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Sah A, Singewald N. The (neuro)inflammatory system in anxiety disorders and PTSD: Potential treatment targets. Pharmacol Ther 2025; 269:108825. [PMID: 39983845 DOI: 10.1016/j.pharmthera.2025.108825] [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: 09/03/2024] [Revised: 01/06/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Targeting the immune system has recently garnered attention in the treatment of stress- associated psychiatric disorders resistant to existing pharmacotherapeutics. While such approaches have been studied in considerable detail in depression, the role of (neuro)inflammation in anxiety-related disorders, or in anxiety as an important transdiagnostic symptom, is much less clear. In this review we first critically review clinical and in part preclinical evidence of central and peripheral immune dysregulation in anxiety disorders and post-traumatic stress disorder (PTSD) and briefly discuss proposed mechanisms of how inflammation can affect anxiety-related symptoms. We then give an overview of existing and potential future targets in inflammation-associated signal transduction pathways and discuss effects of different immune-modulatory drugs in anxiety-related disorders. Finally, we discuss key gaps in current clinical trials such as the lack of prospective studies involving anxiety patient stratification strategies based on inflammatory biomarkers. Overall, although evidence is rather limited so far, there is data to indicate that increased (neuro)inflammation is present in subgroups of anxiety disorder patients. Although exact identification of such immune subtypes of anxiety disorders and PTSD is still challenging, these patients will likely particularly benefit from therapeutic targeting of aspects of the inflammatory system. Different anti-inflammatory treatment approaches (microglia-directed treatments, pro-inflammatory cytokine inhibitors, COX-inhibitors, phytochemicals and a number of novel anti-inflammatory agents) have indeed shown some efficacy even in non-stratified anxiety patient groups and appear promising as novel alternative or complimentary therapeutic options in specific ("inflammatory") subtypes of anxiety disorder and PTSD patients.
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Affiliation(s)
- Anupam Sah
- Institute of Pharmacy, Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, Leopold Franzens University Innsbruck, Innsbruck, Austria
| | - Nicolas Singewald
- Institute of Pharmacy, Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, Leopold Franzens University Innsbruck, Innsbruck, Austria.
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2
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Rajasekera TA, Joseph A, Pan H, Dreyfuss JM, Fida D, Wilson J, Behee M, Fichorova RN, Cinar R, Spagnolo PA. Sex Differences in Endocannabinoid and Inflammatory Markers Associated with Posttraumatic Stress Disorder. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.13.25320467. [PMID: 39974010 PMCID: PMC11838936 DOI: 10.1101/2025.01.13.25320467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Background Posttraumatic stress disorder (PTSD) is one of the most sex-polarized psychiatric disorders, with women exhibiting twice the prevalence of men. The biological mechanisms underlying this sex disparity are not fully understood. Growing evidence suggests that alterations of the stress-buffering endocannabinoid (eCB) system and heightened inflammation are central to PTSD pathophysiology and may contribute to sex-biases in PTSD risk and severity. Here, we examined sex-differences in levels of circulating eCBs and peripheral pro-inflammatory markers in a cohort of men and women with PTSD and non-psychiatric controls. Methods 88 individuals with PTSD and 85 sex- and age- matched controls (HC) were retrospectively selected from the Mass General Brigham Biobank. Serum was assayed to measure circulating eCBs [anandamide (AEA), 2-arachidonyl glycerol (2-AG), oleoylethanolamide (OEA), and arachidonic acid (AA] and inflammatory markers [interleukin-1β (IL-1β), IL-6, IL-8, IL-18, tumor necrosis factor-alpha (TNFα), and C-reactive Protein (CRP)]. Linear regression was used to predict differential abundance of each analyte by disease state (PTSD/HC) within the male and female subgroups. Two-sided t-tests with Benjamini-Hochberg correction were used to examine differences across subgroups. Analyses were repeated in those with comorbid major depressive disorder. Results Male PTSD patients showed a significant decrease in AEA, AA and OEA levels compared to male controls (p's < .001) and to female subgroups (PTSD and HCs) (p< .001). In contrast, among females, PTSD patients showed elevated levels of IL-6 (p<.05) and IL-8 (p<.05). Both male and female PTSD patients exhibited an increase in TNFα concentrations (p<.05), compared to HCs. Similar results were obtained in the subgroup of individuals with comorbid MDD and after controlling for the FAAH 385A genotype. Conclusions Our findings show for the first time that decrease in eCB levels is absent in women with PTSD, who in turn exhibit a broader increase in inflammatory markers, thus suggesting that biological perturbations underlying PTSD may vary by sex.
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Affiliation(s)
- Therese A Rajasekera
- Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA
- Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Anna Joseph
- Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA
| | - Hui Pan
- Harvard Catalyst, Boston, MA, USA
| | | | - Doruntina Fida
- Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA
| | - Julie Wilson
- Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA
| | - Madeline Behee
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Raina N Fichorova
- Harvard Medical School, Boston, MA, USA
- Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA, USA
| | - Resat Cinar
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Primavera A Spagnolo
- Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA
- Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Tucker P, Pfefferbaum B, North CS, Zhao YD, Nitiema P, Zettl R, Jeon-Slaughter H. Learning from Hindsight: Examining Autonomic, Inflammatory, and Endocrine Stress Biomarkers and Mental Health in Healthy Terrorism Survivors Many Years Later. Prehosp Disaster Med 2024; 39:335-343. [PMID: 39773453 PMCID: PMC11802201 DOI: 10.1017/s1049023x24000360] [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: 02/03/2024] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 01/11/2025]
Abstract
INTRODUCTION Terrorism and trauma survivors often experience changes in biomarkers of autonomic, inflammatory and hypothalamic-pituitary-adrenal (HPA) axis assessed at various times. Research suggests interactions of these systems in chronic stress. STUDY OBJECTIVE This unprecedented retrospective study explores long-term stress biomarkers in three systems in terrorism survivors. METHODS Sixty healthy, direct terrorism survivors were compared to non-exposed community members for cardiovascular reactivity to a trauma script, morning salivary cortisol, interleukin 1-β (IL-1β), and interleukin 2-R (IL-2R). Survivors' biomarkers were correlated with psychiatric symptoms and diagnoses and reported functioning and well-being seven years after the Oklahoma City (OKC) bombing.Main outcome measures were the Diagnostic Interview Schedule (DIS) Disaster Supplement for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnoses, Impact of Events Scale-Revised (IES-R), Beck Depression Inventory-II (BDI-II), Distress and Functioning Scale (DAF), and General Physical Well-Being Scale. RESULTS Survivors had higher inflammatory IL-1β, lower anti-inflammatory IL-2R, lower cortisol, higher resting diastolic blood pressure (BP), and less cardiovascular reactivity to a trauma script than comparisons. Survivors' mean posttraumatic stress (PTS) symptom levels did not differ from comparisons, but survivors reported worse well-being. None of survivors' biomarkers correlated with PTS or depressive symptoms or diagnoses or reported functioning. CONCLUSIONS Alterations of biological stress measures in cardiovascular, inflammatory, and cortisol systems coexisted as an apparent generalized long-term response to terrorism rather than related to specific gauges of mental health. Potential interactions of biomarkers long after trauma exposure is discussed considering relevant research. Longer-term follow-up could determine whether biomarkers continue to differ or correlate with subjective measures, or if they accompany health problems over time. Given recent international terrorism, understanding long-term sequelae among direct survivors is increasingly relevant.
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Affiliation(s)
- Phebe Tucker
- Emeritus and Volunteer Faculty, Department of Psychiatry and Behavioral Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OklahomaUSA
| | - Betty Pfefferbaum
- Emeritus and Volunteer Faculty, Department of Psychiatry and Behavioral Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OklahomaUSA
| | - Carol S. North
- Adjunct Professor of Psychiatry (Volunteer), The University of Texas Southwestern Medical Center, Dallas, TexasUSA
| | - Yan Daniel Zhao
- Associate Dean for Research, Presidential Professor, College of Public Health, Biostatistics, and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OklahomaUSA
| | - Pascal Nitiema
- Assistant Professor, Department of Information Systems, W. P. Carey School of Business, Arizona State University, Tempe, ArizonaUSA
| | - Rachel Zettl
- Assistant Professor, Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center and OU Health, Oklahoma City, OklahomaUSA
| | - Haekyung Jeon-Slaughter
- Assistant Professor, Department of Internal Medicine, UT Southwestern Medical Center, Statistician/Section Chief of Analytics, Research Service, VA North Texas HCS, Dallas, TexasUSA
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Rhein C, Apelt I, Werner F, Schäflein E, Adler W, Reichel M, Schug C, Morawa E, Erim Y. Paradoxical effect of anti-inflammatory drugs on IL-6 mRNA expression in patients with PTSD during treatment. J Neural Transm (Vienna) 2024; 131:813-821. [PMID: 38613673 PMCID: PMC11199235 DOI: 10.1007/s00702-024-02770-6] [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: 08/07/2023] [Accepted: 03/23/2024] [Indexed: 04/15/2024]
Abstract
The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.
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Affiliation(s)
- Cosima Rhein
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany.
| | - Isabella Apelt
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
| | - Franziska Werner
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
| | - Eva Schäflein
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
- Department of Psychotherapy and Psychosomatic Medicine, Faculty of Medicine, Technische Universität Dresden (TUD), Dresden, Germany
| | - Werner Adler
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
- Institute of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Martin Reichel
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Caterina Schug
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
| | - Eva Morawa
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
| | - Yesim Erim
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Hartmannstr. 14, 91054, Erlangen, Germany
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Jones MB, Gates R, Gibson L, Broadway D, Bhatti G, Tea J, Guerra A, Li R, Varman B, Elammari M, Jorge RE, Marsh L. Post-Traumatic Stress Disorder and Risk of Degenerative Synucleinopathies: Systematic Review and Meta-Analysis. Am J Geriatr Psychiatry 2023; 31:978-990. [PMID: 37236879 PMCID: PMC11388697 DOI: 10.1016/j.jagp.2023.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023]
Abstract
OBJECTIVE A systematic review was conducted to answer whether adult-onset post-traumatic stress disorder (PTSD) is associated with increased risk of Parkinson's disease (PD) and related synucleinopathies. DESIGN A systematic search of Medline (Ovid), Embase (Elsevier), PsycInfo (Ovid), Cochrane Library (Wiley), and Web of Science (Clarivate) was performed using MeSH headings and equivalent terms for PTSD, PD, DLB, and related disorders. SETTING No restrictions. PARTICIPANTS Eligible articles were published in peer-reviewed journals, sampled adult human populations, and treated PTSD and degenerative synucleinopathies as exposures and outcomes, respectively. MEASUREMENTS Extracted data included diagnostic methods, sample characteristics, matching procedures, covariates, and effect estimates. Bias assessment was performed with the Newcastle-Ottawa scale. Hazard ratios were pooled using the random effects model, and the Hartung-Knapp adjustment was applied due to the small number of studies. RESULTS A total of six articles comprising seven unique samples (total n = 1,747,378) met eligibility criteria. The risk of PD was reported in three retrospective cohort studies and one case-control study. Risk of DLB was reported in one retrospective cohort, one case-control, and one prospective cohort study. No studies addressed potential relationships with multiple system atrophy or pure autonomic failure. Meta-analysis of hazard ratios from four retrospective cohort studies supported the hypothesis that incident PTSD was associated with PD and DLB risk (pooled HR 1.88, 95% C.I. 1.08-3.24; p = 0.035). CONCLUSIONS The sparse literature to-date supports further investigations on the association of mid- to late-life PTSD with Parkinson's and related neurodegenerative disorders.
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Affiliation(s)
- Melissa B Jones
- Michael E. DeBakey VA Medical Center (MBJ, AG, REJ, LM), Houston, TX; Baylor College of Medicine (MBJ, DB, GB, ME, REJ, LM), Houston, TX.
| | - Rachel Gates
- UCHealth University of Colorado Hospital (RG), Aurora, CO
| | | | - Dakota Broadway
- Baylor College of Medicine (MBJ, DB, GB, ME, REJ, LM), Houston, TX
| | - Gursimrat Bhatti
- Baylor College of Medicine (MBJ, DB, GB, ME, REJ, LM), Houston, TX
| | - Juliann Tea
- UT Southwestern Medical Center (JT), Dallas, TX
| | - Ana Guerra
- Michael E. DeBakey VA Medical Center (MBJ, AG, REJ, LM), Houston, TX
| | - Ruosha Li
- University of Texas Health Science Center at Houston (RL), Houston TX
| | | | - Mohamed Elammari
- Baylor College of Medicine (MBJ, DB, GB, ME, REJ, LM), Houston, TX
| | - Ricardo E Jorge
- Michael E. DeBakey VA Medical Center (MBJ, AG, REJ, LM), Houston, TX; Baylor College of Medicine (MBJ, DB, GB, ME, REJ, LM), Houston, TX
| | - Laura Marsh
- Michael E. DeBakey VA Medical Center (MBJ, AG, REJ, LM), Houston, TX; Baylor College of Medicine (MBJ, DB, GB, ME, REJ, LM), Houston, TX
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Dmytriv TR, Tsiumpala SA, Semchyshyn HM, Storey KB, Lushchak VI. Mitochondrial dysfunction as a possible trigger of neuroinflammation at post-traumatic stress disorder (PTSD). Front Physiol 2023; 14:1222826. [PMID: 37942228 PMCID: PMC10628526 DOI: 10.3389/fphys.2023.1222826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 10/09/2023] [Indexed: 11/10/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that occurs in approximately 15% of people as a result of some traumatic events. The main symptoms are re-experiencing and avoidance of everything related to this event and hyperarousal. The main component of the pathophysiology of PTSD is an imbalance in the functioning of the hypothalamic-pituitary-adrenal axis (HPA) and development of neuroinflammation. In parallel with this, mitochondrial dysfunction is observed, as in many other diseases. In this review, we focus on the question how mitochondria may be involved in the development of neuroinflammation and its maintaining at PTSD. First, we describe the differences in the operation of the neuro-endocrine system during stress versus PTSD. We then show changes in the activity/expression of mitochondrial proteins in PTSD and how they can affect the levels of hormones involved in PTSD development, as well as how mitochondrial damage/pathogen-associated molecule patterns (DAMPs/PAMPs) trigger development of inflammation. In addition, we examine the possibility of treating PTSD-related inflammation using mitochondria as a target.
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Affiliation(s)
- Tetiana R. Dmytriv
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Sviatoslav A. Tsiumpala
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Halyna M. Semchyshyn
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Kenneth B. Storey
- Department of Biology, Institute of Biochemistry, Carleton University, Ottawa, ON, Canada
| | - Volodymyr I. Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
- Research and Development University, Ivano-Frankivsk, Ukraine
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7
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von Majewski K, Rohleder N, Ehring T. Peripheral inflammation over the course of a cognitive behavioral intervention in PTSD. Brain Behav Immun Health 2023; 30:100620. [PMID: 37122765 PMCID: PMC10133650 DOI: 10.1016/j.bbih.2023.100620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/24/2023] [Accepted: 04/04/2023] [Indexed: 05/02/2023] Open
Abstract
Inflammation has an important predictive role for long-term health. This is also true when looking at the specific population of trauma survivors with PTSD. There are emerging findings showing that PTSD is related to reduced somatic health as well as evidence linking inflammation with disease outcomes in this group, such as heart diseases and early mortality, regardless of age, gender or conventional risk factors. The effectiveness of cognitive behavioral therapy for PTSD symptom severity has been demonstrated by several previous studies. In contrast, literature is scarce, yet, whether inflammation improves over the course of treatment for PTSD. Therefore, the aim of this study was to investigate whether not only PTSD symptoms, but also inflammation changes over the course of psychological treatment. Twenty-nine PTSD patients were followed while attending an outpatient clinic receiving cognitive behavioral therapy. Inflammation, determined by the C-reactive protein (CRP) assessed via the dried blood spot (DBS) technique, and symptom severity, surveyed by the PTSD Checklist for DSM-5 (PCL) were measured at 5 points before trauma-focused therapy, as well as after four, eight and twelve weeks of intervention; furthermore, a 10-month follow-up assessment was conducted. Results revealed significant improvements of PTSD symptom severity during investigation, but no significant changes in the inflammatory biomarker (CRP). Results in terms of improvement in PTSD symptom severity are in line with prior findings. The results obtained for inflammation may suggest that risk factors for somatic health consequences in PTSD patients remain despite successful psychological treatment. Further longitudinal studies are needed to fully understand the relationship between inflammation and therapeutic outcome and to develop interventions normalizing inflammation in PTSD patients.
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Affiliation(s)
- Kristin von Majewski
- Chair of Health Psychology, Institute of Psychology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Nicolas Rohleder
- Chair of Health Psychology, Institute of Psychology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Corresponding author. Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Nägelsbachstr. 49a, D-91052, Erlangen, Germany.
| | - Thomas Ehring
- Department of Psychology, LMU Munich, Munich, Germany
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Loh MK, Stickling C, Schrank S, Hanshaw M, Ritger AC, Dilosa N, Finlay J, Ferrara NC, Rosenkranz JA. Liposaccharide-induced sustained mild inflammation fragments social behavior and alters basolateral amygdala activity. Psychopharmacology (Berl) 2023; 240:647-671. [PMID: 36645464 DOI: 10.1007/s00213-023-06308-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 01/02/2023] [Indexed: 01/17/2023]
Abstract
RATIONALE Conditions with sustained low-grade inflammation have high comorbidity with depression and anxiety and are associated with social withdrawal. The basolateral amygdala (BLA) is critical for affective and social behaviors and is sensitive to inflammatory challenges. Large systemic doses of lipopolysaccharide (LPS) initiate peripheral inflammation, increase BLA neuronal activity, and disrupt social and affective measures in rodents. However, LPS doses commonly used in behavioral studies are high enough to evoke sickness syndrome, which can confound interpretation of amygdala-associated behaviors. OBJECTIVES AND METHODS The objectives of this study were to find a LPS dose that triggers mild peripheral inflammation but not observable sickness syndrome in adult male rats, to test the effects of sustained mild inflammation on BLA and social behaviors. To accomplish this, we administered single doses of LPS (0-100 μg/kg, intraperitoneally) and measured open field behavior, or repeated LPS (5 μg/kg, 3 consecutive days), and measured BLA neuronal firing, social interaction, and elevated plus maze behavior. RESULTS Repeated low-dose LPS decreased BLA neuron firing rate but increased the total number of active BLA neurons. Repeated low-dose LPS also caused early disengagement during social bouts and less anogenital investigation and an overall pattern of heightened social caution associated with reduced gain of social familiarity over the course of a social session. CONCLUSIONS These results provide evidence for parallel shifts in social interaction and amygdala activity caused by prolonged mild inflammation. This effect of inflammation may contribute to social symptoms associated with comorbid depression and chronic inflammatory conditions.
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Affiliation(s)
- Maxine K Loh
- Discipline of Cellular and Molecular Pharmacology, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, 60064, North Chicago, USA.,Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Courtney Stickling
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Sean Schrank
- Discipline of Cellular and Molecular Pharmacology, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, 60064, North Chicago, USA.,Discipline of Neuroscience, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, North Chicago, USA
| | - Madison Hanshaw
- Discipline of Cellular and Molecular Pharmacology, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, 60064, North Chicago, USA.,Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Alexandra C Ritger
- Discipline of Cellular and Molecular Pharmacology, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, 60064, North Chicago, USA.,Discipline of Neuroscience, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, North Chicago, USA
| | - Naijila Dilosa
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Joshua Finlay
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Nicole C Ferrara
- Discipline of Cellular and Molecular Pharmacology, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, 60064, North Chicago, USA.,Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - J Amiel Rosenkranz
- Discipline of Cellular and Molecular Pharmacology, Department of Foundational Sciences and Humanities, Chicago Medical School, Rosalind Franklin University of Medicine and Science, IL, 60064, North Chicago, USA. .,Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
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9
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Dell’Oste V, Fantasia S, Gravina D, Palego L, Betti L, Dell’Osso L, Giannaccini G, Carmassi C. Metabolic and Inflammatory Response in Post-Traumatic Stress Disorder (PTSD): A Systematic Review on Peripheral Neuroimmune Biomarkers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:2937. [PMID: 36833633 PMCID: PMC9957545 DOI: 10.3390/ijerph20042937] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/05/2023] [Accepted: 02/06/2023] [Indexed: 06/01/2023]
Abstract
Several heterogeneous pathophysiology pathways have been hypothesized for being involved in the onset and course of Post-Traumatic Stress Disorder (PTSD). This systematic review aims to summarize the current evidence on the role of inflammation and immunological dysregulations in PTSD, investigating possible peripheral biomarkers linked to the neuroimmune response to stress. A total of 44 studies on the dysregulated inflammatory and metabolic response in subjects with PTSD with respect to controls were included. Eligibility criteria included full-text publications in the English language, human adult samples, studies involving both subjects with a clinical diagnosis of PTSD and a healthy control group. The research was focused on specific blood neuroimmune biomarkers, namely IL-1β, TNF-α, IL-6 and INF-γ, as well as on the potential harmful role of reduced antioxidant activity (involving catalase, superoxide dismutase and glutathione peroxidase). The possible role of the inflammatory-altered tryptophan metabolism was also explored. The results showed conflicting data on the role of pro-inflammatory cytokines in individuals with PTSD, and a lack of study regarding the other mediators investigated. The present research suggests the need for further studies in human samples to clarify the role of inflammation in the pathogenesis of PTSD, to define potential peripheral biomarkers.
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Affiliation(s)
- Valerio Dell’Oste
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Sara Fantasia
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Davide Gravina
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Lionella Palego
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Laura Betti
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
| | - Liliana Dell’Osso
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | | | - Claudia Carmassi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
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Pivac N, Vuic B, Sagud M, Nedic Erjavec G, Nikolac Perkovic M, Konjevod M, Tudor L, Svob Strac D, Uzun S, Kozumplik O, Uzun S, Mimica N. PTSD, Immune System, and Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:225-262. [PMID: 36949313 DOI: 10.1007/978-981-19-7376-5_11] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Posttraumatic stress disorder (PTSD) is a severe trauma and stress-related disorder associated with different somatic comorbidities, especially cardiovascular and metabolic disorders, and with chronic low-grade inflammation. Altered balance of the hypothalamic-pituitary-adrenal (HPA) axis, cytokines and chemokines, C-reactive protein, oxidative stress markers, kynurenine pathways, and gut microbiota might be involved in the alterations of certain brain regions regulating fear conditioning and memory processes, that are all altered in PTSD. In addition to the HPA axis, the gut microbiota maintains the balance and interaction of the immune, CNS, and endocrine pathways forming the gut-brain axis. Disbalance in the HPA axis, gut-brain axis, oxidative stress pathways and kynurenine pathways, altered immune signaling and disrupted homeostasis, as well as the association of the PTSD with the inflammation and disrupted cognition support the search for novel strategies for treatment of PTSD. Besides potential anti-inflammatory treatment, dietary interventions or the use of beneficial bacteria, such as probiotics, can potentially improve the composition and the function of the bacterial community in the gut. Therefore, bacterial supplements and controlled dietary changes, with exercise, might have beneficial effects on the psychological and cognitive functions in patients with PTSD. These new treatments should be aimed to attenuate inflammatory processes and consequently to reduce PTSD symptoms but also to improve cognition and reduce cardio-metabolic disorders associated so frequently with PTSD.
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Affiliation(s)
- Nela Pivac
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia.
| | - Barbara Vuic
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Marina Sagud
- Department of Psychiatry, University Hospital Center Zagreb, Zagreb, Croatia
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Gordana Nedic Erjavec
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Matea Nikolac Perkovic
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Marcela Konjevod
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Lucija Tudor
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Dubravka Svob Strac
- Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Suzana Uzun
- University of Zagreb School of Medicine, Zagreb, Croatia
- University Psychiatric Hospital Vrapce, Zagreb, Croatia
| | | | - Sandra Uzun
- Department for Anesthesiology, Reanimatology, and Intensive Care, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ninoslav Mimica
- University of Zagreb School of Medicine, Zagreb, Croatia
- University Psychiatric Hospital Vrapce, Zagreb, Croatia
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11
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Hargrave AS, Sumner JA, Ebrahimi R, Cohen BE. Posttraumatic Stress Disorder (PTSD) as a Risk Factor for Cardiovascular Disease: Implications for Future Research and Clinical Care. Curr Cardiol Rep 2022; 24:2067-2079. [PMID: 36306020 DOI: 10.1007/s11886-022-01809-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2022] [Indexed: 01/11/2023]
Abstract
PURPOSE OF REVIEW Posttraumatic stress disorder (PTSD) may be an important risk factor for cardiovascular disease (CVD). We explore the literature linking PTSD to CVD, potential mechanisms, interventions, and clinical implications. We outline gaps in current literature and highlight necessary future research. RECENT FINDINGS PTSD has been independently associated with deleterious effects on cardiovascular health through biological, behavioral, and societal pathways. There are evidence-based psychotherapeutic interventions and pharmacotherapies for PTSD that may mitigate its impact on CVD. However, there are limited studies that rigorously analyze the impact of treating PTSD on cardiovascular outcomes. Trauma-informed CVD risk stratification, education, and treatment offer opportunities to improve patient care. These approaches can include a brief validated screening tool for PTSD identification and treatment. Pragmatic trials are needed to test PTSD interventions among people with CVD and evaluate for improved outcomes.
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Affiliation(s)
- Anita S Hargrave
- Department of Internal Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA. .,Medical Service, San Francisco VA Health Care System, San Francisco, CA, 94121, USA.
| | - Jennifer A Sumner
- Department of Psychology, University of California Los Angeles (UCLA), Los Angeles, CA, 90095-1563, USA
| | - Ramin Ebrahimi
- Department of Medicine, Cardiology Section, Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, CA, USA.,Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, 90095, USA
| | - Beth E Cohen
- Department of Internal Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA.,Medical Service, San Francisco VA Health Care System, San Francisco, CA, 94121, USA
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12
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Smiley CE, Wood SK. Stress- and drug-induced neuroimmune signaling as a therapeutic target for comorbid anxiety and substance use disorders. Pharmacol Ther 2022; 239:108212. [PMID: 35580690 DOI: 10.1016/j.pharmthera.2022.108212] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 10/18/2022]
Abstract
Stress and substance use disorders remain two of the most highly prevalent psychiatric conditions and are often comorbid. While individually these conditions have a debilitating impact on the patient and a high cost to society, the symptomology and treatment outcomes are further exacerbated when they occur together. As such, there are few effective treatment options for these patients, and recent investigation has sought to determine the neural processes underlying the co-occurrence of these disorders to identify novel treatment targets. One such mechanism that has been linked to stress- and addiction-related conditions is neuroimmune signaling. Increases in inflammatory factors across the brain have been heavily implicated in the etiology of these disorders, and this review seeks to determine the nature of this relationship. According to the "dual-hit" hypothesis, also referred to as neuroimmune priming, prior exposure to either stress or drugs of abuse can sensitize the neuroimmune system to be hyperresponsive when exposed to these insults in the future. This review completes an examination of the literature surrounding stress-induced increases in inflammation across clinical and preclinical studies along with a summarization of the evidence regarding drug-induced alterations in inflammatory factors. These changes in neuroimmune profiles are also discussed within the context of their impact on the neural circuitry responsible for stress responsiveness and addictive behaviors. Further, this review explores the connection between neuroimmune signaling and susceptibility to these conditions and highlights the anti-inflammatory pharmacotherapies that may be used for the treatment of stress and substance use disorders.
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Affiliation(s)
- Cora E Smiley
- Department of Pharmacology, Physiology, and Neuroscience; University of South Carolina School of Medicine, Columbia, SC 29209, United States of America; WJB Dorn Veterans Administration Medical Center, Columbia, SC 29209, United States of America.
| | - Susan K Wood
- Department of Pharmacology, Physiology, and Neuroscience; University of South Carolina School of Medicine, Columbia, SC 29209, United States of America; WJB Dorn Veterans Administration Medical Center, Columbia, SC 29209, United States of America.
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13
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Peruzzolo TL, Pinto JV, Roza TH, Shintani AO, Anzolin AP, Gnielka V, Kohmann AM, Marin AS, Lorenzon VR, Brunoni AR, Kapczinski F, Passos IC. Inflammatory and oxidative stress markers in post-traumatic stress disorder: a systematic review and meta-analysis. Mol Psychiatry 2022; 27:3150-3163. [PMID: 35477973 DOI: 10.1038/s41380-022-01564-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 03/31/2022] [Accepted: 04/04/2022] [Indexed: 11/09/2022]
Abstract
Post-traumatic stress disorder (PTSD) has been associated with persistent, low-degree inflammation, which could explain the increased prevalence of autoimmune conditions and accelerated aging among patients. The aim of the present study is to assess which inflammatory and oxidative stress markers are associated with PTSD. We carried out a meta-analytic and meta-regression analysis based on a systematic review of studies comparing inflammatory and oxidative stress markers between patients with PTSD and controls. We undertook meta-analyses whenever values of inflammatory and oxidative stress markers were available in two or more studies. Overall, 28,008 abstracts were identified, and 54 studies were included, with a total of 8394 participants. The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of the studies. Concentrations of C-reactive protein (SMD = 0.64; 95% CI: 0.21 to 1.06; p = 0.0031; k = 12), interleukin 6 (SMD = 0.94; 95% CI: 0.36 to 1.52; p = 0.0014; k = 32), and tumor necrosis factor-α (SMD = 0.89; 95% CI: 0.23 to 1.55; p = 0.0080; k = 24) were significantly increased in patients with PTSD in comparison with healthy controls. Interleukin 1β levels almost reached the threshold for significance (SMD = 1.20; 95% CI: -0.04 to 2.44; p = 0.0569; k = 15). No oxidative stress marker was associated with PTSD. These findings may explain why PTSD is associated with accelerated aging and illnesses in which immune activation has a key role, such as cardiovascular diseases and diabetes. In addition, they pointed to the potential role of inflammatory markers as therapeutic targets.
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Affiliation(s)
- Tatiana Lauxen Peruzzolo
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Jairo Vinícius Pinto
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,University Hospital, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
| | - Thiago Henrique Roza
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Augusto Ossamu Shintani
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ana Paula Anzolin
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Vanessa Gnielka
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - André Moura Kohmann
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Amanda Salvador Marin
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Vitória Ruschel Lorenzon
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - André Russowsky Brunoni
- Centro de Pesquisas Clínicas e Epidemiológicas, Hospital Universitário, Universidade de São Paulo, São Paulo, Brasil.,Departamentos de Clínica Médica e Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil.,Instituto Nacional de Biomarcadores em Psiquiatria (IMBION), Laboratory of Neurosciences (LIM-27), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
| | - Flávio Kapczinski
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Ives Cavalcante Passos
- Laboratory of Molecular Psychiatry, Centro de Pesquisa Experimental (CPE) and Centro de Pesquisa Clínica (CPC), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil. .,Department of Psychiatry, School of Medicine, Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. .,Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil.
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14
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The role of IL-6 in TBI and PTSD, a potential therapeutic target? Clin Neurol Neurosurg 2022; 218:107280. [PMID: 35567833 DOI: 10.1016/j.clineuro.2022.107280] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/15/2022] [Accepted: 05/02/2022] [Indexed: 01/14/2023]
Abstract
This literature review focuses on the role of IL-6 in TBI or PTSD-induced neuroinflammation. While TBI and PTSD are widely prevalent, these diagnoses are particularly common amongst veterans. Given the role of IL-6 in neuroprotection acutely, compared to detrimental chronically, targeting this cytokine at specific time points may be beneficial in modulating neuroinflammation. Current treatments for TBI or PTSD are variably affective. By reviewing the role of IL-6 in these two diagnoses, future studies can focus on therapeutics to treat neuroinflammation and ultimately reduce the devastating impacts of neuroinflammation on cognition in PTSD and TBI.
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15
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The relations between C-reactive protein and trauma exposure, PTSD and depression symptoms, and PTSD psychotherapy treatment response in treatment seeking veterans and service members. Brain Behav Immun 2022; 101:84-92. [PMID: 34990746 DOI: 10.1016/j.bbi.2021.12.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/10/2021] [Accepted: 12/29/2021] [Indexed: 12/28/2022] Open
Abstract
While inflammatory markers have been implicated in the link between PTSD and poor health outcomes, there is a paucity of research investigating C-reactive protein (CRP) and psychotherapy treatment response for posttraumatic stress disorder (PTSD). The present study utilized a large, well-characterized sample of veterans and service members (N = 493) engaged in intensive psychotherapy to investigate the associations between CRP, trauma exposure, related variables, and PTSD and depression, as well as investigating if CRP was associated with PTSD psychotherapy treatment response. Bivariate correlation results indicate that CRP was significantly associated with BMI (r = 0.48) and severity of experiences of childhood physical and sexual abuse (r = 0.14 and 0.15, respectively) and was not significantly associated with baseline PTSD total symptom severity, PTSD symptom clusters, or depression symptom severity (rs ranging from -0.03 to 0.04). In multivariate regression models investigating if CRP and related variables were associated with PTSD baseline symptom severity, CRP was not a significant predictor (β = -0.03). Hierarchical linear modeling did not identify CRP as a significant predictor of PTSD psychotherapy outcome. Given that findings indicate that CRP was broadly elevated in this treatment seeking sample but not associated with PTSD and depression symptom severity, results suggest CRP may not be a specific biomarker for PTSD or depression but may be elevated in psychiatric disease more generally.
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16
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Ghosh S, Mohammed Z, Singh I. Bruton's tyrosine kinase drives neuroinflammation and anxiogenic behavior in mouse models of stress. J Neuroinflammation 2021; 18:289. [PMID: 34895246 PMCID: PMC8665324 DOI: 10.1186/s12974-021-02322-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 11/12/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Current therapies targeting several neurotransmitter systems are only able to partially mitigate the symptoms of stress- and trauma-related disorder. Stress and trauma-related disorders lead to a prominent inflammatory response in humans, and in pre-clinical models. However, mechanisms underlying the induction of neuroinflammatory response in PTSD and anxiety disorders are not clearly understood. The present study investigated the mechanism underlying the activation of proinflammatory NLRP3 inflammasome and IL1β in mouse models of stress. METHODS We used two mouse models of stress, i.e., mice subjected to physical restraint stress with brief underwater submersion, and predator odor stress. Mice were injected with MCC950, a small molecule specific inhibitor of NLRP3 activation. To pharmacologically inhibit BTK, a specific inhibitor ibrutinib was used. To validate the observation from ibrutinib studies, a separate group of mice was injected with another BTK-specific inhibitor LFM-A13. Seven days after the induction of stress, mice were examined for anxious behavior using open field test (OFT), light-dark test (LDT), and elevated plus maze test (EPM). Following the behavior tests, hippocampus and amygdale were extracted and analyzed for various components of NLRP3-caspase 1-IL1β pathway. Plasma and peripheral blood mononuclear cells were also used to assess the induction of NLRP3-Caspase 1-IL-1β pathway in stressed mice. RESULTS Using two different pre-clinical models of stress, we demonstrate heightened anxious behavior in female mice as compared to their male counterparts. Stressed animals exhibited upregulation of proinflammatory IL1β, IL-6, Caspase 1 activity and NLRP3 inflammasome activation in brain, which were significantly higher in female mice. Pharmacological inhibition of NLRP3 inflammasome activation led to anxiolysis as well as attenuated neuroinflammatory response. Further, we observed induction of activated Bruton's tyrosine kinase (BTK), an upstream positive-regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with ibrutinib and LFM-A13. In both sets of experiments, we found BTK inhibition led to anxiolysis and attenuated neuroinflammation, as indicated by significant reduction of NLRP3 inflammasome and proinflammatory IL-1β in hippocampus and amygdala. Analysis of plasma and peripheral blood mononuclear cells indicated peripheral induction of NLRP3-caspase 1-IL1β pathway in stressed mice. CONCLUSION Our study identified BTK as a key upstream regulator of neuroinflammation, which drives anxiogenic behavior in mouse model of stress. Further, we demonstrated the sexually divergent activation of BTK, providing a clue to heightened neuroinflammation and anxiogenic response to stress in females as compared to their male counterparts. Our data from the pharmacological inhibition studies suggest BTK as a novel target for the development of potential clinical treatment of PTSD and anxiety disorders. Induction of pBTK and NLRP3 in peripheral blood mononuclear cells of stressed mice suggest the potential effect of stress on systemic inflammation.
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Affiliation(s)
- Simantini Ghosh
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
- Department of Psychology, Ashoka University, Rai, India.
| | | | - Itender Singh
- Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
- Ambedkar Center for Biomedical Research, Delhi University, New Delhi, India
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17
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Persistent level of mental distress in PTSD patients is not reflected in cytokine levels 1 year after the treatment. Acta Neuropsychiatr 2021; 33:254-260. [PMID: 33902770 DOI: 10.1017/neu.2021.11] [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] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Cross-sectional data show that post-traumatic stress disorder (PTSD) patients often have increased levels of circulating inflammatory markers. There is, however, still a paucity of longitudinal studies with long follow-up times on levels of cytokines in such patients. The current study assesses patients with and without PTSD diagnosis 1 year after discharge from inpatient treatment. METHODS Patients in treatment for serious non-psychotic mental disorders were recruited at the beginning of their treatment stay at a psychiatric centre in Norway. Ninety patients submitted serum samples and filled out the Hopkins Symptom Checklist-90 Revised Global Severity Index (HSCL-90R GSI) questionnaire during their mainstay and at a follow-up stay 1 year after discharge. Of these patients, 33 were diagnosed with PTSD, 48 with anxiety, depression, or eating disorder, while 9 patients had missing data. The patients were diagnosed using the Mini-International Neuropsychiatric Interview (MINI). RESULTS At the follow-up stay (T3), PTSD patients had higher levels of GSI scores than non-PTSD patients (p = 0.048). These levels were unchanged from the year before (T2) in both groups. The levels of circulating cytokines/chemokine did not differ between the PTSD and non-PTSD patients at T3. At T2, however, the PTSD and non-PTSD groups exhibited different levels of interleukin 1β (IL-1β) (p = 0.053), IL-1RA (p = 0.042), and TNF-α (p = 0.037), with the PTSD patients having the higher levels. CONCLUSION Despite exhibiting different mental distress scores, the PTSD and non-PTSD patients did not differ regarding levels of circulating inflammatory markers at 1-year follow-up.
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18
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Wang W, Wang R, Jiang Z, Li H, Zhu Z, Khalid A, Liu D, Pan F. Inhibiting Brd4 alleviated PTSD-like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats. J Neurochem 2021; 158:912-927. [PMID: 34050937 DOI: 10.1111/jnc.15439] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/11/2021] [Accepted: 05/18/2021] [Indexed: 12/30/2022]
Abstract
Post-traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and synaptic plasticity can play a role in the neurophysiological mechanisms underlying PTSD. Bromodomain-containing protein 4 (Brd4) intriguingly affects regulating of inflammatory responses and learning and memory. This study aimed to explore the effect of inhibiting Brd4 on depression/anxiety-like behaviors, spatial and fear memory, and underlying mechanisms in a model of PTSD. Inescapable foot shocks (IFS) with a sound reminder in 6 days were used to induce PTSD-like behaviors which were tested using contextual and cue fear tests, sucrose preference test, open-field test, elevated plus maze test, and Y-maze test. Meanwhile, the Brd4 inhibitor JQ1 was used as an intervention. The results found that IFS induced PTSD-like behaviors and indicated obvious Brd4 expression in microglia of the prefrontal cortex (PFC), hippocampus, and amygdala, pro-inflammatory cytokines over-expression, microglial activation, and nuclear factor-kappa B over-expression in PFC and hippocampus but not in amygdala. Meanwhile, the alterations of immediate early genes (IEGs) were found in PFC, hippocampus, and amygdala. Besides, dendritic spine density was reduced in PFC and hippocampus but was elevated in amygdala of rats with IFS. In addition, treatment with JQ1 significantly reduced freezing time in the contextual and cue fear test, reversed the behavioral impairment, decreased the elevated neuroinflammation, and normalized the alteration in IEGs and dendritic spine densities. The results suggested that Brd4 was involved in IFS-induced PTSD-like behaviors through regulating neuroinflammation, dynamics of IEGs, and synaptic plasticity.
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Affiliation(s)
- Wei Wang
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Rui Wang
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Zhijun Jiang
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Haonan Li
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Zemeng Zhu
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Arslan Khalid
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Dexiang Liu
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
| | - Fang Pan
- Department of Medical Psychology and Ethics, School of Basic Medical Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
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19
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Pashaei Y. Drug repurposing of selective serotonin reuptake inhibitors: Could these drugs help fight COVID-19 and save lives? J Clin Neurosci 2021; 88:163-172. [PMID: 33992179 PMCID: PMC7973060 DOI: 10.1016/j.jocn.2021.03.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/05/2021] [Accepted: 03/11/2021] [Indexed: 02/09/2023]
Abstract
The current 2019 novel coronavirus disease (COVID-19), an emerging infectious disease, is undoubtedly the most challenging pandemic in the 21st century. A total of 92,977,768 confirmed cases of COVID-19 and 1,991,289 deaths were reported globally up to January 14, 2021. COVID-19 also affects people's mental health and quality of life. At present, there is no effective therapeutic strategy for the management of this disease. Therefore, in the absence of a specific vaccine or curative treatment, it is an urgent need to identify safe, effective and globally available drugs for reducing COVID-19 morbidity and fatalities. In this review, we focus on selective serotonin reuptake inhibitors (SSRIs: a class of antidepressant drugs with widespread availability and an optimal tolerability profile) that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials. We also summarize the existing literature on what is known about the link between serotonin (5-HT) and the immune system. From the evidence reviewed here, we propose fluoxetine as an adjuvant therapeutic agent for COVID-19 based on its known immunomodulatory, anti-inflammatory and antiviral properties. Fluoxetine may potentially reduce pro-inflammatory chemokine/cytokines levels (such as CCL-2, IL-6, and TNF-α) in COVID-19 patients. Furthermore, fluoxetine may help to attenuate neurological complications of COVID-19.
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20
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LoSavio ST, Beckham JC, Wells SY, Resick PA, Sherwood A, Coffman CJ, Kirby AC, Beaver TA, Dennis MF, Watkins LL. The effect of reducing posttraumatic stress disorder symptoms on cardiovascular risk: Design and methodology of a randomized clinical trial. Contemp Clin Trials 2021; 102:106269. [PMID: 33429088 PMCID: PMC8009821 DOI: 10.1016/j.cct.2021.106269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/19/2020] [Accepted: 12/31/2020] [Indexed: 12/19/2022]
Abstract
Posttraumatic stress disorder (PTSD) has been associated with accelerated progression of coronary heart disease (CHD). However, the underlying pathophysiological pathway has remained elusive and it is unclear whether there is a direct link between PTSD and CHD risk. This paper describes the methods of a randomized controlled trial developed to examine how changes in PTSD symptoms affect CHD disease pathways. One hundred twenty participants with current PTSD and who are free of known CHD will be randomized to receive either an evidence-based treatment for PTSD (Cognitive Processing Therapy; CPT) or a waitlist control (WL). Before and after CPT/WL, participants undergo assessment of CHD risk biomarkers reflecting autonomic nervous system dysregulation, systemic inflammation, and vascular endothelial dysfunction. The primary hypothesis is that individuals who show improvement in PTSD symptoms will show improvement in CHD risk biomarkers, whereas individuals who fail to improve or show worsening PTSD symptoms will have no change or worsening in CHD biomarkers. This study is expected to provide knowledge of the role of both the direct impact of PTSD symptoms on CHD risk pathways and the role of these systems as candidate mechanisms underlying the relationship between PTSD and CHD risk. Further, results will provide guidance on the utility of cognitive therapy as a tool to mitigate the accelerated progression of CHD in PTSD. Clinical Trials Registration: https://clinicaltrials.gov/ct2/show/NCT02736929; Unique identifier: NCT02736929.
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Affiliation(s)
| | - Jean C Beckham
- Duke University Medical Center, Durham, NC, USA; Durham VA Healthcare System, Durham, NC, USA
| | - Stephanie Y Wells
- Duke University Medical Center, Durham, NC, USA; Durham VA Healthcare System, Durham, NC, USA; VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, United States of America
| | | | | | - Cynthia J Coffman
- VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, United States of America; Center of Innovation to Accelerate Discovery and Practice Transformation, Durham VA Healthcare System, Durham, NC, United States of America
| | - Angela C Kirby
- Duke University Medical Center, Durham, NC, USA; Durham VA Healthcare System, Durham, NC, USA; VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, United States of America
| | - Tiffany A Beaver
- Duke University Medical Center, Durham, NC, USA; Durham VA Healthcare System, Durham, NC, USA
| | - Michelle F Dennis
- Duke University Medical Center, Durham, NC, USA; Durham VA Healthcare System, Durham, NC, USA
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21
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Gipson CD, Rawls S, Scofield MD, Siemsen BM, Bondy EO, Maher EE. Interactions of neuroimmune signaling and glutamate plasticity in addiction. J Neuroinflammation 2021; 18:56. [PMID: 33612110 PMCID: PMC7897396 DOI: 10.1186/s12974-021-02072-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/05/2021] [Indexed: 02/28/2023] Open
Abstract
Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.
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Affiliation(s)
- Cassandra D Gipson
- Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB, Room 363, Lexington, KY, 40536-0509, USA.
| | - Scott Rawls
- Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Michael D Scofield
- Department of Anesthesiology, Medical University of South Carolina, Charleston, USA
- Department of Neuroscience, Medical University of South Carolina, Charleston, USA
| | - Benjamin M Siemsen
- Department of Anesthesiology, Medical University of South Carolina, Charleston, USA
| | - Emma O Bondy
- Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB, Room 363, Lexington, KY, 40536-0509, USA
| | - Erin E Maher
- Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB, Room 363, Lexington, KY, 40536-0509, USA
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22
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Sun Y, Qu Y, Zhu J. The Relationship Between Inflammation and Post-traumatic Stress Disorder. Front Psychiatry 2021; 12:707543. [PMID: 34456764 PMCID: PMC8385235 DOI: 10.3389/fpsyt.2021.707543] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/19/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Stress disorders, such as post-traumatic stress disorder (PTSD), are attracting much attention. However, the relationship between traumatic stress and inflammation is rarely discussed. Subjects and Methods: As studies have linked PTSD to altered susceptibility to various diseases, such a psychiatric condition may lead to long-term systematic changes in physiological functions. We searched PubMed with the keywords "traumatic stress," "stress disorders," "post-traumatic stress disorder," and "inflammation." Results: Based on 65 previously published studies, we reviewed the long-term effects of PTSD, as well as traumatic events, on inflammatory function from both epidemiological and biological perspectives. Post-traumatic stress disorder is related to the immune response, including an increase in inflammatory factors and a reduction in anti-inflammatory factors. Additionally, it has been demonstrated that traumatic stress disorder and immune disease share a common genetic basis at the gene expression level. Conclusions: Understanding this relationship is of great significance for optimizing treatment plans for patients with PTSD.
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Affiliation(s)
- Yajing Sun
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China.,Med-X Center for Informatics, Sichuan University, Chengdu, China
| | - Yuanyuan Qu
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China.,Med-X Center for Informatics, Sichuan University, Chengdu, China
| | - Jianwei Zhu
- Department of Orthopaedic Surgery, West China Hospital, Sichuan University, Chengdu, China
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23
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Lycopene ameliorates PTSD-like behaviors in mice and rebalances the neuroinflammatory response and oxidative stress in the brain. Physiol Behav 2020; 224:113026. [DOI: 10.1016/j.physbeh.2020.113026] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022]
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24
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Gamma oryzanol impairs alcohol-induced anxiety-like behavior in mice via upregulation of central monoamines associated with Bdnf and Il-1β signaling. Sci Rep 2020; 10:10677. [PMID: 32606350 PMCID: PMC7326911 DOI: 10.1038/s41598-020-67689-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Adolescent alcohol exposure may increase anxiety-like behaviors by altering central monoaminergic functions and other important neuronal pathways. The present study was designed to investigate the anxiolytic effect of 0.5% γ-oryzanol (GORZ) and its neurochemical and molecular mechanisms under chronic 10% ethanol consumption. Five-week-old ICR male mice received either control (14% casein, AIN 93 M) or GORZ (14% casein, AIN 93 M + 0.5% GORZ) diets in this study. We showed that GORZ could potentially attenuate alcohol-induced anxiety-like behaviors by significantly improving the main behavioral parameters measured by the elevated plus maze test. Moreover, GORZ treatment significantly restored the alcohol-induced downregulation of 5-hydroxytryptophan and 5-hydroxyindole acetic acid in the hippocampus and improved homovanillic acid levels in the cerebral cortex. Furthermore, a recovery increase in the level of 3-methoxy-4-hydroxyphenylglycol both in the hippocampus and cerebral cortex supported the anxiolytic effect of GORZ. The significant elevation and reduction in the hippocampus of relative mRNA levels of brain-derived neurotrophic factor and interleukin 1β, respectively, also showed the neuroprotective role of GORZ in ethanol-induced anxiety. Altogether, these results suggest that 0.5% GORZ is a promising neuroprotective drug candidate with potential anxiolytic, neurogenic, and anti-neuroinflammatory properties for treating adolescent alcohol exposure.
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25
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Sumner JA, Nishimi KM, Koenen KC, Roberts AL, Kubzansky LD. Posttraumatic Stress Disorder and Inflammation: Untangling Issues of Bidirectionality. Biol Psychiatry 2020; 87:885-897. [PMID: 31932029 PMCID: PMC7211139 DOI: 10.1016/j.biopsych.2019.11.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/21/2019] [Accepted: 11/04/2019] [Indexed: 12/27/2022]
Abstract
Posttraumatic stress disorder (PTSD) has increasingly been linked to heightened systemic inflammation. It matters whether this association is causal (and either bidirectional or unidirectional) or correlational. Investigators have hypothesized that chronic systemic low-grade inflammation may contribute to greater risk of developing PTSD after experiencing trauma and/or serve as a mechanism linking PTSD to adverse physical health outcomes. However, if the PTSD-inflammation relation is correlational, it may not warrant further research aimed at understanding inflammation as a PTSD risk factor or as a pathway linking PTSD with poor health. In this review, we first assess the longitudinal evidence related to PTSD and inflammation to understand more clearly the directionality and causal nature of this relation. Overall, few longitudinal studies rigorously assess the direction of the PTSD-inflammation relation. Some of the evidence indicates that elevated inflammation assessed pretrauma or in the acute aftermath of trauma increases risk for developing PTSD. Fewer studies evaluate the influence of PTSD on subsequent inflammation levels, and findings are mixed. Sample characteristics and study designs, and also the type of inflammation-related measure, vary widely across studies. Based on current evidence, we then recommend several statistical and study design approaches that may help untangle issues of bidirectionality and aid in determining the direction of causality between PTSD and inflammation. Last, we conclude with future research directions and consider potential implications for interventions or treatment approaches based on this growing body of literature.
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Affiliation(s)
- Jennifer A. Sumner
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA,Correspondence to: Jennifer A. Sumner, University of California, Los Angeles, Department of Psychology, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095. Telephone: 1 (310) 794-9860;
| | - Kristen M. Nishimi
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Karestan C. Koenen
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrea L. Roberts
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Laura D. Kubzansky
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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26
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Shiner B, Leonard C, Gui J, Cornelius S, Gradus JL, Schnurr PP, Watts BV. Measurement Strategies for Evidence-Based Antidepressants for Posttraumatic Stress Disorder Delivery: Trends and Associations with Patient-Reported Outcomes. ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH 2020; 48:70-87. [PMID: 32394096 DOI: 10.1007/s10488-020-01047-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
We sought to develop a quality standard for the prescription of antidepressants for posttraumatic stress disorder (PTSD) that is both consistent with the underlying evidence supporting antidepressants as a treatment for PTSD and associated with the best levels of symptom improvement. We quantified antidepressant initiation during the first year of PTSD treatment in a 10-year national cohort of Department of Veterans Affairs (VA) users, and compared outcomes in a subgroup who completed patient-reported outcome measurement (PROM) as part of routine practice. We added progressively stringent measurement requirements. Prescribing quality for PTSD in the VA was stable over time. Use of PROM was rare in the case of antidepressant treatment, limiting our assessment of outcomes.
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Affiliation(s)
- Brian Shiner
- White River Junction VA Medical Center, 215 North Main Street, White River Junction, VT, 05009, USA. .,Geisel School of Medicine at Dartmouth, Hanover, NH, USA. .,National Center for PTSD Executive Division, White River Junction, VT, USA.
| | - Christine Leonard
- White River Junction VA Medical Center, 215 North Main Street, White River Junction, VT, 05009, USA
| | - Jiang Gui
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Sarah Cornelius
- White River Junction VA Medical Center, 215 North Main Street, White River Junction, VT, 05009, USA
| | | | - Paula P Schnurr
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,National Center for PTSD Executive Division, White River Junction, VT, USA
| | - Bradley V Watts
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,VA Office of Systems Redesign and Improvement, Washington, DC, USA
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27
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Yang JJ, Jiang W. Immune biomarkers alterations in post-traumatic stress disorder: A systematic review and meta-analysis. J Affect Disord 2020; 268:39-46. [PMID: 32158005 DOI: 10.1016/j.jad.2020.02.044] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 02/05/2020] [Accepted: 02/26/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Studies have reported the changes of immune biomakers in post-traumatic stress disorder (PTSD), but the results were conflicting. Our aim was to investigate the changes of immune biomarkers in PTSD. METHODS Literatures investigating the changes of immune markers in PTSD published in English were systematically searched through PubMed, Embase and Web of Science. We conducted random effects meta-analyses relating PTSD to immune biomarker concentrations and using subgroup analyses to resolve heterogeneity. RESULTS A total of 2606 articles were screened and 42 samples were included by the systematic review. The levels of interleukin-1β (IL-1β, P = 0.01), IL-2 (P = 0.006), IL-6 (P = 0.0002), interferon-γ (IFN-γ, P = 0.004), tumor necrosis factor-α (TNF-α, P = 0.004), C-reactive protein (CRP, P = 0.0003) and white blood cell (WBC, P = 0.01) were higher in PTSD than healthy controls (HC). Subgroup meta-analyses for psychotropic medication showed the levels of IL-1β and IL-2 were not increased in the PTSD. Subgroup meta-analyses for whether HC exposed to trauma showed the levels of IL-1β and IL-6 were not increased in the PTSD. Egger´s test revealed there was no publication bias. However, there was significant heterogeneity across studies for immune markers other than for WBC (P = 0.14, I2 = 45%). Subgroup analyses based on sex, HC exposed to trauma, PTSD comorbid major depressive disorder, PTSD on psychotropic medications partially or completely resolved heterogeneity for some immune biomarkers. CONCLUSION This meta-analysis provides evidence for elevation of IFN-γ, TNF-α, CRP, and WBC in PTSD.
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Affiliation(s)
- Juan-Juan Yang
- Department of Health Management, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Provice, China
| | - Wei Jiang
- Department of Oncology, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, 710004, Shaanxi Provice, China.
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28
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Zhang L, Hu XZ, Li X, Chen Z, Benedek DM, Fullerton CS, Wynn G, Biomarker team NaifehJames A.1WuHongyan1BenferNatasha1NgTsz Hin H.1AliagaPoblo1DinhHieu1KaoTzu-Cheg2, Ursano RJ. Potential chemokine biomarkers associated with PTSD onset, risk and resilience as well as stress responses in US military service members. Transl Psychiatry 2020; 10:31. [PMID: 32066664 PMCID: PMC7026448 DOI: 10.1038/s41398-020-0693-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 11/21/2019] [Accepted: 11/28/2019] [Indexed: 11/15/2022] Open
Abstract
Cytokines, including chemokines, are small secreted proteins, which specifically effect on the interactions and communications between cells. Pro-inflammatory cytokines are produced predominantly by activated macrophages and are involved in the upregulation of inflammatory reactions. Dysregulation of cytokines is associated with post-traumatic stress disorder (PTSD). Here, we use both before-and-after and case-control studies to search for potential chemokine biomarkers associated with PTSD onset, risk, and resilience as well as stress responses in US military service members deployed to Iraq and Afghanistan. Blood samples and scores of the PTSD Checklist (PCL) were obtained from soldiers pre- and post deployment (pre, post). Forty chemokines were measured using the Bio-Plex Pro Human Chemokine Panel Assays. The before-and-after analysis showed potential markers (CCL2, CCL15, CCL22, CCL25, CXCL2, and CXCL12) are associated with PTSD onset, and CCL3, CXCL11, and CXCL16 are related to stress response. The case-control study demonstrated that CCL13, CCL20, and CXCL6 were possible PTSD risk markers, and CX3CL1 might be a resilience marker. In addition, CCL11, CCL13, CCL20, and CCL25 were correlated with the PCL scores, indicating their association with PTSD symptom severity. Our data, for the first time, suggest that these dysregulated chemokines may serve as biomarkers for PTSD onset, risk, and resilience as well as stress responses, and may benefit developing approaches not only for PTSD diagnosis but also for PTSD treatment.
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Affiliation(s)
- Lei Zhang
- Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
| | - Xian-Zhang Hu
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
| | - Xiaoxia Li
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
| | - Ze Chen
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
| | - David M. Benedek
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
| | - Carol S. Fullerton
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
| | - Gary Wynn
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
| | | | - Robert J. Ursano
- grid.265436.00000 0001 0421 5525Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA
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29
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Waheed A, Dalton B, Wesemann U, Ibrahim MAA, Himmerich H. A Systematic Review of Interleukin-1β in Post-Traumatic Stress Disorder: Evidence from Human and Animal Studies. J Interferon Cytokine Res 2019; 38:1-11. [PMID: 29328883 DOI: 10.1089/jir.2017.0088] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Pro-inflammatory cytokines, such as interleukin (IL)-1β, have been implicated as underlying pathophysiological mechanisms and potential biomarkers of post-traumatic stress disorder (PTSD). This systematic review examines data regarding IL-1β production/concentration in human and animal studies of PTSD. In accordance with PRISMA guidelines, relevant articles from PubMed were reviewed from inception until July 10, 2017. Nineteen studies were eligible for inclusion. Animal studies demonstrated increased hippocampal IL-1β in rodent models of PTSD. Several immunomodulatory drugs were shown to reduce elevated IL-1β levels and anxiety-like behaviors in animals. Human cross-sectional studies showed contradictory results; serum and plasma IL-1β concentrations in PTSD patients were either elevated or did not differ from control groups. In vitro IL-1β production by stimulated cells demonstrated no difference between PTSD and control participants, although spontaneous in vitro production of IL-1β was increased in the PTSD group. The findings from 2 longitudinal studies were inconsistent. Given the conflicting findings, it is premature to consider IL-1β as a biomarker of PTSD. Anti-inflammatory agents may reduce IL-1β, and be a potential basis for future therapeutic agents in PTSD treatment. More longitudinal research is needed to better understand the role of IL-1β in the development and/or maintenance of PTSD.
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Affiliation(s)
- Aysha Waheed
- 1 Department of Psychological Medicine, King's College London , London, United Kingdom .,2 Faculty of Life Sciences and Medicine, King's College London , London, United Kingdom
| | - Bethan Dalton
- 1 Department of Psychological Medicine, King's College London , London, United Kingdom
| | - Ulrich Wesemann
- 3 Department of Psychiatry, Psychotherapy and Psychotraumatology, Bundeswehr Hospital , Berlin, Germany
| | - Mohammad A A Ibrahim
- 4 Department of Immunological Medicine and Allergy, King's Health Partners, King's College Hospital , London, United Kingdom
| | - Hubertus Himmerich
- 1 Department of Psychological Medicine, King's College London , London, United Kingdom
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30
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Wang L, Wang R, Liu L, Qiao D, Baldwin DS, Hou R. Effects of SSRIs on peripheral inflammatory markers in patients with major depressive disorder: A systematic review and meta-analysis. Brain Behav Immun 2019; 79:24-38. [PMID: 30797959 DOI: 10.1016/j.bbi.2019.02.021] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 01/22/2019] [Accepted: 02/20/2019] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Peripheral levels of inflammatory markers are elevated in major depressive disorder (MDD). Selective serotonin reuptake inhibitors (SSRIs) affect levels of inflammatory markers in patients with MDD, but studies have reported inconsistent findings. This systematic review and meta-analysis aims to investigate the effects of SSRI treatment on peripheral levels of a range of inflammatory markers in MDD patients. METHODS Systematic literature search (Pubmed, Web of Science, Embase, Cochrane) for studies published before November 2018. Studies were included if they used SSRI monotherapy and peripheral levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured before and after treatment in patients with MDD. Meta-analysis was conducted using Comprehensive Meta-analysis (version 2). Effect sizes were calculated using bias-corrected standardized mean difference (Hedges' g) between pre- and post-treatment. Sub-group analyses, meta-regression and publication bias estimates were undertaken; sensitivity analyses were performed using different estimated pre- and post-treatment correlations and after removing poor quality studies. RESULTS Twenty two eligible studies including 827 MDD patients were included in the meta-analysis: fifteen studies for IL-6; eleven for TNF-α; eight for IL-10; seven for IL-1β; six for IL-4; five for IL-2; and four for IFN-γ. The pooled effect estimate indicates SSRI treatment decreased levels of pro-inflammatory markers IL-6 (Hedges' g, -0.418; 95%CI, -0.663 to -0.174; I2 = 89.412), TNF-α (Hedges' g, -0.554; 95%CI, -0.990 to -0.118; I2 = 95.438) and IL-1β (Hedges' g = -0.574; 95%CI, -1.014 to -0.135; I2 = 91.622), and anti-inflammatory marker IL-10 (Hedges' g = -0.615; 95%CI, -0.989 to -0.242; I2 = 90.406). There were no significant treatment effects on levels of IL-2, IL-4, or IFN-γ. There was a high level of heterogeneity between studies. Sensitivity analyses indicated the robustness of the primary analyses. CONCLUSIONS The current review and meta-analysis indicates moderate immunomodulating effects of SSRI treatment for MDD, which suggests SSRIs may owe some of their therapeutic effect to their anti-inflammatory properties. High heterogeneity across studies may limit interpretation of the findings and larger randomized clinical trials are warranted.
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Affiliation(s)
- Lina Wang
- Department of Psychiatry, Shandong Mental Health Centre, Jinan, Shandong 250014 China
| | - Ruzhan Wang
- Department of Psychiatry, Shandong Mental Health Centre, Jinan, Shandong 250014 China
| | - Lanfen Liu
- Department of Psychiatry, Shandong Mental Health Centre, Jinan, Shandong 250014 China
| | - Dongdong Qiao
- Department of Psychiatry, Shandong Mental Health Centre, Jinan, Shandong 250014 China
| | - David S Baldwin
- Department of Psychiatry, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Ruihua Hou
- Department of Psychiatry, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
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31
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Wang Y, Karstoft KI, Nievergelt CM, Maihofer AX, Stein MB, Ursano RJ, Bybjerg-Grauholm J, Bækvad-Hansen M, Hougaard DM, Andreassen OA, Werge T, Thompson WK, Andersen SB. Post-traumatic stress following military deployment: Genetic associations and cross-disorder genetic correlations. J Affect Disord 2019; 252:350-357. [PMID: 30999091 DOI: 10.1016/j.jad.2019.04.070] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 02/22/2019] [Accepted: 04/08/2019] [Indexed: 10/27/2022]
Abstract
BACKGROUND Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder that occurs with relatively high frequency after deployment to warzones (∼10%). While twin studies have estimated the heritability to be up to 40%, thus indicating a considerable genetic component in the etiology, the biological mechanisms underlying risk and development of PTSD remain unknown. METHODS Here, we conduct a genome-wide association study (GWAS; N = 2,481) to identify genome regions that associate with PTSD in a highly homogenous, trauma-exposed sample of Danish soldiers deployed to war and conflict zones. We perform integrated analyses of our results with gene-expression and chromatin-contact datasets to prioritized genes. We also leverage on other large GWAS (N>300,000) to investigate genetic correlations between PTSD and other psychiatric disorders and traits. RESULTS We discover, but do not replicate, one region, 4q31, close to the IL15 gene, which is genome-wide significantly associated with PTSD. We demonstrate that gene-set enrichment, polygenic risk score and genetic correlation analyses show consistent and significant genetic correlations between PTSD and depression, insomnia and schizophrenia. LIMITATIONS The limited sample size, the lack of replication, and the PTSD case definition by questionnaire are limitations to the study. CONCLUSIONS Our results suggest that genetic perturbations of inflammatory response may contribute to the risk of PTSD. In addition, shared genetic components contribute to observed correlations between PTSD and depression, insomnia and schizophrenia.
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Affiliation(s)
- Yunpeng Wang
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Boserupvej 2, DK-4000 Roskilde, Denmark; Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway; Department of Psychology, University of Oslo, Harald Schelderups Hus Forskningsveien 3A 0373 Oslo
| | - Karen-Inge Karstoft
- Research and Knowledge Center, The Danish Veteran Center, Garnisonen 1, 4100 Ringsted, Denmark; Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, 1353 Copenhagen, Denmark.
| | - Caroline M Nievergelt
- VA Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla Village Drive 3350, 92161 La Jolla, CA, USA; Department of Psychiatry, School of Medicine, University of California San Diego, Gilman Drive 9500, 92093 La Jolla, CA, USA
| | - Adam X Maihofer
- VA Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla Village Drive 3350, 92161 La Jolla, CA, USA; Department of Psychiatry, School of Medicine, University of California San Diego, Gilman Drive 9500, 92093 La Jolla, CA, USA
| | - Murray B Stein
- Department of Psychiatry, School of Medicine, University of California San Diego, Gilman Drive 9500, 92093 La Jolla, CA, USA; Department of Family Medicine and Public Health, University of California San Diego, Gilman Drive 9500, 92093 La Jolla, CA, USA
| | - Robert J Ursano
- Department of Psychiatry, Uniformed Services University of the Health Sciences, Jones Bridge Road 4301, 20814 Bethesda, MD, USA
| | - Jonas Bybjerg-Grauholm
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Danish Centre for Neonatal Screening, Department of Congenital Diseases, Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen, Denmark
| | - Marie Bækvad-Hansen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Danish Centre for Neonatal Screening, Department of Congenital Diseases, Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen, Denmark
| | - David M Hougaard
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Danish Centre for Neonatal Screening, Department of Congenital Diseases, Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen, Denmark
| | - Ole A Andreassen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
| | - Thomas Werge
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Boserupvej 2, DK-4000 Roskilde, Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Wesley K Thompson
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Boserupvej 2, DK-4000 Roskilde, Denmark; Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway; Division of Biostatistics, Department of Family Medicine and Public Health, University of California, San Diego
| | - Søren B Andersen
- Research and Knowledge Center, The Danish Veteran Center, Garnisonen 1, 4100 Ringsted, Denmark
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Kim YK, Amidfar M, Won E. A review on inflammatory cytokine-induced alterations of the brain as potential neural biomarkers in post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2019; 91:103-112. [PMID: 29932946 DOI: 10.1016/j.pnpbp.2018.06.008] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/17/2018] [Accepted: 06/18/2018] [Indexed: 12/25/2022]
Abstract
The heterogeneity of post-traumatic stress disorder (PTSD) symptoms indicates that multiple neurobiological mechanisms underlie the pathophysiology of the condition. However, no generally accepted PTSD biomarkers in clinical practice currently exist. The sequential responses to recurrent and chronic stress by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) system are considered to play a significant role in the onset and progression of PTSD. Decreased activity of the HPA axis and parasympathetic nervous system, along with increased activity of the sympathetic nervous system, have been observed in PTSD, which may lead to increased levels of proinflammatory cytokines. Such heightened activity of the immune system may cause alterations in the structure and function of brain regions-for example, the amygdala, hippocampus, medial prefrontal cortex, anterior cingulate cortex, and insula-through changes in levels of serotonin and kynurenine pathway metabolites, and direct neurotoxic effects of cytokines. Although chronic inflammation-induced alterations in brain regions critical in controlling emotional behavior and fear regulation may represent a strong candidate biomarker of PTSD, future studies are necessary to further elucidate inflammation-associated neural biomarkers of PTSD. Continued research on therapeutic methods that involve the normalization of the HPA axis, ANS, and immune system is expected to contribute to the development of novel ways to treat PTSD.
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Affiliation(s)
- Yong-Ku Kim
- Department of Psychiatry, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Meysam Amidfar
- Department of Neuroscience, Fasa University of Medical Sciences, Fasa, Iran
| | - Eunsoo Won
- Department of Psychiatry, College of Medicine, Korea University, Seoul, Republic of Korea.
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Hori H, Kim Y. Inflammation and post-traumatic stress disorder. Psychiatry Clin Neurosci 2019; 73:143-153. [PMID: 30653780 DOI: 10.1111/pcn.12820] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/13/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022]
Abstract
While post-traumatic stress disorder (PTSD) is currently diagnosed based solely on classic psychological and behavioral symptoms, a growing body of evidence has highlighted a link between this disorder and alterations in the immune and inflammatory systems. Epidemiological studies have demonstrated that PTSD is associated with significantly increased rates of physical comorbidities in which immune dysregulation is involved, such as metabolic syndrome, atherosclerotic cardiovascular disease, and autoimmune diseases. In line with this, a number of blood biomarker studies have reported that compared to healthy controls, individuals with PTSD exhibit significantly elevated levels of proinflammatory markers, such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and C-reactive protein. Moreover, various lines of animal and human research have suggested that inflammation is not only associated with PTSD but also can play an important role in its pathogenesis and pathophysiology. In this review, we first summarize evidence suggestive of increased inflammation in PTSD. We then examine findings that suggest possible mechanisms of inflammation in this disorder in terms of two different but interrelated perspectives: putative causes of increased proinflammatory activities and potential consequences that inflammation generates. Given that there is currently a dearth of treatment options for PTSD, possibilities of new therapeutic approaches using pharmacological and non-pharmacological treatments/interventions that have anti-inflammatory effects are also discussed. Despite the increasing attention given to the inflammatory pathology of PTSD, there remains much to be elucidated, including more detailed mechanisms of inflammation, potential usefulness of inflammatory biomarkers as diagnostic and prognostic markers, and efficacy of novel treatment strategies targeting inflammation.
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Affiliation(s)
- Hiroaki Hori
- Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Yoshiharu Kim
- Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan
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Wang W, Wang L, Xu H, Cao C, Liu P, Luo S, Duan Q, Ellenbroek B, Zhang X. Characteristics of pro- and anti-inflammatory cytokines alteration in PTSD patients exposed to a deadly earthquake. J Affect Disord 2019; 248:52-58. [PMID: 30711869 DOI: 10.1016/j.jad.2019.01.029] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/03/2019] [Accepted: 01/19/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Many studies have shown that the disturbance of pro-inflammatory and/or anti-inflammatory cytokines is involved in the modulation of traumatic stress and related psychiatric disorders, typically posttraumatic stress disorder (PTSD). However, the specific immune alterations associated with PTSD symptoms are still unclear. The present study compared levels of pro- and anti-inflammatory cytokines between PTSD and non-PTSD controls, and investigated the relationships of immune changes with PTSD symptomatology. METHODS In this study, 51 earthquake-exposed PTSD patients and 136 earthquake-exposed healthy controls were recruited. We assessed trauma exposure, PTSD and depression severity, and quantified a panel of pro- inflammatory cytokines, including interleukin (IL)-1β, IL-2, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), interferon ϒ (IFNϒ), and anti-inflammatory cytokines, including IL-4, IL-10 and IL-13 with enzyme-linked immunosorbent assays. Additionally, total pro-inflammatory cytokines score and total anti-inflammatory cytokines score were calculated to reflect the status of two balance system. RESULTS Behavioral data showed that the PTSD group had greater severity of depression, as well as total symptoms and every symptom cluster in the seven-factor model of PTSD compared to the non-PTSD control group. Immune data showed that PTSD subjects had higher levels of IL-1β and TNFα, as well as total pro-inflammatory cytokine scores compared to controls, suggesting an increase of inflammatory activity in PTSD. In all subjects, the IL-1β levels were correlated with PCL scores, after controlling for covariates, including age, education, marital status and gender, trauma exposure severity and depression. LIMITATIONS The current study did not include a non-traumatized healthy control group, and PTSD was assessed using a self-reported measure. CONCLUSIONS Thus, by including a control group comprised entirely of earthquake-exposed individuals as means to discriminate specific alterations of cytokine levels in PTSD, these findings suggest that the increased inflammatory cytokines, especially IL-1β, may play a role in the pathophysiology of PTSD.
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Affiliation(s)
- Weiwen Wang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Li Wang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Hang Xu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chengqi Cao
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; Shenzhen Key Laboratory of Affective and Social Cognitive Science, Shenzhen University, Shenzhen, 518060, China
| | - Ping Liu
- People's Hospital of Deyang City, Deyang, Sichuan, 618000, China
| | - Shu Luo
- People's Hospital of Deyang City, Deyang, Sichuan, 618000, China
| | - Qing Duan
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China
| | - Bart Ellenbroek
- School of Psychology, Victoria University of Wellington, Kelburn, Wellington, 6012, New Zealand
| | - Xiangyang Zhang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100049, China
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Evidenced-Based Treatment of Posttraumatic Stress Disorder: An Updated Review of Validated Psychotherapeutic and Pharmacological Approaches. Harv Rev Psychiatry 2019; 26:99-115. [PMID: 29734225 DOI: 10.1097/hrp.0000000000000186] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
LEARNING OBJECTIVES After participating in this activity, learners should be better able to:• Evaluate psychotherapeutic and pharmacologic approaches to treating patients with posttraumatic stress disorder. ABSTRACT A strong evidence base exists for psychological and pharmacological interventions for the treatment of posttraumatic stress disorder (PTSD). The published literature investigating the effectiveness of these treatments in reducing the symptoms and impairments associated with PTSD has expanded substantially in recent years. This review provides a concise overview of the empirical literature examining these treatment approaches. Evidence-based, trauma-focused therapies are recommended as first-line interventions, with the most support for cognitive- and exposure-based approaches. Prolonged exposure and cognitive processing therapy are the two most cited and rigorously investigated. Various other evidence-supported protocols are discussed. Pharmacotherapies can be used when evidence-based psychotherapies are not available or are ineffective, or on the basis of patient preference. Pharmacotherapy with the most support for PTSD includes selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Evidence supports the implementation of these interventions across genders, populations, and settings. Given that little research directly compares the effectiveness of different PTSD interventions and their mechanisms of action, it remains uncertain how to best select and tailor treatments to optimize individual outcomes. Future directions and novel, ongoing research are discussed.
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Règue M, Poilbout C, Martin V, Franc B, Lanfumey L, Mongeau R. Increased 5-HT2C receptor editing predisposes to PTSD-like behaviors and alters BDNF and cytokines signaling. Transl Psychiatry 2019; 9:100. [PMID: 30792491 PMCID: PMC6384909 DOI: 10.1038/s41398-019-0431-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 01/24/2019] [Accepted: 01/27/2019] [Indexed: 12/16/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is a trauma- and stress-related disorder with dysregulated fear responses and neurobiological impairments, notably at neurotrophic and inflammation levels. Understanding the mechanisms underlying this disease is crucial to develop PTSD models that meet behavioral and neurobiological validity criteria as well as innovative therapeutic approaches. Serotonin 2C receptors (5-HT2CR) are known for their important role in anxiety, and mice having only the fully edited VGV isoform of 5-HT2CR, which thereby overexpressed brain 5-HT2CR, are of special interest to study PTSD predisposition. Innate and conditioned fear-related behaviors were assessed in VGV and wild-type mice. mRNA expression of brain-derived neurotrophic factor (BDNF), tissue-plasminogen activator (tPA), and pro-inflammatory cytokines (IL-6, IL-1β, and calcineurin) were measured by qRT-PCR. The effect of acute and chronic paroxetine was evaluated on both behavior and gene expression. VGV mice displayed greater fear expression, extensive fear extinction deficits, and fear generalization. Paroxetine restored fear extinction in VGV mice when administered acutely and decreased innate fear and fear generalization when administered chronically. In parallel, Bdnf, tPA, and pro-inflammatory cytokines mRNA levels were dysregulated in VGV mice. Bdnf and tPA mRNA expression was decreased in the hippocampus but increased in the amygdala, and chronic paroxetine normalized Bdnf mRNA levels both in the amygdala and the hippocampus. Amygdalar calcineurin mRNA level in VGV mice was also normalized by chronic paroxetine. VGV-transgenic mice displayed behavioral and neurobiological features that could be accessory to the investigation of PTSD and its treatment. Furthermore, these data point out to the role of 5-HT2CR in neuroplasticity and neuroinflammation.
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MESH Headings
- Amygdala/metabolism
- Animals
- Anxiety/genetics
- Behavior, Animal/drug effects
- Brain-Derived Neurotrophic Factor/genetics
- Brain-Derived Neurotrophic Factor/metabolism
- Cytokines/metabolism
- Disease Models, Animal
- Fear
- Hippocampus/metabolism
- Male
- Maze Learning
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Paroxetine/pharmacology
- RNA Editing
- RNA, Messenger/genetics
- Receptor, Serotonin, 5-HT2C/genetics
- Receptor, Serotonin, 5-HT2C/metabolism
- Signal Transduction
- Stress Disorders, Post-Traumatic/drug therapy
- Stress Disorders, Post-Traumatic/metabolism
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Affiliation(s)
- Mathilde Règue
- Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, 75014, Paris, France
| | - Corinne Poilbout
- Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, 75014, Paris, France
| | - Vincent Martin
- Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, 75014, Paris, France
| | - Bernard Franc
- Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, 75014, Paris, France
| | - Laurence Lanfumey
- Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, 75014, Paris, France
| | - Raymond Mongeau
- EA 4475, Pharmacologie de la circulation cérébrale, Université Paris Descartes, 75006, Paris, France.
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Renna ME, O'Toole MS, Spaeth PE, Lekander M, Mennin DS. The association between anxiety, traumatic stress, and obsessive-compulsive disorders and chronic inflammation: A systematic review and meta-analysis. Depress Anxiety 2018; 35:1081-1094. [PMID: 30199144 DOI: 10.1002/da.22790] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 05/19/2018] [Accepted: 05/29/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Anxiety is characterized by prolonged preparation for real or perceived threat. This may manifest both as psychological and physiological activation, ultimately leading to greater risk for poor health. Chronic inflammation may play an integral role in this relationship, given the influential role that it has in chronic illness. The aim of this meta-analysis is to examine levels of chronic inflammation, measured by inflammatory cytokines and C-reactive protein, in people with anxiety disorders, PTSD (posttraumatic stress disorder), or obsessive-compulsive disorder compared to healthy controls. Several moderating variables, including specific diagnosis and depression comorbidity, were also assessed. METHODS Seventy six full-text articles were screened for eligibility with 41 studies ultimately included in analysis. RESULTS Results demonstrated a significant overall difference between healthy controls (HCs) and people with anxiety disorders in pro-inflammatory cytokines (P = 0.013, Hedge's g = -0.39), which appears to be largely driven by interleukin-1β (IL-1β; P = 0.009, Hedge's g = -0.50), IL-6 (P < 0.001, Hedge's g = -0.93), and tumor necrosis factor-α (P = 0.030, Hedge's g = -0.56). Moderation analyses revealed a moderating effect of diagnosis (P = 0.050), as only individuals with PTSD demonstrated differences in inflammation between HCs (P = 0.004, Hedge's g = -0.68). CONCLUSIONS These data demonstrate the association between inflammatory dysregulation and diagnoses associated with chronic, impactful, and severe anxiety and provides insight into the way that anxiety, and in particular PTSD, is related to certain inflammatory markers. In doing so, these findings may provide an initial step in disentangling the relationship between anxiety and basic health processes.
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Affiliation(s)
- Megan E Renna
- Counseling and Clinical Psychology, Teachers College, Columbia University, New York, New York
| | | | - Phillip E Spaeth
- Counseling and Clinical Psychology, Teachers College, Columbia University, New York, New York
| | - Mats Lekander
- Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden
- Stress Research Institute, Stockholm University, Stockholm, Sweden
| | - Douglas S Mennin
- Counseling and Clinical Psychology, Teachers College, Columbia University, New York, New York
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Morrison FG, Miller MW, Wolf EJ, Logue MW, Maniates H, Kwasnik D, Cherry JD, Svirsky S, Restaino A, Hildebrandt A, Aytan N, Stein TD, Alvarez VE, McKee AC, Huber BR. Reduced interleukin 1A gene expression in the dorsolateral prefrontal cortex of individuals with PTSD and depression. Neurosci Lett 2018; 692:204-209. [PMID: 30366016 DOI: 10.1016/j.neulet.2018.10.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 09/13/2018] [Accepted: 10/13/2018] [Indexed: 12/13/2022]
Abstract
The inflammatory system has been implicated in the pathophysiology of a variety of psychiatric conditions. Individuals with PTSD, depression, and other fear- and anxiety-related disorders exhibit alterations in peripheral circulating inflammatory markers, suggesting dysregulation of the inflammatory system. The relationship between inflammation and PTSD has been investigated almost exclusively in the periphery, and has not been extensively explored in human postmortem brain tissue. Interleukins (ILs) represent a subtype of cytokines and are key signaling proteins in the immune and inflammatory systems. Based on prior research implicating IL signaling in PTSD and depression, we performed a preliminary investigation of IL gene expression in a region of the cortex involved in emotion regulation and PTSD, the dorsolateral prefrontal cortex (dlPFC), using tissue from the newly established VA National PTSD Brain Bank. Gene expression analyses were conducted on post-mortem tissue from the dlPFC from 50 donors: 13 controls, 12 PTSD cases, and 25 depressed cases. RNA was extracted from frozen dlPFC tissue, reverse transcribed to cDNA, and quantitative polymerase chain reaction (qPCR) was performed to assess gene expression of IL1A, IL1B, IL6, IL8, IL10, IL13, and IL15. We found a multiple-testing corrected significant decrease in IL1A expression in the dlPFC for PTSD and depression cases compared to controls (p < 0.005) with age at death, sex, race and RNA integrity number (RIN) included as covariates. To our knowledge this finding is the first demonstration of altered IL expression in brain tissue from deceased individuals with histories of PTSD and/or depression.
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Affiliation(s)
- Filomene G Morrison
- National Center for PTSD at VA Boston Healthcare System, United States; Department of Psychiatry, Boston University School of Medicine, United States
| | - Mark W Miller
- National Center for PTSD at VA Boston Healthcare System, United States; Department of Psychiatry, Boston University School of Medicine, United States
| | - Erika J Wolf
- National Center for PTSD at VA Boston Healthcare System, United States; Department of Psychiatry, Boston University School of Medicine, United States
| | - Mark W Logue
- National Center for PTSD at VA Boston Healthcare System, United States; Department of Psychiatry, Boston University School of Medicine, United States; Biomedical Genetics, Boston University School of Medicine, United States; Department of Biostatistics, Boston University School of Public Health, United States
| | - Hannah Maniates
- National Center for PTSD at VA Boston Healthcare System, United States
| | - David Kwasnik
- Department of Psychiatry, Boston University School of Medicine, United States
| | - Jonathan D Cherry
- Department of Neurology, Boston University School of Medicine, United States
| | - Sarah Svirsky
- Pathology and Laboratory Medicine, VA Boston Healthcare System, United States; Department of Neurology, Boston University School of Medicine, United States
| | - Anthony Restaino
- Department of Neurology, Boston University School of Medicine, United States
| | - Audrey Hildebrandt
- National Center for PTSD at VA Boston Healthcare System, United States; Pathology and Laboratory Medicine, VA Boston Healthcare System, United States
| | - Nurgül Aytan
- Department of Neurology, Boston University School of Medicine, United States
| | - Thor D Stein
- Pathology and Laboratory Medicine, VA Boston Healthcare System, United States; Department of Neurology, Boston University School of Medicine, United States; Department of Pathology, Boston University School of Medicine, United States
| | - Victor E Alvarez
- National Center for PTSD at VA Boston Healthcare System, United States; Pathology and Laboratory Medicine, VA Boston Healthcare System, United States; Department of Neurology, Boston University School of Medicine, United States
| | - Ann C McKee
- Pathology and Laboratory Medicine, VA Boston Healthcare System, United States; Department of Neurology, Boston University School of Medicine, United States; Department of Pathology, Boston University School of Medicine, United States
| | | | - Bertrand R Huber
- National Center for PTSD at VA Boston Healthcare System, United States; Pathology and Laboratory Medicine, VA Boston Healthcare System, United States; Department of Neurology, Boston University School of Medicine, United States.
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Felger JC. Imaging the Role of Inflammation in Mood and Anxiety-related Disorders. Curr Neuropharmacol 2018; 16:533-558. [PMID: 29173175 PMCID: PMC5997866 DOI: 10.2174/1570159x15666171123201142] [Citation(s) in RCA: 287] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 10/23/2017] [Accepted: 11/21/2017] [Indexed: 02/08/2023] Open
Abstract
Background Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have reported evidence that inflammation and release of inflammatory cytokines affect circuitry relevant to both reward and threat sensitivity to contribute to behavioral change. Of relevance to mood and anxiety-related disorders, biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of patients with major depressive disorder (MDD), bipolar disorder, anxiety disorders and post-traumatic stress disorder (PTSD). Methods This review summarized clinical and translational work demonstrating the impact of peripheral inflammation on brain regions and neurotransmitter systems relevant to both reward and threat sensitivity, with a focus on neuroimaging studies involving administration of inflammatory stimuli. Recent translation of these findings to further understand the role of inflammation in mood and anxiety-related disorders is also discussed. Results Inflammation was consistently found to affect basal ganglia and cortical reward and motor circuits to drive reduced motivation and motor activity, as well as anxiety-related brain regions including amygdala, insula and anterior cingulate cortex, which may result from cytokine effects on monoamines and glutamate. Similar relationships between inflammation and altered neurocircuitry have been observed in MDD patients with increased peripheral inflammatory markers, and such work is on the horizon for anxiety disorders and PTSD. Conclusion Neuroimaging effects of inflammation on reward and threat circuitry may be used as biomarkers of inflammation for future development of novel therapeutic strategies to better treat mood and anxiety-related disorders in patients with high inflammation.
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Affiliation(s)
- Jennifer C Felger
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States.,Winship Cancer Institute, Emory University, Atlanta, GA, United States
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Luiz APL, Antico HDA, Skare TL, Boldt ABW, Nisihara R. Adverse childhood experience and rheumatic diseases. Clin Rheumatol 2018; 37:2863-2867. [PMID: 29992393 DOI: 10.1007/s10067-018-4200-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/09/2018] [Accepted: 07/04/2018] [Indexed: 11/26/2022]
Abstract
It has been suggested that the adaptive stress response may be disrupted by life adverse events such as childhood maltreatment. To investigate if the number of adverse childhood experiences (ACEs) increases susceptibility to systemic lupus erythematosus (SLE), spondyloarthritis (SpA), scleroderma (SSc), and rheumatoid arthritis (RA), we interviewed 315 patients with rheumatic disease (100 SLE; 40 SSc; 60 SpA; 115 RA) and 272 controls, using questions of the ACEs study questionnaire validated to ask about experiences of childhood abuse, negligence, domestic violence, and household dysfunctions. The questionnaire score ranges from zero (best result) to 8 (worst scenario). Patients and controls did not differ regarding the median number of ACEs (3 in both groups, patient IQR = 2.5-5 vs. control IQR = 2-5, p = 0.45). Among the patients, 63.8% (201/315) presented ACE score ≥ 3, compared with 59.9% (163/272) of the controls (p = 0.31). The proportion of patients with at least 3 ACEs did also not differ among those with different rheumatic diseases. Specifically, 64% (64/100) of those with SLE, 60% (24/40) of those with SSc, 60% (36/60) of those with SpA, and 66.9% (77/115) of those with RA reported at least 3 ACEs. There was also no difference between the distribution of ACE scores and number of individuals with ACEs ≥ 3 between patients with different rheumatic diseases and controls. Nevertheless, there was a trend for association between higher ACE score and susceptibility to RA (p = 0.06). In this setting, the occurrence of ACEs was not associated with susceptibility to rheumatic diseases in adulthood.
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Affiliation(s)
- Ana Paula Lopes Luiz
- Rheumatology Service, Evangelic University Hospital of Curitiba, Curitiba, Brazil
| | | | - Thelma Larocca Skare
- Rheumatology Service, Evangelic University Hospital of Curitiba, Curitiba, Brazil
| | | | - Renato Nisihara
- Rheumatology Service, Evangelic University Hospital of Curitiba, Curitiba, Brazil.
- Department of Medicine, Positivo University, Curitiba, Brazil.
- Medicine Department, Evangelic University, R. Padre Agostinho, 2770, Curitiba, 80730-000, Brazil.
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41
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Toft H, Neupane SP, Bramness JG, Tilden T, Wampold BE, Lien L. The effect of trauma and alcohol on the relationship between level of cytokines and depression among patients entering psychiatric treatment. BMC Psychiatry 2018; 18:95. [PMID: 29631540 PMCID: PMC5891976 DOI: 10.1186/s12888-018-1677-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 03/27/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Depression is associated with immunological responses as reflected by altered levels of circulating cytokines. Alcohol use and trauma may modulate immune activity, and few studies have investigated these factors in depressed patients. We aimed to explore the association between circulating peripheral cytokine levels and degree of depressive symptoms, taking trauma and alcohol into account. METHODS The study was a cross-sectional assessment of patients at admission to a specialized psychiatric center in Norway. A total of 128 patients were included. Information was gathered using the self-administered questionnaires Beck Depression Inventory-II (BDI-II) and the Alcohol Use Disorders Identification Test (AUDIT), in addition to clinical interviews recording childhood or adult life trauma. Serum levels of the cytokines Interleukin-1β (IL-1β), Interleukin-1 Receptor Antagonist (IL-1RA), Tumor Necrosis Factor-α (TNF-α) and the chemokine Monocyte Chemoattractant Protein-1 (MCP-1) were assessed. A Luminex bead-based multiplex assay was used for cytokine measurements. Patient cytokine levels were compared to those of healthy volunteers by the Mann-Whitney U test. RESULTS Levels of cytokines did not differ across patients with mild, moderate and severe depression. AUDIT score was not related to cytokine levels, but to level of depression. A history of trauma was related to higher levels of IL-1RA and TNF-α (p = 0.048 and p = 0.033, respectively), especially among the severely depressed. Serum levels of MCP-1 and TNF-α were significantly higher among psychiatric patients than in healthy volunteers. CONCLUSIONS Findings indicate that depression was not related to levels of circulating cytokines among patients in treatment, but that traumatized patients had higher levels of IL-1RA and TNF-α than patients without trauma experience. The lack of relationship between cytokine level and depression was evident both in those without and with trauma.
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Affiliation(s)
- Helge Toft
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post Box 104, Ottestad, N-2381, Brumunddal, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Sudan Prasad Neupane
- 0000 0004 0627 386Xgrid.412929.5Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post Box 104, Ottestad, N-2381 Brumunddal, Norway ,0000 0004 1936 8921grid.5510.1Norwegian Center for Addiction Research (SERAF), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørgen G. Bramness
- 0000 0004 0627 386Xgrid.412929.5Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post Box 104, Ottestad, N-2381 Brumunddal, Norway ,0000000122595234grid.10919.30Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
| | - Terje Tilden
- 0000 0004 1936 8921grid.5510.1Research Institute, Modum Bad Psychiatric Center, Vikersund, Norway
| | - Bruce E. Wampold
- 0000 0004 1936 8921grid.5510.1Research Institute, Modum Bad Psychiatric Center, Vikersund, Norway ,0000 0001 2167 3675grid.14003.36University of Wisconsin-Madison, Madison, USA
| | - Lars Lien
- 0000 0004 0627 386Xgrid.412929.5Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post Box 104, Ottestad, N-2381 Brumunddal, Norway ,grid.477237.2Department of Public Health, Hedmark University College, Elverum, Norway
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Abstract
OBJECTIVE Several cross-sectional studies have reported a relationship between posttraumatic stress disorder (PTSD) and epilepsy. However, the temporal association between PTSD and epilepsy has rarely been investigated. We hypothesized that the risk of developing epilepsy later in life would be higher in patients with PTSD than in those without PTSD. METHODS Using the Taiwan National Health Insurance Research Database, 6425 individuals with PTSD and 24,980 age-/sex-matched controls were enrolled between 2002 and 2009 in our study and followed up to the end of 2011. Those who developed epilepsy during the follow-up period were identified. RESULTS Individuals with PTSD had a higher incidence of developing epilepsy (2.65 versus 0.33 per 1000 person-years, p < .001), with an earlier onset of epilepsy (37.53 years [15.80 years] versus 48.11 years [23.97 years], p = .002) than did the controls. Individuals with PTSD had an elevated risk of developing epilepsy (hazard ratio [HR] = 3.72, 95% confidence interval [CI] = 2.27-6.11) during the follow-up after adjustment for demographic data and medical and psychiatric comorbidities. Sensitivity analyses after excluding the observation in the first year (HR = 2.53, 95% CI = 1.44-4.47) and the first 3 years (HR = 2.14, 95% CI = 1.15-4.01) revealed consistent results. CONCLUSIONS These results supported a temporal association between PTSD and the development of epilepsy. Further studies are warranted to investigate the underlying pathophysiological pathways that explain the longitudinal association of PTSD with subsequent epilepsy.
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Toft H, Bramness JG, Lien L, Abebe DS, Wampold BE, Tilden T, Hestad K, Neupane SP. PTSD patients show increasing cytokine levels during treatment despite reduced psychological distress. Neuropsychiatr Dis Treat 2018; 14:2367-2378. [PMID: 30271153 PMCID: PMC6149900 DOI: 10.2147/ndt.s173659] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND A reciprocal relationship between activated innate immune system and changes in mood and behavior has been established. There is still a paucity of knowledge on how the immune system responds during psychiatric treatment. We aimed to explore circulating cytokines and assess psychiatric symptom severity scores during 12 weeks of inpatient psychiatric treatment. METHODS The study was a longitudinal assessment of 124 patients (88 women and 36 men) in treatment at Modum Psychiatric Center, Norway. The patient sample comprised a mixed psychiatric population of whom 39 were diagnosed with posttraumatic stress disorder (PTSD). Serum blood samples for cytokine analysis and measures of mental distress using Global Severity Index were collected at admission (T0), halfway (T1), and before discharge (T2). Other factors assessed were age, gender, and the use of antidepressants and anti-inflammatory drugs. Multilevel modeling was used for longitudinal analyses to assess the repeated cytokine samples within each patient. RESULTS Overall level of IL-1RA was higher in PTSD patients when compared to those without PTSD (P=0.021). The level of IL-1β, MCP-1, and TNF-α increased over time in PTSD compared to non-PTSD patients (P=0.025, P=0.011 and P=0.008, respectively). All patients experienced reduced mental distress as measured by self-reported Global Severity Index scores. Stratified analysis showed that PTSD patients who used anti-inflammatory drugs had higher levels of IL-1β (P=0.007) and TNF-α (P=0.049) than PTSD patients who did not use such drugs. CONCLUSION The study indicates that traumatized patients may have a distinct neuroimmune development during recovery. Their activated immune system shows even further activation during their rehabilitation despite symptom reduction.
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Affiliation(s)
- Helge Toft
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Ottestad, Norway, .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway,
| | - Jørgen G Bramness
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Ottestad, Norway, .,Institute of Clinical Medicine, UiT, Norway´s Arctic University, Tromsø, Norway
| | - Lars Lien
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Ottestad, Norway, .,Department of Health Studies, Inland Norway University of Applied Sciences, Elverum, Norway
| | - Dawit S Abebe
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Ottestad, Norway, .,Department of Nursing and Health Promotion, Oslo Metropolitan University, Oslo, Norway
| | - Bruce E Wampold
- Research Institute, Modum Psychiatric Center, Vikersund, Norway.,Department of Counseling Psychology, University of Wisconsin-Madison, Madison, WI, USA
| | - Terje Tilden
- Research Institute, Modum Psychiatric Center, Vikersund, Norway
| | - Knut Hestad
- Department of Health Studies, Inland Norway University of Applied Sciences, Elverum, Norway.,Department of Research, Innlandet Hospital Trust, Brumunddal, Norway.,Department of Psychology, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Sudan Prasad Neupane
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Ottestad, Norway, .,Norwegian Center for Addiction Research (SERAF), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Lindqvist D, Mellon SH, Dhabhar FS, Yehuda R, Grenon SM, Flory JD, Bierer LM, Abu-Amara D, Coy M, Makotkine I, Reus VI, Aschbacher K, Bersani FS, Marmar CR, Wolkowitz OM. Increased circulating blood cell counts in combat-related PTSD: Associations with inflammation and PTSD severity. Psychiatry Res 2017; 258:330-336. [PMID: 28942957 DOI: 10.1016/j.psychres.2017.08.052] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 08/18/2017] [Accepted: 08/20/2017] [Indexed: 12/18/2022]
Abstract
Inflammation is reported in post-traumatic stress disorder (PTSD). Few studies have investigated circulating blood cells that may contribute to inflammation. We assessed circulating platelets, white blood cells (WBC) and red blood cells (RBC) in PTSD and assessed their relationship to inflammation and symptom severity. One-hundred and sixty-three male combat-exposed veterans (82 PTSD, 81 non-PTSD) had blood assessed for platelets, WBC, and RBC. Data were correlated with symptom severity and inflammation. All cell counts were significantly elevated in PTSD. There were small mediation effects of BMI and smoking on these relationships. After adjusting for these, the differences in WBC and RBC remained significant, while platelet count was at trend level. In all subjects, all of the cell counts correlated significantly with inflammation. Platelet count correlated with inflammation only in the PTSD subjects. Platelet count, but none of the other cell counts, was directly correlated with PTSD severity ratings in the PTSD group. Combat PTSD is associated with elevations in RBC, WBC, and platelets. Dysregulation of all three major lineages of hematopoietic cells in PTSD, as well as their significant correlation with inflammation, suggest clinical significance of these changes.
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Affiliation(s)
- Daniel Lindqvist
- Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States; Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Psychiatry, Lund, Sweden
| | - Synthia H Mellon
- Department of OB/GYN and Reproductive Sciences, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States
| | - Firdaus S Dhabhar
- Department of Psychiatry & Behavioral Sciences, Sylvester Comprehensive Cancer Center, University of Miami, FL, United States
| | - Rachel Yehuda
- James J. Peters Veterans Administration Medical Center Bronx, New York, United States; Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - S Marlene Grenon
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States; Department of Surgery, Veterans Affairs Medical Center, San Francisco, CA, United States
| | - Janine D Flory
- James J. Peters Veterans Administration Medical Center Bronx, New York, United States; Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Linda M Bierer
- James J. Peters Veterans Administration Medical Center Bronx, New York, United States; Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Duna Abu-Amara
- Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, Department of Psychiatry, NYU, New York, United States
| | - Michelle Coy
- Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States
| | - Iouri Makotkine
- James J. Peters Veterans Administration Medical Center Bronx, New York, United States; Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Victor I Reus
- Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States
| | - Kirstin Aschbacher
- Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States
| | - F Saverio Bersani
- Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States; Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
| | - Charles R Marmar
- Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, Department of Psychiatry, NYU, New York, United States.
| | - Owen M Wolkowitz
- Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, United States.
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Neupane SP, Bramness JG, Lien L. Comorbid post-traumatic stress disorder in alcohol use disorder: relationships to demography, drinking and neuroimmune profile. BMC Psychiatry 2017; 17:312. [PMID: 28851339 PMCID: PMC5576315 DOI: 10.1186/s12888-017-1479-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 08/22/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND This study examined how alcohol use disorder (AUD) patients with post-traumatic stress disorder (PTSD) differed from those without PTSD in terms of demography, drinking patterns and C-reactive protein, inflammatory cytokines, tryptophan metabolism parameters, and brain-derived neurotrophic factor (BDNF). METHODS A consecutive sample (N = 187) of treatment-receiving AUD individuals were recruited from Nepalese facilities. They underwent fully structured psychiatric interviews. Serum levels of inflammatory cytokines [interleukin (IL)-6, IL-1 Receptor antagonist (IL-1Ra), IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)] were determined by a multiplex assay, kynurenine and tryptophan levels by high-performance liquid chromatography, and BDNF by enzyme-linked immunosorbent assay (ELISA). RESULTS The prevalence of exposure to severe trauma and PTSD was 74% and 17%, respectively. PTSD comorbidity was not associated with age, gender, or socioeconomic status, but with co-occurring major depression, history of attempted suicide, earlier peak of drinking problems, higher drinking quantity and withdrawal symptoms, experiencing alcoholic blackouts, and drinking problems among parents. None of the assessed neuroimmune parameters was related to comorbid PTSD. CONCLUSIONS The findings support routine trauma screening in AUD treatment samples and screening for risky drinking in trauma populations to help guide interventions. The expected aberrations in neuroimmune functioning may not be found when examined in a sample with multiple psychiatric morbidities.
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Affiliation(s)
- Sudan Prasad Neupane
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post box 104, 2381, Brumunddal, Norway. .,Norwegian Centre for Addiction Research (SERAF), University of Oslo, Oslo, Norway.
| | - Jørgen G. Bramness
- grid.412929.5Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post box 104, 2381 Brumunddal, Norway
| | - Lars Lien
- grid.412929.5Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Post box 104, 2381 Brumunddal, Norway ,grid.477237.2Department of Public Health, Hedmark University College, Elverum, Norway
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Post-traumatic Stress Disorder and Risk of Parkinson Disease: A Nationwide Longitudinal Study. Am J Geriatr Psychiatry 2017; 25:917-923. [PMID: 28416268 DOI: 10.1016/j.jagp.2017.03.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 03/08/2017] [Accepted: 03/20/2017] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Increasing evidence has suggested a relationship between post-traumatic stress disorder (PTSD) and neurodegenerative disorder, such as Alzheimer disease. The association between PTSD and Parkinson disease (PD), however, remains unclear. METHOD Using the Taiwan National Health Insurance Research Database, 7,280 subjects (1,456 patients aged ≥45 years with PTSD and 5,824 age-/sex-matched individuals without PTSD) were enrolled between 2002 and 2009 and followed to the end of 2011. Subjects who developed PD during the follow-up period were identified. RESULTS An increased risk of developing PD was found in patients with PTSD (Wald χ2 = 12.061, hazard ratio [HR]: 3.46, 95% confidence interval [CI]: 1.72-6.96) compared with individuals without PTSD, after adjusting for demographic data and medical and psychiatric comorbidities. The sensitivity tests after excluding the first year observation (Wald χ2 = 7.948, HR: 3.01, 95% CI: 1.40-6.46) and the first 3-year observation (Wald χ2 = 5.099, HR: 3.07, 95% CI: 1.16-8.15) were consistent. CONCLUSIONS Patients with PTSD had an elevated risk of developing PD in later life. Further studies would be required to clarify the exact pathophysiology between PTSD and PD and to investigate whether the prompt intervention for PTSD may reduce this risk.
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Tucker P, Pfefferbaum B, Nitiéma P, Khan Q, Aggarwal R, Walling EE. Possible link of Interleukin-6 and Interleukin-2 with psychiatric diagnosis, ethnicity, disaster or BMI. Cytokine 2017; 96:247-252. [PMID: 28486207 DOI: 10.1016/j.cyto.2017.04.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 04/08/2017] [Accepted: 04/26/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Cytokines are of increasing interest as markers for stress responses, mental disorders and general health. We assessed associations of two cytokines with several factors among relocated hurricane survivors and controls. METHODS We examined 40 relocated hurricane survivors and 40 demographically matched (frequency matching) Oklahoma controls to assess relationships of Interleukin-2 (IL-2) and Interleukin-6 (IL-6) with psychiatric diagnoses (SCID-IV), demographic variables, hurricane exposure and body mass index (BMI). Participants were predominantly African American (n=70, 87.5%). RESULTS Relocated Katrina survivors had higher proportions of current PTSD, major depression and psychiatric diagnoses than controls. Unexpectedly, exposure to Katrina with relocation was not by itself associated with differences in IL-2 or IL-6 levels. The mean IL-2 level was significantly higher in African American participants than other ethnicities (8 Caucasians, 2 Asians) and in those with a current psychiatric disorder. The mean IL-6 level was higher in females than males and in participants with any current psychiatric diagnosis. IL-6 level also correlated positively with participants' BMI. CONCLUSIONS Results suggest that cytokines studied were influenced non-specifically by the presence of a mental disorder, and by demographic variables of gender, ethnicity and BMI. Implications of these findings are discussed, as well as possible long-term impact of the identified interleukin differences on immunologic, inflammatory, neuropsychiatric and other systems.
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Affiliation(s)
- Phebe Tucker
- Dept. of Psychiatry, University of Oklahoma Health Sciences Center, WP 3440, 920 Stanton L Young Blvd., Oklahoma City, OK, United States.
| | - Betty Pfefferbaum
- Dept. of Psychiatry, University of Oklahoma Health Sciences Center, WP 3440, 920 Stanton L Young Blvd., Oklahoma City, OK, United States.
| | - Pascal Nitiéma
- Dept. of Psychiatry, University of Oklahoma Health Sciences Center, WP 3440, 920 Stanton L Young Blvd., Oklahoma City, OK, United States; Biostatistician, Management Information Systems, University of Oklahoma, Norman OK, United States.
| | - Qaiser Khan
- Dept. of Psychiatry, University of Oklahoma Health Sciences Center, WP 3440, 920 Stanton L Young Blvd., Oklahoma City, OK, United States.
| | - Ruchi Aggarwal
- Psychiatry & Behavioral Sciences, Baylor College of Medicine, 2016 Baylor, College of Medicine®; One Baylor Plaza, Houston, TX 77030, United States.
| | - Erin E Walling
- Dept. of Psychiatry, University of Oklahoma Health Sciences Center, WP 3440, 920 Stanton L Young Blvd., Oklahoma City, OK, United States.
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Bandelow B, Baldwin D, Abelli M, Bolea-Alamanac B, Bourin M, Chamberlain SR, Cinosi E, Davies S, Domschke K, Fineberg N, Grünblatt E, Jarema M, Kim YK, Maron E, Masdrakis V, Mikova O, Nutt D, Pallanti S, Pini S, Ströhle A, Thibaut F, Vaghix MM, Won E, Wedekind D, Wichniak A, Woolley J, Zwanzger P, Riederer P. Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry 2017; 18:162-214. [PMID: 27419272 PMCID: PMC5341771 DOI: 10.1080/15622975.2016.1190867] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 05/03/2016] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). METHODS Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. RESULTS The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. CONCLUSIONS Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
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Affiliation(s)
- Borwin Bandelow
- Department of Psychiatry and Psychotherapy, University of Göttingen, Germany
| | - David Baldwin
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Marianna Abelli
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Blanca Bolea-Alamanac
- School of Social and Community Medicine, Academic Unit of Psychiatry, University of Bristol, Bristol, UK
| | - Michel Bourin
- Neurobiology of Anxiety and Mood Disorders, University of Nantes, Nantes, France
| | - Samuel R. Chamberlain
- Hertfordshire Partnership University NHS Foundation Trust and University of Hertfordshire, Parkway, UK
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Eduardo Cinosi
- Department of Neuroscience Imaging and Clinical Sciences, Gabriele D’Annunzio University, Chieti, Italy
| | - Simon Davies
- Centre for Addiction and Mental Health, Geriatric Psychiatry Division, University of Toronto, Toronto, Canada
- School of Social and Community Medicine, Academic Unit of Psychiatry, University of Bristol, Bristol, UK
| | - Katharina Domschke
- Department of Psychiatry Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
| | - Naomi Fineberg
- Hertfordshire Partnership University NHS Foundation Trust and University of Hertfordshire, Parkway, UK
| | - Edna Grünblatt
- Department of Psychiatry Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
- Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Marek Jarema
- Third Department of Psychiatry, Institute of Psychiatry and Neurology, Warszawa, Poland
| | - Yong-Ku Kim
- Department of Psychiatry College of Medicine, Korea University, Seoul, Republic of Korea
| | - Eduard Maron
- Department of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia
- Department of Psychiatry, University of Tartu, Estonia
- Faculty of Medicine Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, UK
| | - Vasileios Masdrakis
- Athens University Medical School, First Department of Psychiatry, Eginition Hospital, Athens, Greece
| | - Olya Mikova
- Foundation Biological Psychiatry, Sofia, Bulgaria
| | - David Nutt
- Faculty of Medicine Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, UK
| | - Stefano Pallanti
- UC Davis Department of Psychiatry and Behavioural Sciences, Sacramento, CA, USA
| | - Stefano Pini
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Andreas Ströhle
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité – University Medica Center Berlin, Berlin, Germany
| | - Florence Thibaut
- Faculty of Medicine Paris Descartes, University Hospital Cochin, Paris, France
| | - Matilde M. Vaghix
- Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK
| | - Eunsoo Won
- Department of Psychiatry College of Medicine, Korea University, Seoul, Republic of Korea
| | - Dirk Wedekind
- Department of Psychiatry and Psychotherapy, University of Göttingen, Germany
| | - Adam Wichniak
- Third Department of Psychiatry, Institute of Psychiatry and Neurology, Warszawa, Poland
| | - Jade Woolley
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Peter Zwanzger
- kbo-Inn-Salzach-Klinikum Wasserburg am Inn, Germany
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany
| | - Peter Riederer
- Department of Psychiatry Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
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Dayan J, Rauchs G, Guillery-Girard B. Rhythms dysregulation: A new perspective for understanding PTSD? ACTA ACUST UNITED AC 2017; 110:453-460. [PMID: 28161453 DOI: 10.1016/j.jphysparis.2017.01.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 01/30/2017] [Indexed: 12/15/2022]
Abstract
Post-traumatic stress disorder (PTSD) is a complex syndrome that may occur after exposure to one or more traumatic events. It associates physiological, emotional, and cognitive changes Brain and hormonal modifications contribute to some impairments in learning, memory, and emotion regulation. Some of these biological dysfunctions may be analyzed in terms of rhythms dysregulation that would be expressed through endocrine rhythmicity, sleep organization, and temporal synchrony in brain activity. In the first part of this article, we report studies on endocrine rhythmicity revealing that some rhythms abnormalities are frequently observed, although not constantly, for both cortisol and sympathetic nervous system (SNS) activity. The most typical changes are a flattening of the diurnal secretion of cortisol and the hyperactivation of the SNS. These results may explain why cognitive functioning, in particular consolidation of emotional memories, attention, learning, vigilance and arousal, is altered in patients with PTSD. The second part of this article focuses on sleep disturbances, one of the core features of PTSD. Abnormal REM sleep reported in various studies may have a pathophysiological role in PTSD and may exacerbate some symptoms such as emotional regulation and memory. In addition, sleep disorders, such as paradoxical insomnia, increase the risk of developing PTSD. We also discuss the potential impact of sleep disturbances on cognition. Finally, temporal synchrony of brain activity and functional connectivity, explored using electroencephalography and functional magnetic resonance imaging, are addressed. Several studies reported abnormalities in alpha, beta and gamma frequency bands that may affect both attentional and memory processes. Other studies confirmed abnormalities in connectivity and recent fMRI data suggest that this could limit top-down control and may be associated with flashback intrusive memories. These data illustrate that a better knowledge of the different patterns of biological rhythms contributes to explain the heterogeneity of PTSD and shed new light on the association with some frequent medical disorders.
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Affiliation(s)
- Jacques Dayan
- Normandie Univ, UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen, Neuropsychologie et Imagerie de la Mémoire Humaine, 14000 Caen, France; CHGR Rennes-I, Pôle Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Rennes, France.
| | - Géraldine Rauchs
- Normandie Univ, UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen, Neuropsychologie et Imagerie de la Mémoire Humaine, 14000 Caen, France
| | - Bérengère Guillery-Girard
- Normandie Univ, UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen, Neuropsychologie et Imagerie de la Mémoire Humaine, 14000 Caen, France
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Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond. Neuropsychopharmacology 2017; 42:254-270. [PMID: 27510423 PMCID: PMC5143487 DOI: 10.1038/npp.2016.146] [Citation(s) in RCA: 476] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 07/01/2016] [Accepted: 07/12/2016] [Indexed: 02/07/2023]
Abstract
The study of inflammation in fear- and anxiety-based disorders has gained interest as growing literature indicates that pro-inflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear- and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear- and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.
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