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Mario A, Ivana L, Claudia MM, Antonello B, Francesco P, Tommaso C, Madia L. Can ketamine therapy overcome treatment-resistant depression in Alzheimer's disease and older adults? Preclinical and clinical evidence. Biomed Pharmacother 2025; 188:118199. [PMID: 40412361 DOI: 10.1016/j.biopha.2025.118199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 05/11/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025] Open
Abstract
Treatment-resistant depression (TRD) presents substantial clinical challenges, particularly in patients with Alzheimer's disease (AD) and older adults experiencing late-life depression. Traditional monoaminergic therapies often fail in this population due to neurodegenerative changes that impact receptor dynamics and neurotransmitter systems. Emerging evidence suggests that N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, esketamine, and arketamine, may offer new avenues for treatment. This review examines the potential of ketamine and its derivatives in treating TRD in older adults and individuals with AD, focusing on their mechanisms of action, clinical efficacy, and limitations in the context of neurodegenerative pathology. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we conducted a systematic search of PubMed, Google Scholar, and Web of Science databases up until January 2025, with no year restrictions. Nineteen human clinical studies and eight preclinical studies met the inclusion criteria. Evidence suggests that ketamine may offer advantages over standard treatments for AD, potentially due to its broader mechanism of action compared to the NMDA antagonist memantine, as observed in animal models of AD. Clinical findings have demonstrated the rapid and robust antidepressant effects of ketamine and esketamine, alleviating depressive symptoms in both AD patients and older adults with TRD, indicating their potential as effective therapeutic options for these complex conditions.
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Affiliation(s)
- Altamura Mario
- Department of Clinical & Experimental Medicine, University of Foggia, Foggia, Italy.
| | - Leccisotti Ivana
- Department of Clinical & Experimental Medicine, University of Foggia, Foggia, Italy
| | | | - Bellomo Antonello
- Department of Clinical & Experimental Medicine, University of Foggia, Foggia, Italy
| | - Panza Francesco
- Cesare Frugoni" Internal and Geriatric Medicine and Memory Unit, University of Bari "Aldo Moro", Bari, Italy
| | - Cassano Tommaso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Lozupone Madia
- Department of Translational Biomedicine and Neuroscience "DiBrain", University of Bari Aldo Moro, Bari, Italy
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Carrol D, Busse WW, Frye CJ, Klaus DR, Bach JC, Floerke H, Bendlin BB, Zetterberg H, Blennow K, Heslegrave A, Hoel R, Rosenkranz MA. Regional brain structural alterations in reward and salience networks in asthma. Brain Behav Immun 2025; 126:80-97. [PMID: 39921150 PMCID: PMC12003077 DOI: 10.1016/j.bbi.2025.01.028] [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: 08/18/2024] [Revised: 01/03/2025] [Accepted: 01/31/2025] [Indexed: 02/10/2025] Open
Abstract
INTRODUCTION Chronic systemic inflammation is highly prevalent and has deleterious effects on the brain, impacting both function and structure, and manifesting in elevations in psychological symptoms transdiagnostically. Asthma is a chronic inflammatory disease of the airway that affects more than 300 million people worldwide and is known to be highly comorbid with psychological and cognitive dysfunction. Though a growing corpus of work has identified functional brain abnormalities associated with asthma, limited research has investigated structural differences which may partially underlie functional changes. Identifying and characterizing asthma-related structural brain changes will shed light on the neurobiology through which asthma impacts mental function and has the potential to inform prophylaxis and treatment. METHODS We examined differences in regional brain volume, cortical thickness, and surface area, in 128 individuals with asthma compared to 134 non-asthma healthy controls. Five regions of interest were examined a priori, based on their previous implication in inflammation-related functional consequences (dorsal and ventral striatum, pallidum, and insula), or previous evidence of asthma-related structural impact (hippocampus and thalamus). We supplemented our region of interest approach with a voxel-wise whole-brain analysis. Additionally, we examined the association of brain structure with depression symptoms, asthma severity, degree of inflammation, and plasma biomarkers of neuroinflammation, neurodegeneration, and Alzheimer's disease specific pathology. RESULTS Compared to non-asthma control participants, those with asthma had smaller nucleus accumbens volumes, thicker orbitofrontal cortices, larger middle frontal cortex surface areas, and greater diencephalon volumes. Those with more severe asthma had smaller nucleus accumbens and dorsal striatal volumes, reduced anterior cingulate cortex surface area, and greater amygdala volume compared to those with mild asthma. In untreated asthma patients, greater depressive symptoms were associated with smaller striatal volume, suggesting a potential CNS-protective effect of medications that reduce airway inflammation in asthma. In addition, a plasma marker of astrogliosis was associated with larger diencephalon, cerebellum, brainstem, and thalamus volumes, but reduced insula thickness and surface area. CONCLUSIONS Patterns of structural brain changes in participants with asthma encompass key regions of reward and salience networks, which may in part give rise to the functional alterations in these networks characteristic of chronic systemic inflammation.
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Affiliation(s)
- Danielle Carrol
- Center for Healthy Minds, University of Wisconsin-Madison Madison WI USA
| | - William W Busse
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health Madison WI USA
| | - Corrina J Frye
- Wasiman Center, University of Wisconsin-Madison Madison WI USA
| | - Danika R Klaus
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health Madison WI USA
| | - Julia C Bach
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health Madison WI USA
| | - Heather Floerke
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health Madison WI USA
| | - Barbara B Bendlin
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison Madison WI USA
| | - Henrik Zetterberg
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison Madison WI USA; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital Mölndal Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square London UK; UK Dementia Research Institute at UCL London UK; Hong Kong Center for Neurodegenerative Diseases Clear Water Bay Hong Kong, China
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital Mölndal Sweden; Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University Paris France; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC Hefei China
| | - Amanda Heslegrave
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital Mölndal Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square London UK
| | - Rachel Hoel
- Center for Healthy Minds, University of Wisconsin-Madison Madison WI USA
| | - Melissa A Rosenkranz
- Center for Healthy Minds, University of Wisconsin-Madison Madison WI USA; Department of Psychiatry, University of Wisconsin-Madison, USA.
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Reneaux M, Mayberg H, Friston K, Pinotsis DA. A computational account of joint SSRI and anti-inflammatory treatment. Front Immunol 2025; 16:1472732. [PMID: 40352929 PMCID: PMC12061865 DOI: 10.3389/fimmu.2025.1472732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 04/01/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Depression is a chronic disorder that impacts millions worldwide. Traditional treatments may not always work. Inflammation seems to be an underlying cause for chronicity and treatment non-response. Methods We present a computational model that elucidates the interplay between inflammation, serotonin levels, and brain activity. Results The model delineates how inflammation impacts extracellular serotonin, while cerebral activity reciprocally influences serotonin concentration. Understanding the reciprocal interplay between the immune system and brain dynamics is important, as unabated inflammation can lead to relapsing depression. The model predicts dynamics within the prefrontal cortex (PFC) and subcallosal cingulate cortex (SCC), mirroring patterns observed in depressive conditions. It also accommodates pharmaceutical interventions that encompass anti-inflammatory and antidepressant agents, concurrently evaluating their efficacy with regard to the severity of depressive symptoms Our model shows that for mild and moderate levels of depression anti-depressant agents or anti-inflammatory agents acting in isolation can bring serotonergic levels and brain activity to control levels. However, for severe depression only joint treatment of anti-depressant and anti-inflammatory agents can bring the serotonergic levels and activity to control levels. Discussion This study is a first step to mechanistically understand the intricate link between the immune system and depression, the role of inflammation and potential treatments. It explores the impact of anti-depressant and anti-inflammatory drug treatments and assesses their relevance with regard to depression severity.
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Affiliation(s)
- Melissa Reneaux
- Centre for Mathematical Neuroscience and Psychology and Department of Psychology, City St. George’s —University of London, London, United Kingdom
- Psychology and Behavior Program, School of Liberal Studies and Media, UPES, Dehradun, India
| | - Helen Mayberg
- Department of Neurology and Neurosurgery, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
| | - Karl Friston
- Wellcome Centre for Human Neuroimaging, University College London (UCL), London, United Kingdom
| | - Dimitris A. Pinotsis
- Centre for Mathematical Neuroscience and Psychology and Department of Psychology, City St. George’s —University of London, London, United Kingdom
- The Picower Institute for Learning & Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
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Zhou N, Shi X, Wang R, Wang C, Lan X, Liu G, Li W, Zhou Y, Ning Y. Proteomic patterns associated with ketamine response in major depressive disorders. Cell Biol Toxicol 2025; 41:26. [PMID: 39792340 PMCID: PMC11723896 DOI: 10.1007/s10565-024-09981-3] [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: 08/05/2024] [Accepted: 12/21/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Major depressive disorder (MDD) is characterized by persistent feelings of sadness and loss of interest. Ketamine has been widely used to treat MDD owing to its rapid effect in relieving depressive symptoms. Importantly, not all patients respond to ketamine treatment. Identifying sub-populations who will benefit from ketamine, as well as those who may not, prior to treatment initiation, would significantly advance precision medicine in patients with MDD. METHODS Here, we used mass spectrometry-based plasma proteomics to analyze matched pre- and post-ketamine treatment samples from a cohort of 30 MDD patients whose treatment outcomes and demographic and clinical characteristics were considered. RESULTS Ketamine responders and non-responders were identified according to their individual outcomes after two weeks of treatment. We analyzed proteomic alterations in post-treatment samples from responders and non-responders and identified a collection of six proteins pivotal to the antidepressive effect of ketamine. Subsequent co-regulation analysis revealed that pathways related to immune response were involved in ketamine response. By comparing the proteomic profiles of samples from the same individuals at the pre- and post-treatment time points, dynamic proteomic rearrangements induced by ketamine revealed that immune-related processes were activated in association with its antidepressive effect. Furthermore, receiver operating characteristic curve analysis of pre-treatment samples revealed three proteins with strong predictive performance in determining the response of patients to ketamine before receiving treatment. CONCLUSIONS These findings provide valuable knowledge about ketamine response, which will ultimately lead to more personalized and effective treatments for patients. TRIAL REGISTRATION The study was registered in the Chinese Clinical Trials Registry (ChiCTR-OOC-17012239) on May 26, 2017.
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Affiliation(s)
- Nan Zhou
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Xiaolei Shi
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Runhua Wang
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Chengyu Wang
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Xiaofeng Lan
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Guanxi Liu
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Weicheng Li
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China
| | - Yanling Zhou
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China.
| | - Yuping Ning
- Research Institute, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370, China.
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, 510000, China.
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Kas MJH, Hyman S, Williams LM, Hidalgo-Mazzei D, Huys QJM, Hotopf M, Cuthbert B, Lewis CM, De Picker LJ, Lalousis PA, Etkin A, Modinos G, Marston HM. Towards a consensus roadmap for a new diagnostic framework for mental disorders. Eur Neuropsychopharmacol 2025; 90:16-27. [PMID: 39341044 DOI: 10.1016/j.euroneuro.2024.08.515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024]
Abstract
Current nosology claims to separate mental disorders into distinct categories that do not overlap with each other. This nosological separation is not based on underlying pathophysiology but on convention-based clustering of qualitative symptoms of disorders which are typically measured subjectively. Yet, clinical heterogeneity and diagnostic overlap in disease symptoms and dimensions within and across different diagnostic categories of mental disorders is huge. While diagnostic categories provide the basis for general clinical management, they do not describe the underlying neurobiology that gives rise to individual symptomatic presentations. The ability to incorporate neurobiology into the diagnostic framework and to stratify patients accordingly will be a critical step forward for the development of new treatments for mental disorders. Furthermore, it will also allow physicians to provide patients with a better understanding of their illness's complexities and management. To realize this ambition, a paradigm shift is needed to build an understanding of how neuropsychiatric conditions can be defined more precisely using quantitative (multimodal) biological processes and markers and thus to significantly improve treatment success. The ECNP New Frontiers Meeting 2024 set out to develop a consensus roadmap for building a new diagnostic framework for mental disorders by discussing its rationale, outlook, and consequences with all stakeholders involved. This framework would instantiate a set of principles and procedures by which research could continuously improve precision diagnostics while moving away from traditional nosology. In this meeting report, the speakers' summaries from their presentations are combined to address three key elements for generating such a roadmap, namely, the application of innovative technologies, understanding the biology of mental illness, and translating biological understanding into new approaches. In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time.
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Affiliation(s)
- Martien J H Kas
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands.
| | - Steven Hyman
- Harvard University and Stanley Center, Broad Institute of MIT and Harvard, USA
| | - Leanne M Williams
- Stanford Center for Precision Mental Health and Wellness, Psychiatry and Behavioral Sciences, Stanford University, Stanford, USA
| | - Diego Hidalgo-Mazzei
- Bipolar and Depressive disorders unit, Department of Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Quentin J M Huys
- Applied Computational Psychiatry Lab, Mental Health Neuroscience Department, Division of Psychiatry and Max Planck Centre for Computational Psychiatry and Ageing Research, Queen Square Institute of Neurology, University College London, UK; Camden and Islington NHS Foundation Trust, London, UK
| | - Matthew Hotopf
- Department of Psychological Medicine, Institute of Psychiatry Psychology & Neuroscience, King's College London, London2, United Kingdom
| | - Bruce Cuthbert
- Contractor for the Research Domain Criteria project, National Institute of Mental Health (NIMH), USA
| | - Cathryn M Lewis
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK
| | - Livia J De Picker
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium; SINAPS, University Psychiatric Hospital Duffel, Belgium
| | - Paris A Lalousis
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Section for Precision Psychiatry, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University of Munich, Munich, Germany
| | - Amit Etkin
- Alto Neuroscience Inc, Los Altos, CA, USA; Stanford University, Stanford, CA, USA
| | - Gemma Modinos
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Hugh M Marston
- CNS Discovery Research, Boehringer Ingelheim Pharma GmbH, Biberach, Germany
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Scassellati C, Cattane N, Benedetti F, Borsello T, Cicala G, Gennarelli M, Genini P, Gialluisi A, Giani A, Iacoviello L, Minelli A, Spina E, Vai B, Vitali E, Cattaneo A. Inflammation and depression: A study protocol to dissect pathogenetic mechanisms in the onset, comorbidity and treatment response. Brain Behav Immun Health 2024; 42:100886. [PMID: 39583163 PMCID: PMC11582470 DOI: 10.1016/j.bbih.2024.100886] [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: 06/19/2024] [Revised: 10/02/2024] [Accepted: 10/05/2024] [Indexed: 11/26/2024] Open
Abstract
About one third of patients suffering from Major Depressive Disorder (MDD) do not respond to any antidepressant medications and 75% experience relapses and general health deterioration. Importantly, inflammation can contribute to such negative outcomes, as well as to cause depression in patients who have been exposed to adverse childhood experiences and/or to viral infections, including COVID-19. Depressed patients also have an increased risk for developing comorbidities, such as cardio-metabolic dysfunctions, where inflammatory alterations, again, play a role in connecting MDD and these comorbid conditions. Here, we present our study protocol funded by the Italian Ministry of Health in the context of the PNRR call (M6/C2_CALL 2022; Project code: PNRR-MAD-2022-12375859). The project aims to clarify the role of inflammation: i) in the onset of depression in association with environmental factors; ii) in the mechanisms associated with treatment response/resistance; iii) in depression and its comorbidity. To reach all these aims, we will perform biochemical, transcriptomic, genetic variants analyses on inflammatory/immune genes, pharmacokinetics and machine learning techniques, taking advantage of different human cohorts (adolescent depressed patients exposed to childhood trauma; adult depressed patients; treatment resistant depression patients; both prevalent and incident depression cases identified within a large population cohort). Moreover, we will use in vitro models (primary cultures of astrocytes, neurons and microglia) treated with pro-inflammatory or stressful challenges and preventive compounds to clarify the underlying mechanisms. This 2-years project will increase the knowledge on the role of inflammation in the prevention and treatment of MDD and in comorbid disorders, and it will also provide experimental evidence for the development of novel targets and tools for innovative personalized intervention strategies.
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Affiliation(s)
- Catia Scassellati
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Nadia Cattane
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Francesco Benedetti
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Tiziana Borsello
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
- Mario Negri Institute for Pharmacological Research - IRCCS, Milan, Italy
| | - Giuseppe Cicala
- Department of Clinical and Experimental Medicine, University of Messina, 98125, Messina, Italy
| | - Massimo Gennarelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Patrizia Genini
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Alessandro Gialluisi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Pozzilli, Italy
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Arianna Giani
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
- Mario Negri Institute for Pharmacological Research - IRCCS, Milan, Italy
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Pozzilli, Italy
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Alessandra Minelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Edoardo Spina
- Department of Clinical and Experimental Medicine, University of Messina, 98125, Messina, Italy
| | - Benedetta Vai
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Erika Vitali
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Annamaria Cattaneo
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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Uslu EY, Yildiz S. Is Serum VEGF-A Level an Indicator of Early-Onset Poststroke Depression? MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1828. [PMID: 39597013 PMCID: PMC11596109 DOI: 10.3390/medicina60111828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024]
Abstract
Background and Objectives: Poststroke depression (PSD) is a psychiatric complication occurring after a stroke, and is known to negatively impact quality of life. In the present study, the possible relationship between serum vascular endothelial growth factor (VEGF-A) levels and early-onset PSD, as well as the predictive value of serum VEGF-A levels for early-onset PSD, were investigated. Materials and Methods: The study included 88 individuals diagnosed with acute ischemic stroke (AIS). Demographic data, clinical characteristics, and serum VEGF-A levels were recorded, and radiological images were examined to determine the lesion locations. The National Institutes of Health Stroke Scale (NIHSS), Montreal Cognitive Assessment (MoCA), and Hamilton depression scale (HAMD-17) were administered to the patients. Furthermore, serum VEGF-A levels were measured in all participants. Results: Although the body mass index (BMI) and VEGF-A levels were similar between the groups, MoCA scores were lower [(19.2 ± 4.4) vs. (22.3 ± 3), p = 0.001] and NIHSS scores were higher [18 (8-28) vs. 14 (3-24), p = 0.006] in individuals with PSD than in those without it. When the patients with PSD were categorized into three groups, patients with severe PSD had higher NIHSS scores [26 (23-27) vs. 15 (8-23), p = 0.006] and lower MoCA scores [(14.3 ± 1) vs. (20.9 ± 3.8), p = 0.005] than those with mild PSD. Moreover, VEGF-A levels and lesion localization were similar between mild, moderate, and severe PSD groups (p = 0.130). The MoCA score was negatively (r = -0.498, p < 0.001) correlated and the NIHSS score was positively correlated (r = 0.497, p < 0.001) with the HAMD-17 score. Conclusions: Our findings suggest that longitudinal studies in large cohorts including healthy control groups are needed to examine the possibility of using serum VEGF-A level as a marker for predicting early-onset PSD.
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Affiliation(s)
- Emine Yildirim Uslu
- Department of Physical Medicine and Rehabilitation, Elazığ Fethi Sekin City Hospital, Elazığ 23280, Turkey;
| | - Sevler Yildiz
- Department of Psychiatry, Elazığ Fethi Sekin City Hospital, Elazığ 23280, Turkey
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Wessa C, Janssens J, Coppens V, El Abdellati K, Vergaelen E, van den Ameele S, Baeken C, Zeeuws D, Milaneschi Y, Lamers F, Penninx B, Claes S, Morrens M, De Picker L. Efficacy of inflammation-based stratification for add-on celecoxib or minocycline in major depressive disorder: Protocol of the INSTA-MD double-blind placebo-controlled randomised clinical trial. Brain Behav Immun Health 2024; 41:100871. [PMID: 39350954 PMCID: PMC11440344 DOI: 10.1016/j.bbih.2024.100871] [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: 07/21/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 10/04/2024] Open
Abstract
Introduction Different lines of evidence confirm the involvement of the immune system in the pathophysiology of major depressive disorder. Up to 30% of depressed patients present with an immune-mediated subtype, characterized by peripheral inflammation (high-sensitive C-reactive protein (hsCRP) ≥ 3 mg/l) and an atypical symptom profile with fatigue, anhedonia, increased appetite, and hypersomnia. This immune-mediated subtype of MDD is associated with poorer response to first-line antidepressant treatment. Consequently, strategies for immune-targeted augmentation should be prioritised towards patients with this subtype. Meta-analyses have shown modest but heterogeneous treatment effects with immune-targeted augmentation in unstratified MDD cohorts, with celecoxib and minocycline as most promising first-line treatment options. However, no study has prospectively evaluated the effectiveness of a priori stratification by baseline inflammation levels for add-on celecoxib or minocycline in MDD. Methods The INSTA-MD trial is a multicentre, 12-week, randomised, double-blind, placebo-controlled, parallel-group stratified clinical trial of adjunctive minocycline or celecoxib to treatment-as-usual for patients with MDD. Two hundred forty adult patients with Major Depressive Disorder who failed to remit with one or two trials of antidepressant treatment will be enrolled and allocated to high-hsCRP (hsCRP ≥3 mg/L) or low-hsCRP (hsCRP <3 mg/L) strata, where disproportional stratified sampling will ensure equally sized strata. Participants in each hsCRP stratum will be randomised to augment their ongoing antidepressant treatment with either adjunctive minocycline, celecoxib or placebo for a duration of 12 weeks, resulting in six treatment arms of each 40 participants. The primary objective is to evaluate the efficacy of immune-targeted augmentation with minocycline or celecoxib versus placebo, and the use of baseline hsCRP stratification to predict treatment response. Additionally, we will perform a head-to-head analysis between the two active compounds. The primary outcome measure is change in the Hamilton Depression Rating Scale (HDRS-17) total score. Secondary outcome measures will be response and remission rates, and change in inflammation-specific symptoms, adverse events and therapy acceptability (adherence). Further exploratory analyses will be performed with an array of peripheral inflammatory biomarkers, metabolic outcomes and physiological data. Expected impact The aim of INSTA-MD is to advance the use of immune-targeted precision psychiatry, by supporting the implementation of targeted hsCRP screening and treatment of immune-mediated MDD as a cost-effective intervention in primary care settings. Based on previous studies, we expect immune-targeted augmentation with minocycline or celecoxib to yield a superior remission rate of 15-30% compared to treatment as usual for immune-mediated cases of MDD. By treating immune-related depression early in the treatment algorithm with repurposed first-line anti-inflammatory treatments, we can significantly improve the outcomes of these patients, and reduce the global societal and economic burden of depression. Ethics and dissemination This protocol has been approved by the Medical Ethics Review Board (CTR - 04/08/2023). Registration details Trial registration number NCT05644301 (Clinical trial.gov), EU-CT 2022-501692-35-00.
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Affiliation(s)
- C Wessa
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
- Scientific Initiative for Neuropsychiatric and Psychopharmacological Studies, University Psychiatric Centre Duffel, Belgium
| | - J Janssens
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
| | - V Coppens
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
- Scientific Initiative for Neuropsychiatric and Psychopharmacological Studies, University Psychiatric Centre Duffel, Belgium
| | - K El Abdellati
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
| | - E Vergaelen
- Catholic University Leuven, Belgium
- University Psychiatric Centre KU Leuven, Belgium
| | - S van den Ameele
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
- UVC Brugmann, Brussels, Belgium
| | - C Baeken
- Department of Psychiatry, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Faculty of Medicine and Health Sciences, Department of Head and Skin, Ghent Experimental Psychiatry (GHEP) lab, Ghent University, Ghent, Belgium
- Eindhoven University of Technology, Department of Electrical Engineering, Eindhoven, the Netherlands
| | - D Zeeuws
- Department of Psychiatry, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Y Milaneschi
- Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
| | - F Lamers
- Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
| | - B Penninx
- Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
| | - S Claes
- Catholic University Leuven, Belgium
- University Psychiatric Centre KU Leuven, Belgium
| | - M Morrens
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
- Scientific Initiative for Neuropsychiatric and Psychopharmacological Studies, University Psychiatric Centre Duffel, Belgium
| | - L De Picker
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium
- Scientific Initiative for Neuropsychiatric and Psychopharmacological Studies, University Psychiatric Centre Duffel, Belgium
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Métivier L, Vivien D, Goy R, Agin V, Bui E, Benbrika S. Plasminogen Activator Inhibitor-1 in the Pathophysiology of Late Life Depression. Int J Geriatr Psychiatry 2024; 39:e70015. [PMID: 39578639 DOI: 10.1002/gps.70015] [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: 05/16/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024]
Abstract
INTRODUCTION Late life depression (LLD) is characterized by specific clinical features including a high frequency of vascular form and frequent antidepressant treatment resistance. The expression and functions of the serine protease inhibitor, Plasminogen Activator Inhibitor-1 (PAI-1) is known to be altered by aging, vascular damage, insulin levels associated with a sedentary lifestyle, chronic stress leading to hypercortisolemia, and inflammatory changes linked to stress responses. These phenomena would be implicated in LLD like vascular depression. This article thus aims to review the existing literature regarding the association between LLD and plasmatic levels of PAI-1, a marker of hypofibrinolysis. We hypothesize that increased age would be associated with changes in PAI-1 plasma level and function which influence LLD pathogenesis and its treatment. RESULTS Although a large number of studies on PAI-1 changes in the elderly exist, studies about its implications in LLD are sparse. Despite heterogeneous findings regarding the direction of variation in plasmatic PAI-1 levels among elderly participants with LLD, all studies demonstrated an association between PAI-1 levels and current or remitted depressive symptoms. Moreover, disruptions in the concentrations of other biological markers influencing PAI-1 expression, such as cytokines or adipokines, were also observed, notably an increase in the levels of interleukins 6 and 8. DISCUSSION LLD genesis appears to be influenced by PAI-1 regulatory loops which are implicated in senescence or cell death. The resistance to antidepressant treatment appears to be linked to distinct biological profiles involving inflammatory and fibrinolytic factors. Taken together these data suggest that PAI-1 pathway may be a promising target of treatment development efforts for LLD, and depression in general.
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Affiliation(s)
- L Métivier
- INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, Caen, France
- Fédération Hospitalo-Universitaire (FHU A2M2P), GIP Cyceron, Normandie Univ, UNICAEN, Caen, France
| | - D Vivien
- INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, Caen, France
- Fédération Hospitalo-Universitaire (FHU A2M2P), GIP Cyceron, Normandie Univ, UNICAEN, Caen, France
- Department of Clinical Research, Caen-Normandie University Hospital, Caen, France
| | - R Goy
- INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, Caen, France
- Fédération Hospitalo-Universitaire (FHU A2M2P), GIP Cyceron, Normandie Univ, UNICAEN, Caen, France
| | - V Agin
- INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, Caen, France
- Fédération Hospitalo-Universitaire (FHU A2M2P), GIP Cyceron, Normandie Univ, UNICAEN, Caen, France
- Department of Clinical Research, Caen-Normandie University Hospital, Caen, France
| | - E Bui
- INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, Caen, France
- Fédération Hospitalo-Universitaire (FHU A2M2P), GIP Cyceron, Normandie Univ, UNICAEN, Caen, France
- Department of Clinical Research, Caen-Normandie University Hospital, Caen, France
- CHU de CAEN Normandie, Service de Psychiatrie, Centre Esquirol, Caen, France
| | - S Benbrika
- INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, Caen, France
- Fédération Hospitalo-Universitaire (FHU A2M2P), GIP Cyceron, Normandie Univ, UNICAEN, Caen, France
- Department of Clinical Research, Caen-Normandie University Hospital, Caen, France
- CHU de CAEN Normandie, Service de Psychiatrie, Centre Esquirol, Caen, France
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Wang J, Behl T, Rana T, Sehgal A, Wal P, Saxena B, Yadav S, Mohan S, Anwer MK, Chigurupati S, Zaheer I, Shen B, Singla RK. Exploring the pathophysiological influence of heme oxygenase-1 on neuroinflammation and depression: A study of phytotherapeutic-based modulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 127:155466. [PMID: 38461764 DOI: 10.1016/j.phymed.2024.155466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/02/2024] [Accepted: 02/18/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND The heme oxygenase (HO) system plays a significant role in neuroprotection and reduction of neuroinflammation and neurodegeneration. The system, via isoforms HO-1 and HO-2, regulates cellular redox balance. HO-1, an antioxidant defense enzyme, is highlighted due to its association with depression, characterized by heightened neuroinflammation and impaired oxidative stress responses. METHODOLOGY We observed the pathophysiology of HO-1 and phytochemicals as its modulator. We explored Science Direct, Scopus, and PubMed for a comprehensive literature review. Bibliometric and temporal trend analysis were done using VOSviewer. RESULTS Several phytochemicals can potentially alleviate neuroinflammation and oxidative stress-induced depressive symptoms. These effects result from inhibiting the MAPK and NK-κB pathways - both implicated in the overproduction of pro-inflammatory factors - and from the upregulation of HO-1 expression mediated by Nrf2. Bibliometric and temporal trend analysis further validates these associations. CONCLUSION In summary, our findings suggest that antidepressant agents can mitigate neuroinflammation and depressive disorder pathogenesis via the upregulation of HO-1 expression. These agents suppress pro-inflammatory mediators and depressive-like symptoms, demonstrating that HO-1 plays a significant role in the neuroinflammatory process and the development of depression.
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Affiliation(s)
- Jiao Wang
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; Department of Computer Science and Information Technology, University of A Coruña, A Coruña, Spain
| | - Tapan Behl
- Amity School of Pharmaceutical Sciences, Amity University, Mohali, Punjab, India.
| | - Tarapati Rana
- Chitkara College of Pharmacy, Chitkara University, Rajpura-140401, Punjab, India; Government Pharmacy College, Seraj-175123, Mandi, Himachal Pradesh, India
| | - Aayush Sehgal
- GHG Khalsa College of Pharmacy, Gurusar Sadhar-141104, Ludhiana, Punjab, India
| | - Pranay Wal
- Pranveer Singh Institute of Technology, Pharmacy, Kanpur, Uttar Pradesh, India
| | - Bhagawati Saxena
- Department of Pharmacology, Institute of Pharmacy, Nirma University, S.G. Highway, Ahmedabad, 382481, India
| | - Shivam Yadav
- School of Pharmacy, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India
| | - Syam Mohan
- Substance Abuse and Toxicology Research Center, Jazan University, Jazan 45142, Saudi Arabia; School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, 248007, Uttarakhand, India; Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj-11942, Saudi Arabia
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah-51452, Kingdom of Saudi Arabia; Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Saveetha Nagar, Thandalam, Chennai-602105, India
| | - Imran Zaheer
- Department of Pharmacology, College of Medicine, (Al-Dawadmi Campus), Shaqra University, Al-Dawadmi, 11961, Kingdom of Saudi Arabia
| | - Bairong Shen
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
| | - Rajeev K Singla
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab-144411, India.
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Zheng XX, Zhang CF, Li LQ, Ye JR, Ren SY, Zhang Z, He X, Chu SF, Chen NH. Improvement of astrocytic gap junction involves the anti-depressive effect of celecoxib through inhibition of NF-κB. Brain Res Bull 2024; 207:110871. [PMID: 38211740 DOI: 10.1016/j.brainresbull.2024.110871] [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: 04/28/2023] [Revised: 12/25/2023] [Accepted: 01/04/2024] [Indexed: 01/13/2024]
Abstract
CONTEXT Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has been shown to exhibit anti-depressive effects in clinical trials. However, the direct mechanism underlying its effect on neuroinflammation remains unclear. Neuroinflammatory reaction from astrocytes leads to depression, and our previous study found that gap junction disorder between astrocytes aggravated neuroinflammatory reaction in depressed mice. OBJECTIVE To investigate the potential mechanism of celecoxib's effects on astrocytic gap junctions during the central nervous inflammation-induced depression. MATERIALS & METHODS Stereotaxic injection of lipopolysaccharide (LPS) into the prefrontal cortex (PFC) to establish a model of major depressive disorder (MDD). Celecoxib was administrated into PFC 15 min after LPS injection. The depressive performance was tested by tail suspension test and forced swimming test, and the levels of proinflammation cytokines were determined at mRNA and protein levels. Resting-state functional connection (rsFC) was employed to assess changes in the default mode network (DMN). Additionally, astrocytic gap junctions were also determined by lucifer yellow (LY) diffusion and transmission electron microscope (TEM), and the expression of connexin 43 (Cx43) was measured by western blotting, quantitative polymerase chain reaction, and immunofluorescence. RESULTS LPS injection induced significant depressive performance, which was ameliorated by celecoxib treatment. Celecoxib also improved rsFC in the DMN. Furthermore, celecoxib improved astrocytic gap junctions as evidenced by increased LY diffusion, shortened gap junction width, and normalized levels of phosphorylated Cx43. Celecoxib also blocked the phosphorylation of p65, and inhibition of p65 abolished the improvement of Cx43. DISCUSSION & CONCLUSION Anti-depressive effects of celecoxib are mediated, at least in part, by the inhibition of nuclear factor- kappa B (NF-κB) and the subsequent improvement of astrocytic gap junction function.
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Affiliation(s)
- Xiao-Xi Zheng
- School of traditional Chinese Medicine, GuangDong Pharmaceutical University, GuangZhou 510006, China
| | - Cheng-Feng Zhang
- School of traditional Chinese Medicine, GuangDong Pharmaceutical University, GuangZhou 510006, China
| | - Li-Qing Li
- School of traditional Chinese Medicine, GuangDong Pharmaceutical University, GuangZhou 510006, China
| | - Jun-Rui Ye
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Si-Yu Ren
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Zhao Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Xin He
- School of traditional Chinese Medicine, GuangDong Pharmaceutical University, GuangZhou 510006, China
| | - Shi-Feng Chu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Nai-Hong Chen
- School of traditional Chinese Medicine, GuangDong Pharmaceutical University, GuangZhou 510006, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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Xi L, Fang F, Zhou J, Xu P, Zhang Y, Zhu P, Tu J, Sun Q. Association of hemoglobin-to-red blood cell distribution width ratio and depression in older adults: A cross sectional study. J Affect Disord 2024; 344:191-197. [PMID: 37832737 DOI: 10.1016/j.jad.2023.10.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 09/05/2023] [Accepted: 10/08/2023] [Indexed: 10/15/2023]
Abstract
BACKGROUND The association between hemoglobin-to-red blood cell distribution width ratio (HRR) and the depression in old adults was not clear. METHODS We extracted data on depression, general characteristics, lifestyle, medical history, drug use, and blood indicators from the National Health and Nutrition Examination Survey 2005-2018 to investigate the relationship between HRR and depression. RESULTS A total of 4141 individuals were evaluated, among whom 266 (6.4 %) were identified as having depression. HRR was significantly lower in the low depression group, and Spearman correlation analysis revealed an inverse association between HRR and depression scores (r = -0.148, P < 0.001). Multiple linear regression showed that HRR was associated with depression after adjusted for general characteristics, life style, medical history, drug use and blood indicators (P = 0.010). ROC analysis demonstrated that in participants with depression, the area under the curve (AUC) for HRR was 0.612, surpassing both Hb(0.586) and RDW(0.401). These findings were statistically significant (P < 0.05). LIMITATIONS Only participants aged 65-79 years are selected for this study and this was a cross-sectional study that can only represent an association between HRR and depression, but not a cause-and-effect relationship. CONCLUSIONS HRR, being more potent than Hb or RDW, emerges as an independent risk factor for depression. It has the potential to facilitate early depression detection, aiding in the prevention of clinical deterioration or relapses, and could also serve as a viable treatment target.
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Affiliation(s)
- Lijuan Xi
- Yangzhou University School of Nursing School of Public Health, Yangzhou, Jiangsu, China.
| | - Fang Fang
- Subei People's Hospital, Yangzhou, Jiangsu, China
| | - Jiajie Zhou
- Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Peirong Xu
- Yangzhou University School of Nursing School of Public Health, Yangzhou, Jiangsu, China
| | - Yan Zhang
- Yangzhou University School of Nursing School of Public Health, Yangzhou, Jiangsu, China
| | - Pingting Zhu
- Yangzhou University School of Nursing School of Public Health, Yangzhou, Jiangsu, China
| | - Jiayuan Tu
- Yangzhou University School of Nursing School of Public Health, Yangzhou, Jiangsu, China
| | - Qiannan Sun
- Subei People's Hospital, Yangzhou, Jiangsu, China
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Jitte S, Keluth S, Bisht P, Wal P, Singh S, Murti K, Kumar N. Obesity and Depression: Common Link and Possible Targets. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:1425-1449. [PMID: 38747226 DOI: 10.2174/0118715273291985240430074053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/15/2024] [Accepted: 03/27/2024] [Indexed: 10/22/2024]
Abstract
Depression is among the main causes of disability, and its protracted manifestations could make it even harder to treat metabolic diseases. Obesity is linked to episodes of depression, which is closely correlated to abdominal adiposity and impaired food quality. The present review is aimed at studying possible links between obesity and depression along with targets to disrupt it. Research output in Pubmed and Scopus were referred for writing this manuscript. Obesity and depression are related, with the greater propensity of depressed people to gain weight, resulting in poor dietary decisions and a sedentary lifestyle. Adipokines, which include adiponectin, resistin, and leptin are secretory products of the adipose tissue. These adipokines are now being studied to learn more about the connection underlying obesity and depression. Ghrelin, a gut hormone, controls both obesity and depression. Additionally, elevated ghrelin levels result in anxiolytic and antidepressant-like effects. The gut microbiota influences the metabolic functionalities of a person, like caloric processing from indigestible nutritional compounds and storage in fatty tissue, that exposes an individual to obesity, and gut microorganisms might connect to the CNS through interconnecting pathways, including neurological, endocrine, and immunological signalling systems. The alteration of brain activity caused by gut bacteria has been related to depressive episodes. Monoamines, including dopamine, serotonin, and norepinephrine, have been widely believed to have a function in emotions and appetite control. Emotional signals stimulate arcuate neurons in the hypothalamus that are directly implicated in mood regulation and eating. The peptide hormone GLP-1(glucagon-like peptide- 1) seems to have a beneficial role as a medical regulator of defective neuroinflammation, neurogenesis, synaptic dysfunction, and neurotransmitter secretion discrepancy in the depressive brain. The gut microbiota might have its action in mood and cognition regulation, in addition to its traditional involvement in GI function regulation. This review addressed the concept that obesity-related low-grade mild inflammation in the brain contributes to chronic depression and cognitive impairments.
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Affiliation(s)
- Srikanth Jitte
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali 844102, Bihar, India
| | - Saritha Keluth
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali 844102, Bihar, India
| | - Priya Bisht
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali 844102, Bihar, India
| | - Pranay Wal
- PSIT- Pranveer Singh Institute of Technology, Pharmacy, Kanpur 209305, Uttar Pradesh, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali 844102, Bihar, India
| | - Krishna Murti
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali 844102, Bihar, India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali 844102, Bihar, India
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Shi Q, Ding J, Su H, Du Y, Pan T, Zhong X. Association of Long-Term HbA1c Variability with Anxiety and Depression in Patients with Type 2 Diabetes: A Cross-Sectional Retrospective Study. Psychol Res Behav Manag 2023; 16:5053-5068. [PMID: 38144235 PMCID: PMC10747221 DOI: 10.2147/prbm.s441058] [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: 10/14/2023] [Accepted: 12/07/2023] [Indexed: 12/26/2023] Open
Abstract
Purpose To explore the relationship between long-term glycemic variability and anxiety and depression in patients with type 2 diabetes. Participants and Methods A cohort comprising 214 individuals diagnosed with type 2 diabetes participated in this study. Comprehensive demographic and laboratory information was gathered for them. The evaluation of anxiety relied on the 7-item Generalized Anxiety Disorder Scale (GAD-7), while depression was assessed utilizing the 9-item Health Questionnaire (PHQ-9). Based on the presence or absence of anxiety and depression, participants were categorized into either the mood disorder or control groups. Subsequently, univariate and stepwise multiple binary logistic regression analyses were conducted to investigate the potential correlations between factors and the presence of anxiety and depression. Results The prevalence of anxiety disorders is 23%, and depression is 32%. The prevalence of smoking, diabetic autonomic neuropathy, stroke, and osteoporosis in the mood disorder group was significantly higher than that in the control group (P < 0.05), the glycated hemoglobin A1c variability score (HVS), mean hemoglobin A1c value, total cholesterol, urinary albumin/creatinine and systemic immune-inflammatory index (SII) were significantly higher in the control group (P < 0.05). The level of high-density lipoprotein in the mood disorder group was significantly lower than the control group (P < 0.05). In stepwise multiple binary logistic regression analyses, the main factors associated with anxiety were depression (P < 0.001, OR=117.581) and gender (P < 0.001, OR=9.466), and the main factors related to depression included anxiety (P < 0.001, OR=49.424), smoking (P=0.042, OR=2.728), HVS (P=0.004, OR=8.664), and SII (P=0.014, OR=1.002). Conclusion Persistent fluctuations in blood glucose levels have been linked to anxiety and depression. Consequently, maintaining an optimal level of glycemic control and minimizing fluctuations becomes imperative in the comprehensive management of diabetes.
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Affiliation(s)
- Qian Shi
- Department of Endocrinology, the Second Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230601, People’s Republic of China
| | - Jingcheng Ding
- Department of Endocrinology, the Second Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230601, People’s Republic of China
| | - Hong Su
- Department of Epidemiology and Health Statistics, Anhui Medical University, Hefei City, Anhui Province, 230601, People’s Republic of China
| | - Yijun Du
- Department of Endocrinology, the Second Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230601, People’s Republic of China
| | - Tianrong Pan
- Department of Endocrinology, the Second Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230601, People’s Republic of China
| | - Xing Zhong
- Department of Endocrinology, the Second Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230601, People’s Republic of China
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Zhou YM, Yuan JJ, Xu YQ, Gou YH, Zhu YYX, Chen C, Huang XX, Ma XM, Pi M, Yang ZX. Fecal microbiota as a predictor of acupuncture responses in patients with postpartum depressive disorder. Front Cell Infect Microbiol 2023; 13:1228940. [PMID: 38053532 PMCID: PMC10694210 DOI: 10.3389/fcimb.2023.1228940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 10/31/2023] [Indexed: 12/07/2023] Open
Abstract
Background There are several clinical and molecular predictors of responses to antidepressant therapy. However, these markers are either too subjective or complex for clinical use. The gut microbiota could provide an easily accessible set of biomarkers to predict therapeutic efficacy, but its value in predicting therapy responses to acupuncture in patients with depression is unknown. Here we analyzed the predictive value of the gut microbiota in patients with postpartum depressive disorder (PPD) treated with acupuncture. Methods Seventy-nine PPD patients were enrolled: 55 were treated with acupuncture and 24 did not received any treatment. The 17-item Hamilton depression rating scale (HAMD-17) was used to assess patients at baseline and after eight weeks. Patients receiving acupuncture treatment were divided into an acupuncture-responsive group or non-responsive group according to HAMD-17 scores changes. Baseline fecal samples were obtained from the patients receiving acupuncture and were analyzed by high-throughput 16S ribosomal RNA sequencing to characterize the gut microbiome. Results 47.27% patients responded to acupuncture treatment and 12.5% patients with no treatment recovered after 8-week follow-up. There was no significant difference in α-diversity between responders and non-responders. The β-diversity of non-responders was significantly higher than responders. Paraprevotella and Desulfovibrio spp. were significantly enriched in acupuncture responders, and these organisms had an area under the curve of 0.76 and 0.66 for predicting responder patients, respectively. Conclusions Paraprevotella and Desulfovibrioare may be useful predictive biomarkers to predict PPD patients likely to respond to acupuncture. Larger studies and validation in independent cohorts are now needed to validate our findings.
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Affiliation(s)
- Yu-Mei Zhou
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jin-Jun Yuan
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Yu-Qin Xu
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Yan-Hua Gou
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Yannas Y. X. Zhu
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Chen Chen
- Department of Acupuncture and Tuina, Shenzhen Maternal and Child Health Care Hospital, Shenzhen, China
| | - Xing-Xian Huang
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Xiao-Ming Ma
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Min- Pi
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Zhuo-Xin Yang
- Department of Acupuncture, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
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Xu YQ, Gou Y, Yuan JJ, Zhu YX, Ma XM, Chen C, Huang XX, Yang ZX, Zhou YM. Peripheral Blood Inflammatory Cytokine Factors Expressions are Associated with Response to Acupuncture Therapy in Postpartum Depression Patients. J Inflamm Res 2023; 16:5189-5203. [PMID: 38026248 PMCID: PMC10655746 DOI: 10.2147/jir.s436907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Background Increasing evidences demonstrate that immune dysregulation can result in depression, and it is reported that persistent inflammatory response is related to the unresponsiveness of antidepressant treatment. Purpose This study aimed to explore the reason why some responded but some not responded to acupuncture in treating postpartum depression (PPD), and whether it related to the levels of inflammatory cytokines. Patients and Methods Women diagnosed with PPD were recruited in to accept 8-week acupuncture. All subjects were assessed the 17-item Hamilton Depression Rating Scale (HDRS17) at baseline, week 1, week 2, week 4 and week 8 during the treatment. A panel of 9 cytokines was measured at baseline and 8 weeks. Results Of the 121 participants, 96 completed the 8-week assessment and 46 completed the blood sample collection. HDRS17 scores of 96 subjects showed significant statistical reduction since the first week (P = 0.002) and reached to 5.31 (P < 0.000) at the end of therapy. And we divided the 46 subjects into responders and non-responders according to the response rate of HDRS17 scores. Responders and non-responders did not differ significantly between-group in changes in the 9 cytokines. In responders, IL-6, IL-10 and IFN-γ levels were statistically lower (P = 0.006; P = 0.033; P = 0.024), while TGF-β1 was statistically higher after 8 weeks treatment (P < 0.000). In non-responders, the levels of IL-5, TNF-α and TGF-β1 were statistically higher (P = 0.018; P < 0.000; P < 0.000), while IFN-γ was statistically lower (P = 0.005). Conclusion Acupuncture could alleviate depressive symptoms of patients with PPD and might through adjusting peripheral inflammatory response by up-regulating anti-inflammatory cytokines and down-regulating pro-inflammatory cytokines.
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Affiliation(s)
- Yu-Qin Xu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - YanHua Gou
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Jin-Jun Yuan
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Yan-Xian Zhu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Xiao-Ming Ma
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Chen Chen
- Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Xing-Xian Huang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Zhuo-Xin Yang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Yu-Mei Zhou
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
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Mandal S, Spoorthy MS, Godi SM, Nanda R, Mukherjee B, Mishra NR. Inflammatory Markers in Patients With Major Depressive Disorder: A Prospective, Clinic-Based, Cohort Study From India. Cureus 2023; 15:e43059. [PMID: 37680396 PMCID: PMC10481369 DOI: 10.7759/cureus.43059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2023] [Indexed: 09/09/2023] Open
Abstract
Background Patients with major depressive disorder have varying response rates to treatment. Multiple factors such as non-adherence, comorbidity, chronic stressors, and biological factors may be responsible for this variation. Inflammatory (pro and anti) markers have been well studied as a cause for depression, predisposing factors, and a consequence of depression. Among these, interleukins (ILs), interferons, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) have been studied repeatedly. We conducted a pilot study to assess the levels of these inflammatory markers in patients with major depressive disorder. The specific objectives of this study were to compare and correlate changes in pro- and anti-inflammatory markers throughout different phases of depression, including pretreatment and posttreatment periods, and to evaluate the pattern of pro- and anti-inflammatory markers in patients who experienced remission or showed a positive response to treatment. Methodology This was a prospective, clinic-based, cohort study done for a period of one and a half years. Patients aged 18-65 years with depressive disorder per the International Classification of Diseases Tenth Edition and who scored more than 7 on the Hamilton Depression Rating Scale were included in this study. A total of 81 patients were recruited who were followed up till eight weeks after inclusion. A total of 31 patients completed the eight weeks of follow-up. Levels of IL-10 and TNF-α were assessed at baseline, two weeks, four weeks, and eight weeks of follow-up. Results This study tried to compare the levels of pro- and anti-inflammatory markers across pretreatment and various posttreatment phases of depression. Results showed that the levels of pro-inflammatory cytokine TNF-α increased from baseline till eight weeks of follow-up, and levels of IL-10 decreased from baseline till eight weeks of follow-up. However, these changes were not statistically significant. Conclusions This study supports the hypothesis that inflammatory markers can be trait markers of depression rather than the consequence or result.
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Affiliation(s)
- Sucharita Mandal
- Psychiatry, All India Institute of Medical Sciences, Kalyani, Kalyani, IND
| | | | - Sangha Mitra Godi
- Psychiatry, All India Institute of Medical Sciences, Mangalagiri, Mangalagiri, IND
| | - Rachita Nanda
- Biochemistry, All India Institute of Medical Sciences, Raipur, Raipur, IND
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18
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Ballesio A, Zagaria A, Vacca M, Pariante CM, Lombardo C. Comparative efficacy of psychological interventions on immune biomarkers: A systematic review and network meta-analysis (NMA). Brain Behav Immun 2023; 111:424-435. [PMID: 37187256 DOI: 10.1016/j.bbi.2023.05.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 03/25/2023] [Accepted: 05/12/2023] [Indexed: 05/17/2023] Open
Abstract
Psychological interventions are viable, cost-effective strategies for improving clinical and psychological impact of inflammation-related conditions. However, their efficacy on immune system function remains controversial. We performed a systematic review and frequentist random-effects network meta-analysis of randomised controlled trials (RCTs) assessing the effects of psychological interventions, against a control condition, on biomarkers of innate and adaptive immunity in adults. PubMed, Scopus, PsycInfo, and Web of Science were searched from inception up to Oct 17, 2022. Cohen's d at 95% confidence interval (CI) was calculated to assess the effect sizes of each class of intervention against active control conditions at post-treatment. The study was registered in PROSPERO (CRD42022325508). Of the 5024 articles retrieved, we included 104 RCTs reporting on 7820 participants. Analyses were based on 13 types of clinical interventions. Compared with the control conditions, cognitive therapy (d = - 0.95, 95% CI: -1.64 to - 0.27), lifestyle (d = - 0.51, 95% CI: -0.99 to - 0.02), and mindfulness-based (d = - 0.38, 95% CI: -0.66 to - 0.09) interventions were associated with post-treatment reduction of proinflammatory cytokines and markers. Mindfulness-based interventions were also significantly associated with post-treatment increase in anti-inflammatory cytokines (d = 0.69, 95% CI: 0.09 to 1.30), while cognitive therapy was associated also with post-treatment increase in white blood cell count (d = 1.89, 95% CI: 0.05 to 3.74). Results on natural killer cells activity were non-significant. Grade of evidence was moderate for mindfulness and low-to-moderate for cognitive therapy and lifestyle interventions; however, substantial overall heterogeneity was detected in most of the analyses.
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Affiliation(s)
- Andrea Ballesio
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.
| | - Andrea Zagaria
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Mariacarolina Vacca
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Carmine M Pariante
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Caterina Lombardo
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
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19
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Wang SC, Yokoyama JS, Tzeng NS, Tsai CF, Liu MN. Treatment resistant depression in elderly. PROGRESS IN BRAIN RESEARCH 2023; 281:25-53. [PMID: 37806715 DOI: 10.1016/bs.pbr.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Treatment refractory depression (TRD) in the elderly is a common psychiatric disorder with high comorbidity and mortality. Older adults with TRD often have complicated comorbidities and several predisposing risk factors, which may lead to neuropsychiatric dysfunction and poor response to treatment. Several hypotheses suggest the underlying mechanisms, including vascular, immunological, senescence, or abnormal protein deposition. Treatment strategies for TRD include optimization of current medication dose, augmentation, switching to an alternative agent or class, and combination of different antidepressant classes, as well as nonpharmacological adjuvant interventions such as biophysical stimulation and psychotherapy. In summary, treatment recommendations for TRD in the elderly favor a multimodal approach, combining pharmacological and nonpharmacological treatments.
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Affiliation(s)
- Sheng-Chiang Wang
- School of Medicine, National Defense Medical Center, Taipei, Taiwan; Department of Psychiatry, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan; Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, United States
| | - Jennifer S Yokoyama
- Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, United States; Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States
| | - Nian-Sheng Tzeng
- Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; Student Counseling Center, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Fen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Mu-N Liu
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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20
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Zhu TT, Wang H, Gu HW, Ju LS, Wu XM, Pan WT, Zhao MM, Yang JJ, Liu PM. Melanin-like polydopamine nanoparticles mediating anti-inflammatory and rescuing synaptic loss for inflammatory depression therapy. J Nanobiotechnology 2023; 21:52. [PMID: 36765377 PMCID: PMC9913011 DOI: 10.1186/s12951-023-01807-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/05/2023] [Indexed: 02/12/2023] Open
Abstract
Inflammatory depression is closely related to neuroinflammation. However, current anti-inflammatory drugs have low permeability to cross blood-brain barrier with difficulties reaching the central nervous system to provide therapeutic effectiveness. To overcome this limitation, the nano-based drug delivery technology was used to synthesize melanin-like polydopamine nanoparticles (PDA NPs) (~ 250 nm) which can cross the blood-brain barrier. Importantly, PDA NPs with abundant phenolic hydroxyl groups function as excellent free radical scavengers to attenuate cell damage caused by reactive oxygen species or acute inflammation. In vitro experiments revealed that PDA NPs exhibited excellent antioxidative properties. Next, we aimed to investigate the therapeutic effect of PDA NPs on inflammatory depression through intraperitoneal injection to the lipopolysaccharide-induced inflammatory depression model in mice. PDA NPs significantly reversed the depression-like behavior. PDA NPs was also found to reduce the peripheral and central inflammation induced by LPS, showing that alleviated splenomegaly, reduced serum inflammatory cytokines, inhibited microglial activation and restored synaptic loss. Various experiments also showed that PDA NPs had good biocompatibility both in vivo and in vitro. Our work suggested that PDA NPs may be biocompatible nano-drugs in treating inflammatory depression but their clinical application requires further study.
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Affiliation(s)
- Ting-Ting Zhu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - He Wang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Han-Wen Gu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Ling-Sha Ju
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xin-Miao Wu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Wei-Tong Pan
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Ming-Ming Zhao
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Jian-Jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China.
| | - Pan-Miao Liu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Neuroscience Research InstituteZhengzhou University Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China.
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21
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Silva TMVD, Stein AM, Coelho FGDM, Rueda AV, Camarini R, Galduróz RF. Circulating levels of vascular endothelial growth factor in patients with Alzheimer's disease: A case-control study. Behav Brain Res 2023; 437:114126. [PMID: 36167216 DOI: 10.1016/j.bbr.2022.114126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) and platelets seem to reflect the Alzheimer's disease (AD) associated either with vascular impairment or disease. This study aimed to compare the circulating levels of VEGF and platelets between AD patients and healthy older adults. METHODS Seventy-two older adults, divided in 40 older adults (Clinical Dementia Rating Scale - CDR = 0); and 32 Alzheimer's disease patients (clinically diagnosed - CRD = 1) participated in the present study. The groups were paired by sex, age, comorbidities and educational level. The primary outcomes included circulating plasma VEGF and platelet levels obtained by blood collection. RESULTS The VEGF levels were significantly different between the groups (p = 0.03), with having a large effect size ( η2 =18.15), in which the AD patients presented lower levels compared to healthy older adults. For platelets, the comparison showed a tendency to difference (p = 0.06), with a large effect size (η2 =12.95) between the groups. CONCLUSION The VEGF levels and the platelet numbers were reduced in AD patients, suggesting that angiogenic factors could be modified due to AD.
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Affiliation(s)
- Thays Martins Vital da Silva
- Instituto Federal do Triangulo Mineiro, Campus Patos de Minas, Brazil; Institute of Biosciences, UNESP (Universidade Estadual Paulista) Physical Activity and Aging Lab (LAFE), Campus Rio Claro, Brazil
| | - Angelica Miki Stein
- Institute of Biosciences, UNESP (Universidade Estadual Paulista) Physical Activity and Aging Lab (LAFE), Campus Rio Claro, Brazil; UTFPR, Federal University of Technology - Paraná (UTFPR), Campus Curitiba, Brazil; Department of Physical Education, Midwestern Parana State University (UNICENTRO), Guarapuava, Brazil.
| | - Flávia Gomes de Melo Coelho
- Institute of Biosciences, UNESP (Universidade Estadual Paulista) Physical Activity and Aging Lab (LAFE), Campus Rio Claro, Brazil
| | - Andre Veloso Rueda
- Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Campus São Paulo, Brazil
| | - Rosana Camarini
- Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Campus São Paulo, Brazil
| | - Ruth Ferreira Galduróz
- Institute of Biosciences, UNESP (Universidade Estadual Paulista) Physical Activity and Aging Lab (LAFE), Campus Rio Claro, Brazil; Center of Mathematics, Computing and Cognition, University Federal of ABC (UFABC), Campus São Bernardo, Brazil
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Bhatt S, Devadoss T, Jha NK, Baidya M, Gupta G, Chellappan DK, Singh SK, Dua K. Targeting inflammation: a potential approach for the treatment of depression. Metab Brain Dis 2023; 38:45-59. [PMID: 36239867 DOI: 10.1007/s11011-022-01095-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 09/29/2022] [Indexed: 02/03/2023]
Abstract
Major depressive disorder (MDD) or Depression is one of the serious neuropsychiatric disorders affecting over 280 million people worldwide. It is 4th important cause of disability, poor quality of life, and economic burden. Women are more affected with the depression as compared to men and severe depression can lead to suicide. Most of the antidepressants predominantly work through the modulation on the availability of monoaminergic neurotransmitter (NTs) levels in the synapse. Current antidepressants have limited efficacy and tolerability. Moreover, treatment resistant depression (TRD) is one of the main causes for failure of standard marketed antidepressants. Recently, inflammation has also emerged as a crucial factor in pathological progression of depression. Proinflammatory cytokine levels are increased in depressive patients. Antidepressant treatment may attenuate depression via modulation of pathways of inflammation, transformation in structure of brain, and synaptic plasticity. Hence, targeting inflammation may be emerged as an effective approach for the treatment of depression. The present review article will focus on the preclinical and clinical studies that targets inflammation. In addition, it also concentrates on the therapeutic approaches' that targets depression via influence on the inflammatory signaling pathways. Graphical abstract demonstrate the role of various factors in the progression and neuroinflammation, oxidative stress. It also exhibits the association of neuroinflammation, oxidative stress with depression.
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Affiliation(s)
- Shvetank Bhatt
- School of Pharmacy, Dr. Vishwanath Karad MIT World Peace University, Maharashtra, 411038, Pune, India.
| | - Thangaraj Devadoss
- Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Mumbai Agra Highway, Maharashtra, 424001, Dhule, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, 201310, Greater Noida, Uttar Pradesh, India
| | - Moushumi Baidya
- Department of Pharmaceutical Technology, JIS University, 700109, Kolkata, West Bengal, India
- Department of Pharmaceutical Technology, Bharat Pharmaceutical Technology, 799130, Agartala, West Tripura, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India
- Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospitals, Saveetha University, Chennai, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, 248007, Dehradun, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T Road, Phagwara, Punjab, India
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, 2007, Ultimo, NSW, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, 2007, Ultimo, NSW, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, 2007, Ultimo, NSW, Australia
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Ritchie G, Strodl E, Parham S, Bambling M, Cramb S, Vitetta L. An exploratory study of the gut microbiota in major depression with anxious distress. J Affect Disord 2023; 320:595-604. [PMID: 36209779 DOI: 10.1016/j.jad.2022.10.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES To explore differences in the diversity and composition of the gut microbiome between major depressive disorder (MDD) with and without anxious distress. METHODS The study comprised 117 participants (79 female, 36 male, 2 other, mean age 38.2 ± 13.4 years) with a current major depressive episode (MDE) with (n = 63) and without (n = 54) the anxious distress specifier. A clinical psychologist administered the structured clinical interview for the DSM-5-RV to confirm a diagnosis of depression. Participants provided stool samples which were immediately frozen and stored at -80 °C. These samples were analysed using the Illumina 16S Metagenomics sequencing protocol in which the sequencing primers target the V3 and V4 regions of the 16S rRNA gene. Participants also completed mental health questionnaires to assess severity of depression (BDI-II), generalized anxiety (GAD-7), and stress (PSS). RESULTS There were no significant group differences in α-diversity (Shannon's diversity Index; Simpson Index), richness (ACE; Chao1), (Pielou's) evenness, or beta diversity (Bray-Curtis dissimilarity index and weighted UniFrac distance) of gut bacteria. Significant group differences in the relative abundance of gut microbiota however were observed at each taxonomical level, including across 15 genera and 18 species. LIMITATIONS This was an exploratory study that needs to be replicated across larger samples and compared with a healthy control group. CONCLUSIONS The research contributes to knowledge of the depressive gut microbial profile unique to the anxious distress subtype of MDD.
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Affiliation(s)
- Gabrielle Ritchie
- Faculty of Health, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
| | - Esben Strodl
- Faculty of Health, Queensland University of Technology, Kelvin Grove, Queensland, Australia
| | - Sophie Parham
- Faculty of Health, Queensland University of Technology, Kelvin Grove, Queensland, Australia
| | - Matthew Bambling
- Faculty of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Susanna Cramb
- Australian Centre for Health Services Innovation & Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, Australia
| | - Luis Vitetta
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.; Medlab Clinical, Sydney, New South Wales, Australia
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24
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Is depression the missing link between inflammatory mediators and cancer? Pharmacol Ther 2022; 240:108293. [PMID: 36216210 DOI: 10.1016/j.pharmthera.2022.108293] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/14/2022] [Accepted: 09/26/2022] [Indexed: 11/05/2022]
Abstract
Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying pathophysiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain. Three major routes to depression in cancer in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway involving cytokines, increases tryptophan catabolism, resulting in diminished levels of serotonin which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and other newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.
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Baseline Pro-Inflammatory Cytokine Levels Moderate Psychological Inflexibility in Behavioral Treatment for Chronic Pain. J Clin Med 2022; 11:jcm11092285. [PMID: 35566411 PMCID: PMC9102370 DOI: 10.3390/jcm11092285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/05/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Background: The medical and scientific communities struggle to understand chronic pain and find effective treatments. Multimodal approaches are encouraging but show significant individual differences. Methods: Seventy-eight persons (56 women) with chronic pain received Acceptance and Commitment Therapy and provided blood samples before and after treatment. The participants completed surveys with the blood sampling. Blood plasma was analyzed for IL-6 and TNF-α levels with the Olink Inflammation Panel (Olink Bioscience Uppsala, Sweden). The treatment effects and moderating effects of low-grade inflammation on changes in outcomes were analyzed using linear mixed models. Results: Pain interference (p < 0.001) and psychological inflexibility (p < 0.001) improved significantly during treatment, but pain intensity did not (p = 0.078). Cytokine levels did not change over the course of the treatment (IL-6/TNF-α p = 0.086/0.672). Mean baseline levels of IL-6 and TNF-α moderated improvement in psychological inflexibility during the course of treatment (p = 0.044), but cytokine levels did not moderate changes in pain interference (p = 0.205) or pain intensity (p = 0.536). Conclusions: Higher baseline inflammation levels were related to less improvement in psychological inflexibility. Low-grade inflammation may be one factor underlying the variability in behavioral treatment in chronic pain.
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Scotton E, Antqueviezc B, Vasconcelos M, Dalpiaz G, Paul Géa L, Ferraz Goularte J, Colombo R, Ribeiro Rosa A. Is (R)-ketamine a Potential Therapeutic Agent for Treatment-Resistant Depression with Less Detrimental Side Effects? A Review of Molecular Mechanisms Underlying Ketamine and its Enantiomers. Biochem Pharmacol 2022; 198:114963. [PMID: 35182519 DOI: 10.1016/j.bcp.2022.114963] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/18/2022]
Abstract
Approximately one-third of individuals with major depressive disorder are resistant to conventional antidepressants (i.e., monoamine-based therapies), and, even among respondents, a proper therapeutic effect may require weeks of treatment. Ketamine, a racemic mixture of the two enantiomers, (R)-ketamine and (S)-ketamine, is an N-methyl-d-aspartate receptor (NMDAR) antagonist and has been shown to have rapid-acting antidepressant properties in patients with treatment-resistant depression (TRD). Although (R)-ketamine has a lower affinity for NMDAR, it presents greater potency and longer-lasting antidepressant properties, with no major side effects, than racemic ketamine or (S)-ketamine in preclinical findings. Thereby, ketamine and its enantiomers have not only an antagonistic effect on NMDAR but also a strong synaptogenic-modulatory effect, which is impaired in TRD pathophysiology. In this review, we summarize the current evidence regarding the modulation of neurotransmission, neuroplasticity, and neural network activity as putative mechanisms of these rapid-acting antidepressants, highlighting differences on intracellular signaling pathways of synaptic proteins such as mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF). In addition, we discuss probable mechanisms involved in the side effects of ketamine and its enantiomers.
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Affiliation(s)
- Ellen Scotton
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Department of Pharmacology, Programa de Pós-Graduação em Farmacologia e Terapêutica, UFRGS, Porto Alegre, RS, Brazil.
| | - Bárbara Antqueviezc
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
| | - Mailton Vasconcelos
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Instituto de Psicologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Giovana Dalpiaz
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
| | - Luiza Paul Géa
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
| | - Jéferson Ferraz Goularte
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Psiquiatria e Ciências do Comportamento, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Rafael Colombo
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Biotecnologia, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil.
| | - Adriane Ribeiro Rosa
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Department of Pharmacology, Programa de Pós-Graduação em Farmacologia e Terapêutica, UFRGS, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Psiquiatria e Ciências do Comportamento, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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27
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Moraga-Amaro R, Guerrin CGJ, Reali Nazario L, Lima Giacobbo B, J O Dierckx RA, Stehberg J, de Vries EFJ, Doorduin J. A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats. Stress 2022; 25:145-155. [PMID: 35384793 DOI: 10.1080/10253890.2022.2045269] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Worldwide, millions of people suffer from treatment-resistant depression. Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant effect even in treatment-resistant patients. A proposed mechanism for the antidepressant effect of ketamine is the reduction of neuroinflammation. To further explore this hypothesis, we investigated whether a single dose of ketamine can modulate protracted neuroinflammation in a repeated social defeat (RSD) stress rat model, which resembles features of depression. To this end, male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A combination of behavioral analyses and PET scans of the inflammatory marker TSPO in the brain were performed. Rats submitted to RSD showed anhedonia-like behavior in the sucrose preference test, decreased weight gain, and increased TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195 PET. Whole brain TSPO levels correlated with corticosterone levels in several brain regions of RSD exposed animals, but not in controls. Ketamine injection 1 day after RSD disrupted the correlation between TSPO levels and serum corticosterone levels, but had no effect on depressive-like symptoms, weight gain or the protracted RSD-induced increase in TSPO expression in male rats. These results suggest that ketamine does not exert its effect on the hypothalamic-pituitary-adrenal axis by modulation of neuroinflammation.
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Affiliation(s)
- Rodrigo Moraga-Amaro
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
| | - Cyprien G J Guerrin
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
| | - Luiza Reali Nazario
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
| | - Bruno Lima Giacobbo
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
| | - Jimmy Stehberg
- Laboratorio de Neurobiología, Instituto de Ciencias Biomédicas, Facultad de Medicina y Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Erik F J de Vries
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
| | - Janine Doorduin
- Department of Nuclear Medicine and Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, GZ, The Netherlands
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28
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Yang NN, Lin LL, Li YJ, Li HP, Cao Y, Tan CX, Hao XW, Ma SM, Wang L, Liu CZ. Potential Mechanisms and Clinical Effectiveness of Acupuncture in Depression. Curr Neuropharmacol 2022; 20:738-750. [PMID: 35168522 PMCID: PMC9878952 DOI: 10.2174/1570159x19666210609162809] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 11/22/2022] Open
Abstract
Major depressive disorder is the most common mental disorder with significant economic burden and limited treatments. Acupuncture has emerged as a promising non-pharmacological treatment for reducing depressive symptoms. However, the potential mechanisms and clinical effectiveness of acupuncture are not fully understood. This review aimed to: (1) summarize the available evidence on the mechanisms and clinical effectiveness of acupuncture for depression, and then (2) compare with pharmacological interventions, guiding future studies. Studies with animal models of depression and patients have shown that acupuncture could increase hippocampal and network neuroplasticity and decrease brain inflammation, potentially to alleviating depressive disorders. Overall clinical studies indicated that acupuncture could relieve primary depression, particularly milder cases, and was helpful in the management of post-stroke depression, pain-related depression, and postpartum depression both as an isolated and adjunct treatment. It was emphasized that acupuncture combined with antidepressant pharmacological treatment not only enhanced the improvement of primary and secondary depressive symptoms but also reduced the side effects of the medical treatment, which is the main cause for high dropout rates with drug treatment. In summary, substantial evidence from animal and human researches supported the beneficial effect of acupuncture in depression. However, most clinical trials of acupuncture were small, and it is unclear whether their findings can be generalized, so more studies are needed.
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Affiliation(s)
- Na-Na Yang
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Lu-Lu Lin
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yue-Jie Li
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hong-Ping Li
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yan Cao
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chun-Xia Tan
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiao-Wan Hao
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Si-Ming Ma
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Lu Wang
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cun-Zhi Liu
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tunia, Beijing University of Chinese Medicine, Beijing 100029, China
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29
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Guo ZP, Sörös P, Zhang ZQ, Yang MH, Liao D, Liu CH. Use of Transcutaneous Auricular Vagus Nerve Stimulation as an Adjuvant Therapy for the Depressive Symptoms of COVID-19: A Literature Review. Front Psychiatry 2021; 12:765106. [PMID: 34975571 PMCID: PMC8714783 DOI: 10.3389/fpsyt.2021.765106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) comprises more than just severe acute respiratory syndrome. It also interacts with the cardiovascular, nervous, renal, and immune systems at multiple levels, increasing morbidity in patients with underlying cardiometabolic conditions and inducing myocardial injury or dysfunction. Transcutaneous auricular vagus nerve stimulation (taVNS), which is derived from auricular acupuncture, has become a popular therapy that is increasingly accessible to the general public in modern China. Here, we begin by outlining the historical background of taVNS, and then describe important links between dysfunction in proinflammatory cytokine release and related multiorgan damage in COVID-19. Furthermore, we emphasize the important relationships between proinflammatory cytokines and depressive symptoms. Finally, we discuss how taVNS improves immune function via the cholinergic anti-inflammatory pathway and modulates brain circuits via the hypothalamic-pituitary-adrenal axis, making taVNS an important treatment for depressive symptoms on post-COVID-19 sequelae. Our review suggests that the link between anti-inflammatory processes and brain circuits could be a potential target for treating COVID-19-related multiorgan damage, as well as depressive symptoms using taVNS.
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Affiliation(s)
- Zhi-Peng Guo
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Peter Sörös
- Research Center Neurosensory Science, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Zhu-Qing Zhang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ming-Hao Yang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Dan Liao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Chun-Hong Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing Institute of Traditional Chinese Medicine, Beijing, China
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30
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Hazelgrove K. The role of the immune system in postpartum psychosis. Brain Behav Immun Health 2021; 18:100359. [PMID: 34704078 PMCID: PMC8521124 DOI: 10.1016/j.bbih.2021.100359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Postpartum psychosis is the most severe psychiatric disorder associated with childbirth. The risk is particularly high for women with a history of bipolar disorder or schizoaffective disorder, or those who have suffered a previous episode of postpartum psychosis. However, the aetiology of the illness remains unclear. Pregnancy and the early postpartum are times of significant immunological change. Furthermore, alterations to the immune system have been implicated in the onset and course of various psychopathologies, both related and unrelated to childbirth. Emerging evidence, from studies on immune related disorders, immune cells and inflammatory markers, suggests that the immune system might also be involved in the pathophysiology of postpartum psychosis. Furthermore, recent research has also begun to explore the potential mechanisms underlying immune dysfunction in postpartum psychosis (e.g., disturbances in the Treg-CCN3 protein-(re)myelination axis). Nevertheless, more research is required to understand whether immune dysfunction is a cause or consequence of postpartum psychosis and to clarify the exact mechanisms involved. The aim of this short review is to present the current findings on immune system dysregulation in postpartum psychosis, discuss possible mechanisms underlying the association, highlight potential challenges and confounders and provide suggestions for future research.
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Affiliation(s)
- Katie Hazelgrove
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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31
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Foley ÉM, Parkinson JT, Kappelmann N, Khandaker GM. Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms. COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY 2021; 8:100079. [PMID: 34729541 PMCID: PMC7611902 DOI: 10.1016/j.cpnec.2021.100079] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Whether depressed patients with evidence of inflammation are more appropriate candidates for immunotherapies is being tested in several clinical trials, which are selecting patients based on elevated C-reactive protein (CRP) and inflammation-related symptoms. However, studies of the clinical and phenotypic profile of depressed patients with elevated CRP are relatively scarce. We have investigated detailed clinical characteristics of 84 depressed patients, grouped as those with (CRP≥3 mg/L) and without (CRP<3 mg/L) inflammation. All patients met the International Classification of Diseases 10th Revision criteria for current depressive episode and had somatic symptoms of depression. We report that depressed patients with inflammation are more likely to be older (P=0.04), have higher body mass index (P<0.01), and be on non-selective serotonin reuptake inhibitor antidepressants (P=0.04). After adjusting for potential confounders, the inflammation group had higher depression severity (adjusted mean difference, 8.82; 95% CI, 3.91–13.72), somatic symptoms (adjusted mean difference, 3.25; 95% CI, 1.58–4.92), state anxiety (adjusted mean difference, 9.25; 95% CI, 3.82–14.67), perceived stress (adjusted mean difference, 4.58; 95% CI, 1.98–7.18), and fatigue (adjusted mean difference, 9.71; 95% CI, 3.09–6.33), but not anhedonia. The inflamed group also had poorer quality of life (adjusted mean difference, −0.18; 95% CI, −0.32–0.05). At individual depressive symptom level, the inflammation group had increased guilty feelings (adjusted odds ratio [OR], 7.28; 95% CI, 2.09–31.17), pessimism (adjusted OR, 5.38; 95% CI, 1.53–22.73), concentration difficulties (adjusted OR, 4.56; 95% CI, 1.32–19.02), and indecisiveness (adjusted OR, 4.21; 95% CI, 1.15–18.54). Our findings highlight the clinical features associated with inflammation in depressed patients with somatic symptoms, including poor quality of life, supporting the need for intervention targeting this group. These results could also aid patient and outcome selection in future clinical trials testing immunotherapies in depression. Replication of these findings in larger samples is required.
We studied clinical features of depressed patients with somatic symptoms with/without evidence of inflammation . Elevated CRP (≥3mg/L) was associated with higher age, higher BMI, and non-SSRI treatment. Elevated CRP (≥3mg/L) was associated with higher depression severity, fatigue, state anxiety, and stress. Elevated CRP (≥3mg/L) was associated with poorer subjective wellbeing and quality of life. Elevated CRP (≥3mg/L) was associated with both somatic and psychological symptoms of depression.
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Affiliation(s)
- Éimear M Foley
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Joel T Parkinson
- Department of Psychiatry, University of Cambridge, Cambridge, UK.,Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Nils Kappelmann
- Department of Research in Translational Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.,International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
| | - Golam M Khandaker
- Department of Psychiatry, University of Cambridge, Cambridge, UK.,MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.,Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.,Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.,Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UK
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32
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Zhou Q, Lv X, Zhou S, Liu Q, Tian H, Zhang K, Wei J, Wang G, Chen Q, Zhu G, Wang X, An C, Zhang N, Huang Y, Si T, Yu X, Shi C. Inflammatory cytokines, cognition, and response to antidepressant treatment in patients with major depressive disorder. Psychiatry Res 2021; 305:114202. [PMID: 34536696 DOI: 10.1016/j.psychres.2021.114202] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Inflammation and cognition are related to major depressive disorder (MDD), but the role in treatment response remains unclear. In this study, we investigated correlation between inflammatory cytokines and cognition in MDD patients treated with antidepressant medication. METHODS The participants were 149 MDD patients. Cytokines before therapy, cognitive assessments and severity of depression before and after therapy were tested. Logistic regression was used to explore underlying risks treatment response. RESULTS There were significant differences in smoking, alcohol drinking, and Stroop Color Test(SCT), Stroop Color-Word Test (SCWT), and Continuous Performance Test(CPT) scores between response group (RG) and non-response group (NRG) at baseline. Performance of patients in RG improved more in Brief Assessment of Cognition in Schizophrenia (BACS), Color Trial Test-I (CTT-I), SCT and SCWT after treatment. Levels of baseline IL-18 were associated with baseline learning and memory, and executive function. Treatment response was associated with drinking, performance of CPT and SCT. CONCLUSION MDD patients with different treatment responses have different cognitive defects, especially in speed of processing and executive function. Expression of cytokines is associated with cognition and may influence treatment response. Better speed of processing and executive function, and poorer attention at baseline may respond better to antidepressant treatment.
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Affiliation(s)
- Qi Zhou
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Xiaozhen Lv
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Shuzhe Zhou
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Qi Liu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Hongjun Tian
- Nankai University Affiliated Anding Hospital, Tianjin Mental Health Center, Tianjin, China
| | - Kerang Zhang
- Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jing Wei
- Department of Psychological Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Gang Wang
- Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Qiaoling Chen
- Department of Psychiatry, Dalian Seventh People's Hospital, Dalian, China
| | - Gang Zhu
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Liaoning, China
| | - Xueyi Wang
- Department of Psychiatry, The First Hospital of Hebei Medical University, Mental Health Institute of Hebei Medical University, Shijiazhuang, China
| | - Cuixia An
- Department of Psychiatry, The First Hospital of Hebei Medical University, Mental Health Institute of Hebei Medical University, Shijiazhuang, China
| | - Nan Zhang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yu Huang
- National Engineering Research Center for Software Engineering, Peking University, Beijing, China
| | - Tianmei Si
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Xin Yu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China..
| | - Chuan Shi
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China..
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33
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Kverno K. Brain Fog: A Bit of Clarity Regarding Etiology, Prognosis, and Treatment. J Psychosoc Nurs Ment Health Serv 2021; 59:9-13. [PMID: 34714198 DOI: 10.3928/02793695-20211013-01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Brain fog is a lay term used to describe cognitive difficulties. Brain fog can be a response to lack of sleep, poor nutrition, medications, or drugs; however, the term is often used to describe the subjective experience of neuroinflammation. Chronic low-level inflammation is the most detrimental to the mind and body. The purpose of the current article is to examine the mechanisms, associated symptoms, and treatments for neuroinflammation and brain fog. The state of the science is lacking evidence for specific treatments targeting the mechanisms/pathways of neuroinflammation for precision-based care, yet there are pharmacological and nonpharmacological interventions that can reduce inflammation and improve functioning. [Journal of Psychosocial Nursing and Mental Health Services, 59(11), 9-13.].
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34
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Lauden A, Geishin A, Merzon E, Korobeinikov A, Green I, Golan-Cohen A, Vinker S, Manor I, Weizman A, Magen E. Higher rates of allergies, autoimmune diseases and low-grade inflammation markers in treatment-resistant major depression. Brain Behav Immun Health 2021; 16:100313. [PMID: 34589804 PMCID: PMC8474658 DOI: 10.1016/j.bbih.2021.100313] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 07/17/2021] [Accepted: 07/28/2021] [Indexed: 12/28/2022] Open
Abstract
Only 30% of patients with major depressive disorder (MDD) reach full recovery or remission. Treatment-resistant depression (TRD) is MDD that does not respond to adequate treatment attempts with at least two antidepressants. TRD is associated more with immune activation than with treatment responsive depression. The current retrospective population-based cross-sectional study, utilizing data from a large nation-wide health maintenance organization in Israel which provides services to estimated 725,000 members, aimed to assess the clinical signs and laboratory markers of autoimmune comorbidity and low-grade inflammation, in patients with TRD. Included were participants aged 18-70 years, diagnosed twice within one year with ICD-9-CM MDD and two control groups, MDD responders (MDD-r) consisting of people with MDD and no TRD and a non-MDD group that included people with no MDD or TRD. The case (570 subjects in TRD group) to control ratio in both control groups (2850 subjects in MDD-r and 2850 subjects in non-MDD control group) was 1:5. Compared to MDD-r, the overall proportion of allergic diseases was higher among the TRD than among the MDD-r [OR 1.52 (1.19-1.94); p < 0.001]. Any systemic autoimmune disease was associated with increased likelihood of MDD-r [OR 1.52 (1.04-2.24); p = 0.03] or TRD [OR 2.22 (1.30-3.78); p = 0.003]. Higher rates of positive (>1:80) antinuclear antibodies [33 (5.79%)] were found among the TRD than among the MDD-r [98 (3.44%); p = 0.011). More allergy and autoimmune comorbidities and presence of low-grade inflammation biomarkers, were found mainly in TRD.
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Affiliation(s)
- Ari Lauden
- Leumit Health Services, Israel
- Psychiatric Division, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
| | | | - Eugene Merzon
- Leumit Health Services, Israel
- Department of Family Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Ilan Green
- Leumit Health Services, Israel
- Department of Family Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Avivit Golan-Cohen
- Leumit Health Services, Israel
- Psychiatric Division, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
| | - Shlomo Vinker
- Leumit Health Services, Israel
- Department of Family Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Iris Manor
- ADHD Outpatient Clinic, Geha Mental Health Center, Petah Tikva, Israel and Department of Psychiatry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Abraham Weizman
- Research Unit, Geha Mental Health Center, Petah Tikva, Israel and Laboratory of Molecular Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel and Department of Psychiatry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eli Magen
- Leumit Health Services, Israel
- Clinical Immunology and Allergy Division, Medicine C Department, Barzilai University Medical Center, Ben Gurion University of the Negev, Israel
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35
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Yang C, Nolte IM, Ma Y, An X, Bosker FJ, Li J. The associations of CNR1 SNPs and haplotypes with vulnerability and treatment response phenotypes in Han Chinese with major depressive disorder: A case-control association study. Mol Genet Genomic Med 2021; 9:e1752. [PMID: 34355541 PMCID: PMC8457701 DOI: 10.1002/mgg3.1752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 03/30/2021] [Accepted: 07/09/2021] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Understanding how genetic polymorphisms are associated with the pathophysiology of major depressive disorder (MDD) may aid in diagnosis and the development of personalized treatment strategies. CNR1 is the gene coding Cannabinoid type 1 receptor which is highly involved in emotional processing and in regulating neurotransmitter releases. We aimed to investigate the associations of CNR1 single-nucleotide polymorphisms (SNPs) with MDD susceptibility and treatment response. METHODS The study reported data on 181 Han Chinese with MDD and 80 healthy controls. The associations of CNR1 genetic polymorphisms with MDD susceptibility and treatment response were examined, wherein the MDD patients were subgrouped further by responding to antidepressant treatment, compared with healthy controls separately. RESULTS The CNR1 SNPs rs806367 and rs6454674 and haplotype C-T-T-C of rs806366, rs806367, rs806368, and rs806370 were associated with increased susceptibility for MDD and antidepressant treatment resistance, but the association was not detected in other SNPs or the haplotype block of rs806368 and rs806370. CONCLUSION The CNR1 is a promising candidate for the genetic association study of MDD. Larger and well-characterized samples are required to confirm the genetic association of CNR1 with MDD because of the limitations such as relatively small sample size and lack of information for correcting confounding factors.
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Affiliation(s)
- Chenghao Yang
- Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin, China.,University Centre of Psychiatry, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Ilja M Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Yanyan Ma
- Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin, China
| | - Xuguang An
- Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin, China
| | - Fokko J Bosker
- University Centre of Psychiatry, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.,Research School Behavioral and Cognitive Neurosciences (BCN), University of Groningen, Groningen, The Netherlands
| | - Jie Li
- Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin, China
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36
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Huang Z, Tan S. P2X7 Receptor as a Potential Target for Major Depressive Disorder. Curr Drug Targets 2021; 22:1108-1120. [PMID: 33494675 DOI: 10.2174/1389450122666210120141908] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/04/2020] [Accepted: 11/06/2020] [Indexed: 11/22/2022]
Abstract
Major depressive disorder (MDD) is a common mental disorder. Although the genetic, biochemical, and psychological factors have been related to the development of MDD, it is generally believed that a series of pathological changes in the brain caused by chronic stress is the main cause of MDD. However, the specific mechanisms underlying chronic stress-induced MDD are largely undermined. Recent investigations have found that increased pro-inflammatory cytokines and changes in the inflammatory pathway in the microglia cells in the brain are the potential pathophysiological mechanism of MDD. P2X7 receptor (P2X7R) and its mediated signaling pathway play a key role in microglia activation. The present review aimed to present and discuss the accumulating data on the role of P2X7R in MDD. Firstly, we summarized the research progress in the correlation between P2X7R and MDD. Subsequently, we presented the P2X7R mediated microglia activation in MDD and the role of P2X7R in increased blood-brain barrier (BBB) permeability caused by chronic stress. Lastly, we also discussed the potential mechanism underlying-P2X7R expression changes after chronic stress. In conclusion, P2X7R is a key molecule regulating the activation of microglia. Chronic stress activates microglia in the hippocampus by secreting interleukin- 1β (IL-1β) and other inflammatory cytokines, and increasing the BBB permeability, thus promoting the occurrence and development of MDD, which indicated that P2X7R might be a promising therapeutic target for MDD.
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Affiliation(s)
- Zeyi Huang
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, 421001, Hunan, China
| | - Sijie Tan
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, 421001, Hunan, China
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37
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Chukaew P, Leow A, Saengsawang W, Rasenick MM. Potential depression and antidepressant-response biomarkers in human lymphoblast cell lines from treatment-responsive and treatment-resistant subjects: roles of SSRIs and omega-3 polyunsaturated fatty acids. Mol Psychiatry 2021; 26:2402-2414. [PMID: 32327735 PMCID: PMC7928235 DOI: 10.1038/s41380-020-0724-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/13/2020] [Accepted: 03/31/2020] [Indexed: 12/22/2022]
Abstract
While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not achieved in many patients. Therefore, biomarkers for depression and drug-response would help tailor treatment strategies. This study made use of banked human lymphoblast cell lines (LCLs) from normal and depressed subjects; the latter divided into remitters and non-remitters. Due to the fact that previous studies have shown effects on growth factors, cytokines, and elements of the cAMP-generating system as potential biomarkers for depression and antidepressant action, these were examined in LCLs. Initial gene and protein expression profiles for signaling cascades related to neuroendocrine and inflammatory functions differ among the three groups. Growth factor genes, including VEGFA and BDNF were significantly down-regulated in cells from depressed subjects. In addition, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to act as both antidepressants and anti-inflammatories, but the mechanisms for these effects are not established. Here we showed that n-3 PUFAs and escitalopram (selective serotonin reuptake inhibitors, SSRIs) treatment increased adenylyl cyclase (AC) and BDNF gene expression in LCLs. These data are consistent with clinical observations showing that n-3 PUFA and SSRI have antidepressant affects, which may be additive. Contrary to observations made in neuronal and glial cells, n-3 PUFA treatment attenuated cAMP accumulation in LCLs. However, while lymphoblasts show paradoxical responses to neurons and glia, patient-derived lymphoblasts appear to carry potential depression biomarkers making them an important tool for studying precision medicine in depressive patients. Furthermore, these data validate usefulness of n-3 PUFAs in treatment for depression.
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Affiliation(s)
- Phatcharee Chukaew
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA
| | - Alex Leow
- Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL, USA
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Witchuda Saengsawang
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Mark M Rasenick
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA.
- Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL, USA.
- Jesse Brown Westside VA Medical Center, Chicago, IL, USA.
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38
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Hazelgrove K, Biaggi A, Waites F, Fuste M, Osborne S, Conroy S, Howard LM, Mehta MA, Miele M, Nikkheslat N, Seneviratne G, Zunszain PA, Pawlby S, Pariante CM, Dazzan P. Risk factors for postpartum relapse in women at risk of postpartum psychosis: The role of psychosocial stress and the biological stress system. Psychoneuroendocrinology 2021; 128:105218. [PMID: 33892376 DOI: 10.1016/j.psyneuen.2021.105218] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 02/24/2021] [Accepted: 03/30/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Postpartum psychosis is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high for women with a history of bipolar disorder, schizoaffective disorder or those who have suffered a previous episode of postpartum psychosis. Whilst there is a lot of evidence linking stress to psychosis unrelated to childbirth, the role of stress in the onset of postpartum psychosis has not been fully investigated. METHODS A prospective longitudinal study of 112 pregnant women, 51 at risk of postpartum psychosis because of a DSM-IV diagnosis of bipolar disorder (n = 41), schizoaffective disorder (n = 6) or a previous postpartum psychosis (n = 4) and 61 healthy women with no past or current DSM-IV diagnosis and no family history of postpartum psychosis. Women were followed up from the third trimester of pregnancy to 4 weeks' post partum. Women at risk who had a psychiatric relapse in the first 4 weeks' post partum (AR-unwell) (n = 22), were compared with those at risk who remained well (AR-well) (n = 29) on measures of psychosocial stress (severe childhood maltreatment and stressful life events) and biological stress (cortisol and inflammatory biomarkers). RESULTS Logistic regression analyses revealed that severe childhood maltreatment (OR = 4.9, 95% CI 0.5-49.2) and higher daily cortisol in the third trimester of pregnancy (OR=3.7, 95% CI 1.2-11.6) predicted psychiatric relapse in the first 4 weeks' post partum in women at risk of postpartum psychosis after adjusting for clinical and sociodemographic covariates. CONCLUSION The current study provides evidence for the role of psychosocial stress and the biological stress system in the risk of postpartum relapse in women at risk of postpartum psychosis.
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Affiliation(s)
- Katie Hazelgrove
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Alessandra Biaggi
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Freddie Waites
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Montserrat Fuste
- Perinatal Parent-Infant Mental Health Service, Goodmayes Hospital, North East London Foundation Trust, London IG3 8XD, UK.
| | - Sarah Osborne
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Susan Conroy
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Louise M Howard
- Section of Women's Mental Health, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Mitul A Mehta
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Maddalena Miele
- Perinatal Mental Health Service, St Mary's Hospital, Imperial College London and Central North West London NHS Foundation Trust, London W2 1PF, UK.
| | - Naghmeh Nikkheslat
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Gertrude Seneviratne
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Patricia A Zunszain
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Susan Pawlby
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Carmine M Pariante
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
| | - Paola Dazzan
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
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Curzytek K, Leśkiewicz M. Targeting the CCL2-CCR2 axis in depressive disorders. Pharmacol Rep 2021; 73:1052-1062. [PMID: 34031863 PMCID: PMC8142870 DOI: 10.1007/s43440-021-00280-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/13/2021] [Accepted: 05/17/2021] [Indexed: 12/04/2022]
Abstract
Since affective disorders are considered to be underlain by the immune system malfunction, an important role in their pathophysiology is assigned to the proinflammatory mediators. Recently, chemokines, the group of chemotactic cytokines, have become a focus for basic and clinical scientists in the context of the development and treatment of brain diseases. Among them, chemokine CCL2 and its main receptor CCR2 have become candidate mediators of abnormal brain-immune system dialogue in depression. Besides the chemotactic activity, the CCL2-CCR2 axis is involved in various neurobiological processes, neurogenesis, neurotransmission, neuroinflammation, neurodegeneration, as well as neuroregeneration. Given the range of immunomodulatory possibilities that the CCL2-CCR2 pair can exert on the nervous system, its proinflammatory properties were initially thought to be a major contributor to the development of depressive disorders. However, further research suggests that the malfunctions of the nervous system are rather associated with impaired homeostatic properties manifested by the CCL2-CCR2 dyad dysfunctions. This review aims to present literature data on the action of the CCL2-CCR2 axis in the central nervous system under physiological and pathological conditions, as well as the contribution of this ligand-receptor system to the processes underlying affective disorders. Additionally, this article draws attention to the importance of the CCL2-CRR2 pathway as a potential pharmacological target with antidepressant potential.
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Affiliation(s)
- Katarzyna Curzytek
- Department of Experimental Neuroendocrinology, Laboratory of Immunoendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343, Kraków, Poland.
| | - Monika Leśkiewicz
- Department of Experimental Neuroendocrinology, Laboratory of Immunoendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343, Kraków, Poland
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40
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Diaz AP, Fernandes BS, Quevedo J, Sanches M, Soares JC. Treatment-resistant bipolar depression: concepts and challenges for novel interventions. ACTA ACUST UNITED AC 2021; 44:178-186. [PMID: 34037084 PMCID: PMC9041963 DOI: 10.1590/1516-4446-2020-1627] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/16/2021] [Indexed: 02/06/2023]
Abstract
Treatment-resistant bipolar depression (TRBD) has been reported in about one-quarter of patients with bipolar disorders, and few interventions have shown clear and established effectiveness. We conducted a narrative review of the published medical literature to identify papers discussing treatment-resistant depression concepts and novel interventions for bipolar depression that focus on TRBD. We searched for potentially relevant English-language articles published in the last decade. Selected articles (based on the title and abstract) were retrieved for a more detailed evaluation. A number of promising new interventions, both pharmacological and non-pharmacological, are being investigated for TRBD treatment, including ketamine, lurasidone, D-cycloserine, pioglitazone, N-acetylcysteine, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cyclooxygenase 2 inhibitors, magnetic seizure therapy, intermittent theta-burst stimulation, deep transcranial magnetic stimulation, vagus nerve stimulation therapy, and deep brain stimulation. Although there is no consensus about the concept of TRBD, better clarification of the neurobiology associated with treatment non-response could help identify novel strategies. More research is warranted, mainly focusing on personalizing current treatments to optimize response and remission rates.
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Affiliation(s)
- Alexandre P Diaz
- Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Brisa S Fernandes
- Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Joao Quevedo
- Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.,Laboratório de Psiquiatria Translacional, Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Universidade do Extremo Sul Catarinense (UNESC), Criciúma, SC, Brazil
| | - Marsal Sanches
- Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Jair C Soares
- Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
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41
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Carboni E, Carta AR, Carboni E, Novelli A. Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success? Front Neurosci 2021; 15:657714. [PMID: 33994933 PMCID: PMC8120160 DOI: 10.3389/fnins.2021.657714] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/31/2021] [Indexed: 12/27/2022] Open
Abstract
Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.
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Affiliation(s)
- Ezio Carboni
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Anna R. Carta
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Elena Carboni
- Unit of Paediatrics, ASST Cremona Maggiore Hospital, Cremona, Italy
| | - Antonello Novelli
- Department of Psychology and University Institute of Biotechnology of Asturias, University of Oviedo, Oviedo, Spain
- Sanitary Institute of the Princedom of Asturias, Oviedo, Spain
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42
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Perry BI, Zammit S, Jones PB, Khandaker GM. Childhood inflammatory markers and risks for psychosis and depression at age 24: Examination of temporality and specificity of association in a population-based prospective birth cohort. Schizophr Res 2021; 230:69-76. [PMID: 33684738 PMCID: PMC8224182 DOI: 10.1016/j.schres.2021.02.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/29/2021] [Accepted: 02/16/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Cross-sectional studies have reported elevated concentrations of inflammatory markers in psychosis and depression. However, questions regarding temporality and specificity of association, crucial for understanding the potential role of inflammation, remain. METHODS Based on 2224 ALSPAC birth cohort participants, we used regression analyses to test associations of interleukin-6 (IL-6) and C-reactive protein (CRP) levels at age 9 with risks for psychosis (psychotic experiences; negative symptoms; psychotic disorder), and depression (depressive episode; symptom score) at age 24. Regression models were adjusted for sex, ethnicity, social class and body mass index. We tested for linearity (using quadratic terms) and specificity (using bi-variate probit regression) of association, and used multiple imputation to explore the impact of missing data. RESULTS After adjustments, higher IL-6 levels at age 9 were associated with increased risk of psychotic disorder (OR = 1.56; 95% C.I., 1.09-2.21 per SD increase in IL-6; OR=2.60; 95% C.I., 1.04-6.53 for the top compared with bottom third of IL-6) and depressive episode (OR = 1.14; 95% C.I., 0.99-1.32 per SD increase in IL-6; OR = 1.49; 95% C.I., 1.02-2.18 for the top compared with bottom third of IL-6). IL-6 was associated with negative symptoms after adjusting for depression (β = 0.09; 95% C.I., 0.01-0.22). There was no evidence for outcome-specific associations of IL-6. Childhood CRP was not associated with adult psychosis or depression. CONCLUSIONS Evidence for similar, longitudinal, dose-response associations suggest that elevated childhood IL-6 could be a shared risk factor for adult psychosis and depression. The IL-6 pathway may represent a novel target for treatment and prevention of these disorders.
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Affiliation(s)
- Benjamin I Perry
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
| | - Stanley Zammit
- Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Peter B Jones
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Golam M Khandaker
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK; Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Avon and Wiltshire Mental Health Partnership NHS Trust, UK
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43
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Ioannou M, Foiselle M, Mallet J, Stam EL, Godin O, Dubertret C, Terro E, Sommer IEC, Haarman BCM, Leboyer M, Schoevers RA. Towards precision medicine: What are the stratification hypotheses to identify homogeneous inflammatory subgroups. Eur Neuropsychopharmacol 2021; 45:108-121. [PMID: 33189523 DOI: 10.1016/j.euroneuro.2020.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 10/13/2020] [Accepted: 11/02/2020] [Indexed: 12/17/2022]
Abstract
Diverse lines of research testify a link, presumably causal, between immune dysregulation and the development, course and clinical outcome of psychiatric disorders. However, there is a large heterogeneity among the patients' individual immune profile and this heterogeneity prevents the development of precise diagnostic tools and the identification of therapeutic targets. The aim of this review was to delineate possible subgroups of patients on the basis of clinical dimensions, investigating whether they could lead to particular immune signatures and tailored treatments. We discuss six clinical entry points; genetic liability to immune dysregulation, childhood maltreatment, metabolic syndrome, cognitive dysfunction, negative symptoms and treatment resistance. We describe the associated immune signature and outline the effects of anti-inflammatory drugs so far. Finally, we discuss advantages of this approach, challenges and future research directions.
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Affiliation(s)
- M Ioannou
- University of Groningen, University Medical Center Groningen, Research School of Behavioral and Cognitive Neurosciences (BCN), Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Biomedical Sciences, Cells and Systems, Groningen, The Netherlands.
| | - M Foiselle
- Hôpitaux de Paris, Université Paris Est Créteil DMU Impact, Department of Addictology and Psychiatry, Mondor University Hospitals, Créteil, France; INSERM U955, IMRB, Team 15, "Translational NeuroPsychiatry", Créteil, France; Fondation FondaMental, Créteil, France
| | - J Mallet
- Hôpitaux de Paris Department of Psychiatry, Louis-Mourier Hospital, Colombes, France; INSERM UMR1266, Institute of Psychiatry and Neuroscience of Paris, France; Université de Paris, Faculté de médecine, Paris, France; Fondation FondaMental, Créteil, France
| | - E L Stam
- University of Groningen, University Medical Center Groningen, Research School of Behavioral and Cognitive Neurosciences (BCN), Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - O Godin
- INSERM U955, IMRB, Team 15, "Translational NeuroPsychiatry", Créteil, France; Fondation FondaMental, Créteil, France
| | - C Dubertret
- Hôpitaux de Paris Department of Psychiatry, Louis-Mourier Hospital, Colombes, France; INSERM UMR1266, Institute of Psychiatry and Neuroscience of Paris, France; Université de Paris, Faculté de médecine, Paris, France
| | - E Terro
- INSERM U955, IMRB, Team 15, "Translational NeuroPsychiatry", Créteil, France
| | - I E C Sommer
- University of Groningen, University Medical Centre Groningen, Department of Biomedical Sciences, Cells and Systems, Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - B C M Haarman
- University of Groningen, University Medical Center Groningen, Research School of Behavioral and Cognitive Neurosciences (BCN), Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - M Leboyer
- Hôpitaux de Paris, Université Paris Est Créteil DMU Impact, Department of Addictology and Psychiatry, Mondor University Hospitals, Créteil, France; INSERM U955, IMRB, Team 15, "Translational NeuroPsychiatry", Créteil, France; Fondation FondaMental, Créteil, France
| | - R A Schoevers
- University of Groningen, University Medical Center Groningen, Research School of Behavioral and Cognitive Neurosciences (BCN), Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands
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Branchi I, Poggini S, Capuron L, Benedetti F, Poletti S, Tamouza R, Drexhage HA, Penninx BWJH, Pariante CM. Brain-immune crosstalk in the treatment of major depressive disorder. Eur Neuropsychopharmacol 2021; 45:89-107. [PMID: 33386229 DOI: 10.1016/j.euroneuro.2020.11.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/04/2020] [Accepted: 11/30/2020] [Indexed: 02/08/2023]
Abstract
A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation.
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Affiliation(s)
- Igor Branchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
| | - Silvia Poggini
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Lucile Capuron
- University of Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France
| | - Francesco Benedetti
- Division of Neuroscience, Psychiatry and Clinical Psychobiology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Sara Poletti
- Division of Neuroscience, Psychiatry and Clinical Psychobiology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy
| | - Ryad Tamouza
- Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), Laboratoire Neuro-psychiatrie translationnelle, AP-HP, Université Paris Est Créteil, INSERM U955, IMRB, Hôpital Henri Mondor, Fondation FondaMental, F-94010 Créteil, France
| | - Hemmo A Drexhage
- Department of Immunology, ErasmusMC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Brenda W J H Penninx
- Department of Psychiatry, Amsterdam UMC, Department of Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Carmine M Pariante
- Department of Psychological Medicine, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
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- Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), Laboratoire Neuro-psychiatrie translationnelle, AP-HP, Université Paris Est Créteil, INSERM U955, IMRB, Hôpital Henri Mondor, Fondation FondaMental, F-94010 Créteil, France
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45
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Gay F, Romeo B, Martelli C, Benyamina A, Hamdani N. Cytokines changes associated with electroconvulsive therapy in patients with treatment-resistant depression: a Meta-analysis. Psychiatry Res 2021; 297:113735. [PMID: 33497973 DOI: 10.1016/j.psychres.2021.113735] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 01/14/2021] [Indexed: 12/11/2022]
Abstract
One third of depressive patients do not achieve remission after several steps of treatment and are considered as treatment resistant. Electroconvulsive therapy (ECT) improves symptoms in 70 to 90% of such cases. Resistant depression is associated with a dysregulation of the immune system with a dysbalance between the pro- and the anti-inflammatory cytokines. Therefore, we aimed to measure the kinetic of cytokines levels before, during and at the end of ECT. To test this hypothesis, we performed a meta-analysis assessing cytokines plasma levels before, during and after ECT in patients with major depressive disorders. After a systematic database search, means and standard deviations were extracted to calculate standardized mean differences. We found that IL-6 levels increased after 1 or 2 ECT session (p = 0.01) then decrease after 4 ECT sessions (p < 0.01) with no difference at the end of ECT (p = 0.94). A small number of studies were included and there was heterogeneity across them. The present meta-analysis reveals that ECT induces an initial increase of IL-6 levels and a potential decrease of TNF-α levels. No changes on IL-4 and IL-10 levels were found. Further work is necessary to clarify the impact of ECT on peripheral cytokines.
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Affiliation(s)
- F Gay
- APHP, Paul Brousse Hospital, Department of Psychiatry and Addictology, F-94800 Villejuif, France
| | - B Romeo
- APHP, Paul Brousse Hospital, Department of Psychiatry and Addictology, F-94800 Villejuif, France; Unité de recherche Psychiatrie-Comorbidités-Addictions - PSYCOMADD 4872 - Université Paris-Sud - AP-HP - Université Paris Saclay.
| | - C Martelli
- APHP, Paul Brousse Hospital, Department of Psychiatry and Addictology, F-94800 Villejuif, France; Unité de recherche Psychiatrie-Comorbidités-Addictions - PSYCOMADD 4872 - Université Paris-Sud - AP-HP - Université Paris Saclay; Institut National de la Santé et de la Recherche Médicale U1000, Research unit, NeuroImaging and Psychiatry, Paris Sud University, Paris Saclay University, Paris Descartes University, Digiteo Labs, Bâtiment 660, Gif-sur-Yvette, France
| | - A Benyamina
- APHP, Paul Brousse Hospital, Department of Psychiatry and Addictology, F-94800 Villejuif, France; Unité de recherche Psychiatrie-Comorbidités-Addictions - PSYCOMADD 4872 - Université Paris-Sud - AP-HP - Université Paris Saclay
| | - N Hamdani
- Unité de recherche Psychiatrie-Comorbidités-Addictions - PSYCOMADD 4872 - Université Paris-Sud - AP-HP - Université Paris Saclay; Cédiapsy, 1 avenue Jean Moulin 75014 Paris
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46
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Isung J, Granqvist M, Trepci A, Huang J, Schwieler L, Kierkegaard M, Erhardt S, Jokinen J, Piehl F. Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects. Sci Rep 2021; 11:1669. [PMID: 33462306 PMCID: PMC7814004 DOI: 10.1038/s41598-021-81306-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 01/04/2021] [Indexed: 02/01/2023] Open
Abstract
Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.
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Affiliation(s)
- Josef Isung
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
| | - Mathias Granqvist
- Division of Physiotherapy, Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, and Academic Specialist Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Ada Trepci
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Jesse Huang
- Division of Physiotherapy, Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, and Academic Specialist Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Lilly Schwieler
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Marie Kierkegaard
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Academic Specialist Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Sophie Erhardt
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Jussi Jokinen
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
- Department of Clinical Sciences, Umeå University, Umeå, Sweden
| | - Fredrik Piehl
- Division of Physiotherapy, Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, and Academic Specialist Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
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47
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Juruena MF, Jelen LA, Young AH, Cleare AJ. New Pharmacological Interventions in Bipolar Disorder. Curr Top Behav Neurosci 2021; 48:303-324. [PMID: 33547595 DOI: 10.1007/7854_2020_181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder. These mechanisms can interact to exacerbate inflammation, impair neurogenesis, and increase oxidative stress damage, cellular mitochondrial dysfunction, changes in neurotrophins and in epigenetic mechanisms, neuroendocrine dysfunction, activation of neuronal death pathways, and dysfunction in neurotransmission systems. In this review, we explore the up-to-date knowledge of the neurobiological underpinnings of bipolar disorders. The difficulty in developing new drugs for bipolar disorder is very much associated with the lack of knowledge about the precise pathophysiology of this disorder. Pharmacological treatment for bipolar patients is vital; to progress to effective medications, it is essential to understand the neurobiology in bipolar patients better and identify novel therapeutic targets.
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Affiliation(s)
- Mario F Juruena
- Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Luke A Jelen
- Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Allan H Young
- Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Anthony J Cleare
- Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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48
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Kurczewska E, Ferensztajn-Rochowiak E, Rybakowski F, Michalak M, Rybakowski J. Treatment-resistant depression: Neurobiological correlates and the effect of sleep deprivation with sleep phase advance for the augmentation of pharmacotherapy. World J Biol Psychiatry 2021; 22:58-69. [PMID: 32295463 DOI: 10.1080/15622975.2020.1755449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES To assess the neurobiology of treatment-resistant depression (TRD), and factors connected with improvement after total sleep deprivation (TSD) with sleep phase advance (SPA), for the augmentation of pharmacotherapy. METHODS The study comprised 43 patients with TRD, (15 male, 28 female), aged 48 ± 13 years, with the illness duration 12 ± 9 years, and the depressive episode 8 ± 7 months. TRD was defined as a lack of significant improvement despite at least two antidepressant treatments and the augmentation with mood-stabilisers. Clinical improvement (response) was a reduction of ≥50% of points in the Hamilton Depression Rating Scale (HDRS), and the remission criterion was ≤7 points in HDRS, lasting until the 14th day after TSD + SPA. RESULTS TRD severity was associated with greater activity of the hypothalamic-pituitary-adrenal axis, the pro-inflammatory status of the immune system and lower reactivity of the hypothalamic-pituitary-thyroid axis. The response was achieved by 18 of 42 subjects, and connected with the later onset and shorter duration of the disease. In responders, there was a decrease in cortisol and interferon-gamma. In all subjects, a decrease in thyroid hormones was observed. CONCLUSIONS TRD can improve after augmentation of pharmacotherapy by TSD + SPA and some biological changes may be compatible with a decrease in allostatic load.
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Affiliation(s)
- Ewa Kurczewska
- Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Filip Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
| | - Michał Michalak
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland
| | - Janusz Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.,Department of Psychiatric Nursing, Poznan University of Medical Sciences, Poznan, Poland
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49
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Nobis A, Zalewski D, Waszkiewicz N. Peripheral Markers of Depression. J Clin Med 2020; 9:E3793. [PMID: 33255237 PMCID: PMC7760788 DOI: 10.3390/jcm9123793] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/09/2020] [Accepted: 11/19/2020] [Indexed: 12/22/2022] Open
Abstract
Major Depressive Disorder (MDD) is a leading cause of disability worldwide, creating a high medical and socioeconomic burden. There is a growing interest in the biological underpinnings of depression, which are reflected by altered levels of biological markers. Among others, enhanced inflammation has been reported in MDD, as reflected by increased concentrations of inflammatory markers-C-reactive protein, interleukin-6, tumor necrosis factor-α and soluble interleukin-2 receptor. Oxidative and nitrosative stress also plays a role in the pathophysiology of MDD. Notably, increased levels of lipid peroxidation markers are characteristic of MDD. Dysregulation of the stress axis, along with increased cortisol levels, have also been reported in MDD. Alterations in growth factors, with a significant decrease in brain-derived neurotrophic factor and an increase in fibroblast growth factor-2 and insulin-like growth factor-1 concentrations have also been found in MDD. Finally, kynurenine metabolites, increased glutamate and decreased total cholesterol also hold promise as reliable biomarkers for MDD. Research in the field of MDD biomarkers is hindered by insufficient understanding of MDD etiopathogenesis, substantial heterogeneity of the disorder, common co-morbidities and low specificity of biomarkers. The construction of biomarker panels and their evaluation with use of new technologies may have the potential to overcome the above mentioned obstacles.
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Affiliation(s)
- Aleksander Nobis
- Department of Psychiatry, Medical University of Bialystok, pl. Brodowicza 1, 16-070 Choroszcz, Poland; (D.Z.); (N.W.)
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50
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Fukuda AM, Hindley LE, Kang JWD, Tirrell E, Tyrka AR, Ayala A, Carpenter LL. Peripheral vascular endothelial growth factor changes after transcranial magnetic stimulation in treatment-resistant depression. Neuroreport 2020; 31:1121-1127. [PMID: 32956213 PMCID: PMC7541741 DOI: 10.1097/wnr.0000000000001523] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To determine if vascular endothelial growth factor (VEGF) changes with transcranial magnetic stimulation (TMS) in treatment-resistant major depressive disorder (MDD). METHODS Serum from a naturalistic population of 15 patients with MDD was collected at baseline and after standard TMS treatment. VEGF concentration was determined via ELISA. Inventory of Depressive Symptomatology Self Report and Patient Health Questionnaire were used as a measure of depression symptom severity, clinical response and remission. Mann-Whitney U and Kendall's Tau Correlation were used for continuous variables. RESULTS VEGF increased from pre- to post-TMS (+30.3%) in remitters whereas VEGF decreased in non-remitters (-9.87%) (P < 0.05). This same pattern was observed when comparing mean %change in VEGF between responders (+14.7%) and non-responders (-14.9%) (P = 0.054). Correlation was present between change in VEGF concentration (baseline to post) and change in Inventory of Depressive Symptomatology-Self Report at Tx30 (r = -0.371, P < 0.054), reflecting greater increases in VEGF linked to greater improvement in depressive symptoms following the standard 6-week course of TMS. CONCLUSION Patients with a successful treatment with TMS had significantly greater increase in VEGF from baseline to after treatment compared to non-responders/non-remitters and a larger increase in VEGF was associated with greater improvement in depressive symptoms after TMS. This is the first report examining VEGF levels in depressed patients receiving TMS. This study provides correlative data supporting further investigation into VEGF's role as an important mediator in the processes underpinning TMS' antidepressant effects and as a potential biomarker of clinical outcomes.
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Affiliation(s)
- Andrew M. Fukuda
- Butler Hospital TMS Clinic and Neuromodulation Research Facility, 345 Blackstone Boulevard, Providence, RI, 02906, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI, 02912, USA
- Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, Rhode Island 02906, USA
| | - Lauren E. Hindley
- Butler Hospital TMS Clinic and Neuromodulation Research Facility, 345 Blackstone Boulevard, Providence, RI, 02906, USA
| | - Jee Won Diane Kang
- Butler Hospital TMS Clinic and Neuromodulation Research Facility, 345 Blackstone Boulevard, Providence, RI, 02906, USA
| | - Eric Tirrell
- Butler Hospital TMS Clinic and Neuromodulation Research Facility, 345 Blackstone Boulevard, Providence, RI, 02906, USA
| | - Audrey R Tyrka
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI, 02912, USA
- Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, Rhode Island 02906, USA
| | - Alfred Ayala
- Division of Surgical Research/Department of Surgery, Rhode Island Hospital/Brown University School of Medicine, Providence 02903, USA
| | - Linda L. Carpenter
- Butler Hospital TMS Clinic and Neuromodulation Research Facility, 345 Blackstone Boulevard, Providence, RI, 02906, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI, 02912, USA
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