title: The genome-wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response.
abstract: Antidepressant-induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long-term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome-wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome-wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose-dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome-wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.|National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience at the Maudsley Hospital and King's College London, London, United Kingdom.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Powell
authors.affiliation: King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.
authors.forename: Tytus
authors.initials: T
authors.lastname: Murphy
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.|National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience at the Maudsley Hospital and King's College London, London, United Kingdom.
authors.forename: Simone
authors.initials: S
authors.lastname: de Jong
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.|National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience at the Maudsley Hospital and King's College London, London, United Kingdom.
authors.forename: Sang Hyuck
authors.initials: SH
authors.lastname: Lee
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.|College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Hodgson
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.|Department of Psychiatry, Dalhousie University, Halifax, Canada.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.affiliation: King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Price
authors.affiliation: King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.
authors.forename: Sandrine
authors.identifier: http://orcid.org/0000-0003-1260-8083
authors.initials: S
authors.lastname: Thuret
authors.affiliation: King's College London, Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), London, United Kingdom.|National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience at the Maudsley Hospital and King's College London, London, United Kingdom.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D002478:Cells, Cultured; D015283:Citalopram / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram
keywords: antidepressant response; antidepressants; genetic pathway analysis; hippocampal neurogenesis; hippocampal volume; transcriptomics