70 results on '"Laura M. Fiori"'
Search Results
2. Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes
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Malosree Maitra, Haruka Mitsuhashi, Reza Rahimian, Anjali Chawla, Jennie Yang, Laura M. Fiori, Maria Antonietta Davoli, Kelly Perlman, Zahia Aouabed, Deborah C. Mash, Matthew Suderman, Naguib Mechawar, Gustavo Turecki, and Corina Nagy
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Science - Abstract
Abstract Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.
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- 2023
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3. Circular RNA circCCNT2 is upregulated in the anterior cingulate cortex of individuals with bipolar disorder
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Rixing Lin, Juan Pablo Lopez, Cristiana Cruceanu, Caroline Pierotti, Laura M. Fiori, Alessio Squassina, Caterina Chillotti, Christoph Dieterich, Nikolaos Mellios, and Gustavo Turecki
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Gene expression dysregulation in the brain has been associated with bipolar disorder, but little is known about the role of non-coding RNAs. Circular RNAs are a novel class of long noncoding RNAs that have recently been shown to be important in brain development and function. However, their potential role in psychiatric disorders, including bipolar disorder, has not been well investigated. In this study, we profiled circular RNAs in the brain tissue of individuals with bipolar disorder. Total RNA sequencing was initially performed in samples from the anterior cingulate cortex of a cohort comprised of individuals with bipolar disorder (N = 13) and neurotypical controls (N = 13) and circular RNAs were identified and analyzed using “circtools”. Significant circular RNAs were validated by RT-qPCR and replicated in the anterior cingulate cortex in an independent cohort (24 bipolar disorder cases and 27 controls). In addition, we conducted in vitro studies using B-lymphoblastoid cells collected from bipolar cases (N = 19) and healthy controls (N = 12) to investigate how circular RNAs respond following lithium treatment. In the discovery RNA sequencing analysis, 26 circular RNAs were significantly differentially expressed between bipolar disorder cases and controls (FDR
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- 2021
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4. Association between the expression of lncRNA BASP-AS1 and volume of right hippocampal tail moderated by episode duration in major depressive disorder: a CAN-BIND 1 report
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Antoine Yrondi, Laura M. Fiori, Nikita Nogovitsyn, Stefanie Hassel, Jean François Théroux, Zahia Aouabed, Benicio N. Frey, Raymond W. Lam, Roumen Milev, Daniel J. Müller, Jane A. Foster, Claudio Soares, Susan Rotzinger, Stephen C. Strother, Glenda M. MacQueen, Stephen R. Arnott, Andrew D. Davis, Mojdeh Zamyadi, Jacqueline Harris, Sidney H. Kennedy, and Gustavo Turecki
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract The pathophysiology of major depressive disorder (MDD) encompasses an array of changes at molecular and neurobiological levels. As chronic stress promotes neurotoxicity there are alterations in the expression of genes and gene-regulatory molecules. The hippocampus is particularly sensitive to the effects of stress and its posterior volumes can deliver clinically valuable information about the outcomes of antidepressant treatment. In the present work, we analyzed individuals with MDD (N = 201) and healthy controls (HC = 104), as part of the CAN-BIND-1 study. We used magnetic resonance imaging (MRI) to measure hippocampal volumes, evaluated gene expression with RNA sequencing, and assessed DNA methylation with the (Infinium MethylationEpic Beadchip), in order to investigate the association between hippocampal volume and both RNA expression and DNA methylation. We identified 60 RNAs which were differentially expressed between groups. Of these, 21 displayed differential methylation, and seven displayed a correlation between methylation and expression. We found a negative association between expression of Brain Abundant Membrane Attached Signal Protein 1 antisense 1 RNA (BASP1-AS1) and right hippocampal tail volume in the MDD group (β = −0.218, p = 0.021). There was a moderating effect of the duration of the current episode on the association between the expression of BASP1-AS1 and right hippocampal tail volume in the MDD group (β = −0.48, 95% C.I. [−0.80, −0.16]. t = −2.95 p = 0.004). In conclusion, we found that overexpression of BASP1-AS1 was correlated with DNA methylation, and was negatively associated with right tail hippocampal volume in MDD.
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- 2021
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5. Treatment-emergent and trajectory-based peripheral gene expression markers of antidepressant response
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Laura M. Fiori, Massimiliano Orri, Zahia Aouabed, Jean François Théroux, Rixing Lin, Corina Nagy, Benicio N. Frey, Raymond W. Lam, Glenda M. MacQueen, Roumen Milev, Daniel J. Müller, Sagar V. Parikh, Susan Rotzinger, Rudolf Uher, Jane A. Foster, Sidney H. Kennedy, and Gustavo Turecki
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (N = 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (CERCAM, DARS-AS1, FAM228B, HBEGF) whose change over time was independently associated with a response status. For all except HBEGF, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in DARS-AS1 and HBEGF also differentiated later responders from nonresponders. Additionally, HBEGF was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.
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- 2021
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6. GPR56/ADGRG1 is associated with response to antidepressant treatment
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Raoul Belzeaux, Victor Gorgievski, Laura M. Fiori, Juan Pablo Lopez, Julien Grenier, Rixing Lin, Corina Nagy, El Chérif Ibrahim, Eduardo Gascon, Philippe Courtet, Stéphane Richard-Devantoy, Marcelo Berlim, Eduardo Chachamovich, Jean-François Théroux, Sylvie Dumas, Bruno Giros, Susan Rotzinger, Claudio N. Soares, Jane A. Foster, Naguib Mechawar, Gregory G. Tall, Eleni T. Tzavara, Sidney H. Kennedy, and Gustavo Turecki
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Science - Abstract
It is not fully understood why some patients respond or do not respond to antidepressant treatment. Here the authors show that in the blood of individuals with depression, GPR56 expression increases in responders to antidepressant treatment, but not in non-responders.
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- 2020
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7. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes
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Juan Pablo Lopez, Laura M. Fiori, Cristiana Cruceanu, Rixing Lin, Benoit Labonte, Hannah M. Cates, Elizabeth A. Heller, Vincent Vialou, Stacy M. Ku, Christophe Gerald, Ming-Hu Han, Jane Foster, Benicio N. Frey, Claudio N. Soares, Daniel J. Müller, Faranak Farzan, Francesco Leri, Glenda M. MacQueen, Harriet Feilotter, Kathrin Tyryshkin, Kenneth R. Evans, Peter Giacobbe, Pierre Blier, Raymond W. Lam, Roumen Milev, Sagar V. Parikh, Susan Rotzinger, Steven C. Strother, Cathryn M. Lewis, Katherine J. Aitchison, Gayle M. Wittenberg, Naguib Mechawar, Eric J. Nestler, Rudolf Uher, Sidney H. Kennedy, and Gustavo Turecki
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Science - Abstract
Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.
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- 2017
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8. Investigating epigenetic consequences of early-life adversity: some methodological considerations
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Laura M. Fiori and Gustavo Turecki
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DNA methylation ,epigenetics ,early-life adversity ,childhood abuse ,stress ,Psychiatry ,RC435-571 - Abstract
Stressful and traumatic events occurring during early childhood have been consistently associated with the development of psychiatric disorders later in life. This relationship may be mediated in part by epigenetic mechanisms, such as DNA methylation, which are influenced by the early-life environment. Epigenetic patterns can have lifelong effects on gene expression and on the functioning of biological processes relevant to stress reactivity and psychopathology. Optimization of epigenetic research activity necessitates a discussion surrounding the methodologies used for DNA methylation analysis, selection of tissue sources, and timing of psychological and biological assessments. Recent studies related to early-life adversity and methylation, including both candidate gene and epigenome-wide association studies, have drawn from the variety of available techniques to generate interesting data in the field. Further discussion is warranted to address the limitations inherent to this field of research, along with future directions for epigenetic studies of adversity-related psychopathology.
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- 2016
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9. Bridging Basic and Clinical Research in Early Life Adversity, DNA Methylation, and Major Depressive Disorder
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Amanda Brown, Laura M. Fiori, and Gustavo Turecki
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epigenetics ,major depressive disorder ,early life adversity ,DNA methylation ,biomarkers ,antidepressant therapies ,Genetics ,QH426-470 - Abstract
Early life adversity (ELA)- including childhood physical, emotional, and sexual abuse, as well as childhood neglect- is an important predictive factor for negative psychopathology, including Major Depressive Disorder (MDD). ELA can epigenetically regulate key emotional and behavioral systems in ways that can stably persist into adulthood and contribute to the development of MDD and other psychopathology. DNA methylation has been one of the most investigated forms of epigenetic regulation in ELA to MDD pathway. From these studies, genes and sites associated with ELA/MDD have been identified and should be further investigated in order to identify potential avenues for intervention.
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- 2019
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10. Broadening our horizons: Gene expression profiling to help better understand the neurobiology of suicide and depression
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Laura M. Fiori and Gustavo Turecki
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Suicide ,Major depression ,Gene expression ,Microarray ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The complexity of the neurobiological alterations underlying major depression and suicide is significant. Gene expression studies using high-throughput genomic technologies have provided important insight into novel genes and pathways displaying alterations associated with major depression and suicide, thereby providing a global view of the pathological changes taking place, as well as indicating potential new targets for therapeutic interventions. This review discusses the methodologies which have been used to profile gene expression patterns in depression and suicide, as well as examines several of the metabolic pathways which have been frequently implicated by studies using this approach. Future directions to be taken towards increasing our understanding of the origin and downstream effects of altered gene expression are also discussed.
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- 2012
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11. SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants
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Rixing Lin, Aron Kos, Juan Pablo Lopez, Julien Dine, Laura M. Fiori, Jennie Yang, Yair Ben-Efraim, Zahia Aouabed, Pascal Ibrahim, Haruka Mitsuhashi, Tak Pan Wong, El Cherif Ibrahim, Catherine Belzung, Pierre Blier, Faranak Farzan, Benicio N. Frey, Raymond W. Lam, Roumen Milev, Daniel J. Müller, Sagar V. Parikh, Claudio Soares, Rudolf Uher, Corina Nagy, Naguib Mechawar, Jane A. Foster, Sidney H. Kennedy, Alon Chen, Gustavo Turecki, McGill Group for Suicide Studies, McGill University = Université McGill [Montréal, Canada]-Douglas Mental Health University Institute, Max Plank Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, Department of Brain Sciences, Weizmann Institute of Science, Neuroscience Division, Douglas Research Centre, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), UMR 1253 IBrain Imagerie & Cerveau Equipe 1 : 'Psychiatrie Neuro-Fonctionnelle' (PNF), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Mood Disorders Research Unit, University of Ottawa Institute of Mental Health Research, eBrain Lab, Simon Fraser University, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario], Department of Psychiatry, University of British Columbia, Departments of Psychiatry and Psychology, Queens University, Centre for Mental Health, Department of Psychiatry, University Health Network, Krembil Research Institute, University of Toronto, University of Michigan Hospital, Department of Psychiatry, Nova Scotia Health Authority, Mood Disorders Program, St. Joseph's Healthcare Hamilton, and St Michael’s Hospital, Li Ka Shing Knowledge Institute, Centre for Depression and Suicide Studies, Toronto
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[SDV]Life Sciences [q-bio] - Abstract
International audience; Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90 , was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 ( NRG3 ) as one of the targets of SNORD90 , which we show is regulated through the accumulation of N 6 -methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.
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- 2023
12. Association between the expression of lncRNA BASP-AS1 and volume of right hippocampal tail moderated by episode duration in major depressive disorder: a CAN-BIND 1 report
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Gustavo Turecki, Claudio N. Soares, Andrew D. Davis, Stephen R. Arnott, Jacqueline K. Harris, Nikita Nogovitsyn, Sidney H. Kennedy, Laura M. Fiori, Glenda MacQueen, Benicio N. Frey, Roumen Milev, Jane A. Foster, Stefanie Hassel, Antoine Yrondi, Susan Rotzinger, Stephen C. Strother, Daniel J. Müller, Jean-François Théroux, Zahia Aouabed, Raymond W. Lam, and Mojdeh Zamyadi
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medicine.medical_specialty ,Hippocampus ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Hippocampal formation ,Cellular and Molecular Neuroscience ,Internal medicine ,Gene expression ,medicine ,Humans ,Chronic stress ,Biological Psychiatry ,Depressive Disorder, Major ,business.industry ,RNA ,Methylation ,DNA Methylation ,medicine.disease ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Endocrinology ,DNA methylation ,Major depressive disorder ,RNA, Long Noncoding ,business ,RC321-571 - Abstract
The pathophysiology of major depressive disorder (MDD) encompasses an array of changes at molecular and neurobiological levels. As chronic stress promotes neurotoxicity there are alterations in the expression of genes and gene-regulatory molecules. The hippocampus is particularly sensitive to the effects of stress and its posterior volumes can deliver clinically valuable information about the outcomes of antidepressant treatment. In the present work, we analyzed individuals with MDD (N = 201) and healthy controls (HC = 104), as part of the CAN-BIND-1 study. We used magnetic resonance imaging (MRI) to measure hippocampal volumes, evaluated gene expression with RNA sequencing, and assessed DNA methylation with the (Infinium MethylationEpic Beadchip), in order to investigate the association between hippocampal volume and both RNA expression and DNA methylation. We identified 60 RNAs which were differentially expressed between groups. Of these, 21 displayed differential methylation, and seven displayed a correlation between methylation and expression. We found a negative association between expression of Brain Abundant Membrane Attached Signal Protein 1 antisense 1 RNA (BASP1-AS1) and right hippocampal tail volume in the MDD group (β = −0.218, p = 0.021). There was a moderating effect of the duration of the current episode on the association between the expression of BASP1-AS1 and right hippocampal tail volume in the MDD group (β = −0.48, 95% C.I. [−0.80, −0.16]. t = −2.95 p = 0.004). In conclusion, we found that overexpression of BASP1-AS1 was correlated with DNA methylation, and was negatively associated with right tail hippocampal volume in MDD.
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- 2021
13. Neuron-derived extracellular vesicles enriched from plasma show altered size and miRNA cargo as a function of antidepressant drug response
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Gustavo Turecki, Saumeh Saeedi, Jane A. Foster, Sidney H. Kennedy, Laura M. Fiori, Corina Nagy, Marina Wakid, Jean-François Théroux, Jennie Yang, Naguib Mechawar, Susan Rotzinger, and Pascal Ibrahim
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0303 health sciences ,L1 ,business.industry ,Immunoprecipitation ,Pharmacology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,0302 clinical medicine ,medicine.anatomical_structure ,Text mining ,microRNA ,Medicine ,Biomarker (medicine) ,Antidepressant ,Escitalopram ,Neuron ,business ,Molecular Biology ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEV) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N = 20) and did not respond (N = 20) to escitalopram treatment, as well as controls (N = 20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEV by immunoprecipitation with L1CAM. EVs and NDEVs were characterized, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed that they were smaller than other EVs isolated from plasma (p
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- 2021
14. Treatment-emergent and trajectory-based peripheral gene expression markers of antidepressant response
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Raymond W. Lam, Laura M. Fiori, Rixing Lin, Daniel J Müller, Sidney H. Kennedy, Rudolf Uher, Jean-François Théroux, Gustavo Turecki, Zahia Aouabed, Massimiliano Orri, Roumen Milev, Glenda MacQueen, Jane A. Foster, Benicio N. Frey, Corina Nagy, Sagar V. Parikh, and Susan Rotzinger
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Oncology ,medicine.medical_specialty ,Gene Expression ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Citalopram ,Molecular neuroscience ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Internal medicine ,Gene expression ,Medicine ,Escitalopram ,Humans ,Gene ,Biological Psychiatry ,Depression (differential diagnoses) ,030304 developmental biology ,Psychiatric Status Rating Scales ,0303 health sciences ,Depressive Disorder, Major ,business.industry ,Depression ,RNA ,medicine.disease ,Antidepressive Agents ,Psychiatry and Mental health ,Treatment Outcome ,Cohort ,Major depressive disorder ,Antidepressant ,business ,030217 neurology & neurosurgery ,Biomarkers ,medicine.drug ,RC321-571 - Abstract
Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (N = 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (CERCAM, DARS-AS1, FAM228B, HBEGF) whose change over time was independently associated with a response status. For all except HBEGF, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in DARS-AS1 and HBEGF also differentiated later responders from nonresponders. Additionally, HBEGF was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.
- Published
- 2021
15. Multi-omic modeling of antidepressant response implicates dynamic immune and inflammatory changes in individuals who respond to treatment
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Shih-Chieh Fuh, Laura M. Fiori, Gustavo Turecki, Corina Nagy, and Yue Li
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Multidisciplinary - Abstract
Background Major depressive disorder (MDD) is a leading cause of disability worldwide, and is commonly treated with antidepressant drugs (AD). Although effective, many patients fail to respond to AD treatment, and accordingly identifying factors that can predict AD response would greatly improve treatment outcomes. In this study, we developed a machine learning tool to integrate multi-omic datasets (gene expression, DNA methylation, and genotyping) to identify biomarker profiles associated with AD response in a cohort of individuals with MDD. Materials and methods Individuals with MDD (N = 111) were treated for 8 weeks with antidepressants and were separated into responders and non-responders based on the Montgomery–Åsberg Depression Rating Scale (MADRS). Using peripheral blood samples, we performed RNA-sequencing, assessed DNA methylation using the Illumina EPIC array, and performed genotyping using the Illumina PsychArray. To address this rich multi-omic dataset with high dimensional features, we developed integrative Geneset-Embedded non-negative Matrix factorization (iGEM), a non-negative matrix factorization (NMF) based model, supplemented with auxiliary information regarding gene sets and gene-methylation relationships. In particular, we factorize the subjects by features (i.e., gene expression or DNA methylation) into subjects-by-factors and factors-by-features. We define the factors as the meta-phenotypes as they represent integrated composite scores of the molecular measurements for each subject. Results Using our model, we identified a number of meta-phenotypes which were related to AD response. By integrating geneset information into the model, we were able to relate these meta-phenotypes to biological processes, including a meta-phenotype related to immune and inflammatory functions as well as other genes related to depression or AD response. The meta-phenotype identified several genes including immune interleukin 1 receptor like 1 (IL1RL1) and interleukin 5 receptor (IL5) subunit alpha (IL5RA), AKT/PIK3 pathway related phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), and sphingomyelin phosphodiesterase 3 (SMPD3), which has been identified as a target of AD treatment. Conclusions The derived meta-phenotypes and associated biological functions represent both biomarkers to predict response, as well as potential new treatment targets. Our method is applicable to other diseases with multi-omic data, and the software is open source and available on Github (https://github.com/li-lab-mcgill/iGEM).
- Published
- 2023
16. Machine Learning Analysis of Blood microRNA Data in Major Depression: A Case-Control Study for Biomarker Discovery
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Laura M. Fiori, Gustavo Turecki, Bill Qi, and Yannis Trakadis
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0301 basic medicine ,AcademicSubjects/MED00415 ,Machine learning ,computer.software_genre ,Regular Research Articles ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Rating scale ,Predictive Value of Tests ,microRNA ,Medicine ,Humans ,Pharmacology (medical) ,Circulating MicroRNA ,RNA-Seq ,Biomarker discovery ,diagnosis and treatment ,Depression (differential diagnoses) ,Pharmacology ,Depressive Disorder, Major ,business.industry ,AcademicSubjects/SCI01870 ,Case-control study ,MicroRNA ,medicine.disease ,Antidepressive Agents ,Psychiatry and Mental health ,Affect ,030104 developmental biology ,machine learning ,Treatment Outcome ,Case-Control Studies ,Major depressive disorder ,Antidepressant ,Artificial intelligence ,Supervised Machine Learning ,business ,Unsupervised clustering ,major depression ,computer ,030217 neurology & neurosurgery ,Biomarkers ,Unsupervised Machine Learning - Abstract
Background There is a lack of reliable biomarkers for major depressive disorder (MDD) in clinical practice. However, several studies have shown an association between alterations in microRNA levels and MDD, albeit none of them has taken advantage of machine learning (ML). Method Supervised and unsupervised ML were applied to blood microRNA expression profiles from a MDD case-control dataset (n = 168) to distinguish between (1) case vs control status, (2) MDD severity levels defined based on the Montgomery-Asberg Depression Rating Scale, and (3) antidepressant responders vs nonresponders. Results MDD cases were distinguishable from healthy controls with an area-under-the receiver-operating characteristic curve (AUC) of 0.97 on testing data. High- vs low-severity cases were distinguishable with an AUC of 0.63. Unsupervised clustering of patients, before supervised ML analysis of each cluster for MDD severity, improved the performance of the classifiers (AUC of 0.70 for cluster 1 and 0.76 for cluster 2). Antidepressant responders could not be successfully separated from nonresponders, even after patient stratification by unsupervised clustering. However, permutation testing of the top microRNA, identified by the ML model trained to distinguish responders vs nonresponders in each of the 2 clusters, showed an association with antidepressant response. Each of these microRNA markers was only significant when comparing responders vs nonresponders of the corresponding cluster, but not using the heterogeneous unclustered patient set. Conclusions Supervised and unsupervised ML analysis of microRNA may lead to robust biomarkers for monitoring clinical evolution and for more timely assessment of treatment in MDD patients.
- Published
- 2020
17. Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report
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Raymond W. Lam, Glenda MacQueen, Laura M. Fiori, Roumen Milev, Benicio N. Frey, Sidney H. Kennedy, Jane A. Foster, Antoine Yrondi, Gustavo Turecki, and Daniel J. Müller
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Adult ,Male ,AcademicSubjects/MED00415 ,Adolescent ,Side effect ,Nausea ,Serotonin reuptake inhibitor ,Gene Expression ,Citalopram ,Pharmacology ,Regular Research Articles ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Humans ,Medicine ,Escitalopram ,Pharmacology (medical) ,miRNA ,030304 developmental biology ,Depressive Disorder, Major ,0303 health sciences ,Messenger RNA ,antidepressant ,major depressive disorder ,AcademicSubjects/SCI01870 ,business.industry ,Middle Aged ,medicine.disease ,3. Good health ,side effects ,MicroRNAs ,Psychiatry and Mental health ,Antidepressant ,Major depressive disorder ,Female ,medicine.symptom ,business ,Selective Serotonin Reuptake Inhibitors ,030217 neurology & neurosurgery ,medicine.drug - Abstract
IntroductionAntidepressant drugs are effective therapies for major depressive disorder; however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effects. The aim of this study was to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment and their downstream effects on target gene expression.MethodsA total 160 patients with major depressive disorder from the CAN-BIND-1 cohort were included. Side effects were assessed with the Toronto Side Effect Scale after 2 weeks of treatment with escitalopram. We assessed the relationship between side effects and changes in peripheral expression of miRNAs between baseline and week 2. For miRNA whose expression changed, we used target prediction algorithms to identify putative messenger RNA (mRNA) targets and assessed their expression.ResultsNausea was experienced by 42.5% of patients. We identified 45 miRNAs whose expression changed on initiation of escitalopram treatment, of which 10 displayed a negative association with intensity of nausea (miR15b-5p, miR17-5p, miR20a-5p, miR20b-5p, miR103a-3p, miR103b, miR106a-5p, miR182-5p, miR185-5p, and miR660-5p). Additionally, we found negative associations between 4 microRNAs (miR20a-5p, miR106a-5p, miR185-5p, miR660-5p) and mRNA targets. The expression of the miR185-5p target, CAMK2δ was significantly decreased [log 2 mean = −0.048 (0.233)] between weeks 0 and 2 (P = .01)].ConclusionsWe identified an overexpression of miR185-5p during escitalopram treatment of major depressive disorder, which was negatively associated with intensity of nausea, and identified a potential mRNA target that may mediate this effect.
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- 2019
18. Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum
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Erin S. Calipari, Gilles Maussion, Volodymyr Yerko, Kathryn Vaillancourt, Deborah C. Mash, Gustavo Turecki, Laura M. Fiori, Carl Ernst, Corina Nagy, Jean-François Théroux, Eric J. Nestler, Naguib Mechawar, Benoit Labonté, and Gang G. Chen
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medicine.medical_specialty ,Science ,Caudate nucleus ,Striatum ,Nucleus accumbens ,Biology ,Article ,drugs ,Cocaine dependence ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Epigenetics ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Tyrosine hydroxylase ,molecular mechanism of gene regulation ,molecular neuroscience ,Methylation ,medicine.disease ,3. Good health ,Endocrinology ,DNA methylation ,030217 neurology & neurosurgery - Abstract
Summary Cocaine dependence is a chronic, relapsing disorder caused by lasting changes in the brain. Animal studies have identified cocaine-related alterations in striatal DNA methylation; however, it is unclear how methylation is related to cocaine dependence in humans. We generated methylomic profiles of the nucleus accumbens using human postmortem brains from a cohort of individuals with cocaine dependence and healthy controls (n = 25 per group). We found hypermethylation in a cluster of CpGs within the gene body of tyrosine hydroxylase (TH), containing a putative binding site for the early growth response 1 (EGR1) transcription factor, which is hypermethylated in the caudate nucleus of cocaine-dependent individuals. We replicated this finding and found it to be specific to striatal neuronal nuclei. Furthermore, this locus demonstrates enhancer activity which is attenuated by methylation and enhanced by EGR1 overexpression. These results suggest that cocaine dependence alters the epigenetic regulation of dopaminergic signaling genes., Graphical abstract, Highlights • Chronic cocaine dependence alters DNA methylation in human nucleus accumbens • The TH gene contains a binding site for EGR1, a cocaine-induced DNA binding protein • The EGR1 binding site is hypermethylated after chronic cocaine in striatal neurons • This region has enhancer activity that is responsive to EGR1 and methylation levels, Drugs; Molecular mechanism of gene regulation; Molecular neuroscience
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- 2021
19. Oxytocin receptor expression and epigenetic regulation in the anterior cingulate cortex of individuals with a history of severe childhood abuse
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Zahia Aouabed, Naguib Mechawar, Gary G. Chen, Gustavo Turecki, Michael J. Meaney, Laura M. Fiori, Daniel Almeida, Pierre-Eric Lutz, and Tie-Yuan Zhang
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Cingulate cortex ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Biology ,Oxytocin ,Gyrus Cinguli ,Polymorphism, Single Nucleotide ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Humans ,Epigenetics ,Child ,Biological Psychiatry ,Anterior cingulate cortex ,030304 developmental biology ,0303 health sciences ,Endocrine and Autonomic Systems ,16. Peace & justice ,Oxytocin receptor ,Rats ,Psychiatry and Mental health ,Suicide ,medicine.anatomical_structure ,Receptors, Oxytocin ,DNA methylation ,Licking ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples. We, therefore, aimed to characterize the relationship between early-life adversity and oxytocin receptor (OXTR) expression in the brain, using post-mortem human samples, as well as a rodent model of naturally occurring variation in early-life environment. Focusing on the dorsal anterior cingulate cortex, we compared OXTR expression and epigenetic regulation between MDD suicides with (N = 26) and without history of childhood abuse (N = 24), as well as psychiatrically healthy controls (N = 23). We also compared Oxtr expression in the cingulate cortex of adult rats raised by dams displaying high (N = 13) and low levels (N = 12) of licking and grooming (LG) behaviour. Overall, our results indicate that childhood abuse associates with an upregulation of OXTR expression, and that similarly, this relationship is also observed in the cingulate cortex of adult rats raised by low-LG dams. Additionally, we found an effect of rs53576 genotype on expression, showing that carriers of the A variant also show upregulated OXTR expression. The effects of early-life adversity and rs53576 genotype on OXTR expression are, however, not explained by differences in DNA methylation within and around the MT region of the OXTR gene.
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- 2021
20. Neuron-derived extracellular vesicles extracted from plasma show altered size and miRNA cargo as a function of antidepressant drug response
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Corina Nagy, Laura M. Fiori, Saumeh Saeedi, Sidney H. Kennedy, Marina Wakid, Susan Rotzinger, Gustavo Turecki, Naguib Mechawar, Jean-François Théroux, Jennie Yang, Pascal Ibrahim, and Jane A. Foster
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medicine.anatomical_structure ,L1 ,Pulse (signal processing) ,Immunoprecipitation ,Chemistry ,microRNA ,medicine ,Biomarker (medicine) ,Antidepressant ,Neuron ,Pharmacology ,Function (biology) - Abstract
Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEVs) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N=20) and did not respond (N=20) to escitalopram treatment, as well as controls (N=20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEVs by immunoprecipitation with L1CAM. EV size was measured using tunable resistive pulse sensing, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed they were smaller than other EVs isolated from plasma (p
- Published
- 2021
21. miR-323a regulates ERBB4 and is involved in depression
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Laura M. Fiori, Rixing Lin, Maria Holzapfel, Carola Eggert, Claudia Kühne, El Chérif Ibrahim, Rosa Eva Huettl, Gustavo Turecki, Juan Pablo Lopez, Naguib Mechawar, Alon Chen, Catherine Belzung, Aron Kos, Jean-François Théroux, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Max Plank Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, Weizmann Institute of Science, Department of Neurobiology, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Weizmann Institute of Science [Rehovot, Israël]
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0301 basic medicine ,Small RNA ,Receptor, ErbB-4 ,Receptor tyrosine kinase ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Downregulation and upregulation ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,microRNA ,Animals ,Humans ,Molecular Biology ,Gene ,ERBB4 ,Depressive Disorder, Major ,biology ,Depression ,Sequence Analysis, RNA ,Gene Expression Profiling ,Phenotype ,3. Good health ,MicroRNAs ,Psychiatry and Mental health ,030104 developmental biology ,[SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,Cancer research ,biology.protein ,Neuregulin ,030217 neurology & neurosurgery - Abstract
International audience; Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate
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- 2020
22. Neuron-derived extracellular vesicles enriched from plasma show altered size and miRNA cargo as a function of antidepressant drug response
- Author
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Saumeh, Saeedi, Corina, Nagy, Pascal, Ibrahim, Jean-Francois, Théroux, Marina, Wakid, Laura M, Fiori, Jennie, Yang, Susan, Rotzinger, Jane A, Foster, Naguib, Mechawar, Sidney H, Kennedy, and Gustavo, Turecki
- Subjects
Neurons ,Extracellular Vesicles ,MicroRNAs ,Plasma ,Humans ,Antidepressive Agents - Abstract
Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEV) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N = 20) and did not respond (N = 20) to escitalopram treatment, as well as controls (N = 20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEV by immunoprecipitation with L1CAM. EVs and NDEVs were characterized, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed that they were smaller than other EVs isolated from plasma (p 0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p 0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p 0.05), and NDEV size increased with ADT response (p 0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p, and miR-486-5p together (p 0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p 0.05). Together, this study indicates that changes in peripherally isolated NDEV can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.
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- 2020
23. The Role of Epigenetic Dysregulation in Suicidal Behaviors
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Laura M, Fiori and Gustavo, Turecki
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Epigenomics ,Mental Disorders ,Humans ,DNA Methylation ,Epigenesis, Genetic - Abstract
Suicidal behaviors have been associated with both heritable genetic variables and environmental risk factors. Epigenetic processes, such as DNA methylation, have important roles in mediating the effects of the environment on behavior. Dysregulation of these processes has been observed in many psychiatric disorders, and evidence suggests that they may also be involved in suicidal behaviors. Herein, we have summarized candidate gene and epigenome-wide studies which have investigated DNA methylation in relation to suicidal behaviors, as well as discussed some of the limitations of the field to date.
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- 2020
24. Neural and molecular correlates of psychological pain during major depression, and its link with suicidal ideas
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Gustavo Turecki, Fabricio Perreira, Fabrice Jollant, Raoul Belzeaux, Pierre-Eric Lutz, Stéphane Richard-Devantoy, Laura M. Fiori, Institut des Neurosciences Cellulaires et Intégratives (INCI), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,Visual analogue scale ,[SDV]Life Sciences [q-bio] ,Pain ,Suicide, Attempted ,Serotonergic ,Suicidal Ideation ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,Desvenlafaxine Succinate ,medicine ,Humans ,Serotonin and Noradrenaline Reuptake Inhibitors ,Suicidal ideation ,Biological Psychiatry ,ComputingMilieux_MISCELLANEOUS ,Pain Measurement ,Pharmacology ,Depressive Disorder, Major ,Neural correlates of consciousness ,business.industry ,Middle Aged ,Magnetic Resonance Imaging ,Antidepressive Agents ,030227 psychiatry ,Opioid ,Psychological pain ,Antidepressant ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.symptom ,business ,medicine.drug ,Clinical psychology - Abstract
Objectives Psychological pain increases the risk of suicidal ideas and acts, and represents a potential therapeutic target. However, the mechanisms of mental pain remain unclear. Here, we assessed the peripheral transcriptomic and central neural correlates of mental pain during a depressive episode. Methods 172 adult un-medicated depressed patients were recruited. Leucocytes were extracted for RNA quantification at baseline (T0) and after 8 weeks (T8) of an antidepressant treatment. Ninety-nine genes of the cortisol, immune, opioid, serotonergic, and kynurenine systems were a priori selected, and 41 were sufficiently expressed to be analyzed. At both T0 and T8, mean level of mental pain over the last 15 days was measured with a visual analog scale. A subset of 38 patients was additionally scanned with Magnetic Resonance Imaging at T0. Resting-state sequences of 4 networks (default-mode, basal ganglia, central executive, salience) were examined. Results Mean psychological pain scores significantly decreased between T0 and T8. At conservative p-corrected levels, T0 mental pain was significantly correlated with 11 brain clusters encompassing the prefrontal, parietal, and temporal cortices, the striatum, and the cerebellum. There was no direct association between peripheral gene expression and mean mental pain at any time points or in terms of temporal changes. However, expressions of 5HTR2B at p-corrected levels, and 5HTR3A, TPH1, and OPRL1 were correlated with the activity of several identified brain clusters at T0. Finally, while suicidal ideas and mental pain were correlated, the neural and molecular correlates of suicidal ideas were not the same. Conclusion Our study suggests that the serotonergic and nociceptin systems are associated with the activity of a cortico-subcortical brain network underlying the perception of mental pain during depression. Mental pain may be a necessary but insufficient condition for the emergence of suicidal ideation during depression.
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- 2020
25. Epigenetics of suicidal behaviors
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Laura M. Fiori and Gustavo Turecki
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- 2020
26. Contributors
- Author
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Abigail Bray, Julia D. Brown, Craig J. Bryan, Heidi Bryan, Phoebe Carrington-Jones, Sera Davidow, Pat Dudgeon, Thomas E. Ellis, T. Mark Ellison, Clemens Fartacek, Nicolas Fay, Laura M. Fiori, Sarah E. George, Patricia Gooding, Natasha A.R. Goods, Kamelia Harris, Dominique P. Harrison, Geoffrey R. Hooke, Abdul-Rahman Hudaib, Amy Joscelyne, Shraddha Kashyap, E. David Klonsky, Michael J. Kyron, David Lawrence, Jason Y.S. Leong, Caroline Mazel-Carlton, Andrew C. Page, Martin Plöderl, Günter Schiepek, Werner G.K. Stritzke, Gustavo Turecki, Roz Walker, Tricia J. Wylde, and Bita Zareian
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- 2020
27. GPR56/ADGRG1 is associated with response to antidepressant treatment
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Claudio N. Soares, Sidney H. Kennedy, Susan Rotzinger, Eleni T. Tzavara, Bruno Giros, Rixing Lin, Eduardo Chachamovich, Marcelo T. Berlim, Philippe Courtet, Laura M. Fiori, Victor Gorgievski, Sylvie Dumas, El Chérif Ibrahim, Juan Pablo Lopez, Naguib Mechawar, Stéphane Richard-Devantoy, Eduardo Gascon, Julien Grenier, Raoul Belzeaux, Gregory G. Tall, Corina Nagy, Gustavo Turecki, Jean-François Théroux, Jane A. Foster, Ibrahim, El Chérif, Santé Mentale et Addictions - Validation du concept spadine pour le traitement de la dépression - - VASPAC2013 - ANR-13-SAMA-0002 - SAMENTA - VALID, Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Neuroplasticité et thérapie des addictions (ERL 3649), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Department of Emergency Psychiatry and Acute Care, Lapeyronie Hospital, CHU Montpellier, Oramacell [Paris, France], Centre for Mental Health, Department of Psychiatry, University Health Network, Krembil Research Institute, University of Toronto, St Michael’s Hospital, Li Ka Shing Knowledge Institute, Centre for Depression and Suicide Studies, Toronto, Department of Pharmacology, University of Michigan, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Centre for Mental Health, Department of Psychiatry, University Health Network,Krembil Research Insitute, University of Toronto, VG holds a Labex-Biopsy Fellowship. ETT is supported by Fondation de Recherche sur le Cerveau and Fondation de France. ETT is a past recipient of the Bodossakis Foundation Young Scientist Award. RB, ECI, ETT and GT were supported by ERA-NET NEURON (Grant ANTARES). GT holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award. He is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899), and by the Fonds de recherche du Québec – Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders and Related Disorders. We would like to thank ML Niepon (Institute of Vision, Paris) for slide scanning for the FISH experiments, ANR-13-SAMA-0002,VASPAC,Validation du concept spadine pour le traitement de la dépression(2013), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), INSERM UMR-S 1124 ERL 3649, Université Paris Descartes, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
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0301 basic medicine ,Adult ,Male ,Science ,[SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,General Physics and Astronomy ,Prefrontal Cortex ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Receptors, G-Protein-Coupled ,Cohort Studies ,03 medical and health sciences ,Glycogen Synthase Kinase 3 ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Medicine ,Animals ,Humans ,Prefrontal cortex ,lcsh:Science ,Protein kinase B ,Depression (differential diagnoses) ,Gene knockdown ,Depressive Disorder, Major ,Multidisciplinary ,business.industry ,Depression ,Diagnostic markers ,General Chemistry ,Middle Aged ,Antidepressive Agents ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Treatment Outcome ,[SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,Antidepressant ,Female ,lcsh:Q ,Reuptake inhibitor ,business ,030217 neurology & neurosurgery ,Selective Serotonin Reuptake Inhibitors ,Executive dysfunction - Abstract
It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response., It is not fully understood why some patients respond or do not respond to antidepressant treatment. Here the authors show that in the blood of individuals with depression, GPR56 expression increases in responders to antidepressant treatment, but not in non-responders.
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- 2020
28. The Role of Epigenetic Dysregulation in Suicidal Behaviors
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Gustavo Turecki and Laura M. Fiori
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Genetics ,03 medical and health sciences ,Candidate gene ,2019-20 coronavirus outbreak ,0302 clinical medicine ,Coronavirus disease 2019 (COVID-19) ,Environmental risk ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,DNA methylation ,Epigenetics ,Psychology ,030217 neurology & neurosurgery ,030227 psychiatry - Abstract
Suicidal behaviors have been associated with both heritable genetic variables and environmental risk factors. Epigenetic processes, such as DNA methylation, have important roles in mediating the effects of the environment on behavior. Dysregulation of these processes has been observed in many psychiatric disorders, and evidence suggests that they may also be involved in suicidal behaviors. Herein, we have summarized candidate gene and epigenome-wide studies which have investigated DNA methylation in relation to suicidal behaviors, as well as discussed some of the limitations of the field to date.
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- 2020
29. Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants
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Glenda MacQueen, Benicio N. Frey, Daniel J. Müller, Roumen Milev, Claudio N. Soares, Faranak Farzan, Sidney H. Kennedy, Sagar V. Parikh, Francesco Leri, Laura M. Fiori, Jean-François Théroux, Peter Giacobbe, Gary Gang Chen, Pierre Blier, Zahia Aouabed, Qingqin Li, Susan Rotzinger, Jane A. Foster, Raoul Belzeaux, Rudolf Uher, Raymond W. Lam, Chelsey Ju, and Gustavo Turecki
- Subjects
Male ,Oncology ,Genome-wide association study ,0302 clinical medicine ,0303 health sciences ,Depression ,Middle Aged ,Antidepressive Agents ,3. Good health ,Psychiatry and Mental health ,CpG site ,DNA methylation ,Major depressive disorder ,Female ,medicine.drug ,Adult ,Canada ,medicine.medical_specialty ,Adolescent ,Citalopram ,Predictive markers ,Polymorphism, Single Nucleotide ,Article ,lcsh:RC321-571 ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Humans ,Escitalopram ,Clinical significance ,Epigenetics ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,030304 developmental biology ,Psychiatric Status Rating Scales ,Depressive Disorder, Major ,business.industry ,Chimerin Proteins ,Case-control study ,DNA Methylation ,Janus Kinase 2 ,medicine.disease ,ROC Curve ,Case-Control Studies ,Linear Models ,CpG Islands ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18–60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.
- Published
- 2019
30. Investigation of miR-1202, miR-135a, and miR-16 in Major Depressive Disorder and Antidepressant Response
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Eduardo Chachamovich, Gustavo Turecki, Juan Pablo Lopez, Jane A. Foster, Sidney H. Kennedy, Susan Rotzinger, Stéphane Richard-Devantoy, Laura M. Fiori, Marcelo T. Berlim, and Fabrice Jollant
- Subjects
Oncology ,medicine.medical_specialty ,Clinical Decision-Making ,Duloxetine Hydrochloride ,Citalopram ,03 medical and health sciences ,Depressive Disorder, Treatment-Resistant ,0302 clinical medicine ,Internal medicine ,Desvenlafaxine Succinate ,microRNA ,Medicine ,Humans ,Pharmacology (medical) ,antidepressant response ,Pharmacology ,Psychiatric Status Rating Scales ,Depressive Disorder, Major ,major depressive disorder ,business.industry ,medicine.disease ,Antidepressive Agents ,3. Good health ,030227 psychiatry ,Peripheral ,Psychiatry and Mental health ,MicroRNAs ,Treatment Outcome ,ROC Curve ,Endogenous depression ,Antidepressant ,Major depressive disorder ,Brief Reports ,business ,030217 neurology & neurosurgery ,Mir 135a ,Biomarkers ,medicine.drug - Abstract
Background Major depressive disorder is a debilitating illness, which is most commonly treated with antidepressant drugs. As the majority of patients do not respond on their first trial, there is great interest in identifying biological factors that indicate the most appropriate treatment for each patient. Studies suggest that microRNA represent excellent biomarkers to predict antidepressant response. Methods We investigated the expression of miR-1202, miR-135a, and miR-16 in peripheral blood from 2 cohorts of depressed patients who received 8 weeks of antidepressant therapy. Expression was quantified at baseline and after treatment, and its relationship to treatment response and depressive symptoms was assessed. Results In both cohorts, responders displayed lower baseline miR-1202 levels compared with nonresponders, which increased following treatment. Conclusions Ultimately, our results support the involvement of microRNA in antidepressant response and suggest that quantification of their levels in peripheral samples represents a valid approach to informing treatment decisions.
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- 2017
31. Co-Variation of Peripheral Levels of miR-1202 and Brain Activity and Connectivity During Antidepressant Treatment
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Fabrice Jollant, Gustavo Turecki, Eduardo Chachamovich, Stéphane Richard-Devantoy, Juan Pablo Lopez, Laura M. Fiori, Paola Niola, Marcelo T. Berlim, and Fabricio Pereira
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Adult ,Male ,Brain activity and meditation ,Rest ,Precuneus ,Motor Activity ,Neuropsychological Tests ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,Desvenlafaxine Succinate ,Neural Pathways ,medicine ,Humans ,Serotonin and Noradrenaline Reuptake Inhibitors ,Pharmacology ,Brain Mapping ,Depressive Disorder, Major ,Resting state fMRI ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Antidepressive Agents ,030227 psychiatry ,Desvenlafaxine ,Inhibition, Psychological ,MicroRNAs ,Psychiatry and Mental health ,Treatment Outcome ,medicine.anatomical_structure ,Schizophrenia ,Posterior cingulate ,Major depressive disorder ,Female ,Original Article ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
MicroRNAs are short non-coding molecules that play a major role in regulating gene expression. Peripheral levels of miR-1202 have been shown to predict and mediate antidepressant response. However, it is not clear to what extent these peripheral measures reflect central neural changes in vivo. We approached this problem with the combined use of peripheral miR-1202 measures and neuroimaging. At baseline and after 8 weeks of desvenlafaxine (50–100 mg die), 20 patients were scanned with 3T magnetic resonance imaging, first at rest then during the Go/NoGo task, a classical test of response inhibition. Blood samples were collected at both time points. During resting state, lower baseline miR-1202 levels were predictive of increased connectivity from T0 to T8 between the posterior cingulate and the prefrontal, parietal, and occipital cortices. Changes in miR-1202 levels following desvenlafaxine treatment were negatively correlated with changes in activity in right precuneus within the default-mode network, and in connectivity between the posterior cingulate and the temporal and prefrontal cortices, and the precuneus. During the Go/NoGo task, baseline miR-1202 levels and changes in these levels were correlated with activity changes in different regions, including bilateral prefrontal, insular, cingulate, and temporal cortices, and left putamen and claustrum. Finally, secondary analyses in a subset of patients showed a trend for a significant correlation between miR-1202 levels and glutamate levels measured by spectroscopy. Changes in peripheral miR-1202 levels were therefore associated with changes in brain activity and connectivity in a network of brain regions associated with depression and antidepressant response. These effects may be mediated by the glutamatergic system.
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- 2017
32. Bridging Basic and Clinical Research in Early Life Adversity, DNA Methylation, and Major Depressive Disorder
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Laura M. Fiori, Amanda Brown, and Gustavo Turecki
- Subjects
0301 basic medicine ,antidepressant therapies ,lcsh:QH426-470 ,Review ,behavioral disciplines and activities ,03 medical and health sciences ,0302 clinical medicine ,Intervention (counseling) ,mental disorders ,medicine ,Genetics ,Epigenetics ,Genetics (clinical) ,early life adversity ,DNA methylation ,epigenetics ,major depressive disorder ,business.industry ,biomarkers ,medicine.disease ,Early life ,lcsh:Genetics ,030104 developmental biology ,Clinical research ,Sexual abuse ,030220 oncology & carcinogenesis ,Molecular Medicine ,Major depressive disorder ,business ,Psychopathology ,Clinical psychology - Abstract
Early life adversity (ELA)- including childhood physical, emotional, and sexual abuse, as well as childhood neglect- is an important predictive factor for negative psychopathology, including Major Depressive Disorder (MDD). ELA can epigenetically regulate key emotional and behavioral systems in ways that can stably persist into adulthood and contribute to the development of MDD and other psychopathology. DNA methylation has been one of the most investigated forms of epigenetic regulation in ELA to MDD pathway. From these studies, genes and sites associated with ELA/MDD have been identified and should be further investigated in order to identify potential avenues for intervention.
- Published
- 2019
33. Efficacy of Vitamin B6 in Lithium-Associated Tremor
- Author
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J.M. Azorin, Bruno Etain, Raoul Belzeaux, Laure Varin, Laura M. Fiori, Manuel Dias Alves, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation FondaMental [Créteil], and Etain, Bruno
- Subjects
Lithium (medication) ,[SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,MEDLINE ,MESH: Tremor ,MESH: Lithium Compounds ,Pharmacology ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,MESH: Bipolar Disorder ,medicine ,Pharmacology (medical) ,MESH: Humans ,MESH: Middle Aged ,business.industry ,MESH: Antioxidants ,MESH: Adult ,MESH: Antimanic Agents ,MESH: Male ,030227 psychiatry ,Psychiatry and Mental health ,[SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,MESH: Vitamin B 6 ,Vitamin b6 ,business ,MESH: Female ,030217 neurology & neurosurgery ,medicine.drug - Abstract
International audience
- Published
- 2017
34. Validation study of microRNAs previously associated with antidepressant response in older adults treated for late-life depression with venlafaxine
- Author
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Farhana Islam, Victoria S. Marshe, Sidney H. Kennedy, Eric J. Lenze, Jane A. Foster, Jordan F. Karp, Benoit H. Mulsant, Daniel M. Blumberger, James L. Kennedy, Gustavo Turecki, Malgorzata Maciukiewicz, Volodymyr Yerko, Daniel J. Müller, Laura M. Fiori, Jennie Yang, and Charles F. Reynolds
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Treatment response ,Venlafaxine ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,microRNA ,medicine ,Humans ,Biological Psychiatry ,Depression (differential diagnoses) ,Aged ,Pharmacology ,Depression ,business.industry ,Venlafaxine Hydrochloride ,Middle Aged ,Late life depression ,Antidepressive Agents ,030227 psychiatry ,MicroRNAs ,Treatment Outcome ,Sample size determination ,Antidepressive Agents, Second-Generation ,Antidepressant ,Female ,business ,Biomarkers ,Pharmacogenetics ,medicine.drug - Abstract
Background MicroRNAs (miRNAs) are small 22 nucleotides long, non-coding RNAs that are potential biomarkers for antidepressant treatment response. We aimed to replicate previous associations of miRNAs with antidepressant treatment response in a sample of older adults diagnosed with late-life depression. Methods Our sample included 184 older adults diagnosed with moderately severe depression that received open-label venlafaxine (up to 300 mg/day) for approximately 12 weeks. We quantified miRNA expression levels at baseline and week 12 for miRNAs miR-1202, miR-135a-5p, miR-16-5p, miR-146a-5p, miR-146b-5p, miR-425-3p, and miR-24-3p to explore their association with remission status, response trajectories, and time-to-remission. Results At T0 and T12, there were no differences in miRNA expression levels between remitters and non-remitters. However, remitters showed a trend toward higher baseline miR-135a-5p (Median = 11.3 [9.9, 15.7], p = .083). Prior to correction, baseline miR-135a-5p expression levels showed an association with remission status (OR = 1.8 [1.0, 3.3], p = .037). Individuals with higher baseline miR-135a-5p showed better response trajectories (F = 4.5, FDR-corrected p = 4.4 × 10−4), particularly at weeks 10 and 12 (p Limitations Although the sample size was relatively modest, our findings are consistent with the literature suggesting that higher miR-135a-5p levels may be associated with better antidepressant treatment response. Conclusions However, the miRNA signature of antidepressant response in older adults may be different as compared to younger adults.
- Published
- 2020
35. Predicting Worsening Suicidal Ideation With Clinical Features and Peripheral Expression of Messenger RNA and MicroRNA During Antidepressant Treatment
- Author
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Raymond W. Lam, Faranak Farzan, Claudio N. Soares, Juan Pablo Lopez, Glenda MacQueen, Francesco Leri, Roumen Milev, Laura M. Fiori, Rudolf Uher, Benicio N. Frey, Daniel J. Müller, Laurent Boyer, Mohamed Boucekine, Sidney H. Kennedy, Sagar V. Parikh, Peter Giacobbe, Gustavo Turecki, Raoul Belzeaux, Susan Rotzinger, Pierre Blier, and Jane A. Foster
- Subjects
0301 basic medicine ,Oncology ,Adult ,Genetic Markers ,Male ,medicine.medical_specialty ,Adolescent ,Nerve Tissue Proteins ,Placebo ,Duloxetine Hydrochloride ,law.invention ,Suicidal Ideation ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,microRNA ,Medicine ,Duloxetine ,Animals ,Humans ,030212 general & internal medicine ,RNA, Messenger ,Suicidal ideation ,Aged ,Depressive Disorder, Major ,business.industry ,Microfilament Proteins ,Area under the curve ,Middle Aged ,medicine.disease ,Prognosis ,Antidepressive Agents ,Psychiatry and Mental health ,MicroRNAs ,030104 developmental biology ,chemistry ,Major depressive disorder ,Antidepressant ,Stathmin ,Female ,medicine.symptom ,business - Abstract
OBJECTIVE To investigate how the combination of clinical and molecular biomarkers can predict worsening of suicidal ideation during antidepressant treatment. METHODS Samples were obtained from 237 patients with major depressive disorder (DSM-IV criteria) treated with either duloxetine or placebo in an 8-week randomized controlled trial. Data were collected between 2007 and 2011. The relationship between treatment-worsening suicidal ideation (TWSI) and a number of clinical variables, as well as peripheral expression of messenger RNA (mRNA) and microRNA (miRNA), was assessed at baseline. We generated 4 predictive models for TWSI: clinical, mRNA, miRNA, and a combined model comprising the best predictive variables from clinical, mRNA, and miRNA data. RESULTS Eleven patients (9.8%) presented with TWSI in the duloxetine group. Among the clinical variables, only baseline depressive severity was found to be mildly predictive of TWSI. Two mRNAs (stathmin 1 [STMN1] and protein phosphatase 1 regulatory subunit 9B [PPP1R9B]) and 2 miRNAs (miR-3688 and miR-5695) were identified that were significantly predictive of TWSI when mRNA and miRNA were assessed separately (P = .002, .044, .004, and .005, respectively). The best model included baseline depression severity and expression of STMN1 and miR-5695 and predicted TWSI with area under the curve = 0.94 (P < .001). Additionally, the combined model did not significantly predict TWSI in the placebo group. CONCLUSIONS This study generated a predictive tool for TWSI that combines both biological and clinical variables. These biological variables can be easily quantified in peripheral tissues, thus rendering them viable targets to be used in both clinical practice and future studies of suicidal behaviors. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00635219, NCT00599911, and NCT01140906.
- Published
- 2018
36. Transcriptomic and epigenomic biomarkers of antidepressant response
- Author
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Gustavo Turecki, Rixing Lin, Laura M. Fiori, Chelsey Ju, Raoul Belzeaux, Marc-Aurele Chay, Pierre-Eric Lutz, Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry [Montréal], McGill University = Université McGill [Montréal, Canada], and Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,Epigenomics ,Genetic Markers ,Small RNA ,[SDV]Life Sciences [q-bio] ,Computational biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Gene expression ,Humans ,ComputingMilieux_MISCELLANEOUS ,Depressive Disorder, Major ,biology ,DNA Methylation ,Antidepressive Agents ,Psychiatry and Mental health ,Clinical Psychology ,MicroRNAs ,030104 developmental biology ,Histone ,DNA methylation ,biology.protein ,Biomarker (medicine) ,030217 neurology & neurosurgery - Abstract
Background Antidepressant treatment is associated with a high rate of poor response, and thus, biomarker development is warranted. Methods We aimed to synthesize studies investigating gene expression, small RNAs, and epigenomic biomarkers of antidepressant response. We conducted a narrative review of the literature. Results Firstly, we detailed the challenges involved, in terms of biological tissues, relevant study time frames, and mandatory statistical tools. Secondly we synthesized results obtained in gene expression studies, focusing mainly on genome-wide studies, particularly small non-coding RNA, including micro-RNA and other small RNA species. In addition, we reviewed the potential biomarkers of antidepressant response arising from studies investigating DNA methylation variation and histone modifications. Limitations We did not conduct a meta-analysis due to the heterogeneity of the study. Conclusion Although promising, the field of gene expression and epigenomic biomarkers of antidepressant response is still in its infancy, and needs further development to define useful biomarkers in clinical practice.
- Published
- 2018
37. Evidence of Reduced Agmatine Concentrations in the Cerebral Cortex of Suicides
- Author
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Gustavo Turecki, Laura M. Fiori, Daniel Almeida, and Gary G. Chen
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Agmatine ,polyamines ,Spermine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,Cerebral Cortex ,Depressive Disorder, Major ,business.industry ,Human brain ,16. Peace & justice ,medicine.disease ,Spermidine ,Psychiatry and Mental health ,Polyamine Catabolism ,Suicide ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Case-Control Studies ,Antidepressant ,Major depressive disorder ,Brief Reports ,high-resolution capillary gas chromatography-mass spectrometry ,business ,Polyamine ,030217 neurology & neurosurgery - Abstract
Background The polyamines are a group of ubiquitous low-molecular–weight aliphatic molecules that play an essential role in various physiological functions of the mammalian CNS. Previous literature has indicated alterations in the expression of polyamine-related genes in the brains of individuals who died by suicide, including downregulation of spermidine/spermine N1-acetyltransferase, a key enzyme involved in polyamine catabolism. One such polyamine, agmatine, has been shown to act as an antidepressant in animal models of depressive-like behavior. However, agmatine concentrations have not been explored in postmortem human brain of individuals who died by suicide. Methods To measure agmatine in postmortem human brain tissue, we employed our previously published high-resolution capillary gas chromatography in combination with mass spectrometry method. Using this method, we analyzed agmatine levels in a total of 120 tissue samples from Brodmann areas 4, 11, and 44 of 40 male subjects comprising controls (n=13), individuals who died by suicide and met criteria for major depressive disorder (n=14), and subjects who died by suicide and did not meet criteria for major depressive disorder (n=13). Results Agmatine fell within the expected nanomolar range and was significantly reduced in the cortex of suicides, irrespective of meeting criteria for major depressive disorder compared with controls. Conclusions This is the first gas chromatography-mass spectrometry study to analyze agmatine concentrations in human postmortem brain of individuals who died by suicide. These results add to our mechanistic understanding of the role that the polyamine stress response pathway may play in the neurobiology of major depression and/or suicide.
- Published
- 2018
38. Integrated Genome-Wide Methylation and Expression Analyses Reveal Functional Predictors of Response to Antidepressants
- Author
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Claudio N. Soares, Roumen Milev, Faranak Farzan, Daniel J. Müller, Sidney H. Kennedy, Rudolf Uher, Jean-François Théroux, Francesco Leri, Laura M. Fiori, Raymond W. Lam, Qingqin Li, Chelsey Ju, Susan Rotzinger, Raoul Belzeaux, Sagar V. Parikh, Pierre Blier, Peter Giacobbe, Glenda MacQueen, Jane A. Foster, Gustavo Turecki, Benicio N. Frey, Zahia Aouabed, and Gary Gang Chen
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,medicine.disease ,Clinical trial ,Internal medicine ,DNA methylation ,Cohort ,medicine ,Major depressive disorder ,Biomarker (medicine) ,Escitalopram ,Epigenetics ,business ,Depression (differential diagnoses) ,medicine.drug - Abstract
Background: Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond to adequate trials. Understanding who is likely to respond to antidepressant treatment and/or what mediates this response is of considerable clinical importance. As part of the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) initiative, we aimed to identify differential DNA methylation marks as epigenetic predictors of antidepressant response (ADR) in MDD patients. Methods: Healthy participants (n=112) and depressed participants (n=211) between 18-60 years of age were recruited across six Canadian clinical centers. Eligible depressed patients with MDD by DSM-IV-TR criteria and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥24 were enrolled. Genome-wide DNA methylation analysis was conducted using the Infinium MethylationEPIC Beadchipb with DNA extracted from baseline peripheral blood samples prior to beginning an eight-week trial of escitalopram. Genome-wide mRNA expression analysis was conducted on the HumanHT-12 v4 Expression Beadchip in RNA extracted from leukocytes at baseline. Depressed patients were classified as non-responders (NRES) and responders (RES) according to changes in MADRS scores following eight weeks of treatment. Differentially methylated positions (DMPs) were identified in regions of differentially expressed genes and validated using a targeted sequencing approach. Replication was conducted with patients participating in a similar trial, the Douglas Biomarker Study. CAN-BIND-1 clinical trial was registered with the ClinicalTrials.gov identification #: NCT101655706. Findings: After depressed participants concluded the 8-week trial, 82 RES and 95 NRES were included in this study. Genome-wide differential DNA methylation revealed 2,572 DMPs (p
- Published
- 2018
39. Using Epigenetic Tools to Investigate Antidepressant Response
- Author
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Raoul Belzeaux, Rixing Lin, Chelsey Ju, Laura M. Fiori, and Gustavo Turecki
- Subjects
0301 basic medicine ,Treatment response ,business.industry ,medicine.disease ,Non-coding RNA ,Bioinformatics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,microRNA ,Medicine ,Major depressive disorder ,Antidepressant ,Epigenetics ,business ,030217 neurology & neurosurgery - Abstract
Major depressive disorder is a chronic and debilitating illness. It is most commonly treated with antidepressant drugs, however, as the majority of patients do not respond on their first trial or following several adequate trials, there is great interest in identifying biological factors that may help select the most appropriate treatment for each patient and in understanding biological processes that mediate treatment response. Epigenetic factors, such as non-coding RNAs (ncRNAs), hold potential as biomarkers of antidepressant response. In this chapter, we review key methodological considerations when investigating ncRNA biomarkers, including biological samples and technologies which have been used in these studies. Secondly, we summarize findings from studies investigating ncRNAs in antidepressant treatment response. Finally, we discuss some of the future directions which will be necessary for the development of clinically relevant epigenetic tools.
- Published
- 2018
40. Childhood Maltreatment and Stress-Related Psychopathology: The Epigenetic Memory Hypothesis
- Author
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Laura M. Fiori, Daniel Almeida, Pierre-Eric Lutz, Gustavo Turecki, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry [Montréal], and McGill University = Université McGill [Montréal, Canada]
- Subjects
Adult ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,childhood maltreatment ,early-life adversity ,Affect (psychology) ,Article ,Epigenesis, Genetic ,stress ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Child Abuse ,Epigenetics ,Child ,Psychiatry ,Socioeconomic status ,Epigenesis ,Pharmacology ,DNA methylation ,epigenetics ,business.industry ,Adult Survivors of Child Abuse ,Mental Disorders ,Behavioral pattern ,Mental health ,030227 psychiatry ,3. Good health ,business ,Stress, Psychological ,030217 neurology & neurosurgery ,Psychopathology ,Clinical psychology - Abstract
International audience; Childhood maltreatment (CM) is all too frequent among western societies, with an estimated prevalence of 10 to 15%. CM associates with increased risk of several psychiatric disorders, and therefore represents a worrying public and socioeconomic burden. While associated clinical outcomes are well characterized, determining by which mechanisms early-life adverse experiences affect mental health over the lifespan is a major challenge. Epigenetic mechanisms, in particular DNA methylation, represent a form of molecular memory that may modify brain function over extended periods of time, as well as serve as a bio-marker of behavioral phenotypes associated with CM. Here, we review human studies suggesting that DNA methylation is a crucial substrate mediating neurobiological consequences of CM throughout life, thereby potentiating maladaptive behavioral patterns and psychopathological risk.
- Published
- 2015
41. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes
- Author
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Hannah M. Cates, Francesco Leri, Gustavo Turecki, Laura M. Fiori, Roumen Milev, Steven C. Strother, Rixing Lin, Juan Pablo Lopez, Glenda MacQueen, Naguib Mechawar, Cristiana Cruceanu, Benicio N. Frey, Stacy M. Ku, Katherine J. Aitchison, Elizabeth A. Heller, Sidney H. Kennedy, Kenneth R. Evans, Raymond W. Lam, Kathrin Tyryshkin, Peter Giacobbe, Vincent Vialou, Daniel J. Müller, Rudolf Uher, Sagar V. Parikh, Cathryn M. Lewis, Christophe Gerald, Claudio N. Soares, Faranak Farzan, Susan Rotzinger, Benoit Labonté, Ming-Hu Han, Pierre Blier, Jane A. Foster, Eric J. Nestler, Harriet Feilotter, Gayle M. Wittenberg, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Icahn School of Medicine at Mount Sinai [New York] (MSSM), McMaster University [Hamilton, Ontario], St. Michael's Hospital, Queen's University [Kingston, Canada], University of Toronto, Centre for Addiction and Mental Health [Toronto] (CAMH), British Columbia, University of Guelph, University of Calgary, University of Ottawa [Ottawa], University of British Columbia (UBC), Vancouver Coastal Health Research Institute (VCH), University of Michigan [Ann Arbor], University of Michigan System, Rotman Research Institute at the Baycrest Centre (RRI), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Alberta, Dalhousie University [Halifax], Janssen Research & Development, and vialou, vincent
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Male ,General Physics and Astronomy ,Bioinformatics ,law.invention ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Randomized controlled trial ,law ,Wnt Signaling Pathway ,Regulation of gene expression ,Multidisciplinary ,Wnt signaling pathway ,Brain ,Middle Aged ,Antidepressive Agents ,3. Good health ,Major depressive disorder ,Antidepressant ,Female ,Adult ,MAP Kinase Signaling System ,Science ,Duloxetine Hydrochloride ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Young Adult ,microRNA ,medicine ,Journal Article ,Duloxetine ,Animals ,Humans ,Aged ,Depressive Disorder, Major ,business.industry ,[SCCO.NEUR]Cognitive science/Neuroscience ,[SCCO.NEUR] Cognitive science/Neuroscience ,Computational Biology ,General Chemistry ,medicine.disease ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,HEK293 Cells ,chemistry ,Gene Expression Regulation ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems., Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.
- Published
- 2017
42. Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers
- Author
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Juan Pablo Lopez, Naguib Mechawar, Jeffrey A. Gross, Laura M. Fiori, Benoit Labonté, Volodymyr Yerko, and Gustavo Turecki
- Subjects
Adult ,Male ,Prefrontal Cortex ,Poison control ,Bioinformatics ,Young Adult ,Downregulation and upregulation ,Acetyltransferases ,microRNA ,Gene expression ,Polyamines ,Humans ,Pharmacology (medical) ,Prefrontal cortex ,Gene ,Pharmacology ,Oxidoreductases Acting on CH-NH Group Donors ,Messenger RNA ,Depression ,RNA ,MicroRNAs ,Suicide ,Psychiatry and Mental health ,Gene Expression Regulation ,Case-Control Studies ,Psychology ,Neuroscience - Abstract
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in the posttranscriptional regulation of mRNA. These molecules have been the subject of growing interest as they are believed to control the regulation of a large number of genes, including those expressed in the brain. Evidence suggests that miRNAs could be involved in the pathogenesis of neuropsychiatric disorders. Alterations in metabolic enzymes of the polyamine system have been reported to play a role in predisposition to suicidal behaviour. We have previously shown the expression of the polyamine genes SAT1 and SMOX to be down-regulated in the brains of suicide completers. In this study, we hypothesized that the dysregulation of these genes in depressed suicide completers could be influenced by miRNA posttranscriptional regulation. Using a stringent target prediction analysis, we identified several miRNAs that target the 3’UTR of SAT1 and SMOX. We profiled the expression of 10 miRNAs in the prefrontal cortex (BA44) of suicide completers (N=15) and controls (N=16) using qRT-PCR. We found that several miRNAs showed significant up-regulation in the prefrontal cortex of suicide completers compared to psychiatric healthy controls. Furthermore, we demonstrated a significant correlation between these miRNAs and the expression levels of both SAT1 and SMOX. Our results suggest a relationship between miRNAs and polyamine gene expression in the suicide brain, and postulate a mechanism for SAT1 and SMOX down-regulation by post-transcriptional activity of miRNAs. Received 31 January 2013; Reviewed 26 March 2013; Revised 15 July 2013; Accepted 21 July 2013
- Published
- 2013
43. Investigating epigenetic consequences of early-life adversity: some methodological considerations
- Author
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Gustavo Turecki and Laura M. Fiori
- Subjects
0301 basic medicine ,Candidate gene ,lcsh:RC435-571 ,DNA methylation ,epigenetics ,early-life adversity ,childhood abuse ,stress ,Developmental psychology ,Highlights from ISTSS 2015 ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Psychiatry ,Early childhood ,Epigenetics ,Childhood abuse ,Clinical Research Article ,Early life ,3. Good health ,030104 developmental biology ,Psychology ,Stress reactivity ,030217 neurology & neurosurgery ,Psychopathology ,Clinical psychology - Abstract
Stressful and traumatic events occurring during early childhood have been consistently associated with the development of psychiatric disorders later in life. This relationship may be mediated in part by epigenetic mechanisms, such as DNA methylation, which are influenced by the early-life environment. Epigenetic patterns can have lifelong effects on gene expression and on the functioning of biological processes relevant to stress reactivity and psychopathology. Optimization of epigenetic research activity necessitates a discussion surrounding the methodologies used for DNA methylation analysis, selection of tissue sources, and timing of psychological and biological assessments. Recent studies related to early-life adversity and methylation, including both candidate gene and epigenome-wide association studies, have drawn from the variety of available techniques to generate interesting data in the field. Further discussion is warranted to address the limitations inherent to this field of research, along with future directions for epigenetic studies of adversity-related psychopathology.Keywords: DNA methylation; epigenetics; early-life adversity; childhood abuse; stress(Published: 8 November 2016)Responsible Editors: Bernet Elzinga, Leiden University, Netherlands; Christian Schmahl, Central Institute of Mental Health, Germany.This paper is part of the Special Issue: Back to Basics: Integrating Clinical and Scientific Knowledge to Advance the Field of Trauma - Highlights of the ISTSS-2015. More papers from this issue can be found at www.ejpt.netFor the abstract or full text in other languages, please see Supplementary files under ‘Article Tools’Citation: European Journal of Psychotraumatology 2016, 7: 31593 - http://dx.doi.org/10.3402/ejpt.v7.31593
- Published
- 2016
44. 753. The Influence of Early Life Trauma on Epigenetic Markers in a CAN-BIND Sample of Responders and Non-Responders to Escitalopram
- Author
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Chelsey Ju, Gustavo Turecki, Sidney H. Kennedy, Laura M. Fiori, Susan Rotzinger, Jane A. Foster, and Kate L. Harkness
- Subjects
Non responders ,medicine.medical_specialty ,medicine ,Escitalopram ,Sample (statistics) ,Epigenetics ,Psychology ,Psychiatry ,Biological Psychiatry ,Early life ,Clinical psychology ,medicine.drug - Published
- 2017
45. Global gene expression profiling of the polyamine system in suicide completers
- Author
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Aurélie Labbe, Jordie Croteau, Simon Noël, Alexandre Bureau, Gustavo Turecki, Laura M. Fiori, and Chantal Mérette
- Subjects
Male ,Adenosylmethionine Decarboxylase ,DNA, Complementary ,Spermine oxidase ,Spermidine ,Spermine Synthase ,Gene Expression ,Spermine ,Ornithine decarboxylase ,chemistry.chemical_compound ,Polyamines ,Humans ,Pharmacology (medical) ,Aspartate Aminotransferases ,Pharmacology ,Genetics ,Oxidoreductases Acting on CH-NH Group Donors ,biology ,Mood Disorders ,Gene Expression Profiling ,Chromosome Mapping ,Microarray Analysis ,Gene expression profiling ,Suicide ,Psychiatry and Mental health ,chemistry ,Biochemistry ,Adenosylmethionine decarboxylase ,Spermine synthase ,biology.protein ,Polyamine - Abstract
In recent years, gene expression, genetic association, and metabolic studies have implicated the polyamine system in psychiatric conditions, including suicide. Given the extensive regulation of genes involved in polyamine metabolism, as well as their interconnections with the metabolism of other amino acids, we were interested in further investigating the expression of polyamine-related genes across the brain in order to obtain a more comprehensive view of the dysregulation of this system in suicide. To this end, we examined the expression of genes related to polyamine metabolism across 22 brain regions in a sample of 29 mood-disordered suicide completers and 16 controls, and identified 14 genes displaying differential expression. Among these, altered expression of spermidine/spermine N1-acetyltransferase, spermine oxidase, and spermine synthase, has previously been observed in brains of suicide completers, while the remainder of the genes represent novel findings. In addition to genes with direct involvement in polyamine metabolism, including S-adenosylmethionine decarboxylase, ornithine decarboxylase antizymes 1 and 2, and arginase II, we identified altered expression of several more distally related genes, including aldehyde dehydrogenase 3 family, member A2, brain creatine kinase, mitochondrial creatine kinase 1, glycine amidinotransferase, glutamic-oxaloacetic transaminase 1, and arginyl-tRNA synthetase-like. Many of these genes displayed altered expression across several brain regions, strongly implying that dysregulated polyamine metabolism is a widespread phenomenon in the brains of suicide completers. This study provides a broader view of the nature and extent of the dysregulation of the polyamine system in suicide, and highlights the importance of this system in the neurobiology of suicide.
- Published
- 2011
46. Gene expression profiling of suicide completers
- Author
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Laura M. Fiori and Gustavo Turecki
- Subjects
0301 basic medicine ,Microarray ,business.industry ,Gene Expression Profiling ,Poison control ,Computational biology ,Suicide prevention ,Genetic determinism ,Gene expression profiling ,Suicide ,03 medical and health sciences ,Psychiatry and Mental health ,030104 developmental biology ,0302 clinical medicine ,Gene expression ,Humans ,Medicine ,DNA microarray ,business ,Gene ,Neuroscience ,030217 neurology & neurosurgery ,Oligonucleotide Array Sequence Analysis - Abstract
Despite strong evidence for a role of biological factors in the etiology and pathology of suicide, the study of traditional neurotransmitter systems has been able to explain only a small proportion of the neurobiology of what is now recognized as a complex genetic trait. The use of microarrays to simultaneously examine the expression levels of thousands of gene transcripts has vastly expanded our capacity to detect the involvement of additional genes and pathways in suicidality, and has opened many new avenues for the discovery of the biological underpinnings of suicide completion. This review examines microarray studies which have been used to identify genes displaying altered expression in suicide completers, and highlights some of the important methodological considerations and metabolic pathways which have emerged from these analyses.
- Published
- 2010
47. Evidence of Altered Polyamine Concentrations in Cerebral Cortex of Suicide Completers
- Author
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Alain Gratton, Laura M. Fiori, Orval A. Mamer, Naguib Mechawar, Gustavo Turecki, Gary Gang Chen, and Luc Moquin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Spermidine ,Poison control ,Spermine ,Gas Chromatography-Mass Spectrometry ,chemistry.chemical_compound ,Internal medicine ,Gene expression ,Putrescine ,medicine ,Humans ,Cerebral Cortex ,Psychiatric Status Rating Scales ,Pharmacology ,Analysis of Variance ,Middle Aged ,Suicide ,Psychiatry and Mental health ,Polyamine Catabolism ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Cerebral cortex ,Postmortem Changes ,Original Article ,Polyamine - Abstract
Recent studies have implicated alterations in the expression of polyamine-related genes in the brains of suicide completers including widespread downregulation of spermidine/spermine N1-acetyltransferase, the key enzyme in polyamine catabolism, suggesting compensatory mechanisms attempting to increase brain levels of polyamines. Given the complexity of the polyamine system, quantification of the levels of the polyamines is an essential step in understanding the downstream effects of dysregulated gene expression. We developed a method using high-resolution capillary gas chromatography (GC) in combination with mass spectrometry (MS) for quantitation of polyamines from post-mortem brain tissue, which allowed us to accurately measure spermidine and putrescine concentrations in post-mortem brain tissues. Using this method, we analyzed putrescine and spermidine levels in a total of 126 samples from Brodmann areas 4, 8/9, and 11, from 42 subjects, comprising 16 suicide completers with major depression, 13 non-depressed suicide completers, and 13 control subjects. Both putrescine and spermidine levels fell within the expected nanomolar ranges and were significantly elevated in the brain of suicide completers with a history of major depression as compared with controls. These results were not accounted by possible confounders. This is the first GC-MS study to analyze the expression of putrescine and spermidine from post-mortem brain tissue and confirms the hypothesis raised by previous studies indicating alterations in putrescine and spermidine levels in suicide/major depression.
- Published
- 2010
48. Genetic and Epigenetic Methods for Analysis of the Dopamine D2 Receptor Gene
- Author
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Paul R. Albert, Mireille Daigle, and Laura M. Fiori
- Subjects
Genetics ,Dopamine receptor D2 ,Epigenetics ,Biology ,Gene - Published
- 2014
49. Peripheral Levels of the Micro-RNA MiR-1202 are Correlated with Changes in Brain Activity and Connectivity During an Antidepressant Treatment
- Author
-
Fabricio Pereira, Gustavo Turecki, Laura M. Fiori, Yang Ding, Fabrice Jollant, Juan Pablo Lopez, Stéphane Richard-Devantoy, and Paola Niola
- Subjects
Psychiatry and Mental health ,Glutamatergic ,medicine.anatomical_structure ,Resting state fMRI ,Neuroimaging ,Brain activity and meditation ,Posterior cingulate ,Glutamate receptor ,Precuneus ,medicine ,Psychology ,Neuroscience ,Peripheral - Abstract
IntroductionMicro-RNAs are short non-coding sequences playing a major role in regulating gene expression. Peripheral levels of the micro-RNA miR-1202 have been shown to predict antidepressant response and to change during treatment. However, it is not clear to what extent these peripheral measures reflect central neural changes in vivo.ObjectivesWe aimed at investigating a potential link between peripheral micro-RNA and neuroimaging measures.MethodsAt baseline and after 8 weeks of desvenlafaxine (50–100 mg die), twenty depressed patients were scanned with 3 T magnetic resonance imaging, first at rest then during the Go/NoGo task, a classical test of response inhibition. Blood samples were taken for RNA extraction.ResultsDuring resting state, baseline miR-1202 levels were predictive of decreased connectivity between the posterior cingulate and the prefrontal, occipital and parietal cortices. Changes in miR-1202 levels were correlated with changes in activity in right precuneus within the default-mode network, and with decreased connectivity between the posterior cingulate and the temporal and prefrontal cortices, and the precuneus. During the Go/NoGo task, baseline levels and changes in these levels were correlated with activity changes in different regions, including bilateral prefrontal, insular, cingulate, and temporal cortices. Finally, secondary analyses suggest an association between miR-1202 levels and glutamate levels measured by spectroscopy in dorsomedial prefrontal cortex.ConclusionsThis is the first study showing that baseline and changes in peripheral levels of one micro-RNA were associated with changes in brain activity and connectivity during an antidepressant treatment. MiR-1202 may act through the modulation of the glutamatergic system.
- Published
- 2017
50. Genetic and Neurobiological Approaches to Understanding Suicidal Behaviors
- Author
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Matthew K. Nock, Laura M. Fiori, Carl Ernst, and Gustavo Turecki
- Subjects
Suicidal behavior ,Neurotransmitter systems ,Psychology ,Clinical psychology - Published
- 2014
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