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Campbell TS, Donoghue K, Roth TL. Gene Expression After Exercise Is Disrupted by Early-Life Stress. Dev Psychobiol 2025; 67:e70017. [PMID: 39780028 PMCID: PMC11711301 DOI: 10.1002/dev.70017] [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] [Indexed: 01/11/2025]
Abstract
Exercise can be leveraged as an important tool to improve neural and psychological health, either on its own or to bolster the efficacy of evidence-based treatment modalities. Research in both humans and animal models shows that positive experiences, such as exercise, promote neuroprotection while, in contrast, aversive experiences, particularly those in early development, are often neurologically and psychologically disruptive. In the current study, we employed a preclinical model to investigate the therapeutic benefits of exercise on gene expression in the brains of adult rats. Long Evans rats were exposed to maltreatment stress or nurturing care during infancy, with some rats later given voluntary running wheels as an aerobic exercise intervention from Postnatal Days 70 to 90. Our results showed that irisin gene expression, which promotes neuroprotection, was differentially affected by exercise and early exposure to stress. We add to a rapidly growing area of research on the neuroprotective benefits of exercise and shed light on important molecular mechanisms that may affect the efficacy of exercise in different individuals.
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Affiliation(s)
- Taylor S. Campbell
- Department of Psychological & Brain SciencesUniversity of DelawareNewarkDelawareUSA
| | - Katelyn Donoghue
- Department of Psychological & Brain SciencesUniversity of DelawareNewarkDelawareUSA
| | - Tania L. Roth
- Department of Psychological & Brain SciencesUniversity of DelawareNewarkDelawareUSA
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2
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Kroflin K, Zannas AS. Epigenetic Regulation in Psychosomatics and Psychotherapy. Am J Psychother 2024; 77:173-179. [PMID: 39344301 DOI: 10.1176/appi.psychotherapy.20230061] [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] [Indexed: 10/01/2024]
Abstract
Epigenetic modifications play a pivotal role in the regulation of gene expression and cell function, offering potential markers of disease states and therapeutic outcomes. Recent advancements in neuroscience have spurred interest in studying the epigenetic underpinnings of psychosomatic medicine. This review presents a new perspective on the role of epigenetic regulation in the realms of psychosomatics and psychotherapy. The authors first highlight epigenetic patterns associated with prevalent psychosomatic disorders, including irritable bowel syndrome, fibromyalgia, psoriasis, and lichen planus. For these conditions, psychotherapy serves as a treatment modality and can be conceptualized as an epigenetic intervention that beneficially affects the epigenome as part of the therapeutic process. Focusing on cognitive-behavioral and mindfulness-based therapies, the authors highlight evidence on psychotherapy-associated epigenetic signatures occurring at genes that are involved in stress response, inflammation, neurotransmission, neuroplasticity, and aging. Educating patients about the potential of psychotherapy to affect the epigenome may enhance patient engagement with and adherence to treatment, and psychotherapy-induced epigenetic changes have the potential to promote transgenerational disease prevention, underscoring the far-reaching implications of this therapeutic approach. Challenges persist in epigenetic studies, and this review aimed to catalyze further research in this burgeoning field, with the goal of enhancing patient care.
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Affiliation(s)
- Karla Kroflin
- University of Zagreb School of Medicine, Zagreb, Croatia (Kroflin); Department of Psychiatry and Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill (Zannas)
| | - Anthony S Zannas
- University of Zagreb School of Medicine, Zagreb, Croatia (Kroflin); Department of Psychiatry and Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill (Zannas)
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3
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Gescher DM, Schanze D, Vavra P, Wolff P, Zimmer-Bensch G, Zenker M, Frodl T, Schmahl C. Differential methylation of OPRK1 in borderline personality disorder is associated with childhood trauma. Mol Psychiatry 2024; 29:3734-3741. [PMID: 38862675 PMCID: PMC11609100 DOI: 10.1038/s41380-024-02628-z] [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: 09/19/2023] [Revised: 05/21/2024] [Accepted: 05/28/2024] [Indexed: 06/13/2024]
Abstract
According to a growing body of neurobiological evidence, the core symptoms of borderline personality disorder (BPD) may be linked to an opioidergic imbalance between the hedonic and stimulatory activity of mu opioid receptors (MOR) and the reward system inhibiting effects of kappa opioid receptors (KOR). Childhood trauma (CT), which is etiologically relevant to BPD, is also likely to lead to epigenetic and neurobiological adaptations by extensive activation of the stress and endogenous opioid systems. In this study, we investigated the methylation differences in the promoter of the KOR gene (OPRK1) in subjects with BPD (N = 47) and healthy controls (N = 48). Comparing the average methylation rates of regulatorily relevant subregions (specified regions CGI-1, CGI-2, EH1), we found no differences between BPD and HC. Analyzing individual CG nucleotides (N = 175), we found eight differentially methylated CG sites, all of which were less methylated in BPD, with five showing highly interrelated methylation rates. This differentially methylated region (DMR) was found on the falling slope (5') of the promoter methylation gap, whose effect is enhanced by the DMR hypomethylation in BPD. A dimensional assessment of the correlation between disease severity and DMR methylation rate revealed DMR hypomethylation to be negatively associated with BPD symptom severity (measured by BSL-23). Finally, analyzing the influence of CT on DMR methylation, we found DMR hypomethylation to correlate with physical and emotional neglect in childhood (quantified by CTQ). Thus, the newly identified DMR may be a biomarker of the risks caused by CT, which likely epigenetically contribute to the development of BPD.
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MESH Headings
- Humans
- Borderline Personality Disorder/genetics
- Female
- DNA Methylation/genetics
- Male
- Receptors, Opioid, kappa/genetics
- Receptors, Opioid, kappa/metabolism
- Adult
- Promoter Regions, Genetic/genetics
- Epigenesis, Genetic/genetics
- Receptors, Opioid, mu/genetics
- Receptors, Opioid, mu/metabolism
- Child Abuse/psychology
- Adverse Childhood Experiences
- Child
- Middle Aged
- Young Adult
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Affiliation(s)
- Dorothee Maria Gescher
- Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
- Department for General Psychiatry, Center of Psychosocial Medicine, Medical Faculty, Heidelberg University, Heidelberg, Germany.
- Department of Psychiatry and Psychotherapy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
| | - Denny Schanze
- Institute of Human Genetics, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Peter Vavra
- Department of Biological Psychology, Institute of Psychology, Otto-von-Guericke University, Magdeburg, Germany
| | - Philip Wolff
- Division of Neuroepigenetics, Institute of Zoology (Biology II), RWTH Aachen University, Aachen, Germany
| | - Geraldine Zimmer-Bensch
- Division of Neuroepigenetics, Institute of Zoology (Biology II), RWTH Aachen University, Aachen, Germany
| | - Martin Zenker
- Institute of Human Genetics, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Thomas Frodl
- Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Department of Psychiatry and Psychotherapy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
- German Center for Mental Health (DZPG), Jena-Magdeburg-Halle, Germany
- Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany
| | - Christian Schmahl
- Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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4
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Værøy H, Skar-Fröding R, Hareton E, Fetissov SO. Possible roles of neuropeptide/transmitter and autoantibody modulation in emotional problems and aggression. Front Psychiatry 2024; 15:1419574. [PMID: 39381606 PMCID: PMC11458397 DOI: 10.3389/fpsyt.2024.1419574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/30/2024] [Indexed: 10/10/2024] Open
Abstract
The theoretical foundations of understanding psychiatric disorders are undergoing changes. Explaining behaviour and neuroendocrine cell communication leaning towards immunology represents a different approach compared to previous models for understanding complex central nervous system processes. One such approach is the study of immunoglobulins or autoantibodies, and their effect on peptide hormones in the neuro-endocrine system. In the present review, we provide an overview of the literature on neuropeptide/transmitter and autoantibody modulation in psychiatric disorders featuring emotional problems and aggression, including associated illness behaviour. Finally, we discuss the role of psycho-immunology as a growing field in the understanding of psychiatric disorders, and that modulation and regulation by IgG autoAbs represent a relatively new subcategory in psycho-immunology, where studies are currently being conducted.
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Affiliation(s)
- Henning Værøy
- R&D Department, Division of Mental Health Services, Akershus University Hospital, Lørenskog, Norway
| | - Regina Skar-Fröding
- R&D Department, Division of Mental Health Services, Akershus University Hospital, Lørenskog, Norway
| | - Elin Hareton
- Department of Multidiciplinary Laboratory Medicine and Medical Biochemistry, (TLMB), Akershus University Hospital, Lørenskog, Norway
| | - Sergueï O. Fetissov
- Neuroendocrine, Endocrine and Germinal Differentiation and Communication Laboratory, Inserm UMR1239, University of Rouen Normandie, Rouen, France
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5
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Edelmann S, Balaji J, Pasche S, Wiegand A, Nieratschker V. DNA Methylation of PXDN Is Associated with Early-Life Adversity in Adult Mental Disorders. Biomolecules 2024; 14:976. [PMID: 39199364 PMCID: PMC11353138 DOI: 10.3390/biom14080976] [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: 06/30/2024] [Revised: 08/01/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open
Abstract
Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN-cg10888111-in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.
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Affiliation(s)
- Susanne Edelmann
- Department of Psychiatry and Psychotherapy, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany
- German Center for Mental Health (DZPG), Partner Site Tuebingen, 72076 Tuebingen, Germany
| | - Jeysri Balaji
- Department of Psychiatry and Psychotherapy, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany
| | - Sarah Pasche
- Department of Psychiatry and Psychotherapy, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany
| | - Ariane Wiegand
- Max Planck Fellow Group Precision Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, 80336 Munich, Germany
| | - Vanessa Nieratschker
- Department of Psychiatry and Psychotherapy, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany
- German Center for Mental Health (DZPG), Partner Site Tuebingen, 72076 Tuebingen, Germany
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6
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Tomasetti C, Autullo G, Ballerini A, de Bartolomeis A, Dell'Osso B, Fiorentini A, Tonioni F, Villari V, De Berardis D. Treating depression in patients with borderline personality disorder: clinical clues on the use of antidepressants. Ann Gen Psychiatry 2024; 23:21. [PMID: 38816843 PMCID: PMC11140967 DOI: 10.1186/s12991-024-00507-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/23/2024] [Indexed: 06/01/2024] Open
Abstract
Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD.
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Affiliation(s)
- Carmine Tomasetti
- Department of Mental Health, Alzheimer Center of Giulianova, Hospital "Maria SS dello Splendore", ASL Teramo, Giulianova (TE), Italy.
| | - G Autullo
- Psychiatry and Psychology Institute, Catholic University of Sacred Heart of Rome, Rome, Italy
| | - A Ballerini
- Psychiatry Unit, Department of Health Science, University of Florence, Largo Brambilla 3, Florence, 50134, Italy
| | - A de Bartolomeis
- Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Dentistry, University of Naples "Federico II", Naples, Italy
| | - B Dell'Osso
- Department of Mental Health, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
| | - A Fiorentini
- Department of Neurosciences and Mental Health, Ca' Granda Ospedale Maggiore Policlinico, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), University of Milan, Milan, Italy
| | - F Tonioni
- Psychiatric Emergency Service, Department of Neuroscience and Mental Health, A.O.U. "Città della Salute e della Scienza", Turin, Italy
| | - V Villari
- Psychiatry and Psychology Institute, Catholic University of Sacred Heart of Rome, Rome, Italy
| | - D De Berardis
- Department of Mental Health, Mental Health Center of Giulianova, ASL Teramo, Teramo, Italy
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7
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Penadés R, Almodóvar-Payá C, García-Rizo C, Ruíz V, Catalán R, Valero S, Wykes T, Fatjó-Vilas M, Arias B. Changes in BDNF methylation patterns after cognitive remediation therapy in schizophrenia: A randomized and controlled trial. J Psychiatr Res 2024; 173:166-174. [PMID: 38537483 DOI: 10.1016/j.jpsychires.2024.03.014] [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: 10/20/2023] [Revised: 03/09/2024] [Accepted: 03/13/2024] [Indexed: 04/17/2024]
Abstract
Although cognitive remediation therapy (CRT) produces cognitive benefits in schizophrenia, we do not yet understand whether molecular changes are associated with this cognitive improvement. A gene central to synaptic plasticity, the BDNF, has been proposed as one potential route. This study assesses whether BDNF methylation changes following CRT-produced cognitive improvement are detected. A randomized and controlled trial was performed with two groups (CRT, n = 40; TAU: Treatment as Usual, n = 20) on a sample of participants with schizophrenia. CRT was delivered by trained therapists using a web-based computerized program. Mixed Models, where the interaction of treatment (CRT, TAU) by time (T0: 0 weeks, T1: 16 weeks) was the main effect were used. Then, we tested the association between the treatment and methylation changes in three CpG islands of the BDNF gene. CRT group showed significant improvements in some cognitive domains. Between-groups differential changes in 5 CpG units over time were found, 4 in island 1 (CpG1.2, CpG1.7, CpG1.10, CpG1.17) and 1 in island 3 (CpG3.2). CRT group showed increases in methylation in CpG1.2, CpG1.7 and decreases in pG1.10, CpG1.17, and CpG3.2. Differences in the degree of methylation were associated with changes in Speed of Processing, Working Memory, and Verbal Learning within the CRT group. Those findings provide new data on the relationship between cognitive improvement and changes in peripheral methylation levels of BDNF gene, a key factor involved in neuroplasticity regulation. Trial Registration: NCT04278027.
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Affiliation(s)
- Rafael Penadés
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain; Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
| | - Carmen Almodóvar-Payá
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Clemente García-Rizo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain; Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Victoria Ruíz
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain
| | - Rosa Catalán
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain; Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Sergi Valero
- ACE Alzheimer Center Barcelona, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Til Wykes
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; South London & Maudsley NHS Foundation Trust, London Hospital, London, United Kingdom
| | - Mar Fatjó-Vilas
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Bárbara Arias
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
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Taylor JY, Jones-Patten A, Prescott L, Potts-Thompson S, Joyce C, Tayo B, Saban K. The race-based stress reduction intervention (RiSE) study on African American women in NYC and Chicago: Design and methods for complex genomic analysis. PLoS One 2024; 19:e0295293. [PMID: 38598554 PMCID: PMC11006145 DOI: 10.1371/journal.pone.0295293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 11/19/2023] [Indexed: 04/12/2024] Open
Abstract
RiSE study aims to evaluate a race-based stress-reduction intervention as an effective strategy to improve coping and decrease stress-related symptoms, inflammatory burden, and modify DNA methylation of stress response-related genes in older AA women. This article will describe genomic analytic methods to be utilized in this longitudinal, randomized clinical trial of older adult AA women in Chicago and NYC that examines the effect of the RiSE intervention on DNAm pre- and post-intervention, and its overall influence on inflammatory burden. Salivary DNAm will be measured at baseline and 6 months following the intervention, using the Oragene-DNA kit. Measures of perceived stress, depressive symptoms, fatigue, sleep, inflammatory burden, and coping strategies will be assessed at 4 time points including at baseline, 4 weeks, 8 weeks, and 6 months. Genomic data analysis will include the use of pre-processed and quality-controlled methylation data expressed as beta (β) values. Association analyses will be performed to detect differentially methylated sites on the targeted candidate genes between the intervention and non-intervention groups using the Δβ (changes in methylation) with adjustment for age, health behaviors, early life adversity, hybridization batch, and top principal components of the probes as covariates. To account for multiple testing, we will use FDR adjustment with a corrected p-value of <0.05 regarded as statistically significant. To assess the relationship between inflammatory burden and Δβ among the study samples, we will repeat association analyses with the inclusion of individual inflammation protein measures. ANCOVA will be used because it is more statistically powerful to detect differences.
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Affiliation(s)
- Jacquelyn Y. Taylor
- Center for Research on People of Color, Columbia University School of Nursing, New York, New York, United States of America
| | - Alexandria Jones-Patten
- Center for Research on People of Color, Columbia University School of Nursing, New York, New York, United States of America
| | - Laura Prescott
- Center for Research on People of Color, Columbia University School of Nursing, New York, New York, United States of America
| | - Stephanie Potts-Thompson
- Center for Research on People of Color, Columbia University School of Nursing, New York, New York, United States of America
| | - Cara Joyce
- Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Bamidele Tayo
- Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Karen Saban
- Marcella Niehoff School of Nursing, Center for Translational Research and Education, Loyola University Chicago, Maywood, Illinois, United States of America
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Carvalho Silva R, Martini P, Hohoff C, Mattevi S, Bortolomasi M, Menesello V, Gennarelli M, Baune BT, Minelli A. DNA methylation changes in association with trauma-focused psychotherapy efficacy in treatment-resistant depression patients: a prospective longitudinal study. Eur J Psychotraumatol 2024; 15:2314913. [PMID: 38362742 PMCID: PMC10878335 DOI: 10.1080/20008066.2024.2314913] [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: 08/29/2023] [Accepted: 01/30/2024] [Indexed: 02/17/2024] Open
Abstract
Background: Stressful events increase the risk for treatment-resistant depression (TRD), and trauma-focused psychotherapy can be useful for TRD patients exposed to early life stress (ELS). Epigenetic processes are known to be related to depression and ELS, but there is no evidence of the effects of trauma-focused psychotherapy on methylation alterations.Objective: We performed the first epigenome-wide association study to investigate methylation changes related to trauma-focused psychotherapies effects in TRD patients.Method: Thirty TRD patients assessed for ELS underwent trauma-focused psychotherapy, of those, 12 received trauma-focused cognitive behavioural therapy, and 18 Eye Movement Desensitization and Reprocessing (EMDR). DNA methylation was profiled with Illumina Infinium EPIC array at T0 (baseline), after 8 weeks (T8, end of psychotherapy) and after 12 weeks (T12 - follow-up). We examined differentially methylated CpG sites and regions, as well as pathways analysis in association with the treatment.Results: Main results obtained have shown 110 differentially methylated regions (DMRs) with a significant adjusted p-value area associated with the effects of trauma-focused psychotherapies in the entire cohort. Several annotated genes are related to inflammatory processes and psychiatric disorders, such as LTA, GFI1, ARID5B, TNFSF13, and LST1. Gene enrichment analyses revealed statistically significant processes related to tumour necrosis factor (TNF) receptor and TNF signalling pathway. Stratified analyses by type of trauma-focused psychotherapy showed statistically significant adjusted p-value area in 141 DMRs only for the group of patients receiving EMDR, with annotated genes related to inflammation and psychiatric disorders, including LTA, GFI1, and S100A8. Gene set enrichment analyses in the EMDR group indicated biological processes related to inflammatory response, particularly the TNF signalling pathway.Conclusion: We provide preliminary valuable insights into global DNA methylation changes associated with trauma-focused psychotherapies effects, in particular with EMDR treatment.
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Affiliation(s)
- Rosana Carvalho Silva
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Paolo Martini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Christa Hohoff
- Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
| | - Stefania Mattevi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | - Valentina Menesello
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, 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
| | - Bernhard T. Baune
- Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
- Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, Australia
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
| | - 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
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Wannemüller A, Kumsta R, Moser D, Jöhren HP, Margraf J. DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment. J Psychiatr Res 2024; 170:73-80. [PMID: 38103452 DOI: 10.1016/j.jpsychires.2023.12.001] [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: 07/10/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.
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Affiliation(s)
- André Wannemüller
- Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Germany.
| | - Robert Kumsta
- Department of Genetic Psychology, Ruhr-Universität Bochum, Germany
| | - Dirk Moser
- Department of Genetic Psychology, Ruhr-Universität Bochum, Germany
| | | | - Jürgen Margraf
- Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Germany
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11
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Petruso F, Giff A, Milano B, De Rossi M, Saccaro L. Inflammation and emotion regulation: a narrative review of evidence and mechanisms in emotion dysregulation disorders. Neuronal Signal 2023; 7:NS20220077. [PMID: 38026703 PMCID: PMC10653990 DOI: 10.1042/ns20220077] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Emotion dysregulation (ED) describes a difficulty with the modulation of which emotions are felt, as well as when and how these emotions are experienced or expressed. It is a focal overarching symptom in many severe and prevalent neuropsychiatric diseases, including bipolar disorders (BD), attention deficit/hyperactivity disorder (ADHD), and borderline personality disorder (BPD). In all these disorders, ED can manifest through symptoms of depression, anxiety, or affective lability. Considering the many symptomatic similarities between BD, ADHD, and BPD, a transdiagnostic approach is a promising lens of investigation. Mounting evidence supports the role of peripheral inflammatory markers and stress in the multifactorial aetiology and physiopathology of BD, ADHD, and BPD. Of note, neural circuits that regulate emotions appear particularly vulnerable to inflammatory insults and peripheral inflammation, which can impact the neuroimmune milieu of the central nervous system. Thus far, few studies have examined the link between ED and inflammation in BD, ADHD, and BPD. To our knowledge, no specific work has provided a critical comparison of the results from these disorders. To fill this gap in the literature, we review the known associations and mechanisms linking ED and inflammation in general, and clinically, in BD, ADHD, and BD. Our narrative review begins with an examination of the routes linking ED and inflammation, followed by a discussion of disorder-specific results accounting for methodological limitations and relevant confounding factors. Finally, we critically discuss both correspondences and discrepancies in the results and comment on potential vulnerability markers and promising therapeutic interventions.
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Affiliation(s)
| | - Alexis E. Giff
- Department of Neuroscience, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Switzerland
| | - Beatrice A. Milano
- Sant’Anna School of Advanced Studies, Pisa, Italy
- University of Pisa, Pisa, Italy
| | | | - Luigi Francesco Saccaro
- Department of Psychiatry, Faculty of Medicine, University of Geneva, Switzerland
- Department of Psychiatry, Geneva University Hospital, Switzerland
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12
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Lacroix A, Ramoz N, Girard M, Plansont B, Poupon D, Gorwood P, Nubukpo P. BDNF CpG methylation and serum levels covary during alcohol withdrawal in patients with alcohol use disorder: A pilot study. World J Biol Psychiatry 2023; 24:854-859. [PMID: 37526632 DOI: 10.1080/15622975.2023.2242924] [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: 04/04/2023] [Revised: 07/04/2023] [Accepted: 07/27/2023] [Indexed: 08/02/2023]
Abstract
OBJECTIVES Brain-derived neurotrophic factor (BDNF) levels vary in various conditions including alcohol use disorder (AUD). We aimed to identify drivers of these variations. METHODS Twelve patients with AUD were assessed at hospitalisation for alcohol withdrawal and four months later. We looked for associations between the change in serum BDNF levels and (1) length of abstinence, (2) anxiety (Hamilton Anxiety Scale) and depression (Beck-Depression Inventory), (3) one functional BDNF genotype (rs6265) and (4) methylation levels of 12 CpG sites within the BDNF gene (located in exons I, IV and IX). RESULTS While abstinence remained, serum BDNF level increased. This increase correlated with the variation of methylation levels of the BDNF gene, and more specifically of exon I. We found no significant effect of length of abstinence, rs6265, depression or anxiety on serum BDNF level. CONCLUSIONS Epigenetic regulation of the BDNF gene may be involved in variations of BDNF blood level associated with alcohol abstinence.
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Affiliation(s)
- Aurélie Lacroix
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
| | - Nicolas Ramoz
- Université Paris Cité, INSERM, U1266 (Institute of Psychiatry and Neuroscience of Paris), Paris, France
| | - Murielle Girard
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
| | - Brigitte Plansont
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
| | - Daphnée Poupon
- Clinique des Maladies Mentales et de l'Encéphale (CMME), Sainte-Anne Hospital, GHU Paris Psychiatrie et Neurosciences, Paris, France
| | - Philip Gorwood
- Université Paris Cité, INSERM, U1266 (Institute of Psychiatry and Neuroscience of Paris), Paris, France
- Clinique des Maladies Mentales et de l'Encéphale (CMME), Sainte-Anne Hospital, GHU Paris Psychiatrie et Neurosciences, Paris, France
| | - Philippe Nubukpo
- Unité de Recherche et d'Innovation, Fédération de la recherche et de l'innovation, Centre Hospitalier Esquirol, Limoges, France
- Inserm U1094, IRD U270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of Chronic Diseases in Tropical Zone, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France
- Pôle Universitaire d'Addictologie, Centre Hospitalier Esquirol, Limoges, France
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13
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Ansari D, Lakkimsetti M, Olaleye KT, Bhullar JVK, Shah RZ, Arisoyin AE, Nadeem H, Sacal Slovik SC, Habib FZ, Abdin ZU, Zia Ul Haq M. Genetic Influences on Outcomes of Psychotherapy in Borderline Personality Disorder: A Narrative Review of Implications for Personalized Treatment. Cureus 2023; 15:e43702. [PMID: 37724239 PMCID: PMC10505449 DOI: 10.7759/cureus.43702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 08/18/2023] [Indexed: 09/20/2023] Open
Abstract
Borderline personality disorder (BPD) manifests as instability in mood, relationships, self-image, and behavior, representing a challenging mental health issue. This review scrutinizes genetic factors influencing BPD and the corresponding treatment outcomes. The primary objective of this narrative review is to illuminate the association between genetic factors and BPD treatment outcomes, discussing the potential of genetic testing for personalized therapy. The review is derived from observational and experimental studies on BPD, genetic factors, and psychotherapy from 2000 to 2023, sourced primarily through PubMed. Reviews and meta-analyses were excluded. Our review suggests that genetic factors account for 40-60% of BPD variation, with significant roles played by epigenetic alterations like DNA methylation and microRNAs, particularly in the context of childhood trauma. Gene-environment interactions are also vital for BPD's development. Treatments such as dialectical behavior therapy, mentalization-based therapy, and schema therapy have shown efficacy, with success variability possibly linked to genetic factors. However, existing research is constrained by recall bias, diverse methodologies, and limited sample sizes. Future research necessitates long-term follow-up, diverse populations, and controlled variables to enhance our comprehension of BPD treatment outcomes' genetic foundations. The review underlines the promise of personalized medicine in BPD treatment, driven by genetic insights.
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Affiliation(s)
- Danya Ansari
- Psychiatry, Islamabad Medical and Dental College, Islamabad, PAK
| | | | | | | | - Rida Z Shah
- Psychiatry and Behavioral Sciences, Dow University of Health Sciences, Karachi, PAK
| | | | - Huzaifa Nadeem
- Psychiatry, Combined Military Hospital (CMH) Lahore Medical College, Lahore, PAK
| | | | | | - Zain U Abdin
- Medicine, District Head Quarter Hospital, Faisalabad, PAK
| | - Muhammad Zia Ul Haq
- Epidemiology and Public Health, Emory University Rollins School of Public Health, Atlanta, USA
- Noncommunicable Diseases and Mental Health, World Health Organization, Cairo, EGY
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14
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Rivi V, Rigillo G, Toscano Y, Benatti C, Blom JMC. Narrative Review of the Complex Interaction between Pain and Trauma in Children: A Focus on Biological Memory, Preclinical Data, and Epigenetic Processes. CHILDREN (BASEL, SWITZERLAND) 2023; 10:1217. [PMID: 37508714 PMCID: PMC10378710 DOI: 10.3390/children10071217] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023]
Abstract
The incidence and collective impact of early adverse experiences, trauma, and pain continue to increase. This underscores the urgent need for translational efforts between clinical and preclinical research to better understand the underlying mechanisms and develop effective therapeutic approaches. As our understanding of these issues improves from studies in children and adolescents, we can create more precise preclinical models and ultimately translate our findings back to clinical practice. A multidisciplinary approach is essential for addressing the complex and wide-ranging effects of these experiences on individuals and society. This narrative review aims to (1) define pain and trauma experiences in childhood and adolescents, (2) discuss the relationship between pain and trauma, (3) consider the role of biological memory, (4) decipher the relationship between pain and trauma using preclinical data, and (5) examine the role of the environment by introducing the importance of epigenetic processes. The ultimate scope is to better understand the wide-ranging effects of trauma, abuse, and chronic pain on children and adolescents, how they occur, and how to prevent or mitigate their effects and develop effective treatment strategies that address both the underlying causes and the associated physiological and psychological effects.
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Affiliation(s)
- Veronica Rivi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Giovanna Rigillo
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Ylenia Toscano
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Cristina Benatti
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
- Centre of Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Johanna Maria Catharina Blom
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
- Centre of Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41125 Modena, Italy
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15
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Chbeir S, Carrión V. Resilience by design: How nature, nurture, environment, and microbiome mitigate stress and allostatic load. World J Psychiatry 2023; 13:144-159. [PMID: 37303926 PMCID: PMC10251360 DOI: 10.5498/wjp.v13.i5.144] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/11/2023] [Accepted: 04/17/2023] [Indexed: 05/19/2023] Open
Abstract
Resilience to psychological stress is defined as adaption to challenging life experiences and not the absence of adverse life events. Determinants of resilience include personality traits, genetic/epigenetic modifications of genes involved in the stress response, cognitive and behavioral flexibility, secure attachment with a caregiver, social and community support systems, nutrition and exercise, and alignment of circadian rhythm to the natural light/dark cycle. Therefore, resilience is a dynamic and flexible process that continually evolves by the intersection of different domains in human’s life; biological, social, and psychological. The objective of this minireview is to summarize the existing knowledge about the multitude factors and molecular alterations that result from resilience to stress response. Given the multiple contributing factors in building resilience, we set out a goal to identify which factors were most supportive of a causal role by the current literature. We focused on resilience-related molecular alterations resulting from mind-body homeostasis in connection with psychosocial and environmental factors. We conclude that there is no one causal factor that differentiates a resilient person from a vulnerable one. Instead, building resilience requires an intricate network of positive experiences and a healthy lifestyle that contribute to a balanced mind-body connection. Therefore, a holistic approach must be adopted in future research on stress response to address the multiple elements that promote resilience and prevent illnesses and psychopathology related to stress allostatic load.
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Affiliation(s)
- Souhad Chbeir
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
| | - Victor Carrión
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
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16
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Ben David G, Amir Y, Salalha R, Sharvit L, Richter-Levin G, Atzmon G. Can Epigenetics Predict Drug Efficiency in Mental Disorders? Cells 2023; 12:1173. [PMID: 37190082 PMCID: PMC10136455 DOI: 10.3390/cells12081173] [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: 01/31/2023] [Revised: 03/23/2023] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
Psychiatric disorders affect millions of individuals and their families worldwide, and the costs to society are substantial and are expected to rise due to a lack of effective treatments. Personalized medicine-customized treatment tailored to the individual-offers a solution. Although most mental diseases are influenced by genetic and environmental factors, finding genetic biomarkers that predict treatment efficacy has been challenging. This review highlights the potential of epigenetics as a tool for predicting treatment efficacy and personalizing medicine for psychiatric disorders. We examine previous studies that have attempted to predict treatment efficacy through epigenetics, provide an experimental model, and note the potential challenges at each stage. While the field is still in its infancy, epigenetics holds promise as a predictive tool by examining individual patients' epigenetic profiles in conjunction with other indicators. However, further research is needed, including additional studies, replication, validation, and application beyond clinical settings.
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Affiliation(s)
- Gil Ben David
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel; (G.B.D.); (R.S.)
| | - Yam Amir
- Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel; (Y.A.)
| | - Randa Salalha
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel; (G.B.D.); (R.S.)
| | - Lital Sharvit
- Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel; (Y.A.)
| | - Gal Richter-Levin
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel; (G.B.D.); (R.S.)
- Department of Psychology, Faculty of Social Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel
- Integrated Brain and Behavior Research Center (IBBR), University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel
| | - Gil Atzmon
- Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, Haifa 3498838, Israel; (Y.A.)
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17
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Treble-Barna A, Heinsberg LW, Stec Z, Breazeale S, Davis TS, Kesbhat AA, Chattopadhyay A, VonVille HM, Ketchum AM, Yeates KO, Kochanek PM, Weeks DE, Conley YP. Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: A systematic review. Neurosci Biobehav Rev 2023; 147:105078. [PMID: 36764636 PMCID: PMC10164361 DOI: 10.1016/j.neubiorev.2023.105078] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/17/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023]
Abstract
Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
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Affiliation(s)
- Amery Treble-Barna
- Department of Physical Medicine & Rehabilitation, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Lacey W Heinsberg
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Zachary Stec
- Department of Physical Medicine & Rehabilitation, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Stephen Breazeale
- Department of Health and Human Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Tara S Davis
- Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, PA 15261, USA.
| | | | - Ansuman Chattopadhyay
- Molecular Biology Information Service, Health Sciences Library System, University of Pittsburgh, USA
| | - Helena M VonVille
- Health Sciences Library System, University of Pittsburgh, PA 15261, USA.
| | - Andrea M Ketchum
- Emeritus Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Keith Owen Yeates
- Department of Psychology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N1N4, Canada.
| | - Patrick M Kochanek
- Safar Center for Resuscitation Research, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Daniel E Weeks
- Department of Human Genetics and Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Yvette P Conley
- Department of Human Genetics, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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18
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Forte A, Lessa P, Chaves A, de Aquino P, Brito L, Pinheiro L, Juruena M, de Lucena D, de Rezende P, de Vasconcelos S. Oxidative stress and inflammatory process in borderline personality disorder (BPD): a narrative review. Braz J Med Biol Res 2023; 56:e12484. [PMID: 36946840 PMCID: PMC10021502 DOI: 10.1590/1414-431x2023e12484] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/13/2023] [Indexed: 03/23/2023] Open
Abstract
Borderline personality disorder (BPD) is a severe psychiatric condition that affects up to 2.7% of the population and is highly linked to functional impairment and suicide. Despite its severity, there is a lack of knowledge about its pathophysiology. Studies show genetic influence and childhood violence as factors that may contribute to the development of BPD; however, the involvement of neuroinflammation in BPD remains poorly investigated. This article aimed to explore the pathophysiology of BPD according to the levels of brain-derived neurotrophic factor (BDNF), inflammatory cytokines, and oxidative stress substances that exacerbate neuronal damage. Few articles have been published on this theme. They show that patients with BPD have a lower level of BDNF and a higher level of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in peripheral blood, associated with increased plasma levels of oxidative stress markers, such as malondialdehyde and 8-hydroxy-2-deoxyguanosine. Therefore, more research on the topic is needed, mainly with a pre-clinical and clinical focus.
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Affiliation(s)
- A.R.C.C. Forte
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - P.H.C. Lessa
- Curso de Medicina, Departamento de Ciências Biológicas e da Saúde (DCBS), Universidade Federal do Amapá, Macapá, AP, Brasil
| | - A.J.M. Chaves
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - P.E.A. de Aquino
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - L.M. Brito
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - L.C. Pinheiro
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - M.F. Juruena
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - D.F. de Lucena
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - P.H.F. de Rezende
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - S.M.M. de Vasconcelos
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
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19
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Zhou A, Ancelin ML, Ritchie K, Ryan J. Childhood adverse events and BDNF promoter methylation in later-life. Front Psychiatry 2023; 14:1108485. [PMID: 36911114 PMCID: PMC9998928 DOI: 10.3389/fpsyt.2023.1108485] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 02/13/2023] [Indexed: 03/14/2023] Open
Abstract
Studies have shown that the effects of early-life stress and trauma can be enduring, with long-term negative effects on health. Epigenetics, including DNA methylation, have been implicated as a potential mechanism for these effects. Brain-derived neurotropic factor (BDNF) is a neurotransmitter involved in learning and memory, and altered BDNF promoter methylation measured in peripheral tissue has been found with early-life stress. However, whether such methylation differences remain stable into later life, is unknown. This study aimed to investigate the association between childhood adversity and BDNF promoter methylation in adults aged 65 years and over. Data came from a large study of older community-dwelling individuals in France (ESPRIT). Information on three major childhood adverse events, namely abuse/maltreatment, war/natural disaster, and financial difficulties/poverty, was obtained by retrospective reporting from participants of ESPRIT study. BDNF promoter I and IV methylation was assessed in blood and buccal tissue. Linear regression analysis was performed, adjusting for age, sex, education, depression, and morbidity. Among 927 participants, there was no strong evidence that childhood abuse/maltreatment or financial difficulties/poverty were associated with BDNF methylation in older individuals. For war/natural disaster, differential methylation at four of twenty-nine CpG sites was observed, however, these would not have remained significant after correction for multiple testing. Together, these findings do not support a long-term association between adverse childhood events and BDNF methylation in older age, but further large prospective studies are needed, which do not target specific genes, but consider DNA methylation across the genome.
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Affiliation(s)
- Aoshuang Zhou
- Division of Epidemiology, Jockey Club School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Marie-Laure Ancelin
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Karen Ritchie
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Joanne Ryan
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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20
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You JS, Lee CW, Park JY, Jang Y, Yu H, Yoon J, Kwon SS, Oh S, Park YS, Ryoo HA, Lee JH, Lee D, Lee J, Kim Y, Cho N, Ihm HK, Park CHK, Lee YC, Won HH, Kang HS, Beak JH, Ha TH, Myung W. Borderline Personality Pathology in Major Depressive Disorder, Bipolar I and II Disorder, and Its Relationship With Childhood Trauma. Psychiatry Investig 2022; 19:909-918. [PMID: 36444154 PMCID: PMC9708861 DOI: 10.30773/pi.2022.0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/21/2022] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Mood disorder and borderline personality pathology (BPP) are frequently comorbid and relate to childhood trauma. We investigated the relationship between childhood trauma and BPP features in mood disorder patients versus controls. METHODS A total of 488 mood disorder patients, particularly major depressive disorder (MDD), bipolar I disorder (BD I), and bipolar II disorder (BD II), and 734 controls were included. We examined between-group BPP-related differences and correlated between BPP and childhood trauma using the Childhood Trauma Questionnaire-Short Form (CTQ) and the Personality Assessment Inventory-Borderline Features Scale. RESULTS BD II patients showed significantly higher BPP. Emotional abuse and neglect were prominently associated with BPP, while affective instability and negative relationships exhibited a stronger association with childhood trauma. We also found a positive relationship between childhood trauma and BPP in MDD, BD I, and BD II patients. CONCLUSION The findings of the present study imply that BPP features are more likely to be found in patients with BD II than BD I or MDD. Mood disorder patients with severe childhood trauma may have higher BPP features. Thus, further study of the relationship between childhood trauma and BPP features could improve the therapeutic approaches and help understand patients with mood disorders.
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Affiliation(s)
- Ji Seon You
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.,Department of Psychiatry, Asan Medical Center, Seoul, Republic of Korea
| | - Chan Woo Lee
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ji Yoon Park
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yoonjeong Jang
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyeona Yu
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Joohyun Yoon
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sarah Soonji Kwon
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sunghee Oh
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yun Seong Park
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyun A Ryoo
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jong Hun Lee
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Daseul Lee
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jakyung Lee
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yeoju Kim
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Nayoung Cho
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hong Kyu Ihm
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - C Hyung Keun Park
- Department of Psychiatry, Asan Medical Center, Seoul, Republic of Korea
| | - Yeong Chan Lee
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
| | - Hong-Hee Won
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
| | - Hyo Shin Kang
- Department of Psychology, Kyungpook National University, Daegu, Republic of Korea
| | - Ji Hyun Beak
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Tae Hyon Ha
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.,Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Woojae Myung
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.,Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
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No evidence for intervention-associated DNA methylation changes in monocytes of patients with posttraumatic stress disorder. Sci Rep 2022; 12:17347. [PMID: 36253434 PMCID: PMC9576776 DOI: 10.1038/s41598-022-22177-1] [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: 08/03/2021] [Accepted: 10/11/2022] [Indexed: 01/10/2023] Open
Abstract
DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent studies have observed correlations between DNA methylation changes and therapy outcome. However, most did not control for changes in cell composition. This study had two aims: first, we sought to replicate therapy-associated changes in DNA methylation of commonly assessed candidate genes in isolated monocytes from 60 female patients with post-traumatic stress disorder (PTSD). Our second, exploratory goal was to identify novel genomic regions with substantial pre-to-post intervention DNA methylation changes by performing whole-genome bisulfite sequencing (WGBS) in two patients with PTSD. Equivalence testing and Bayesian analyses provided evidence against physiologically meaningful intervention-associated DNA methylation changes in monocytes of PTSD patients in commonly investigated target genes (NR3C1, FKBP5, SLC6A4, OXTR). Furthermore, WGBS yielded only a limited set of candidate regions with suggestive evidence of differential DNA methylation pre- to post-therapy. These differential DNA methylation patterns did not prove replicable when investigated in the entire cohort. We conclude that there is no evidence for major, recurrent intervention-associated DNA methylation changes in the investigated genes in monocytes of patients with PTSD.
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22
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Early Life Stress Affects Bdnf Regulation: A Role for Exercise Interventions. Int J Mol Sci 2022; 23:ijms231911729. [PMID: 36233029 PMCID: PMC9569911 DOI: 10.3390/ijms231911729] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/17/2022] Open
Abstract
Early life stress (ELS) encompasses exposure to aversive experiences during early development, such as neglect or maltreatment. Animal and human studies indicate that ELS has maladaptive effects on brain development, leaving individuals more vulnerable to developing behavioral and neuropsychiatric disorders later in life. This result occurs in part to disruptions in Brain derived neurotrophic factor (Bdnf) gene regulation, which plays a vital role in early neural programming and brain health in adulthood. A potential treatment mechanism to reverse the effects of ELS on Bdnf expression is aerobic exercise due to its neuroprotective properties and positive impact on Bdnf expression. Aerobic exercise opens the door to exciting and novel potential treatment strategies because it is a behavioral intervention readily and freely available to the public. In this review, we discuss the current literature investigating the use of exercise interventions in animal models of ELS to reverse or mitigate ELS-induced changes in Bdnf expression. We also encourage future studies to investigate sensitive periods of exercise exposure, as well as sufficient duration of exposure, on epigenetic and behavioral outcomes to help lead to standardized practices in the exercise intervention field.
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23
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Pino O, Cadena RT, Poli D. A Comprehensive Review on Multifaceted Mechanisms Involved in the Development of Breast Cancer Following Adverse Childhood Experiences (ACEs). INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:12615. [PMID: 36231913 PMCID: PMC9565960 DOI: 10.3390/ijerph191912615] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND AND AIM OF THE WORK Adverse Childhood Experiences (ACEs) may give rise to harmful effects on health throughout life. Epigenetic changes explain how preexisting risk factors may contribute to produce altered biological responses and cancer risk. The main aim of the review is to summarize studies examining the means in which Adverse Childhood Experiences (ACEs) can modulate individual vulnerability to breast cancer (BC) development through multifaceted mechanisms. METHODS Studies selection, data extraction, and assessments agreed to PRISMA criteria. We included original research with clinical samples following BC interventions, investigating potential mechanisms linking ACEs and BC in adults. RESULTS From the 3321 papers found, nine articles involving 2931 participants were selected. All studies included ACEs retrospective assessments and psychological measures, and seven of them considered biomarkers. Individuals exposed to greater ACEs were at increased BC risk compared with individuals with no ACEs. Associations were found between child abuse and/or neglect, depression, perceived stress, fatigue, and plasma levels of cytokines interleukin (IL-6), C-reactive protein (CRP), soluble tumor necrosis factor receptor type II (sTNF-RII), interleukin IL-1 receptor antagonist (IL-1ra), and psycho-physiological adjustments that may lead to BC. CONCLUSIONS Exposure to multiple ACEs appears a risk factor for BC development in adulthood. Although the clinical relevance of findings such as this is ambiguous, the review added evidence for a link between the presence of childhood adversity and BC occurrence, pointing to psychological, hormonal, and immunological dysregulations.
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Affiliation(s)
- Olimpia Pino
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | | | - Diana Poli
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via Fontana Candida 1, Monte Porzio Catone, 00078 Rome, Italy
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24
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Quevedo Y, Booij L, Herrera L, Hernández C, Jiménez JP. Potential epigenetic mechanisms in psychotherapy: a pilot study on DNA methylation and mentalization change in borderline personality disorder. Front Hum Neurosci 2022; 16:955005. [PMID: 36171872 PMCID: PMC9510615 DOI: 10.3389/fnhum.2022.955005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/18/2022] [Indexed: 11/21/2022] Open
Abstract
Genetic and early environmental factors are interwoven in the etiology of Borderline Personality Disorder (BPD). Epigenetic mechanisms offer the molecular machinery to adapt to environmental conditions. There are gaps in the knowledge about how epigenetic mechanisms are involved in the effects of early affective environment, development of BPD, and psychotherapy response. We reviewed the available evidence of the effects of psychotherapy on changes in DNA methylation and conducted a pilot study in a sample of 11 female adolescents diagnosed with BPD, exploring for changes in peripheral DNA methylation of FKBP5 gene, which encodes for a stress response protein, in relation to psychotherapy, on symptomatology and underlying psychological processes. For this purpose, measures of early trauma, borderline and depressive symptoms, psychotherapy outcome, mentalization, and emotional regulation were studied. A reduction in the average FKBP5 methylation levels was observed over time. Additionally, the decrease in FKBP5 methylation observed occurred only in those individuals who had early trauma and responded to psychotherapy. The results suggest an effect of psychotherapy on epigenetic mechanisms associated with the stress response. The finding that epigenetic changes were only observed in patients with early trauma suggests a specific molecular mechanism of recovery. The results should be taken with caution given the small sample size. Also, further research is needed to adjust for confounding factors and include endocrinological markers and therapeutic process variables.
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Affiliation(s)
- Yamil Quevedo
- Departamento de Psiquiatría y Salud Mental Oriente, Universidad de Chile, Santiago, Chile
- Millenium Institute for Depression and Personality Research, Santiago, Chile
| | - Linda Booij
- Department of Psychology, Concordia University, Montreal, QC, Canada
- Sainte-Justine Hospital Research Centre, Montreal, QC, Canada
| | - Luisa Herrera
- Programa de Genética Humana, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile
| | - Cristobal Hernández
- Millenium Institute for Depression and Personality Research, Santiago, Chile
- Escuela de Psicología, Universidad Adolfo Ibañez, Santiago, Chile
| | - Juan Pablo Jiménez
- Departamento de Psiquiatría y Salud Mental Oriente, Universidad de Chile, Santiago, Chile
- Millenium Institute for Depression and Personality Research, Santiago, Chile
- *Correspondence: Juan Pablo Jiménez
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25
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Robakis TK, Roth MC, King LS, Humphreys KL, Ho M, Zhang X, Chen Y, Li T, Rasgon NL, Watson KT, Urban AE, Gotlib IH. Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants. Mol Psychiatry 2022; 27:3306-3315. [PMID: 35577912 PMCID: PMC9666564 DOI: 10.1038/s41380-022-01592-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 04/05/2022] [Accepted: 04/19/2022] [Indexed: 11/08/2022]
Abstract
The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106 individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.
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Affiliation(s)
- Thalia K Robakis
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Marissa C Roth
- Department of Psychology and Human Development, Peabody College of Vanderbilt University, Nashville, TN, USA
| | - Lucy S King
- Department of Psychology, Stanford University, Stanford, CA, USA
| | - Kathryn L Humphreys
- Department of Psychology and Human Development, Peabody College of Vanderbilt University, Nashville, TN, USA
| | - Marcus Ho
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Xianglong Zhang
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | | | | | - Natalie L Rasgon
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Kathleen T Watson
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Alexander E Urban
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Ian H Gotlib
- Department of Psychology, Stanford University, Stanford, CA, USA
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26
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Di Benedetto MG, Scassellati C, Cattane N, Riva MA, Cattaneo A. Neurotrophic factors, childhood trauma and psychiatric disorders: A systematic review of genetic, biochemical, cognitive and imaging studies to identify potential biomarkers. J Affect Disord 2022; 308:76-88. [PMID: 35378148 DOI: 10.1016/j.jad.2022.03.071] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 03/01/2022] [Accepted: 03/29/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Exposure to traumatic experience represents one of the key environmental factors influencing the risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric disorders. METHODS A systematic review was conducted, considering genetic, biochemical and expression studies along with cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-Ottawa Scale). RESULTS 103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor β1 (TGF-β1). LIMITATIONS Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range and ethnicity of samples for BDNF studies; limited studies for other neurotrophins. CONCLUSIONS Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive functions and specific brain region architecture.
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Affiliation(s)
- Maria Grazia Di Benedetto
- Biological Psychiatry Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Catia Scassellati
- Biological Psychiatry Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Nadia Cattane
- Biological Psychiatry Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Marco Andrea Riva
- Biological Psychiatry Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Annamaria Cattaneo
- Biological Psychiatry Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
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27
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Kim JJ, Sapio MR, Vazquez FA, Maric D, Loydpierson AJ, Ma W, Zarate CA, Iadarola MJ, Mannes AJ. Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats. Front Mol Neurosci 2022; 15:892345. [PMID: 35706427 PMCID: PMC9190438 DOI: 10.3389/fnmol.2022.892345] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription in a pharmacokinetically controlled fashion. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Cellular level gene localization was performed with multiplex fluorescent in situ hybridization. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9–12 significant genes per brain region, p < 0.01 per gene) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling (Nuclear Factor Erythroid-Derived 2-Like 2) containing 12–25 increasing genes (p < 0.01) per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. At the cellular level, in situ hybridization localized up-regulation of the plasticity-associated gene Bdnf, and the transcription factors Nr4a1 and Fos, in cortical layers III and V. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine.
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Affiliation(s)
- Jenny J. Kim
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Matthew R. Sapio
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Fernando A. Vazquez
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Dragan Maric
- Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Amelia J. Loydpierson
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Wenting Ma
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Carlos A. Zarate
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
| | - Michael J. Iadarola
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Michael J. Iadarola, ,
| | - Andrew J. Mannes
- Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
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28
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A pilot study of multilevel analysis of BDNF in paternal and maternal perinatal depression. Arch Womens Ment Health 2022; 25:237-249. [PMID: 34989854 PMCID: PMC8784499 DOI: 10.1007/s00737-021-01197-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/14/2021] [Indexed: 12/20/2022]
Abstract
Depression in the perinatal period is common in mothers worldwide. Emerging research indicates that fathers are also at risk of developing perinatal depression. However, knowledge regarding biological risk factors and pathophysiological mechanisms of perinatal depression is still scarce, particularly in fathers. It has been suggested that the neurotrophin BDNF may play a role in maternal perinatal depression; however, there is currently no data regarding paternal perinatal depression. For this pilot study, 81 expecting parents were recruited and assessed at several time points. We screened for depression using EPDS and MADRS, investigated several psychosocial variables, and took blood samples for BDNF val66met genotyping, epigenetic, and protein analysis. Between pregnancy and 12 months postpartum (pp), we found that 3.7 to 15.7% of fathers screened positive for depression, and 9.6 to 24% of mothers, with at least a twofold increased prevalence in both parents using MADRS compared with EPDS. We also identified several psychosocial factors associated with perinatal depression in both parents. The data revealed a trend that lower BDNF levels correlated with maternal depressive symptoms at 3 months pp. In the fathers, no significant correlations between BDNF and perinatal depression were found. Pregnant women demonstrated lower BDNF methylation and BDNF protein expression compared with men; however, these were found to increase postpartum. Lastly, we identified correlations between depressive symptoms and psychosocial/neurobiological factors. The data suggest that BDNF may play a role in maternal perinatal depression, but not paternal.
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29
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Epigenetic correlates of the psychological interventions outcomes: A systematic review and meta-analysis. JOURNAL OF AFFECTIVE DISORDERS REPORTS 2022. [DOI: 10.1016/j.jadr.2022.100310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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30
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Bandeira IC, Giombelli L, Werlang IC, Abujamra AL, Secchi TL, Brondani R, Bragatti JA, Bizzi JWJ, Leistner-Segal S, Bianchin MM. Methylation of BDNF and SLC6A4 Gene Promoters in Brazilian Patients With Temporal Lobe Epilepsy Presenting or Not Psychiatric Comorbidities. Front Integr Neurosci 2021; 15:764742. [PMID: 34912196 PMCID: PMC8667271 DOI: 10.3389/fnint.2021.764742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/25/2021] [Indexed: 01/09/2023] Open
Abstract
The relationship between epilepsy and psychiatric comorbidities has been recognized for centuries, but its pathophysiological mechanisms are still misunderstood. It is biologically plausible that genetic or epigenetic variations in genes that codify important neurotransmitters involved in epilepsy as well as in psychiatric disorders may influence the development of the latter in patients with epilepsy. However, this possibility remains poorly investigated. The aim of this study was to evaluate the methylation profile of the BDNF and SLC6A4, two genes importantly involved in neuroplasticity, in patients with temporal lobe epilepsy (TLE) regarding the development or not of psychiatric comorbidities. One hundred and thirty-nine patients with TLE, 90 females and 45 males, were included in the study. The mean age of patients was 44.0 (+12.0) years, and mean duration of epilepsy was 25.7 (+13.3) years. The Structured Clinical Interview for DSM-IV shows that 83 patients (59.7%) had neuropsychiatric disorders and 56 (40.3%) showed no psychiatric comorbidity. Mood disorders were the most common psychiatric disorder observed, being present in 64 (46.0%) of all 139 patients. Thirty-three (23.7%) patients showed anxiety disorders, 10 (7.2%) patients showed history of psychosis and 8 (5.8%) patients showed history of alcohol//drug abuse. Considering all 139 patients, 18 (12.9%) demonstrated methylation of the promoter region of both BDNF and SLC6A4 genes. A significant decreased methylation profile was observed only in TLE patients with mood disorders when compared with TLE patients without a history of mood disorders (O.R. = 3.45; 95% C.I. = 1.08–11.11; p = 0.04). A sub-analysis showed that TLE patients with major depressive disorder mostly account for this result (O.R. = 7.20; 95% C.I. = 1.01–56.16; p = 0.042). A logistic regression analysis showed that the independent factors associated with a history of depression in our TLE patients was female sex (O.R. = 2.30; 95% C.I. = 1.02–5.18; p = 0.044), not controlled seizures (O.R. = 2.51; 95% C.I. = 1.16–5.41; p = 0.019) and decreased methylation in BDNF and SLC6A4 genes (O.R. = 5.32; 95% C.I. = 1.14–25.00; p = 0.033). Our results suggest that BDNF or SLC6A4 genes profile methylation is independently associated with depressive disorders in patients with epilepsy. Further studies are necessary to clarify these matters.
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Affiliation(s)
- Isabel Cristina Bandeira
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Lucas Giombelli
- Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Isabel Cristina Werlang
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Ana Lucia Abujamra
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Thais Leite Secchi
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Rosane Brondani
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - Sandra Leistner-Segal
- Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Marino Muxfeldt Bianchin
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Centro de Tratamento de Epilepsia Refratária (CETER), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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31
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Wadji DL, Tandon T, Ketcha Wanda GJM, Wicky C, Dentz A, Hasler G, Morina N, Martin-Soelch C. Child maltreatment and NR3C1 exon 1 F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: A systematic review. CHILD ABUSE & NEGLECT 2021; 122:105304. [PMID: 34488052 DOI: 10.1016/j.chiabu.2021.105304] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 06/10/2021] [Accepted: 08/26/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Epigenetics offers one promising method for assessing the psychobiological response to stressful experiences during childhood. In particular, deoxyribonucleic acid (DNA) methylation has been associated with an altered hypothalamus-pituitary-adrenal (HPA) axis and the onset of mental disorders. Equally, there are promising leads regarding the association between the methylation of the glucocorticoid receptor gene (NR3C1-1F) and child maltreatment and its link with HPA axis and psychopathology. OBJECTIVE The current study aimed to assess the evidence of a link among child maltreatment, NR3C1-1F methylation, HPA axis deregulation, and symptoms of psychopathology. METHODS We followed the Prisma guidelines and identified 11 articles that met our inclusion criteria. RESULTS We found that eight studies (72.72%) reported increased NR3C1-1F methylation associated with child maltreatment, specifically physical abuse, emotional abuse, sexual abuse, neglect, and exposure to intimate partner violence, while three studies (27.27%) found no significant association. Furthermore, a minority of studies (36.36%) provided additional measures of symptoms of psychopathology or cortisol in order to examine the link among NR3C1-1F methylation, HPA axis deregulation, and psychopathology in a situation of child maltreatment. These results suggest that NR3C1-1F hypermethylation is positively associated with higher HPA axis activity, i.e. increased production of cortisol, as well as symptoms of psychopathology, including emotional lability-negativity, externalizing behavior symptoms, and depressive symptoms. CONCLUSION NR3C1-1F methylation could be one mechanism that links altered HPA axis activity with the development of psychopathology.
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Affiliation(s)
- D L Wadji
- I-Reach Lab, Unit of Clinical and Health Psychology, University of Fribourg, Switzerland.
| | - T Tandon
- I-Reach Lab, Unit of Clinical and Health Psychology, University of Fribourg, Switzerland
| | - G J M Ketcha Wanda
- Clinical psychology Lab, Department of Psychology, University of Yaoundé I, Cameroon
| | - C Wicky
- Department of Biology, University of Fribourg, Switzerland
| | - A Dentz
- I-Reach Lab, Unit of Clinical and Health Psychology, University of Fribourg, Switzerland
| | - G Hasler
- Department of Psychiatric, University of Fribourg, Fribourg, Switzerland
| | - N Morina
- Department of Consultant-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, University of Zurich, Switzerland
| | - C Martin-Soelch
- I-Reach Lab, Unit of Clinical and Health Psychology, University of Fribourg, Switzerland
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Borderline Personality Disorder: Risk Factors and Early Detection. Diagnostics (Basel) 2021; 11:diagnostics11112142. [PMID: 34829488 PMCID: PMC8620075 DOI: 10.3390/diagnostics11112142] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/13/2022] Open
Abstract
Personality disorders (PDs) exert a great toll on health resources, and this is especially true for borderline personality disorder (BPD). As all PDs, BPD arises during adolescence or young adulthood. It is therefore important to detect the presence of this PD in its earlier stages in order to initiate appropriate treatment, thus ameliorating the prognosis of this condition. This review aims to highlight the issues associated with BPD diagnosis in order to promote its early detection and treatment. To do so, we conducted a search on PubMed database of current evidence regarding BPD early diagnosis, focusing on risk factors, which represent important conditions to assess during young patient evaluation, and on diagnostic tools that can help the clinician in the assessment process. Our findings show how several risk factors, both environmental and genetic/neurobiological, can contribute to the onset of BPD and help identify at-risk patients who need careful monitoring. They also highlight the importance of a careful clinical evaluation aided by psychometric tests. Overall, the evidence gathered confirms the complexity of BDP early detection and its crucial importance for the outcome of this condition.
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Allison J, Kaliszewska A, Uceda S, Reiriz M, Arias N. Targeting DNA Methylation in the Adult Brain through Diet. Nutrients 2021; 13:nu13113979. [PMID: 34836233 PMCID: PMC8618930 DOI: 10.3390/nu13113979] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolism and nutrition have a significant role in epigenetic modifications such as DNA methylation, which can influence gene expression. Recently, it has been suggested that bioactive nutrients and gut microbiota can alter DNA methylation in the central nervous system (CNS) through the gut-brain axis, playing a crucial role in modulating CNS functions and, finally, behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation during adulthood. We will provide an overview of potential interactions among diet, gastrointestinal microbiome and epigenetic alterations on brain methylation and behavior. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, we will explore new ways to modulate DNA hydroxymethylation, which is particularly abundant in neural tissue, through diet.
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Affiliation(s)
- Joseph Allison
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, London SE5 8AF, UK; (J.A.); (A.K.)
| | - Aleksandra Kaliszewska
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, London SE5 8AF, UK; (J.A.); (A.K.)
| | - Sara Uceda
- BRABE Group, Department of Psychology, Faculty of Life and Natural Sciences, University of Nebrija, C/del Hostal, 28248 Madrid, Spain; (S.U.); (M.R.)
| | - Manuel Reiriz
- BRABE Group, Department of Psychology, Faculty of Life and Natural Sciences, University of Nebrija, C/del Hostal, 28248 Madrid, Spain; (S.U.); (M.R.)
| | - Natalia Arias
- BRABE Group, Department of Psychology, Faculty of Life and Natural Sciences, University of Nebrija, C/del Hostal, 28248 Madrid, Spain; (S.U.); (M.R.)
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), 33003 Oviedo, Spain
- Health Research Institute of the Principality of Asturias—ISPA, 33011 Oviedo, Spain
- Correspondence: ; Tel.: +34-91-452-1101
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Thumfart KM, Jawaid A, Bright K, Flachsmann M, Mansuy IM. Epigenetics of childhood trauma: Long term sequelae and potential for treatment. Neurosci Biobehav Rev 2021; 132:1049-1066. [PMID: 34742726 DOI: 10.1016/j.neubiorev.2021.10.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/17/2021] [Accepted: 10/29/2021] [Indexed: 12/17/2022]
Abstract
Childhood trauma (CT) can have persistent effects on the brain and is one of the major risk factors for neuropsychiatric diseases in adulthood. Recent advances in the field of epigenetics suggest that epigenetic factors such as DNA methylation and histone modifications, as well as regulatory processes involving non-coding RNA are associated with the long-term sequelae of CT. This narrative review summarizes current knowledge on the epigenetic basis of CT and describes studies in animal models and human subjects examining how the epigenome and transcriptome are modified by CT in the brain. It discusses psychological and pharmacological interventions that can counteract epigenetic changes induced by CT and the need to establish longitudinal assessment after CT for developing more effective diagnostics and treatment strategies based on epigenetic targets.
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Affiliation(s)
- Kristina M Thumfart
- Laboratory of Neuroepigenetics, Brain Research Institute, University of Zürich and Institute for Neuroscience of the Swiss Federal Institute of Technology, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland
| | - Ali Jawaid
- Laboratory of Neuroepigenetics, Brain Research Institute, University of Zürich and Institute for Neuroscience of the Swiss Federal Institute of Technology, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland; Laboratory for Translational Research in Neuropsychiatric Disorders (TREND), BRAINCITY: Center of Excellence for Neural Plasticity and Brain Disorders, Nencki Institute of Experimental Biology, Ludwika Pasteura 3, Warsaw, 02-093, Poland
| | - Kristina Bright
- Swiss Federal Institute of Technology Zurich, Zurich, Switzerland
| | - Marc Flachsmann
- Swiss Federal Institute of Technology Zurich, Zurich, Switzerland
| | - Isabelle M Mansuy
- Laboratory of Neuroepigenetics, Brain Research Institute, University of Zürich and Institute for Neuroscience of the Swiss Federal Institute of Technology, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
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Ibrahim P, Almeida D, Nagy C, Turecki G. Molecular impacts of childhood abuse on the human brain. Neurobiol Stress 2021; 15:100343. [PMID: 34141833 PMCID: PMC8187840 DOI: 10.1016/j.ynstr.2021.100343] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/24/2021] [Accepted: 05/13/2021] [Indexed: 12/17/2022] Open
Abstract
Childhood abuse (CA) is a prevalent global health concern, increasing the risk of negative mental health outcomes later in life. In the literature, CA is commonly defined as physical, sexual, and emotional abuse, as well as neglect. Several mental disorders have been associated with CA, including depression, bipolar disorder, schizophrenia, and post-traumatic stress disorder, along with an increased risk of suicide. It is thought that traumatic life events occurring during childhood and adolescence may have a significant impact on essential brain functions, which may persist throughout adulthood. The interaction between the brain and the external environment can be mediated by epigenetic alterations in gene expression, and there is a growing body of evidence to show that such changes occur as a function of CA. Disruptions in the HPA axis, myelination, plasticity, and signaling have been identified in individuals with a history of CA. Understanding the molecular impact of CA on the brain is essential for the development of treatment and prevention measures. In this review, we will summarize studies that highlight the molecular changes associated with CA in the human brain, along with supporting evidence from peripheral studies and animal models. We will also discuss some of the limitations surrounding the study of CA and propose extracellular vesicles as a promising future approach in the field.
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Affiliation(s)
- Pascal Ibrahim
- Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, Quebec, Canada
| | - Daniel Almeida
- Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, Quebec, Canada
| | - Corina Nagy
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, Quebec, Canada
- Department of Psychiatry, McGill University, Montreal, Quebec, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, Quebec, Canada
- Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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Piotrkowicz M, Janoska-Jazdzik M, Koweszko T, Szulc A. The Influence of Psychotherapy on Peripheral Brain-Derived Neurotrophic Factor Concentration Levels and Gene Methylation Status: A Systematic Review. J Clin Med 2021; 10:4424. [PMID: 34640441 PMCID: PMC8509187 DOI: 10.3390/jcm10194424] [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: 07/31/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 01/02/2023] Open
Abstract
Psychotherapy is a well-established method of treating many mental disorders. It has been proven that psychotherapy leads to structural and functional changes in the brain; however, knowledge about the molecular and cellular mechanisms of these changes is limited. Neuroplasticity and one of its mediators, brain-derived neurotrophic factor (BDNF), are potential research targets in this field. To define the role of BDNF concentration in serum, or in plasma, and BDNF promoter gene methylation in saliva or leucocytes, in psychotherapy, an extensive literature search was conducted in the PubMed and Web of Science databases. The literature review was conducted based on papers published up until May 2021 that included pre and post psychotherapy measurements of either BDNF concentration levels or promoter gene methylation status. Ten studies were indicated as eligible for analysis: eight studies that investigated peripheral BDNF concentration levels, one study that investigated methylation status, and one study that included an evaluation of both subject matters. Patients underwent cognitive behavioral therapy or interpersonal psychotherapy. Patients were diagnosed with borderline personality disorder, major depressive disorder, anorexia nervosa, bulimia nervosa, or post-traumatic stress disorder. There were only three of the nine studies that showed statistically significant increases in BDNF concentration levels after psychotherapy. The two studies that involved BDNF gene methylation status showed a decrease in methylation after dialectical behavioral therapy of borderline patients.
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Affiliation(s)
- Michal Piotrkowicz
- Department of Psychiatry, Faculty of Health Sciences, Medical University of Warsaw, Partyzantow 2/4, 05-802 Pruszkow, Poland; (M.J.-J.); (T.K.); (A.S.)
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The Impact of Stress Within and Across Generations: Neuroscientific and Epigenetic Considerations. Harv Rev Psychiatry 2021; 29:303-317. [PMID: 34049337 DOI: 10.1097/hrp.0000000000000300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The impact of stress and trauma on biological systems in humans can be substantial. They can result in epigenetic changes, accelerated brain development and sexual maturation, and predisposition to psychopathology. Such modifications may be accompanied by behavioral, emotional, and cognitive overtones during one's lifetime. Exposure during sensitive periods of neural development may lead to long-lasting effects that may not be affected by subsequent environmental interventions. The cumulative effects of life stressors in an individual may affect offspring's methylome makeup and epigenetic clocks, neurohormonal modulation and stress reactivity, and physiological and reproductive development. While offspring may suffer deleterious effects from parental stress and their own early-life adversity, these factors may also confer traits that prove beneficial and enhance fitness to their own environment. This article synthesizes the data on how stress shapes biological and behavioral dimensions, drawing from preclinical and human models. Advances in this field of knowledge should potentially allow for an improved understanding of how interventions may be increasingly tailored according to individual biomarkers and developmental history.
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Rodriguez N, Martinez-Pinteño A, Blázquez A, Ortiz AE, Moreno E, Gassó P, Lafuente A, Lazaro L, Mas S. Integrative DNA Methylation and Gene Expression Analysis of Cognitive Behavioral Therapy Response in Children and Adolescents with Obsessive-Compulsive Disorder; a Pilot Study. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:757-766. [PMID: 34234515 PMCID: PMC8254600 DOI: 10.2147/pgpm.s313015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/05/2021] [Indexed: 11/28/2022]
Abstract
Purpose Here, we propose an integrative analysis of genome-wide methylation and gene expression to provide new insight into the biological mechanisms of Cognitive behavioral therapy (CBT) in pediatric obsessive-compulsive disorder (OCD). Patients and Methods Twelve children and adolescents with OCD receiving CBT for the first time were classified as responders or non-responders after eight weeks of CBT. Differentially methylated positions (DMPs) and gene co-expression modules were identified using specific R software packages. Correlations between the DMPs and gene co-expression modules were investigated. Results Two genes were enriched with significant DMPs (Δβ > ± 0.2, FDR-adjusted p-value < 0.05): PIWIL1 and MIR886. The yellowgreen module of co-expressed genes was associated with CBT response (FDR-adjusted p-value = 0.0003). Significant correlations were observed between the yellowgreen module and the CpGs in PIWIL1 and MIR886 (p < 0.008). Patients showing hypermethylation in these CpGs presented an upregulation in the genes in the yellowgreen module. Conclusion Taken together, the preliminary results of this systems-level approach, despite the study limitations, provide evidence that the epigenetic regulation of ncRNAs could be a predictor of CBT response. Limitations The sample size limited the statistical power, and given that the study was hypothesis-driven, our results should be seen as preliminary.
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Affiliation(s)
- Natalia Rodriguez
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain
| | - Albert Martinez-Pinteño
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain
| | - Ana Blázquez
- Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain.,Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Ana Encarnación Ortiz
- Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain.,Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Elena Moreno
- Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Patricia Gassó
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain.,Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Amalia Lafuente
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain.,Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.,G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
| | - Luisa Lazaro
- Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain.,Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.,G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.,Department of Medicine, University of Barcelona, Barcelona, Spain
| | - Sergi Mas
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain.,Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.,G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
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39
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Womersley JS, Nothling J, Toikumo S, Malan-Müller S, van den Heuvel LL, McGregor NW, Seedat S, Hemmings SMJ. Childhood trauma, the stress response and metabolic syndrome: A focus on DNA methylation. Eur J Neurosci 2021; 55:2253-2296. [PMID: 34169602 DOI: 10.1111/ejn.15370] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 05/13/2021] [Accepted: 06/12/2021] [Indexed: 12/12/2022]
Abstract
Childhood trauma (CT) is well established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high-density lipoprotein and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro-inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental influences provide a means whereby the effects of CT can be biologically embedded and persist into adulthood to affect health and well-being. The methylome regulates the transcription of genes involved in the stress response, metabolism and inflammation. This narrative review examines the evidence for DNA methylation in CT and MetS in order to identify shared neuroendocrine and immune correlates that may mediate the increased risk of MetS following CT exposure. Our review specifically highlights differential methylation of FKBP5, the gene that encodes FK506-binding protein 51 and has pleiotropic effects on stress responding, inflammation and energy metabolism, as a central candidate to understand the molecular aetiology underlying CT-associated MetS risk.
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Affiliation(s)
- Jacqueline S Womersley
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Jani Nothling
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,Gender and Health Research Unit, South African Medical Research Council, Cape Town, South Africa
| | - Sylvanus Toikumo
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Stefanie Malan-Müller
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Leigh L van den Heuvel
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Nathaniel W McGregor
- Systems Genetics Working Group, Department of Genetics, Faculty of Agriculture, Stellenbosch University, Stellenbosch, South Africa
| | - Soraya Seedat
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Sîan M J Hemmings
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation. Prog Neuropsychopharmacol Biol Psychiatry 2021; 108:110188. [PMID: 33259836 DOI: 10.1016/j.pnpbp.2020.110188] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/26/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022]
Abstract
Stressful events during early-life are risk factors for psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is implicated in psychosis pathophysiology and deficits in BDNF mRNA in animal models of psychiatric disease are reported. DNA methylation can control gene expression and may be influenced by environmental factors such as early-life stress. We investigated BDNF methylation in first-episode psychosis (FEP) patients (n = 58), their unaffected siblings (n = 29) and community-based controls (n = 59), each of whom completed the Childhood Trauma Questionnaire (CTQ); BDNF methylation was also tested in male Wistar rats housed isolated or grouped from weaning. DNA was extracted from human blood and rat brain (prefrontal cortex and hippocampus), bisulphite-converted and the methylation of equivalent sequences within BDNF exon IV determined by pyrosequencing. BDNF methylation did not differ significantly between diagnostic groups; however, individuals who had experienced trauma presented higher levels of methylation. We found association between the mean BDNF methylation and total CTQ score in FEP, as well as between individual CpG sites and subtypes of trauma. No significant correlations were found for controls or siblings with child trauma. These results were independent of age, gender, body mass index, BDNF genotype or LINE-1, a measure of global methylation, which showed no significant association with trauma. Isolation rearing resulted in increased BDNF methylation in both brain regions compared to group-housed animals, a correlate of previously reported changes in gene expression. Our results suggest that childhood maltreatment may result in increased BDNF methylation, providing a mechanism underlying the association between early-life stress and psychosis.
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41
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Affiliation(s)
- Gavin P Reynolds
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
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42
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Wilson N, Robb E, Gajwani R, Minnis H. Nature and nurture? A review of the literature on childhood maltreatment and genetic factors in the pathogenesis of borderline personality disorder. J Psychiatr Res 2021; 137:131-146. [PMID: 33677217 DOI: 10.1016/j.jpsychires.2020.12.025] [Citation(s) in RCA: 5] [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] [Received: 06/01/2020] [Revised: 11/22/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Borderline Personality Disorder (BPD) is a psychiatric disorder associated with significant morbidity and mortality. However, the neurobiological alterations underlying the condition remain poorly understood. As a result, existing treatments remain inadequate. One of the main risk factors for the development of BPD is a history of childhood maltreatment. However, it is considered neither causative nor specific to the condition. Current theory is therefore increasingly moving toward a 'Gene x Environment' (GxE) model of the condition. The purpose of the current work was to conduct a systematic literature review, which comprehensively identifies all published molecular level GxE studies that have explored the role of specific genetic loci, in influencing the risk of BPD following exposure to childhood abuse or neglect. METHODS Four electronic databases were used to systematically search for molecular level GxE studies of any design, which focused on the development of BPD following exposure to childhood abuse or neglect, without language or date restrictions. Articles were screened independently by two reviewers and results were synthesized narratively. RESULTS A total of 473 articles were screened of which sixteen were selected for inclusion in our review. Implicated genes were categorised according to their influence on; Neurotransmitter Systems, Neurodevelopment and Neuroendocrine Systems. CONCLUSIONS The identified studies have produced several relevant and statistically significant results. Of particular note, is the repeated finding that genes involved in HPA axis regulation, may be altered by exposure to childhood maltreatment, influencing subsequent susceptibility to BPD. This is both biologically plausible and of potential clinical significance.
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Affiliation(s)
- Naomi Wilson
- Institute of Health and Wellbeing, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.
| | - Emily Robb
- NHS Greater Glasgow and Clyde, Gartnavel General Hospital, 1055 Great Western Rd, Glasgow, G12 0XH, UK.
| | - Ruchika Gajwani
- Institute of Health and Wellbeing, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.
| | - Helen Minnis
- Institute of Health and Wellbeing, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.
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Biopsychosocial correlates of psychological distress in Latina mothers. J Affect Disord 2021; 282:617-626. [PMID: 33445084 PMCID: PMC7889736 DOI: 10.1016/j.jad.2020.12.193] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 12/22/2020] [Accepted: 12/25/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND Few studies have explored the relationship between psychological, psychosocial and biological factors among Latinas. An integrated understanding of how these factors associate with psychological distress is necessary for the development of culturally relevant screening tools and interventions. The study aim was to examine the relationships among (a) psychological distress symptoms, (b) psychosocial factors (discrimination, acculturation, acculturative stress, economic hardship), and (c) biological (DNA methylation of stress-related genes) factors among Latinas during pregnancy and postpartum period. METHODS A sample of 150 pregnant Latinas completed the Inventory of Depression and Anxiety Symptoms II (IDAS-II), psychosocial questionnaires (discrimination, acculturation, acculturative stress, economic hardship) before (24-32 weeks) and after gestation (4-6 weeks postpartum). Blood samples were collected between 24-32 weeks gestation. Correlations were determined between psychosocial and biological measures and psychological distress measures. Multivariable linear regression models were conducted to assess the relationships between IDAS and stressors. RESULTS Several correlations among psychosocial measures,DNA methylation factors and IDAS-II variables were identified. Among the psychosocial measures, everyday discrimination was the most strongly and consistently associated with IDAS-II. DNA methylation of NR3C1 affects the associations between psychological and psychosocial distress. LIMITATIONS We only assessed DNA methylation during pregnancy and focused on four HPA-related genes. Longitudinal assessment of DNA methylation and genome-wide analysis can provide a better picture of the role of methylation in psychological distress. CONCLUSIONS This work may assist clinicians and policy makers in effectively recognizing and preventing maternal mental health disparities based on discrimination and other psychosocial stressors in at-risk groups.
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Hossack MR, Reid MW, Aden JK, Gibbons T, Noe JC, Willis AM. Adverse Childhood Experience, Genes, and PTSD Risk in Soldiers: A Methylation Study. Mil Med 2021; 185:377-384. [PMID: 32976583 DOI: 10.1093/milmed/usz292] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/27/2019] [Accepted: 07/30/2019] [Indexed: 11/12/2022] Open
Abstract
INTRODUCTION Epigenetics can serve as a marker of susceptibility to many known psychiatric diseases. DNA methylation patterns of multiple genes have been studied in both civilian populations and military personnel with post-traumatic stress disorder (PTSD). Many of these genes serve various functions that span the hypothalamic-pituitary-adrenal axis, immune system, and central nervous system (CNS) growth factors and neurotransmission. It is thought that the methylation levels of such genes may be able to identify individuals who are at higher risk of developing PTSD. Our study seeks to establish whether previously reported PTSD genes possess a particular methylation pattern that is predictive of PTSD in active duty military members with combat exposure. MATERIALS AND METHODS This is an institutional review board (IRB)-approved, cross-sectional, case control, gene-environment interaction study. About 170 active military members with and without PTSD were recruited. Patients with a history of structural brain damage, traumatic brain injury (TBI) resulting in loss of consciousness, predeployment diagnosis of PTSD or anxiety disorder, and predeployment prescription of an antidepressant or psychoactive medication were excluded. Validated measures of childhood trauma and adversity (adverse childhood experience [ACE] score), PTSD symptoms (PTSD check-list military version [PCL-M]), and combat exposure scales (CES) were measured via validated questionnaires for all subjects. After extracting DNA from peripheral blood provided by the 170 subjects, we determined methylation percentages, via pyrosequencing assays, for nine target areas within the following seven genes: BDNF, NR3C1, MAN2C1, TLR8, SLC6A4, IL-18, and SKA2. These genes are commonly reported in the literature as being highly correlated with PTSD and early-life traumatic experiences.Methylation levels were measured as a percentage at specific sites within the previously mentioned genes. Data were examined with SPSS v 22.0 Statistics and JMP v13.1 software using a general linear model for methylation × trauma (CES scores) split by diagnosis of PTSD or not, methylation versus childhood trauma (ACE scores), and methylation versus PTSD severity (PCL-M score). Two-way ANOVA was performed to control for antidepressant use. A two-tailed Student t-test was performed for PTSD analyses and was correlated with PTSD diagnosis, demographic information as well as ACE score, PCL-M score, and CES scores. RESULTS Differentially methylated sites that were highly associated with PTSD diagnosis were found in three of seven candidate genes: BDNF, NR3C1, and MAN2C1. When compared to controls, patients with PTSD diagnosis had significantly lower levels of methylation, even after controlling for antidepressant use. PCL-M, ACE, and CES scores were significantly associated with PTSD diagnosis. CONCLUSION Our study suggests that methylation of key genes involved in synaptic plasticity and the hypothalamic-pituitary-adrenal axis is associated with lower levels of methylation in military PTSD subjects exposed to combat when compared to their non-PTSD counterparts. Strengths of this study include controlling for antidepressant use and excluding TBI patients. Similar studies in an active duty population of this size are scarce. What is not clear is whether methylation changes are driving PTSD symptomology or whether they are merely a marker of disease. Future areas of research include prospective studies that measure methylation pre- and postcombat exposure in the same individual.
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Affiliation(s)
- Michael R Hossack
- Department of Neurology, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234
| | - Matthew W Reid
- Defense and Veterans Brain Injury Center, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234
| | - James K Aden
- Graduate Medical Education, Brooke Army Medical Center, 3698 Chambers Pass, Fort Sam Houston, TX 78234
| | - Thomas Gibbons
- Laboratory Services Branch, Clinical Investigations & Research Support, 1255 Wilford Hall Loop, BLDG 4430, Lackland AFB, TX 78236
| | - Jody C Noe
- 59 MDW/SGVUL, Clinical Research Division, 2200 Bergquist Dr, BLDG 4430, Lackland AFB, TX 78236
| | - Adam M Willis
- Department of Neurology, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234.,Department of Neurology and Neurotherapeutics, University of Texas Southwestern, 5303 Harry Hinds Blvd, Dallas, TX 75390.,Department of Mechanical Engineering, Michigan State University, 428 S. Shaw Lane, Room 2555, Engineering Building, East Lansing, MI 48824-1226
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Parade SH, Huffhines L, Daniels TE, Stroud LR, Nugent NR, Tyrka AR. A systematic review of childhood maltreatment and DNA methylation: candidate gene and epigenome-wide approaches. Transl Psychiatry 2021; 11:134. [PMID: 33608499 PMCID: PMC7896059 DOI: 10.1038/s41398-021-01207-y] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/18/2020] [Accepted: 01/07/2021] [Indexed: 01/31/2023] Open
Abstract
Childhood maltreatment is a major risk factor for chronic and severe mental and physical health problems across the lifespan. Increasing evidence supports the hypothesis that maltreatment is associated with epigenetic changes that may subsequently serve as mechanisms of disease. The current review uses a systematic approach to identify and summarize the literature related to childhood maltreatment and alterations in DNA methylation in humans. A total of 100 empirical articles were identified in our systematic review of research published prior to or during March 2020, including studies that focused on candidate genes and studies that leveraged epigenome-wide data in both children and adults. Themes arising from the literature, including consistent and inconsistent patterns of results, are presented. Several directions for future research, including important methodological considerations for future study design, are discussed. Taken together, the literature on childhood maltreatment and DNA methylation underscores the complexity of transactions between the environment and biology across development.
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Affiliation(s)
- Stephanie H Parade
- Initiative on Stress, Trauma, and Resilience, Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA.
- Bradley/Hasbro Children's Research Center, E. P. Bradley Hospital, East Providence, RI, USA.
| | - Lindsay Huffhines
- Initiative on Stress, Trauma, and Resilience, Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA
- Bradley/Hasbro Children's Research Center, E. P. Bradley Hospital, East Providence, RI, USA
| | - Teresa E Daniels
- Initiative on Stress, Trauma, and Resilience, Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA
- Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA
| | - Laura R Stroud
- Initiative on Stress, Trauma, and Resilience, Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA
- Center for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI, USA
| | - Nicole R Nugent
- Initiative on Stress, Trauma, and Resilience, Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Audrey R Tyrka
- Initiative on Stress, Trauma, and Resilience, Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA
- Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA
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46
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Iskric A, Barkley-Levenson E. Neural Changes in Borderline Personality Disorder After Dialectical Behavior Therapy-A Review. Front Psychiatry 2021; 12:772081. [PMID: 34975574 PMCID: PMC8718753 DOI: 10.3389/fpsyt.2021.772081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
The biological component of the biosocial theory of emotion regulation stipulates that borderline personality disorder (BPD) arises from biological vulnerabilities to heightened emotional reactivity. Comprehensive reviews have consistently implicated abnormalities in the amygdala, anterior cingulate cortex, and hippocampus in the neurobiology of BPD. While Dialectical Behavior Therapy (DBT) is the leading evidence-based psychotherapy for the treatment of BPD, there remains a paucity of literature examining changes in the neurobiology of BPD following DBT treatment. Nine studies were identified that examined neurobiological changes in BPD after the completion of DBT. Results indicated that there was significant deactivation of amygdala activity as well as the anterior cingulate cortex in patients with BPD after DBT treatment. As well, several studies found after DBT treatment, BPD patients had a decreased activity in the inferior frontal gyrus in response to arousing stimuli and increased activity in response to inhibitory control. Future research on the neurobiological change after DBT treatment can help clarify biological mechanisms of change in BPD.
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Affiliation(s)
- Adam Iskric
- Department of Psychology, Hofstra University, Hempstead, NY, United States
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Xulu KR, Womersley JS, Sommer J, Hinsberger M, Elbert T, Weierstall R, Kaminer D, Malan-Müller S, Seedat S, Hemmings SMJ. DNA methylation and psychotherapy response in trauma-exposed men with appetitive aggression. Psychiatry Res 2021; 295:113608. [PMID: 33290938 DOI: 10.1016/j.psychres.2020.113608] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 11/25/2020] [Indexed: 12/15/2022]
Abstract
Exposure to violence can lead to appetitive aggression (AA), the positive feeling and fascination associated with violence, and posttraumatic stress disorder (PTSD), characterised by hyperarousal, reexperience and feelings of ongoing threat. Psychotherapeutic interventions may act via DNA methylation, an environmentally sensitive epigenetic mechanism that can influence gene expression. We investigated epigenetic signatures of psychotherapy for PTSD and AA symptoms in South African men with chronic trauma exposure. Participants were assigned to one of three groups: narrative exposure therapy for forensic offender rehabilitation (FORNET), cognitive behavioural therapy or waiting list control (n = 9-10/group). Participants provided saliva and completed the Appetitive Aggression Scale and PTSD Symptom Severity Index at baseline, 8-month and 16-month follow-up. The relationship, over time, between methylation in 22 gene promoter region sites, symptom scores, and treatment was assessed using linear mixed models. Compared to baseline, PTSD and AA symptom severity were significantly reduced at 8 and 16 months, respectively, in the FORNET group. Increased methylation of genes implicated in dopaminergic neurotransmission (NR4A2) and synaptic plasticity (AUTS2) was associated with reduced PTSD symptom severity in participants receiving FORNET. Analyses across participants revealed a proportional relationship between AA and methylation of TFAM, a gene involved in mitochondrial biosynthesis.
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Affiliation(s)
- Khethelo R Xulu
- Department of Psychiatry, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Jacqueline S Womersley
- Department of Psychiatry, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council / Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Jessica Sommer
- Department of Psychology, University of Konstanz, Konstanz, Germany.
| | | | - Thomas Elbert
- Department of Psychology, University of Konstanz, Konstanz, Germany.
| | - Roland Weierstall
- Department of Psychology, University of Konstanz, Konstanz, Germany; Clinical Psychology & Psychotherapy, Medical School Hamburg, Hamburg, Germany.
| | - Debbie Kaminer
- Department of Psychology, University of Cape Town, Cape Town, South Africa.
| | - Stefanie Malan-Müller
- Department of Psychiatry, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Soraya Seedat
- Department of Psychiatry, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council / Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Sian M J Hemmings
- Department of Psychiatry, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council / Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
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Social determinants of health, personalized medicine, and child maltreatment. Pediatr Res 2021; 89:368-376. [PMID: 33288877 DOI: 10.1038/s41390-020-01290-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 11/02/2020] [Accepted: 11/09/2020] [Indexed: 11/08/2022]
Abstract
This review begins with a brief summary of the importance of child maltreatment as a major public health problem, given its prevalence and the substantial human and economic costs involved. The focus then shifts to consideration of personalized medicine and child maltreatment, including genetic and genomics factors, as well as the role of social determinants of health. Research on epigenetics related to child abuse and neglect is presented, followed by that pertaining to a few specific social factors, such as poverty, parental depression and substance use, and domestic (or intimate partner) violence. The review ends with a discussion of interventions to help address social determinants of health with brief descriptions of several model programs, and thoughts concerning the role of personalized medicine in addressing child maltreatment in the foreseeable future. IMPACT: This paper synthesizes knowledge on social determinants of health and advances in genetics and genomics related to the prevention of child maltreatment. It provides examples of model approaches to addressing the prevention of child maltreatment in primary care practices.
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Penadés R, Arias B, Fatjó-Vilas M, González-Vallespí L, García-Rizo C, Catalán R, Bernardo M. Epigenetic Studies in Psychotherapy: A Systematic Review. CURRENT PSYCHIATRY RESEARCH AND REVIEWS 2020. [DOI: 10.2174/2666082216999200622140922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Epigenetic modifications appear to be dynamic and they might be affected
by environmental factors. The possibility of influencing these processes through psychotherapy has
been suggested.
Objective:
To analyse the impact of psychotherapy on epigenetics when applied to mental disorders.
The main hypothesis is that psychological treatments will produce epigenetic modifications related
to the improvement of treated symptoms.
Methods:
A computerised and systematic search was completed throughout the time period from
1990 to 2019 on the PubMed, ScienceDirect and Scopus databases.
Results:
In total, 11 studies were selected. The studies were evaluated for the theoretical framework,
genes involved, type of psychotherapy and clinical challenges and perspectives. All studies showed
detectable changes at the epigenetic level, like DNA methylation changes, associated with symptom
improvement after psychotherapy.
Conclusion:
Methylation profiles could be moderating treatment effects of psychotherapy. Beyond
the detected epigenetic changes after psychotherapy, the epigenetic status before the implementation
could act as an effective predictor of response.
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Affiliation(s)
- Rafael Penadés
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain
| | - Bárbara Arias
- Department of Evolutionary Biology, Ecology and Environmental Sciences, University of Barcelona, Barcelona, Spain
| | - Mar Fatjó-Vilas
- Department of Evolutionary Biology, Ecology and Environmental Sciences, University of Barcelona, Barcelona, Spain
| | | | | | - Rosa Catalán
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain
| | - Miquel Bernardo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain
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50
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Pothier W, Roy MA, Corbière M, Thibaudeau É, Achim AM, Wykes T, Reeder C, Chagnon Y, Cellard C. Personalized cognitive remediation therapy to facilitate return to work or to school in recent-onset psychosis. Neurocase 2020; 26:340-352. [PMID: 33119429 DOI: 10.1080/13554794.2020.1841797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cognitive deficits are barriers to job acquisition or return to school, and can be reduced through Cognitive remediation therapy (CRT). The main goal of this multiple case study was to investigate the effect of personalized CRT on occupational status in three participants with a recent-onset psychosis. Two cases improved their occupational status at post-treatment, and showed improvements in cognitive, psychological, and/or clinical variables. This study suggests that personalized CRT may facilitate job acquisition or return to school. However, the different pathways showed by our cases indicate that personalized CRT may influence occupational status through multiple mechanisms, underlining the relevance of treatment personalization.
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Affiliation(s)
- William Pothier
- École De Psychologie, Université Laval , Québec, QC, Canada.,Centre De Recherche CERVO , Québec, QC, Canada
| | - Marc-André Roy
- Centre De Recherche CERVO , Québec, QC, Canada.,Département De Psychiatrie Et Neurosciences, Université Laval , Québec, QC, Canada
| | - Marc Corbière
- Département d'éducation et pédagogie, Université Du Québec À Montréal (UQÀM) , Montréal, Qc, Canada.,Centre De Recherche De l'Institut Universitaire En Santé Mentale De Montréal , Montréal, QC, Canada
| | - Élisabeth Thibaudeau
- École De Psychologie, Université Laval , Québec, QC, Canada.,Centre De Recherche CERVO , Québec, QC, Canada
| | | | - Til Wykes
- Institute of Psychiatry, Psychology and Neuroscience, King's College London , London, UK
| | - Clare Reeder
- Institute of Psychiatry, Psychology and Neuroscience, King's College London , London, UK
| | - Yvon Chagnon
- École De Psychologie, Université Laval , Québec, QC, Canada
| | - Caroline Cellard
- École De Psychologie, Université Laval , Québec, QC, Canada.,Centre De Recherche CERVO , Québec, QC, Canada
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