differently in aggression. Ten sixty-week-old hens from each line were sampled for blood, brain, and cecal content. Neurotransmitters, cytokines, corticosterone, and heterophil/lymphocyte ratios were determined. Cecal microbiota compositions were determined by bacterial 16s rRNA sequencing, and functional predictions were performed. Our data showed that the central serotonin and tryptophan levels were higher in line 63 compared to line 72 (p < 0.05). Plasma corticosterone, heterophil/lymphocyte ratios, and central norepinephrine were lower in line 63 (p < 0.05). The level of tumor necrosis factor α tended to be higher in line 63. Faecalibacterium, Oscillibacter, Butyricicoccus, and Bacteriodes were enriched in line 63 birds, while Clostridiales vadin BB60, Alistipes, Mollicutes RF39 were dominated in line 72. From the predicted bacterial functional genes, the kynurenine pathway was upregulated in line 72. These results suggested a functional linkage of the line differences in serotonergic activity, stress response, innate immunity, and gut microbiota populations.
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Affiliation(s)
- Jiaying Hu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA;
| | - Timothy A. Johnson
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA;
- Correspondence: (T.A.J.); (H.-W.C.)
| | - Huanmin Zhang
- USDA-Agricultural Research Service, Avian Disease and Oncology Laboratory, East Lansing, MI 48823, USA;
| | - Heng-Wei Cheng
- USDA-Agricultural Research Service, Livestock Behavior Research Unit, West Lafayette, IN 47907, USA
- Correspondence: (T.A.J.); (H.-W.C.)
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Castle R, Bushell WC, Mills PJ, Williams MA, Chopra D, Rindfleisch JA. Global Correlations Between Chronic Inflammation and Violent Incidents: Potential Behavioral Consequences of Inflammatory Illnesses Across Socio-Demographic Levels. Int J Gen Med 2021; 14:6677-6691. [PMID: 34675629 PMCID: PMC8520436 DOI: 10.2147/ijgm.s324367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 09/01/2021] [Indexed: 01/05/2023] Open
Abstract
Introduction This review explores the potential correlation between conditions associated with chronic inflammation and measures of violence across five socioeconomic subgroups. The hypothesis being that since chronic inflammation is associated with increased aggression, an extreme version of which is violence, there should be a correlation between incidents of violence and diseases with one or more inflammatory factors, without an equivalent correlation with the contrast group. An extension of this reasoning would predict a higher correlation among lower socio-demographic index (SDI) populations as a result of fewer resources to prevent either inflammatory disease or violent crime. Methods In order to examine this potential correlation, an analysis was made comparing rates of change in incidence between violence, inflammatory conditions, and a contrast group disease of noninflammatory nature, as determined by Pearson's correlation coefficient. Results In the low socio-demographic index, inflammatory conditions demonstrated 80% correlation with interpersonal violence, middle-low socio-demographic index inflammatory conditions demonstrated 60% correlation with interpersonal violence, middle socio-demographic index inflammatory conditions demonstrated 0% correlation with interpersonal violence, middle-high socio-demographic index inflammatory conditions demonstrated 60% correlation with interpersonal violence, and high socio-demographic index inflammatory conditions demonstrated 40% correlation with interpersonal violence. Discussion The majority of socio-demographic groups showed a significant correlation between rates of change in incidence of violence and inflammatory conditions. This correlation was not found with a similar frequency or strength in diseases not causally linked to inflammation. As predicted in the hypothesis, the highest correlations of inflammatory diseases with violence existed in the lower socio-demographic populations, supporting a link between inflammatory levels and incidences of violence.
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Affiliation(s)
- Ryan Castle
- Science Division, Whole Health Institute, Bentonville, AR, USA
| | | | - Paul J Mills
- Herbert Wertheim School of Public Health and Human Longevity Science, Center of Excellence for Research and Training in Integrative Health, University of California San Diego, La Jolla, CA, USA
| | - Michelle A Williams
- Harvard T.H. Chan School of Public Health, Department of Global Health and Population, Harvard University, Boston, MA, USA
| | | | - James A Rindfleisch
- Education Department, Whole Health School of Medicine and Health Sciences, Bentonville, AR, USA
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12
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Zhang AY, Ganocy SJ, Owusu C, Gao K. Associations Among Irritability, High-Sensitivity C-Reactive Protein/Interleukin-6, and Depression in Patients With Early-Stage Breast Cancer Undergoing Chemotherapy: A Prospective Study. J Acad Consult Liaison Psychiatry 2021; 63:260-267. [PMID: 34506994 DOI: 10.1016/j.jaclp.2021.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/16/2021] [Accepted: 08/28/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Association between irritability and depression has been frequently reported, but the nature of this association in the adult population is poorly understood. OBJECTIVES We examined associations among irritability (e.g., a feeling of agitation), inflammatory biomarkers, and depression during chemotherapy. METHODS Forty-four patients with nonmetastatic breast cancer were assessed at baseline and after 3 months of chemotherapy on The Irritability Scale-Initial Version, severity and new onset of depressive symptoms using the Hamilton Depression Rating Scale, and serum levels of high-sensitivity C-reactive protein and interleukin 6. RESULTS At baseline, high-sensitivity C-reactive protein significantly correlated with physical and mood subscales of The Irritability Scale-Initial Version, but not with depression. Irritability and high-sensitivity C-reactive protein significantly predicted the severity and new onset of moderate to severe depressive symptoms over time, while irritability and interleukin 6 significantly predicted new onset of moderate to severe depressive symptoms. CONCLUSION The findings suggest that irritability is an independent risk factor of depression and associated with increasing high-sensitivity C-reactive protein. Irritability needs to be effectively managed in patients with cancer undergoing chemotherapy to prevent them from developing depressive symptoms. These preliminary findings should be investigated in future large-sample studies.
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Affiliation(s)
- Amy Y Zhang
- Associate Professor of Nursing, Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH.
| | - Stephen J Ganocy
- Assistant Professor of Statistics, Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Cynthia Owusu
- Associate Professor of Medicine, Division of Hematology Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Keming Gao
- Professor of Psychiatry, Case Western Reserve University School of Medicine, Clinical Director of Mood Disorders Program, University Hospitals Cleveland Medical Center, Cleveland, OH
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13
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Lyu C, Tsinovoi CL, Xun P, Song Y, Pu Y, Rosanoff A, Iribarren C, Schreiner PJ, Shikany JM, Jacobs DR, Kahe K. Magnesium intake was inversely associated with hostility among American young adults. Nutr Res 2021; 89:35-44. [PMID: 33894659 PMCID: PMC8098670 DOI: 10.1016/j.nutres.2021.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/20/2021] [Accepted: 01/23/2021] [Indexed: 11/17/2022]
Abstract
Hostility is a complex personality trait associated with many cardiovascular risk factor phenotypes. Although magnesium intake has been related to mood and cardio-metabolic disease, its relation with hostility remains unclear. We hypothesize that high total magnesium intake is associated with lower levels of hostility because of its putative antidepressant mechanisms. To test the hypothesis, we prospectively analyzed data in 4,716 young adults aged 18-30 years at baseline (1985-1986) from four U.S. cities over five years of follow-up using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Magnesium intake was estimated from a dietary history questionnaire plus supplements at baseline. Levels of hostility were assessed using the Cook-Medley scale at baseline and year 5 (1990-1991). Generalized estimating equations were applied to estimate the association of magnesium intake with hostility as repeated measures at the two time-points (baseline and year 5). General linear model was used to determine the association between magnesium intake and change in hostility over 5 years. After adjustment for socio-demographic and major lifestyle factors, a significant inverse association was observed between magnesium intake and hostility level over 5 years of follow-up. Beta coefficients (95% CI) across higher quintiles of magnesium intake were 0 (reference), -1.28 (-1.92, -0.65), -1.45 (-2.09, -0.81), -1.41 (-2.08, -0.75) and -2.16 (-2.85, -1.47), respectively (Plinear-trend<.01). The inverse association was independent of socio-demographic and major lifestyle factors, supplement use, and depression status at year 5. This prospective study provides evidence that in young adults, high magnesium intake was inversely associated with hostility level independent of socio-demographic and major lifestyle factors.
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Affiliation(s)
- Chen Lyu
- Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IA, USA
| | - Cari L Tsinovoi
- Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IA, USA
| | - Pengcheng Xun
- Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IA, USA
| | - Yiqing Song
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IA, USA
| | - Yongjia Pu
- Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IA, USA
| | | | | | - Pamela J Schreiner
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - James M Shikany
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David R Jacobs
- Division of Epidemiology, University of Minnesota, Minneapolis, MN, USA
| | - Ka Kahe
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032, USA.
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14
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Nordgreen J, Edwards SA, Boyle LA, Bolhuis JE, Veit C, Sayyari A, Marin DE, Dimitrov I, Janczak AM, Valros A. A Proposed Role for Pro-Inflammatory Cytokines in Damaging Behavior in Pigs. Front Vet Sci 2020; 7:646. [PMID: 33134341 PMCID: PMC7562715 DOI: 10.3389/fvets.2020.00646] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 08/10/2020] [Indexed: 12/28/2022] Open
Abstract
Sickness can change our mood for the worse, leaving us sad, lethargic, grumpy and less socially inclined. This mood change is part of a set of behavioral symptoms called sickness behavior and has features in common with core symptoms of depression. Therefore, the physiological changes induced by immune activation, for example following infection, are in the spotlight for explaining mechanisms behind mental health challenges such as depression. While humans may take a day off and isolate themselves until they feel better, farm animals housed in groups have only limited possibilities for social withdrawal. We suggest that immune activation could be a major factor influencing social interactions in pigs, with outbreaks of damaging behavior such as tail biting as a possible result. The hypothesis presented here is that the effects of several known risk factors for tail biting are mediated by pro-inflammatory cytokines, proteins produced by the immune system, and their effect on neurotransmitter systems. We describe the background for and implications of this hypothesis.
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Affiliation(s)
- Janicke Nordgreen
- Department of Paraclinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway
| | - Sandra A. Edwards
- School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Laura Ann Boyle
- Teagasc Animal and Grassland Research and Innovation Centre, Fermoy, Ireland
| | - J. Elizabeth Bolhuis
- Adaptation Physiology Group, Wageningen University & Research, Wageningen, Netherlands
| | - Christina Veit
- Department of Paraclinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway
| | - Amin Sayyari
- Department of Production Animal Clinical Science, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway
| | - Daniela E. Marin
- National Institute for Research and Development for Biology and Animal Nutrition, Balotesti, Romania
| | | | - Andrew M. Janczak
- Department of Production Animal Clinical Science, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway
| | - Anna Valros
- Department of Production Animal Medicine, Research Centre for Animal Welfare, University of Helsinki, Helsinki, Finland
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15
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Martinez-Muniz GA, Wood SK. Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy. J Pharmacol Exp Ther 2020; 375:161-174. [PMID: 32759370 PMCID: PMC7569308 DOI: 10.1124/jpet.120.266205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Women are at significantly greater risk of developing stress-related disorders such as depression. The increased risk begins during puberty and continues throughout life until menopause, suggesting a role for ovarian hormones in this increased susceptibility. Importantly, inflammation has been gaining momentum in its role in the pathogenesis of depression. Herein, clinical and preclinical studies have been reviewed to better understand how sex differences within the immune system may contribute to exaggerated risk of depression in females. First, studies that investigate the ability of psychologic stress episodes to engage the inflammatory systems both in the brain and periphery are reviewed with a special focus on sex-specific effects. Moreover, studies are discussed that identify whether imbalanced inflammatory milieu contributes to the development of depression in males versus females and whether these effects are regulated by estradiol. Importantly, we propose a locus coeruleus-norepinephrine-cytokine circuit as a conduit through which stress could increase stress susceptibly in females. Finally, the anti-inflammatory capacity of traditional and nontraditional antidepressants is investigated, with the goal of providing a better understanding of pharmacotherapeutics to enhance strategies to personalize antidepressant treatments between the sexes. The studies reviewed herein strongly support the need for further studies to elucidate whether females are especially sensitive to anti-inflammatory compounds as adjuvants to traditional therapies. SIGNIFICANCE STATEMENT: Women have hve an increased risk of developing stress-related disorders such as depression. In this review, literature from clinical and preclinical studies are integrated to define sex differences in stress-induced inflammatory responses as a potential source for the etiology of sex differences in depressive disorders. Moreover, the anti-inflammatory capacity of traditional and nontraditional antidepressants is reviewed to inform on potential pharmacotherapeutic strategies to personalize antidepressant therapy in a sex-dependent manner.
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Affiliation(s)
- Gustavo A Martinez-Muniz
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina and Dorn Veterans Administration Medical Center, Columbia, South Carolina
| | - Susan K Wood
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina and Dorn Veterans Administration Medical Center, Columbia, South Carolina
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16
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Abstract
BACKGROUND Irritability is common among people who are physically ill, but a physical underpinning of irritability is not assessed by existing measures. A measure that assesses multidimensionality of irritability can help nurses and clinicians provide better care for people with cancer and, thus, reduce a risk for developing depression during cancer treatment. OBJECTIVES We pilot tested a new measure, The Irritability Scale-Initial Version (TISi), for assessing irritability of cancer patients on three dimensions: physical, affective, and behavioral. METHODS We conducted thee pilot studies to develop the 35-item TISi on a 5-point Likert scale. TISi was tested in 48 early-stage, nonmetastasized breast cancer patients at baseline (before) and 3 months (during chemotherapy). Of these patients, 62.5% received neoadjuvant and 37.5% received adjuvant chemotherapy, but none received hormonal treatment before or during the study. Measures of other correlates, including depression, anxiety, symptom distress, and social disconnectedness, were also administered, and biomarkers of hsCRP, TNF-α, IL-6, and BDNF were obtained from blood draws at both assessments. RESULTS TISi has a high internal consistency (Cronbach's α = .97), satisfactory test-retest reliability (retest r = .69, intraclass correlation coefficient = .86), and moderate correlation with other constructs over time (r ≈ .40-.70). Its physical subscale significantly correlated with hsCRP (r = .32, p = .025) at baseline and TNF-α (r = .44, p = .002) at 3 months. A confirmatory factor analysis yields three factor loadings that are in line with conceptualization of the subscales. DISCUSSION The findings support psychometric properties of TISi and its application for assessing cancer patients' irritability in multiple dimensions. Further investigation using a large study sample is necessary for improving construct and criterion validity and reducing item redundancy. CONCLUSION TISi can be used to measure the level of irritability in cancer patients.
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17
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Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders. Psychopharmacology (Berl) 2019; 236:3063-3079. [PMID: 31359117 PMCID: PMC6821593 DOI: 10.1007/s00213-019-05326-9] [Citation(s) in RCA: 215] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 07/08/2019] [Indexed: 12/11/2022]
Abstract
Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774-815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women's susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context-dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period.
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18
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Feng M, Crowley NA, Patel A, Guo Y, Bugni SE, Luscher B. Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine. Neuroscience 2019; 406:109-125. [PMID: 30858110 DOI: 10.1016/j.neuroscience.2019.03.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/27/2022]
Abstract
Neuroinflammation is associated with increased vulnerability to diverse psychiatric conditions, including treatment-resistant major depressive disorder (MDD). Here we assessed whether high fat diet (HFD) induced neuroinflammation may be suitable to model a treatment-resistant depressive-like brain state in mice. Male and female mice were fed a HFD for 18 weeks, followed by quantitation of glucose tolerance, inflammatory markers of brain tissue (TNFα, IL-6, IL-1β, Iba-1), neural excitability in the prelimbic cortex (PLC), as well as assessment of emotional reactivity and hedonic behavior in a battery of behavioral tests. In addition, we assessed the behavioral responsiveness of mice to fluoxetine, desipramine, ketamine, and the Kv7 channel opener and anticonvulsant retigabine. HFD exposure led to glucose intolerance and neuroinflammation in male mice, with similar but non-significant trends in females. Neuroinflammation of males was associated with anxious-depressive-like behavior and defects in working memory, along with neural hyperexcitability and increased Ih currents of pyramidal cells in the PLC. The behavioral changes were largely resistant to chronic treatment with fluoxetine and desipramine, as well as ketamine. By contrast, retigabine (also known as ezogabine) normalized neural excitability and Ih currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.
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Affiliation(s)
- Mengyang Feng
- Department of Biology, Pennsylvania State University, University Park, PA 16802; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802
| | - Nicole A Crowley
- Department of Biology, Pennsylvania State University, University Park, PA 16802; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802
| | - Akshilkumar Patel
- Department of Biology, Pennsylvania State University, University Park, PA 16802; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802
| | - Yao Guo
- Department of Biology, Pennsylvania State University, University Park, PA 16802; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802
| | - Sierra E Bugni
- Department of Biology, Pennsylvania State University, University Park, PA 16802; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802
| | - Bernhard Luscher
- Department of Biology, Pennsylvania State University, University Park, PA 16802; Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA 16802; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802.
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19
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Elshimi E, Morad W, Mohamad NE. Male Sexual Dysfunction Among Egyptian Patients with Chronic Hepatitis C Virus Infection Before and After Direct-Acting Antiviral Drugs. J Sex Med 2019; 16:402-409. [DOI: 10.1016/j.jsxm.2019.01.309] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 02/06/2023]
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Franklin TC, Xu C, Duman RS. Depression and sterile inflammation: Essential role of danger associated molecular patterns. Brain Behav Immun 2018; 72:2-13. [PMID: 29102801 DOI: 10.1016/j.bbi.2017.10.025] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/14/2017] [Accepted: 10/31/2017] [Indexed: 12/12/2022] Open
Abstract
Stress is a major risk factor for psychiatric disorder including major depressive disorder (MDD) and can induce inflammation, which is known to be dysregulated in depression. Several clinical and pre-clinical studies have demonstrated a strong association between depressive symptoms and the expression of factors that increase inflammation. Conversely, administration of anti-inflammatory agents has been shown to ameliorate depressive symptoms, demonstrating the importance of inflammation as a mediator of depression. Although it is clear that inflammation plays a role in the pathophysiology of depression, the mechanism by which inflammation is activated in mood disorders remains unclear. To address this issue, studies have investigated the role of pattern recognition receptor (PRR) activation in stress-induced inflammation and mood disorders. However, the identification of the endogenous factors, referred to as danger-associated molecular patterns (DAMP) that activate these receptors remains understudied. Here we review the role of DAMPs in depression and highlight the clinical evidence for elevation of DAMP signaling in MDD patients and in pre-clinical animal stress models of depression.
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Affiliation(s)
- Tina C Franklin
- Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA
| | - Chelsea Xu
- Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA
| | - Ronald S Duman
- Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
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21
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Takahashi A, Flanigan ME, McEwen BS, Russo SJ. Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci 2018; 12:56. [PMID: 29623033 PMCID: PMC5874490 DOI: 10.3389/fnbeh.2018.00056] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/06/2018] [Indexed: 01/25/2023] Open
Abstract
Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression.
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Affiliation(s)
- Aki Takahashi
- Laboratory of Behavioral Neuroendocrinology, University of Tsukuba, Tsukuba, Japan.,Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States
| | - Meghan E Flanigan
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Bruce S McEwen
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States
| | - Scott J Russo
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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22
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Montalvo-Ortiz JL, Zhang H, Chen C, Liu C, Coccaro EF. Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis. Int J Neuropsychopharmacol 2018; 21:12-20. [PMID: 29106553 PMCID: PMC5789263 DOI: 10.1093/ijnp/pyx087] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Intermittent explosive disorder is defined as a recurrent, problematic, and impulsive aggression that affects 3% to 4% of the US population. While behavioral genetic studies report a substantial degree of genetic influence on aggression and impulsivity, epigenetic mechanisms underlying aggression and intermittent explosive disorder are not well known. METHODS The sample included 44 subjects (22 with a DSM-5 diagnosis of intermittent explosive disorder and 22 comparable subjects without intermittent explosive disorder). Peripheral blood DNA methylome was profiled using the Illumina Infinium HumanMethylation450 Beadchip. Intermittent explosive disorder-associated genome-wide DNA methylation changes were analyzed using the CpGassoc R package, with covariates age, sex, and race being adjusted. A gene-based functional enrichment analysis was performed to identify pathways that were overrepresented by genes harboring highly differentially methylated CpG sites. RESULTS A total of 27 CpG sites were differentially methylated in IED participants (P<5.0×10-5), but none reached genome-wide significant threshold. Functional enrichment analysis revealed that genes mapped by these CpG sites are involved in the inflammatory/immune system, the endocrine system, and neuronal differentiation. CONCLUSIONS Consistent with our previous studies showing an association of inflammatory response with aggressive behavior in intermittent explosive disorder subjects, our gene-based pathway analysis using differentially methylated CpG sites supports inflammatory response as an important mechanism involved in intermittent explosive disorder and reveals other novel biological processes possibly associated with intermittent explosive disorder.
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Affiliation(s)
| | - Huiping Zhang
- Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts
| | - Chao Chen
- State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
| | - Chunyu Liu
- University of Illinois at Chicago, Chicago, Illinois
| | - Emil F Coccaro
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, Illinois
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23
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Bouwens JA, van Duijn E, Cobbaert CM, Roos RAC, van der Mast RC, Giltay EJ. Plasma Cytokine Levels in Relation to Neuropsychiatric Symptoms and Cognitive Dysfunction in Huntington's disease. J Huntingtons Dis 2017; 5:369-377. [PMID: 27983562 DOI: 10.3233/jhd-160213] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND In Huntington's disease (HD) the innate immune system is activated, as reflected by increased plasma levels of different cytokines. OBJECTIVE To explore whether increased cytokine levels are associated with neuropsychiatric symptoms and cognitive dysfunction in HD mutation carriers. METHOD Plasma cytokine levels of TNF-alpha, interleukin (IL)-1ra, IL-1β, IL-5, IL-6, IL-8 and Il-10 were assessed in 124 HD mutation carriers at two time points 2 years apart (totalling 214 observations). Using multilevel regression analysis, cytokines were analysed in relation to neuropsychiatric symptoms and cognitive dysfunction. Depressed mood was assessed with the depression subscale of the Problem Behaviours Assessment (PBA), apathy with the Apathy Scale, and irritability with the Irritability Scale. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and a battery of executive cognitive functioning tests, aggregated into an executive cognitive functioning (ExCog) score. RESULTS Inverse associations were found in adjusted models between IL-6 and ExCog score (β= -0.114; p = 0.01) and between IL-1ra and ExCog score (β= -0.110; p = 0.02). No associations between cytokine levels and any of the other neuropsychiatric symptom scores remained statistically significant in adjusted models. CONCLUSION Higher plasma levels of IL-6 and IL-1ra are weakly associated with cognitive dysfunction in HD, but not with other neuropsychiatric symptoms.
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Affiliation(s)
- Jos A Bouwens
- Department of Psychiatry, Leiden University Medical Center, The Netherlands.,Rodersana Center for Addiction, Oirschot, The Netherlands
| | - Erik van Duijn
- Department of Psychiatry, Leiden University Medical Center, The Netherlands.,Center for Mental Health Care Delfland, Delft, The Netherlands
| | - Christa M Cobbaert
- Department of Clinical Chemistry, Leiden University Medical Center, The Netherlands
| | - Raymund A C Roos
- Department of Neurology, Leiden University Medical Center, The Netherlands
| | - Roos C van der Mast
- Department of Psychiatry, Leiden University Medical Center, The Netherlands.,Department of Psychiatry, CAPRI-University of Antwerp, Belgium
| | - Erik J Giltay
- Department of Psychiatry, Leiden University Medical Center, The Netherlands
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Jeon SA, Lee E, Hwang I, Han B, Park S, Son S, Yang J, Hong S, Kim CH, Son J, Yu JW. NLRP3 Inflammasome Contributes to Lipopolysaccharide-induced Depressive-Like Behaviors via Indoleamine 2,3-dioxygenase Induction. Int J Neuropsychopharmacol 2017; 20:896-906. [PMID: 29016824 PMCID: PMC5737528 DOI: 10.1093/ijnp/pyx065] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 07/27/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Inflammation may play a significant role in the pathogenesis of depression, although the molecular target for the treatment of inflammation-mediated depressive symptoms remains to be elucidated. Recent studies have implicated the NLRP3 inflammasome in various psychiatric disorders, including depression. However, the underlying mechanism by which NLRP3 inflammasome activation mediates the progression of depressive-like behaviors remains poorly understood. METHODS We examined whether NLRP3 deficiency influenced depressive-like behaviors and cerebral inflammation following systemic administration of lipopolysaccharide in mice. To further assess the contribution of the NLRP3 inflammasome to the progression of depression, we evaluated the effects of NLRP3 signaling on levels of indoleamine 2,3-dioxygenase. RESULTS Nlrp3-deficient mice exhibited significant attenuation of depressive-like behaviors and cerebral caspase-1 activation in a lipopolysaccharide-induced model of depression. Treatment with the antidepressant amitriptyline failed to block NLRP3-dependent activation of caspase-1, but inhibited lipopolysaccharide-promoted production of interleukin-1β mRNA via suppressing NF-κB signaling in mouse mixed glial cultures. Interestingly, lipopolysaccharide administration produced NLRP3-dependent increases in indoleamine 2,3-dioxygenase expression and activity of mouse brain. Furthermore, inflammasome-activating stimulations, but not treatment with the inflammasome product interleukin-1β, triggered indoleamine 2,3-dioxygenase mRNA induction in mixed glial cells. CONCLUSIONS Our data indicate that the NLRP3 inflammasome is significantly implicated in the progression of systemic inflammation-induced depression. NLRP3-dependent caspase-1 activation produced significant increases in indoleamine 2,3-dioxygenase levels, which may play a significant role in lipopolysaccharide-induced depression. Collectively, our findings suggest that indoleamine 2,3-dioxygenase is a potential downstream mediator of the NLRP3 inflammasome in inflammation-mediated depressive-like behaviors.
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Affiliation(s)
- Seon-A Jeon
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Eunju Lee
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Inhwa Hwang
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Boyoung Han
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Sangjun Park
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Seunghwan Son
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Jungmin Yang
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Sujeong Hong
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Chul Hoon Kim
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Junghyun Son
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim)
| | - Je-Wook Yu
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Ms Jeon, Ms Lee, Ms Hwang, Ms Han, Dr Park, Mr Son, Mr Yang, Ms Hong, and Dr Yu); Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (Ms Han and Dr Son); Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (Dr Kim).,Correspondence: Je-Wook Yu, PhD, Department of Microbiology and Immunology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, Republic of Korea ()
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Munsterhjelm C, Nordgreen J, Aae F, Heinonen M, Olstad K, Aasmundstad T, Janczak AM, Valros A. To be blamed or pitied? The effect of illness on social behavior, cytokine levels and feed intake in undocked boars. Physiol Behav 2017; 179:298-307. [PMID: 28684135 DOI: 10.1016/j.physbeh.2017.06.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/29/2017] [Accepted: 06/30/2017] [Indexed: 01/07/2023]
Abstract
Tail biting is detrimental to animal welfare and has negative consequences for producer economy. Poor health is one of the risk factors for tail biting. The first aim of this study was therefore to test for links between health status and behavior related to tail biting at the individual level. The second aim of this study was to test whether variation in cytokines was related to variation in social behavior. These small molecules produced upon immune activation are known to influence behavior both in the direction of withdrawal and increased aggression. This could potentially increase non-functional social behavior and thereby the risk of a tail biting outbreak. To investigate this, we collected behavioral data, health data, feeding data and blood samples from undocked boars at a test station farm in Norway. We compared groups with three different diagnoses: osteochondrosis diagnosed by computer tomography scanning (OCSAN), osteochondrosis diagnosed by clinical examination (OCCLIN) and respiratory tract disease (RESP), with healthy controls (CTR). We tested whether the diagnoses were associated with feeding and growth, social behavior and cytokine levels. We then tested whether there were correlations between cytokine levels and social behavior. We also provide raw data on cytokine levels in the extended sample (N=305) as there are few publications on cytokine levels measured in pigs living under commercial conditions. OCCLIN pigs visited the feeder less, and fed longer compared to CTR pigs. Pigs diagnosed with RESP showed a large drop in growth the first week after filming, which corresponds to the week they were likely to have been diagnosed with illness, and a tendency to compensatory increase in the week after that. Social behavior differed between experimental groups with OCSCAN pigs receiving more social behavior (both aggressive and non-aggressive) compared to CTR, and RESP pigs tending to perform more ear- and tail-biting than controls. There were no differences in absolute levels of cytokines between categories. However IL1-ra and IL-12 showed correlations with several behaviors that have been shown by others to be associated with current or future tail biting activity. To our knowledge, this is the first published study indicating a role for illness in non-functional social behavior in pigs and the first showing a correlation between cytokine levels and social behavior.
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Affiliation(s)
- C Munsterhjelm
- Research Centre for Animal Welfare, Department of Production Animal Medicine, University of Helsinki, Finland
| | - J Nordgreen
- Animal Welfare Research Group, Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), Oslo, Norway.
| | - F Aae
- Animal Welfare Research Group, Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), Oslo, Norway
| | - M Heinonen
- Research Centre for Animal Welfare, Department of Production Animal Medicine, University of Helsinki, Finland
| | - K Olstad
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), Oslo, Norway
| | | | - A M Janczak
- Animal Welfare Research Group, Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), Oslo, Norway
| | - A Valros
- Research Centre for Animal Welfare, Department of Production Animal Medicine, University of Helsinki, Finland
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26
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Zaily DG, Marlen CF, Santiago DC, Gillian MD, Carmen VS, Zurina CE, Enrique R. AS, Liz AL, Lisset GF, Sacha LDV, Elena FB. Clinical Evaluation of Terap C Vaccine in Combined Treatment with Interferon and Ribavirin in Patients with Hepatitis C. CURRENT THERAPEUTIC RESEARCH 2017; 85:20-28. [PMID: 29158855 PMCID: PMC5681293 DOI: 10.1016/j.curtheres.2017.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 04/14/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND An estimated 170 million individuals worldwide are infected with the hepatitis C virus (HCV). Although treatment options using a combination of pegylated interferon and ribavirin (P-IFN/RBV) are available, sustained clearance of the virus is only achieved in approximately 40% of individuals infected with HCV genotype 1. Recent advances in the treatment of HCV using directly acting antiviral agents have been achieved; however, treatment can be very expensive and is associated with substantial side effects. The development of a new treatment modality is needed. One possible modality could be specific immunotherapy. Terap C is a therapeutic vaccine candidate composed of pIDKE2, a plasmid expressing HCV structural antigens, with a recombinant HCV core protein, Co.120. OBJECTIVE To assess the safety and efficacy of concomitant therapy with the candidate vaccine, Terap C, IFN α-2b and ribavirin in untreated individuals with HCV genotype 1 infection. METHODS This was a Phase II randomized, placebo-controlled, double-blind clinical trial evaluating the safety and efficacy of Terap C concomitant with IFN α-2b/RBV in 92 treatment-naïve patients with HCV genotype 1 infection. The study was conducted at the Gastroenterology Institute in Havana, Cuba. Patients were randomly assigned to 1 of 5 groups. The control group (Group 1) received IFN α-2b/RBV and placebo for 48 weeks. Groups 2 and 3 were administered Terap C 6 and 9 times, respectively, in addition to standard IFN α-2b/RBV treatment. In groups 4 and 5, Terap C was introduced 12 weeks after the initiation of IFN α-2b/RBV and administered 6 and 9 times, respectively, concomitant with IFN α-2b/RBV. RESULTS All patients showed some adverse events. Out of 3615 adverse events, only 18.8% were considered to be probably associated with administration of Terap C. Most events (47.4%) were considered to be improbably associated with of administration Terap C. Only 33.8% were considered possibly temporarily associated with Terap C, and can be explained by the use of conventional IFN α-2b + RBV or by HCV itself. The most common adverse events (≥65%) observed were pain at the injection site, headache, asthenia, psychiatric disturbances, fever, and gastrointestinal symptoms. Regarding sustained virological response, a 20% superiority was observed in the patients who received concomitant Terap C treatments from the beginning of the study compared with those who started after Week 12. CONCLUSIONS Vaccination with Terap C in patients with chronic HCV infection was safe and well tolerated. Clinical trial protocol code: IG/VHI/HC/0701; Public Register Code: RPCEC00000074.
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Zhang Q, Hong W, Li H, Peng F, Wang F, Li N, Xiang H, Zhang Z, Su Y, Huang Y, Zhang S, Zhao G, Zhou R, Mao L, Lin Z, Cai W, Fang Y, Xie B, Zhao M. Increased ratio of high sensitivity C-reactive protein to interleukin-10 as a potential peripheral biomarker of schizophrenia and aggression. Int J Psychophysiol 2017; 114:9-15. [PMID: 28174109 DOI: 10.1016/j.ijpsycho.2017.02.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 12/11/2016] [Accepted: 02/03/2017] [Indexed: 01/18/2023]
Abstract
BACKGROUND Many studies have indicated that immune dysfunction might be involved in the physiopathology of schizophrenia and aggression. This study aimed to investigate the correlation between high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-10 and clinical characteristics, especially aggression, and to explore the potential role of hsCRP and IL-10 as plasma biomarkers of schizophrenia. METHODS Forty-one patients with schizophrenia and forty healthy individuals were enrolled. Psychopathological severity and aggression were assessed using the Positive and Negative Syndrome Scale (PANSS) and Modified Overt Aggression Scale (MOAS). Plasma concentrations of hsCRP and IL-10 were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS (1) Higher levels of hsCRP (p<0.001), lower levels of logIL-10 (p<0.001) and higher ratio of hsCRP to IL-10 (p<0.001) were observed in the plasma of patients with schizophrenia, compared to healthy controls; (2) ROC (receiver operating characteristic) curve analysis revealed that ratio of hsCRP/IL-10 (predictive value: 0.783, p<0.01; sensitivity: 85.4%; specificity: 67.5%) was more applicable as a biomarker to distinguish patients with schizophrenia from the control group than hsCRP and IL-10 alone (predictive value: 0.718, p<0.01; 0.275, p<0.001, respectively); (3) we found positive correlations between hsCRP and the total score and verbal aggression score of MOAS (r=0.654, p<0.01; r=0.678, p<0.05), and between hsCRP/IL-10 and the total score of MOAS (r=0.636, p<0.01). CONCLUSIONS Our results suggest the possible function of hsCRP and IL-10 in the pathogenesis of schizophrenia and the possible value of hsCRP/IL-10 as a potential peripheral biomarker of schizophrenia. This finding also suggests a relationship between hsCRP, IL-10 and their ratio with aggression in patients with schizophrenia.
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Affiliation(s)
- Qinting Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, Shanghai 200063, China; Collaborative Innovation Center for Brain Science, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Wu Hong
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
| | - Haozhe Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, Shanghai 200063, China
| | - Fanglan Peng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Fan Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Ningning Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Hui Xiang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Zongfeng Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yousong Su
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yueqi Huang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Hangzhou Seventh People's Hospital, Hanzhou 310007, China
| | - Shengyu Zhang
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, Shanghai 200063, China
| | - Guoqin Zhao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Rubai Zhou
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Ling Mao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; XuHui District Mental Health Center of Shanghai, Shanghai 200030, China
| | - Zhiguang Lin
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Weixiong Cai
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, Shanghai 200063, China
| | - Yiru Fang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Bin Xie
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Min Zhao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Collaborative Innovation Center for Brain Science, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai, China.
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Li H, Zhang Q, Li N, Wang F, Xiang H, Zhang Z, Su Y, Huang Y, Zhang S, Zhao G, Zhou R, Mao L, Lin Z, Cai W, Fang Y, Xie B, Zhao M, Hong W. Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia. Psychiatry Res 2016; 246:700-706. [PMID: 27829509 DOI: 10.1016/j.psychres.2016.10.061] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 10/13/2016] [Accepted: 10/20/2016] [Indexed: 12/18/2022]
Abstract
Increasing evidence indicates that immune inflammatory processes, especially autoimmune reaction, should be considered in the pathophysiology of schizophrenia and aggressive behavior. The present study aimed to explore the correlation between immune factors (C3 and Th17-related cytokines) and aggressive behavior in schizophrenia patients. Forty schizophrenia patients and forty age- and gender-matched healthy controls participated in the study. Blood samples were assessed by ELISA upon enrollment. Positive and negative syndrome scale (PANSS) and modified overt aggression scale (MOAS) were used to estimate the severity and aggressive symptoms of schizophrenia patients. Plasma levels of IL-17, IL-23, and TGF-β1 in schizophrenia patients were significantly higher than those in healthy controls [(37.63±17.82) vs. (29.34±10.38)pg/ml, p=0.02; (101.40±135.26) vs. (13.09±5.94) pg/ml, p=0.01; (2864.57±2163.61) vs. (1839.69±1797.73)pg/ml, p=0.04], whereas C3 levels were significantly lower in schizophrenia patients [( 120,479.67± 65,612.50) vs. ( 208,060.21± 217,008.21)ng/ml, p=0.02]. IL-17, IL-23, and TGF-β1 levels were positively related to total scores of MOAS (p=0.02, p=0.02 and p=0.03, respectively) and PANSS (p=0.04, p=0.04 and p=0.02, respectively), whereas C3 levels were negatively related to total PANSS scores (p=0.03). IL-17 and IL-23 levels were positively correlated with PANSS excited component scores (p=0.04 and p=0.01, respectively). Our findings suggested that the Th17-related cytokine levels were positively related to the severity of schizophrenia and aggressive behavior, whereas C3 levels were negatively related to the severity of schizophrenia. This study demonstrated that elevated levels of Th17-related cytokines and decreased levels of C3 could be potential biomarkers for schizophrenia and aggressive behavior.
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Affiliation(s)
- Haozhe Li
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, PR China, Shanghai, China; Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinting Zhang
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, PR China, Shanghai, China; Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ningning Li
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Wang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Xiang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zongfeng Zhang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yousong Su
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yueqi Huang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengyu Zhang
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, PR China, Shanghai, China
| | - Guoqing Zhao
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rubai Zhou
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Mao
- XuHui District Mental Health Center of Shanghai, Shanghai, China
| | - Zhiguang Lin
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weixiong Cai
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Science, Ministry of Justice, PR China, Shanghai, China
| | - Yiru Fang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Xie
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Zhao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wu Hong
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Courtet P, Giner L, Seneque M, Guillaume S, Olie E, Ducasse D. Neuroinflammation in suicide: Toward a comprehensive model. World J Biol Psychiatry 2016. [PMID: 26223957 DOI: 10.3109/15622975.2015.1054879] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Suicidal behaviour (SB) entered the DSM-5, underlying a specific biological vulnerability. Then, recent findings suggested a possible role of the immune system in SB pathogenesis. The objective of this review is to present these main immune factors involved in SB pathogenesis. METHODS We conducted a review using Preferred Reporting Items for Systematic reviews and Meta-Analysis criteria, and combined ("Inflammation") AND ("Suicidal ideation" OR "Suicidal attempt" OR "suicide"). RESULTS Post mortem studies demonstrated associations between suicide and inflammatory cytokines in the orbitofrontal cortex, a brain region involved in suicidal vulnerability. Also, microgliosis and monocyte-macrophage system activation may be a useful marker of suicide neurobiology. Kynurenine may influence inflammatory processes, and related molecular pathways may be involved in SB pathophysiology. Few recent studies associated inflammatory markers with suicidal vulnerability: serotonin dysfunction, impulsivity and childhood trauma. Interestingly, the perception of threat that leads suicidal individuals to contemplate suicide may activate biological stress responses, including inflammatory responses. CONCLUSIONS Translational projects would be crucial to identify a specific marker in SB disorders, to investigate its clinical correlations, and the interaction between inflammatory cytokines and monoamine systems in SB. These researches might lead to new biomarkers and novel directions for therapeutic strategies.
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Affiliation(s)
- Philippe Courtet
- a Department of Emergency Psychiatry , Hôpital Lapeyronie, CHU Montpellier and Post Acute Care , CHU Montpellier , France.,b Inserm, University of Montpellier , Montpellier , France.,c FondaMental Foundation , France
| | | | - Maude Seneque
- a Department of Emergency Psychiatry , Hôpital Lapeyronie, CHU Montpellier and Post Acute Care , CHU Montpellier , France.,b Inserm, University of Montpellier , Montpellier , France.,c FondaMental Foundation , France
| | - Sebastien Guillaume
- a Department of Emergency Psychiatry , Hôpital Lapeyronie, CHU Montpellier and Post Acute Care , CHU Montpellier , France.,b Inserm, University of Montpellier , Montpellier , France.,c FondaMental Foundation , France
| | - Emilie Olie
- a Department of Emergency Psychiatry , Hôpital Lapeyronie, CHU Montpellier and Post Acute Care , CHU Montpellier , France.,b Inserm, University of Montpellier , Montpellier , France.,c FondaMental Foundation , France
| | - Deborah Ducasse
- a Department of Emergency Psychiatry , Hôpital Lapeyronie, CHU Montpellier and Post Acute Care , CHU Montpellier , France.,b Inserm, University of Montpellier , Montpellier , France.,c FondaMental Foundation , France
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Eckhardt B. Hepatitis C Treatment in People Who Inject Drugs. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2016. [DOI: 10.1007/s40506-016-0091-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Coccaro EF, Lee R, Fanning JR, Fuchs D, Goiny M, Erhardt S, Christensen K, Brundin L, Coussons-Read M. Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects. Psychoneuroendocrinology 2016; 71:189-96. [PMID: 27318828 PMCID: PMC5744870 DOI: 10.1016/j.psyneuen.2016.04.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 03/10/2016] [Accepted: 04/27/2016] [Indexed: 11/26/2022]
Abstract
Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.
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Affiliation(s)
- Emil F. Coccaro
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States,Corresponding author at: Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, United States. (E.F. Coccaro)
| | - Royce Lee
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States
| | - Jennifer R. Fanning
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Medical University, Innsbruck, Austria
| | - Michel Goiny
- Department of Physiology & Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Sophie Erhardt
- Department of Physiology & Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Kyle Christensen
- Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, United States,Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Lena Brundin
- Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, United States,Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Mary Coussons-Read
- Department of Psychology, University of Colorado, Colorado Springs, CO, United States
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Wachholz S, Eßlinger M, Plümper J, Manitz MP, Juckel G, Friebe A. Microglia activation is associated with IFN-α induced depressive-like behavior. Brain Behav Immun 2016; 55:105-113. [PMID: 26408795 DOI: 10.1016/j.bbi.2015.09.016] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 09/22/2015] [Accepted: 09/23/2015] [Indexed: 10/23/2022] Open
Abstract
Inflammatory immune activation has been frequently associated with the development of major depression. This association was confirmed in patients receiving long-term treatment with pro-inflammatory interferon-α (IFN-α). Microglia, the resident immune cells in the brain, might serve as an important interface in this immune system-to-brain communication. The aim of the present study was to investigate the role of microglia in an IFN-α mouse model of immune-mediated depression. Male BALB/c mice were treated with daily injections of IFN-α for two weeks. Depressive-like behavior was analyzed in the forced swim and tail suspension test. Activation of microglia was measured by flow cytometry. Pro-inflammatory M1 type (MHC-II, CD40, CD54, CD80, CD86, CCR7), anti-inflammatory M2 type (CD206, CD200R), and maturation markers (CD11c, CCR7) were tested, as well as the chemokine receptor CCR2. IFN-α led to a significant increase in depressive-like behavior and expression of the pro-inflammatory surface markers MHC-II, CD86, and CD54, indicating M1 polarization. Because IFN-α-treated mice showed great individual variance in the behavioral response to IFN-α, they were further divided into vulnerable and non-vulnerable subgroups. Only IFN-α vulnerable mice (characterized by their development of depressive-like behavior in response to IFN-α) showed an increased expression of MHC-II and CD86, while CD54 was similarly enhanced in both subgroups. Thus, IFN-α-induced activation of microglia was specifically associated with depressive-like behavior.
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Affiliation(s)
- Simone Wachholz
- Laboratory of Psychoneuroimmunology, Department of Psychiatry, LWL-University Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Manuela Eßlinger
- Laboratory of Psychoneuroimmunology, Department of Psychiatry, LWL-University Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Jennifer Plümper
- Laboratory of Psychoneuroimmunology, Department of Psychiatry, LWL-University Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Marie-Pierre Manitz
- Laboratory of Psychoneuroimmunology, Department of Psychiatry, LWL-University Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Georg Juckel
- Laboratory of Psychoneuroimmunology, Department of Psychiatry, LWL-University Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Astrid Friebe
- Laboratory of Psychoneuroimmunology, Department of Psychiatry, LWL-University Hospital, Ruhr University Bochum, Bochum, Germany.
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Couch Y, Trofimov A, Markova N, Nikolenko V, Steinbusch HW, Chekhonin V, Schroeter C, Lesch KP, Anthony DC, Strekalova T. Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice. J Neuroinflammation 2016; 13:108. [PMID: 27184538 PMCID: PMC4867526 DOI: 10.1186/s12974-016-0572-0] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 05/06/2016] [Indexed: 12/19/2022] Open
Abstract
Background Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Methods Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. Results When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. Conclusions It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0572-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yvonne Couch
- Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT, Oxford, UK
| | - Alexander Trofimov
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.,Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229, ER, Maastricht, Netherlands.,Institute of Physiologically Active Compounds, Moscow Region, Russia
| | - Natalyia Markova
- Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229, ER, Maastricht, Netherlands.,Institute of Physiologically Active Compounds, Moscow Region, Russia
| | | | - Harry W Steinbusch
- Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229, ER, Maastricht, Netherlands
| | - Vladimir Chekhonin
- Department of Basic and Applied Neurobiology, Serbsky Federal Medical Research Center for Psychiatry and Narcology, Moscow, Russia
| | - Careen Schroeter
- Department of Preventive Medicine, Maastricht Medical Centre Annadal, Maastricht, Netherlands
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.,Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229, ER, Maastricht, Netherlands
| | - Daniel C Anthony
- Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT, Oxford, UK.
| | - Tatyana Strekalova
- Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229, ER, Maastricht, Netherlands.
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Symptoms of anxiety and depression are frequent in patients with acute hepatitis C and are not associated with disease severity. Eur J Gastroenterol Hepatol 2016; 28:187-92. [PMID: 26575158 DOI: 10.1097/meg.0000000000000517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Neuropsychiatric symptoms of hepatitis C virus (HCV) infection and during peginterferon α therapy have been investigated in the chronic stage of the infection, but have not been described during the acute phase of the disease so far. We therefore evaluated anxiety and depression in patients with acute hepatitis C by the Hospital Anxiety and Depression Scale (HADS) within a clinical trial. METHODS Data were analysed from the German Hep-Net Acute HCV-III study. Anxiety and depression were characterized by an anxiety (HADS-A) and a depression subscale (HADS-D). More than eight points in each subscale were considered clinically relevant. Data were prospectively collected at baseline, end of treatment and at the end of the study. RESULTS At baseline, a HADS-A above eight points was observed significantly more frequently than a HADS-D above eight points [n=23/103 (22%) vs. n=12/103 (12%); P=0.041].A pathological HADS-A or HADS-D score did not correlate with age, sex, IL28B genotype, the probable mode of infection, HCV genotype or severity of disease as investigated by alanine aminotransferase and bilirubin levels.Antiviral therapy did not influence anxiety as 12/50 (24%) of patients had HADS-A above 8 at the end of therapy. The proportion of patients with HADS-D above eight points increased from 12% at baseline to 24% (n=12/50) at the end of therapy (P=0.06). HADS results were not associated with lost to follow-up or sustained virological response rates. CONCLUSION HADS data in acute HCV infection indicate that anxiety and depression do not correlate with severity of the disease, mode of acquisition, lost to follow-up and sustained virological response rates.
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MM B, A Y, U Y, GM SED, M A, H AG, E F, MM ES. Major depressive disorder and generalized anxiety disorder and response to treatment in hepatitis C patients in Egypt. Int J Psychiatry Med 2015; 50:147-62. [PMID: 26405268 DOI: 10.1177/0091217415605029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES The aim of the study was to estimate the prevalence and associated correlates of major depressive disorder and generalized anxiety disorder in hepatitis C virus patients before and after treatment and to investigate the relationship between major depressive disorder and generalized anxiety disorder and treatment response. METHODS A total of 116 consecutive hepatitis C virus patients from hepatitis C virus treatment center in Zagazig city, Egypt, were included in the study and divided into treated group (N = 58) and untreated group (N = 58). All hepatitis C virus patients were screened for major depressive disorder and generalized anxiety disorder using hospital anxiety and depression scale, and those who screened positive were interviewed to confirm the diagnosis of major depressive disorder and generalized anxiety disorder using DSM-IV-TR diagnostic criteria. These measures were done at baseline and after 12 weeks of treatment or observation. RESULTS At baseline, 3.5% and 12.1% of hepatitis C virus patients (treated group) had major depressive disorder and generalized anxiety disorder, respectively. After 12 weeks of treatment 37.9% of hepatitis C virus patients (treated group) had major depressive disorder and 46.6% had generalized anxiety disorder. There was a significant statistical difference between hospital anxiety and depression scale scores for depression (3.3 ± 2.3 vs. 6.4 ± 3.2, t = 9.6, p = 0.001) and for anxiety (4.6 ± 2.4 vs. 7.3 ± 3.0, t = 10.2, p = 0.001) before and after treatment. There was also significant statistical difference between treated group and untreated group regarding hospital anxiety and depression scale scores after treatment and observation (depression, treated group 6.4 ± 3.2 vs. untreated group 4.0 ± 2.4, t = 3.7, p = 0.001; anxiety, treated group 7.3 ± 3.0 vs. untreated group 4.5 ± 2.3, t = 4.4, p = 0.001). There was no association between major depressive disorder and generalized anxiety disorder and treatment response. CONCLUSIONS Major depressive disorder and generalized anxiety disorder are common in hepatitis C virus patients after treatment with interferon and ribavirin and were not related to treatment response.
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Affiliation(s)
- Bassiony MM
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Yousef A
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Youssef U
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Salah El-Deen GM
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Abdelghani M
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Al-Gohari H
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - Fouad E
- Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt
| | - El-Shafaey MM
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt
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Restrepo DP, Tamayo A. [Affective syndromes in liver transplant recipients: ¿mediated neurotoxicity immunosuppressive?]. ACTA ACUST UNITED AC 2015; 44:121-7. [PMID: 26578335 DOI: 10.1016/j.rcp.2015.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 10/07/2014] [Accepted: 01/13/2015] [Indexed: 12/26/2022]
Abstract
INTRODUCTION The onset of affective and psychotic in liver transplant patients symptoms, raises the need to explore the possible etiologies of mental symptoms. METHODOLOGY Case report and literature review. RESULTS Four clinical cases of patients undergoing orthotopic liver transplantation, who in the early post transplant showed affective symptoms, delusions and psychomotor agitation for which they needed psychiatric hospitalization and treatment with psychotropic drugs are presented. Three of the patients had clinical improvement and one patient died by suicide. DISCUSSION The development of mental symptoms in the post-transplant period opens the possibility of considering the secondary organic mental disorder a basic condition. CONCLUSIONS The adverse drug reaction may explain affective mental disorders in these four cases were reported.
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Affiliation(s)
- Diana Patricia Restrepo
- Médica Psiquiatra de Enlace, Docente Universidad CES, Estudiante de Maestría en Epidemiología Universidad CES, Medellín, Colombia.
| | - Alejandra Tamayo
- Médica Psiquiatra, Hospital Universitario San Vicente Fundación, Medellín, Colombia
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Stewart BJR, Turnbull D, Mikocka-Walus AA, Harley H, Andrews JM. An Aggravated Trajectory of Depression and Anxiety Co-morbid with Hepatitis C: A Within-groups Study of 61 Australian Outpatients. Clin Pract Epidemiol Ment Health 2015; 11:174-9. [PMID: 26668585 PMCID: PMC4676046 DOI: 10.2174/1745017901511010174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 04/29/2015] [Accepted: 05/20/2015] [Indexed: 02/07/2023]
Abstract
Background: This study aimed to explore the course of
depression and anxiety in chronic hepatitis C patients. Methods:
Data were combined from two studies: (1) Hospital Anxiety and Depression Scale (HADS)
scores in 395 consecutive Australian outpatients from 2006 to 2010 formed the
baseline measurement; and (2) Depression Anxiety Stress Scales (DASS) scores in
a survey of a sub-sample of these patients in 2011 formed the follow-up
measurement. After converting DASS to HADS scores, changes in symptom scores and
rates of case-ness (≥8), and predictors of follow-up symptoms were assessed. Results: Follow-up data were available for 61 patients (70.5% male)
whose age ranged from 24.5 to 74.6 years (M=45.6). The time to follow-up ranged
from 20.7 to 61.9 months (M=43.8). Baseline rates of depression (32.8%) and
anxiety (44.3%) increased to 62.3% and 67.2%, respectively. These findings were
confirmed, independent of the conversion, by comparing baseline HADS and
follow-up DASS scores with British community norms. Baseline anxiety and younger
age predicted depression, while baseline anxiety, high school non-completion,
and single relationship status predicted anxiety. Conclusion: This
study demonstrated a worsening trajectory of depression and anxiety. Further
controlled and prospective research in a larger sample is required to confirm
these findings.
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Affiliation(s)
| | | | | | - Hugh Harley
- Discipline of Medicine, University of Adelaide, Australia
| | - Jane M Andrews
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Australia; ; Discipline of Medicine, University of Adelaide, Australia
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Inflammatory markers and chronic exposure to fluoxetine, divalproex, and placebo in intermittent explosive disorder. Psychiatry Res 2015; 229:844-9. [PMID: 26277033 PMCID: PMC4837655 DOI: 10.1016/j.psychres.2015.07.078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 07/02/2015] [Accepted: 07/24/2015] [Indexed: 01/09/2023]
Abstract
Intermittent Explosive Disorder (IED) is a disorder of impulsive aggression affecting 4-7% of the U.S. population during some period of life. In addition to other biological correlates, elevations of plasma inflammatory markers have been reported in IED, compared with control, subjects. In this study we sought to explore if treatment exposure to anti-aggressive agents, compared with placebo, would be associated with a reduction in circulating levels of inflammatory markers. Thirty IED subjects, from a 12-week, double-blind, randomized, placebo-controlled trial of fluoxetine and divalproex, in which both pre- and post-treatment levels of C-Reactive Protein (CRP), interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α were obtained. Efficacy measures included the Overt Aggression Scale-Modified (OAS-M) score for Aggression and for Irritability, rate of Clinical Global Impression of Improvement (CGI-I), and rate of IED Remitters at study completion. As compared to placebo, neither fluoxetine nor divalproex reduced any of the measures of aggression. In addition, levels of CRP and pro- and anti-inflammatory cytokines showed no changes from pre- to post-treatment for any treatment condition. Correlations between pre- and post- treatment plasma CRP/cytokines were substantial (mean r=0.71, r(2)=0.50, p<0.001). Overall, circulating markers of inflammation markers were unaffected by treatment with fluoxetine or divalproex, consistent with the absence of change in measures of impulsive aggression.
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Fanning JR, Lee R, Gozal D, Coussons-Read M, Coccaro EF. Childhood trauma and parental style: Relationship with markers of inflammation, oxidative stress, and aggression in healthy and personality disordered subjects. Biol Psychol 2015; 112:56-65. [PMID: 26423894 DOI: 10.1016/j.biopsycho.2015.09.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 08/17/2015] [Accepted: 09/08/2015] [Indexed: 10/23/2022]
Abstract
Recent studies suggest that early life trauma is associated with elevations in circulating markers of inflammation in human subjects. History of aggression as a behavior, or aggression as a personality trait, is also associated with elevations of these inflammatory markers. Since early life trauma is associated with the development and maintenance of aggression in later life we examined the relationship of early life adversity, plasma inflammation markers (IL-6 and CRP) and oxidative stress markers (8-OH-DG and 8-ISO), and aggression in adult subjects with (n=79) and without (n=55) personality disorder. We used a series of mediated and moderated path models to test whether the effects of early adversity on later aggression may be mediated through markers of inflammation. Childhood abuse and parental control were associated with basal IL-6 and CRP concentrations. Path modeling suggested that childhood abuse was associated with aggression indirectly through CRP while parental control influenced aggression indirectly through IL-6 and CRP. Furthermore, these effects were independent of the effect of current depression. The results suggest that disruption of inflammatory processes represent one pathway by which early adversity influences aggression.
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Affiliation(s)
- Jennifer R Fanning
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
| | - Royce Lee
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
| | - David Gozal
- Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
| | - Mary Coussons-Read
- Department of Psychology, The University of Colorado, Colorado Springs, CO, United States
| | - Emil F Coccaro
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States.
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Rathbone ATL, Tharmaradinam S, Jiang S, Rathbone MP, Kumbhare DA. A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the "post-inflammatory brain syndrome" PIBS. Brain Behav Immun 2015; 46:1-16. [PMID: 25736063 DOI: 10.1016/j.bbi.2015.02.009] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 02/08/2015] [Accepted: 02/09/2015] [Indexed: 12/22/2022] Open
Abstract
Post-concussion syndrome is an aggregate of symptoms that commonly present together after head injury. These symptoms, depending on definition, include headaches, dizziness, neuropsychiatric symptoms, and cognitive impairment. However, these symptoms are common, occurring frequently in non-head injured controls, leading some to question the existence of post-concussion syndrome as a unique syndrome. Therefore, some have attempted to explain post-concussion symptoms as post-traumatic stress disorder, as they share many similar symptoms and post-traumatic stress disorder does not require head injury. This explanation falls short as patients with post-concussion syndrome do not necessarily experience many key symptoms of post-traumatic stress disorder. Therefore, other explanations must be sought to explain the prevalence of post-concussion like symptoms in non-head injury patients. Many of the situations in which post-concussion syndrome like symptoms may be experienced such as infection and post-surgery are associated with systemic inflammatory responses, and even neuroinflammation. Post-concussion syndrome itself has a significant neuroinflammatory component. In this review we examine the evidence of neuroinflammation in post-concussion syndrome and the potential role systemic inflammation plays in post-concussion syndrome like symptoms. We conclude that given the overlap between these conditions and the role of inflammation in their etiologies, a new term, post-inflammatory brain syndromes (PIBS), is necessary to describe the common outcomes of many different inflammatory insults. The concept of post-concussion syndrome is in its evolution therefore, the new term post-inflammatory brain syndromes provides a better understanding of etiology of its wide-array of symptoms and the wide array of conditions they can be seen in.
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Affiliation(s)
| | - Surejini Tharmaradinam
- Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, Pediatric Neurology, MUMC 3A, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
| | - Shucui Jiang
- Division of Neurosurgery, Department of Surgery, and Hamilton Neurorestorative Group, McMaster University, HSC 4E15, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada
| | - Michel P Rathbone
- Department of Medicine, Division of Neurology, McMaster University - Juravinski Hospital, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
| | - Dinesh A Kumbhare
- Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Toronto, University Health Network - Toronto Rehab - University Centre, 550 University Ave, Toronto, Ontario M5G 2A2, Canada
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Pesce M, Fratta IL, Ialenti V, Patruno A, Ferrone A, Franceschelli S, Rizzuto A, Tatangelo R, Campagna G, Speranza L, Felaco M, Grilli A. Emotions, immunity and sport: Winner and loser athlete's profile of fighting sport. Brain Behav Immun 2015; 46:261-9. [PMID: 25712259 DOI: 10.1016/j.bbi.2015.02.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 02/09/2015] [Accepted: 02/12/2015] [Indexed: 10/23/2022] Open
Abstract
Several studies have focused on the relationship between hormonal changes and affective states in sporting contexts relating to an agonistic outcome. More recently, pro-inflammatory cytokines have also been successfully associated with affective state modulation. The aim of this study was to investigate whether athletes who won or lost show different levels of steroid hormones (testosterone and cortisol), pro-inflammatory cytokine IL-1β, or expressions of anger and anxiety during six training fights in seasonal competitions down to the main seasonal competition. In 25 male kick-boxing athletes (age±SD, 28.68±5.34), anger states (RS score) and anxiety states (AS score) were assessed by STAXI-2 and STAI-Y, respectively. Cortisol (C), testosterone (T) and IL-1β salivary levels were measured by the ELISA method. The saliva samples were taken in the afternoon, 30min prior to the start and 30min from the end of both simulated and official competitions. The results showed that the RS score, T, T/C ratio salivary levels increased during the season, whereas the AS score, C and IL-1β suggested an opposite trend. Close to an official competition, the RS score, T, T/C ratio and IL-1β salivary concentrations were significantly higher, and then decreased during competition. By contrast, the AS score and C levels significantly increased throughout the official competition. In addition, significant differences were found for hormones and IL-1β concentrations as well as psychometric assessment close to the outcome of an official match. Athletes who lost showed an higher AS score and C level, while those who won were characterized by an higher level during the pre-competition RS score, T, T/C ratio, and IL-1β. Note that these factors were positively and significantly correlated at the pre-official competition time, while in a linear regression analysis, IL-1β, T and T/C ratio concentrations explained 43% of the variance in the RS score observed at the same time (adjusted R(2)=0.43, ANOVA P<.05). Our data suggest that the beginning of an agonistic event could trigger emotional responses which correspond to different biological processes instead that of a simulated fight. In particular, IL-1β could be a potential new biological marker of anger and the combined measurement of these factors may be a useful way of understanding athletes' change in relation to their performance.
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Affiliation(s)
- Mirko Pesce
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Irene La Fratta
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy.
| | - Valentina Ialenti
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Antonia Patruno
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Alessio Ferrone
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Sara Franceschelli
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Alessia Rizzuto
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Raffaella Tatangelo
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Giovanna Campagna
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Lorenza Speranza
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Mario Felaco
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Alfredo Grilli
- Medicine and Health Science School, University G. d'Annunzio, Via dei Vestini, 31, 66100 Chieti, Italy
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Coccaro EF, Lee R, Coussons-Read M. Cerebrospinal fluid inflammatory cytokines and aggression in personality disordered subjects. Int J Neuropsychopharmacol 2015; 18:pyv001. [PMID: 25650410 PMCID: PMC4540103 DOI: 10.1093/ijnp/pyv001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 01/04/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters and neuromodulators such as cytokines. While animal studies of cytokines suggest an aggression-facilitating role for central cytokines, especially for interleukin-1β and other cytokines, no cerebrospinal fluid studies of cytokines have yet been reported in regard to human aggression. METHODS Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with DSM-5 Personality Disorder and assayed for cerebrospinal fluid interleukin-6 (log IL-6) and cerebrospinal fluid soluble IL-1 Receptor II protein in the context of their relationship with measures of aggression. RESULTS Cerebrospinal fluid soluble interleukin-1 Receptor II (r=.35, r(2) = .12, P= .03), but not log interleukin-6 (r = -.05, r(2) = .00, P= .76), levels were positively correlated with a composite measure of aggression. Adding relevant covariates, including cerebrospinal fluid levels of serotonin and dopamine metabolites, to the statistical model doubled the strength of this relationship (partial r = .54, r(2) = .29, P= .002). No relationship was seen with history of suicidal behavior or with any measure of impulsivity, negative affectivity, or of general dimensions of personality. CONCLUSION These data suggest a positive relationship between at least one inflammatory cytokine in the central nervous system and aggression in human subjects. This finding adds to the complex picture of the central neurochemistry of impulsive aggression in human subjects.
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Affiliation(s)
- Emil F Coccaro
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, IL (Drs Coccaro and Lee); Department of Psychology, University of Colorado, Colorado Springs, CO (Dr Coussons-Read).
| | - Royce Lee
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, IL (Drs Coccaro and Lee); Department of Psychology, University of Colorado, Colorado Springs, CO (Dr Coussons-Read)
| | - Mary Coussons-Read
- Clinical Neuroscience Research Unit, Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, Chicago, IL (Drs Coccaro and Lee); Department of Psychology, University of Colorado, Colorado Springs, CO (Dr Coussons-Read)
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Suarez EC, Sundy JS, Erkanli A. Depressogenic vulnerability and gender-specific patterns of neuro-immune dysregulation: What the ratio of cortisol to C-reactive protein can tell us about loss of normal regulatory control. Brain Behav Immun 2015; 44:137-47. [PMID: 25241020 PMCID: PMC4275343 DOI: 10.1016/j.bbi.2014.09.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 08/26/2014] [Accepted: 09/07/2014] [Indexed: 12/27/2022] Open
Abstract
We examined whether the ratio of cortisol (CORT) to high-sensitivity C-reactive protein (hsCRP), an index that captures the integrity of homeostatic regulation between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory processes, is associated with vulnerability to depression in a gender specific manner and whether glucocorticoid receptor (GR) sensitivity plays a role in these associations. Fasting blood samples were collected between 08:45 and 09:15 and assayed for CORT, hsCRP, and leukocyte count in 213 healthy, medication-free men and women. The NEO-Personality Inventory was used to assess neuroticism, extraversion and anxiety. We used the Hamilton Depression Interview to assess depressive symptoms, the Buss-Perry anger subscale to measure anger, and the Pittsburgh Sleep Quality Index to evaluate subjective sleep quality and its components. Log-transformed CORT/CRP values were analyzed using multiple regression with Holms' adjusted p-values and age, body mass index (BMI), and race as covariates. GR sensitivity was estimated using the log-transformed ratio of neutrophils (N)-to-monocytes (M). The log-transformed ratio of CORT/CRP did not differ between men and women but was significantly and negatively associated with age and BMI. Severity of depressive symptoms, extraversion, anxiety, and sleep quality were associated with the CORT/CRP ratio in a gender-specific manner. For women, decreasing CORT/CRP ratios, suggestive of an insufficient release of CORT coupled with a heightened inflammatory state, were associated with increasing severity of depressive symptoms, decreasing quality of sleep, increasing frequency of sleep disturbance, and decreasing extraversion. For men, increasing frequency of daytime disturbance and levels of anxiety were associated with increasing CORT/CRP ratio, suggestive of an enhanced release of CORT relative to attenuated levels of hsCRP. For both genders, increasing anger was associated with decreasing CORT/CRP ratios. Although results suggested GR downregulation in women but not men, such differences did not mediate the observed associations. With the use of the CORT/CRP ratio, we showed that vulnerability factors for depression are associated with a loss of normal regulatory controls resulting in gender-specific patterns of neuro-immune dysregulation. That GR downregulation did not influence these associations suggests that the loss of regulatory controls in at risk individuals is primarily at the level of the hormone. Beyond the individual contribution of each component of the CORT/CRP ratio, disruption of normal neuroimmune regulatory feedback provides a plausible biological framework useful in understanding biobehavioral vulnerabilities to depression in a gender specific manner. The CORT/CRP ratio may be a viable biomarker not only for delineating risk for MDD but also progression and treatment responses among patients with MDD; possibilities that are testable in future studies.
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Affiliation(s)
- Edward C. Suarez
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - John S. Sundy
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Alaattin Erkanli
- Department of Biostatistics, Duke University Medical Center, Durham, NC, USA
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Wand APF, Peisah C, Strukovski JA, Brodaty H. Firearms, mental illness, dementia and the clinician. Med J Aust 2014; 201:674-8. [PMID: 25495316 DOI: 10.5694/mja13.11318] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 03/09/2014] [Indexed: 11/17/2022]
Abstract
Clinicians have an obligation to report to state or territory police any concerns about risk of harm from patients with access to firearms. Dementia is an under-recognised medical problem which may increase the risk of firearm injury or violence in those with such access. There are no guidelines for clinicians regarding mandatory screening for access to firearms, and currently the onus is on the firearm licence holder to declare any relevant medical conditions. We propose that clinicians should screen patients for firearm possession and use a combined capacity and risk assessment approach to evaluating fitness for firearm licences.
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Affiliation(s)
- Anne P F Wand
- Older Persons Mental Health Service, St George Hospital, Sydney, NSW, Australia.
| | - Carmelle Peisah
- School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - Julie-Anne Strukovski
- Specialist Mental Health Services for Older People, Northern Sydney Local Health District, Sydney, NSW, Australia
| | - Henry Brodaty
- Dementia Collaborative Research Centre, Centre for Healthy Brain Ageing, University of New South Wales, Sydney, NSW, Australia
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Beurel E, Jope RS. Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits. Transl Psychiatry 2014; 4:e488. [PMID: 25514751 PMCID: PMC4270310 DOI: 10.1038/tp.2014.129] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 09/21/2014] [Accepted: 10/26/2014] [Indexed: 12/15/2022] Open
Abstract
Suicide is one of the leading causes of death in the United States, yet it remains difficult to understand the mechanistic provocations and to intervene therapeutically. Stress is recognized as a frequent precursor to suicide. Psychological stress is well established to cause activation of the inflammatory response, including causing neuroinflammation, an increase of inflammatory molecules in the central nervous system (CNS). Neuroinflammation is increasingly recognized as affecting many aspects of CNS functions and behaviors. In particular, much evidence demonstrates that inflammatory markers are elevated in traits that have been linked to suicidal behavior, including aggression, impulsivity and depression. Lithium is recognized as significantly reducing suicidal behavior, is anti-inflammatory and diminishes aggression, impulsivity and depression traits, each of which is associated with elevated inflammation. The anti-inflammatory effects of lithium result from its inhibition of glycogen synthase kinase-3 (GSK3). GSK3 has been demonstrated to strongly promote inflammation, aggressive behavior in rodents and depression-like behaviors in rodents, whereas regulation of impulsivity by GSK3 has not yet been investigated. Altogether, evidence is building supporting the hypothesis that stress activates GSK3, which in turn promotes inflammation, and that inflammation is linked to behaviors associated with suicide, including particularly aggression, impulsivity and depression. Further investigation of these links may provide a clearer understanding of the causes of suicidal behavior and provide leads for the development of effective preventative interventions, which may include inhibitors of GSK3.
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Affiliation(s)
- E Beurel
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA,Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - R S Jope
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA,Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA,Miller School of Medicine, University of Miami, 1011 NW 15th Street, Gautier Building Room 416, Miami, FL 33136, USA. E-mail:
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46
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Abstract
Cytokines, currently known to be more than 130 in number, are small MW (<30 kDa) key signaling proteins that modulate cellular activities in immunity, infection, inflammation and malignancy. Key to understanding their function is recognition of their pleiotropism and often overlapping and functional redundancies. Classified here into 9 main families, most of the 20 approved cytokine preparations (18 different cytokines; 3 pegylated), all in recombinant human (rh) form, are grouped in the hematopoietic growth factor, interferon, platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) families. In the hematopoietin family, approved cytokines are aldesleukin (rhIL-2), oprelvekin (rhIL-11), filgrastim and tbo-filgrastim (rhG-CSF), sargramostim (rhGM-CSF), metreleptin (rh-leptin) and the rh-erythropoietins, epoetin and darbepoietin alfa. Anakinra, a recombinant receptor antagonist for IL-1, is in the IL-1 family; recombinant interferons alfa-1, alfa-2, beta-1 and gamma-1 make up the interferon family; palifermin (rhKGF) and becaplermin (rhPDGF) are in the PDGF family; and rhBMP-2 and rhBMP-7 represent the TGFβ family. The main physicochemical features, FDA-approved indications, modes of action and side effects of these approved cytokines are presented. Underlying each adverse events profile is their pleiotropism, potency and capacity to release other cytokines producing cytokine 'cocktails'. Side effects, some serious, occur despite cytokines being endogenous proteins, and this therefore demands caution in attempts to introduce individual members into the clinic. This caution is reflected in the relatively small number of cytokines currently approved by regulatory agencies and by the fact that 14 of the FDA-approved preparations carry warnings, with 10 being black box warnings.
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Shapiro PA, Sloan RP, Deochand C, Franceschi AM, Delorenzo C, Mann JJ, Parsey RV. Quantifying serotonin transporters by PET with [11C]-DASB before and after interferon-α treatment. Synapse 2014; 68:548-55. [PMID: 25043294 DOI: 10.1002/syn.21766] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Revised: 05/30/2014] [Accepted: 06/14/2014] [Indexed: 11/07/2022]
Abstract
BACKGROUND Interferon-α (IFN-α) therapy is frequently associated with disabling depression, fatigue, and related neuropsychiatric effects. Although depression in major depressive disorder is associated with low serotonin transporter binding, animal models suggest that IFN-associated mood effects are linked to increased presynaptic serotonin transporter binding. This study tested the hypotheses that IFN administration to human subjects increases presynaptic serotonin binding activity, and that this effect correlates with incident depression symptoms. METHODS Positron emission tomography (PET) scans using [11C]-DASB were obtained for nine hepatitis C patients before and after IFN-α treatment for 8 weeks. Serotonin transporter binding was estimated using the likelihood estimation in graphical analysis (LEGA) model and measured as the volume of distribution (VT) divided by the free fraction of ligand (fP). Depression was measured with the Structured Clinical Interview for DSM-IV Diagnosis (SCID) and the Hamilton Rating Scale for Depression (HAM-D). RESULTS Compared to pre-IFN treatment values, changes in serotonin transporter binding and depression symptoms were not significant. There was no correlation between changes in serotonin transporter binding and depression symptoms. LIMITATIONS The study is limited by small sample size, minimal effect on observed mood symptoms within the sample, and brief duration of follow-up. CONCLUSION These findings do not support the hypothesis of an IFN-induced change in serotonin transporter function as the cause of incident depressive symptoms in patients treated with IFN-α. Additional study of these possible relationships should be of longer duration and include more subjects with more pronounced changes in mood.
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Affiliation(s)
- Peter A Shapiro
- Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York
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Mahajan S, Avasthi A, Grover S, Chawla YK. Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for hepatitis C infection. J Psychosom Res 2014; 77:109-15. [PMID: 25077851 DOI: 10.1016/j.jpsychores.2014.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 05/21/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE This study aimed to evaluate the symptom profile and the role of baseline depressive symptoms in the development of depressive episode in patients receiving pegylated IFN-alpha and ribavirin. METHODS 82 consecutive patients with HCV infection in whom combination of pegylated interferon-α 2a/2b and ribavirin was prescribed were assessed at baseline and thereafter at 2, 4, 8 and 12 weeks. At the baseline, patients were assessed on Patient Health Questionnaire (PHQ-9), Mini International Neuropsychiatric Interview (MINI) and Beck Depression Inventory (BDI-II). Thereafter patients were assessed on PHQ-9 and when ever found to have Major Depressive Disorder as per PHQ-9, they were assessed on MINI. Those found to have Major Depressive Episode (MDE) on MINI were rated on BDI-II for phenomenology and severity of depression. RESULTS Common symptoms of pegylated IFN-alpha and ribavirin induced MDE include sadness, irritability, work inhibition, sleep disturbance, fatigability and loss of appetite. Presence of certain depressive symptoms i.e., presence of little interest or pleasure in doing things, feeling tired or having little energy, poor appetite, social withdrawal and work inhibition at the baseline were associated with development of depression during the course of pegylated IFN-alpha plus ribavirin therapy. CONCLUSION Depressive symptoms in patients with pegylated IFN-alpha and ribavirin induced MDE are influenced by the symptoms of depression prior to starting of pegylated IFN-alpha and ribavirin combination. A short screening questionnaire may be constructed which will include the symptoms which predict the development of depression to screen patients at high risk for the development of depression.
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Affiliation(s)
- Sudhir Mahajan
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajit Avasthi
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sandeep Grover
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
| | - Yogesh K Chawla
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Cazareth J, Guyon A, Heurteaux C, Chabry J, Petit-Paitel A. Molecular and cellular neuroinflammatory status of mouse brain after systemic lipopolysaccharide challenge: importance of CCR2/CCL2 signaling. J Neuroinflammation 2014; 11:132. [PMID: 25065370 PMCID: PMC4237883 DOI: 10.1186/1742-2094-11-132] [Citation(s) in RCA: 164] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 07/15/2014] [Indexed: 12/13/2022] Open
Abstract
Background Genetic and environmental factors are critical elements influencing the etiology of major depression. It is now accepted that neuroinflammatory processes play a major role in neuropsychological disorders. Neuroinflammation results from the dysregulation of the synthesis and/or release of pro- and anti-inflammatory cytokines with central or peripheral origin after various insults. Systemic bacterial lipopolysaccharide (LPS) challenge is commonly used to study inflammation-induced depressive-like behaviors in rodents. In the present study, we investigated immune-to-brain communication in mice by examining the effects of peripheral LPS injection on neuroinflammation encompassing cytokine and chemokine production, microglia and central nervous system (CNS)-associated phagocyte activation, immune cell infiltration and serotonergic neuronal function. Methods LPS was administered to C57BL/6 J mice by intraperitoneal injection; brains were collected and pro-inflammatory cytokine mRNA and proteins were measured. To examine the relative contribution of the different populations of brain immune cells to the occurrence of neuroinflammation after acute systemic inflammation, we precisely characterized them by flow cytometry, studied changes in their proportions and level of activation, and measured the amount of cytokines they released by Cytometric Bead Array™ after cell sorting and ex vivo culture. Because of the central role that the chemokine CCL2 seems to play in our paradigm, we studied the effect of CCL2 on the activity of serotonergic neurons of the raphe nucleus using electrophysiological recordings. Results We report that systemic LPS administration in mice caused a marked increase in pro-inflammatory IL-1β, IL-6, TNFα and CCL2 (monocyte chemoattractant protein-1) mRNA and protein levels in the brain. Moreover, we found that LPS caused microglia and CNS-associated phagocyte activation characterized by upregulation of CCR2, TLR4/CD14, CD80 and IL-4Rα, associated with overproduction of pro-inflammatory cytokines and chemokines, especially CCL2. LPS also induced a marked and selective increase of CCR2+ inflammatory monocytes within the brain. Finally, we showed that CCL2 hyperpolarized serotonergic raphe neurons in mouse midbrain slices, thus probably reducing the serotonin tone in projection areas. Conclusion Together, we provide a detailed characterization of the molecular and cellular players involved in the establishment of neuroinflammation after systemic injection of LPS. This highlights the importance of the CCL2/CCR2 signaling and suggests a possible link with depressive disorders.
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Affiliation(s)
- Arne Schäfer
- Medizinische Klinik und Poliklinik II, Department of Gastroenterology; University of Würzburg; Würzburg Germany
| | - Michael R. Kraus
- Medizinische Klinik und Poliklinik II, Department of Gastroenterology; University of Würzburg; Würzburg Germany
- Kreiskliniken Altötting-Burghausen; Burghausen Germany
| | - Michael Scheurlen
- Medizinische Klinik und Poliklinik II, Department of Gastroenterology; University of Würzburg; Würzburg Germany
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