title: Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning.
abstract: Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. 'Connectivity mapping' is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram). We identified mRNA changes common to both drugs to create an 'antidepressant mRNA signature'. We used this signature to probe the Library of Integrated Network-based Cellular Signatures (LINCS) and to identify other compounds that elicit similar changes to mRNA in neural progenitor cells. Results from LINCS revealed that the tricyclic antidepressant clomipramine elicited mRNA changes most similar to our mRNA signature, and we identified W-7 and vorinostat as functionally relevant drug candidates, which may have repositioning potential. Our results are encouraging and represent the first attempt to use connectivity mapping for drug repositioning in MDD.
authors.affiliation: 1 Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.|2 National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, Maudsley Hospital and King's College London, London, UK.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Powell
authors.affiliation: 3 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Tytus
authors.initials: T
authors.lastname: Murphy
authors.affiliation: 1 Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.|2 National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, Maudsley Hospital and King's College London, London, UK.
authors.forename: Sang H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: 3 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Price
authors.affiliation: 3 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Thuret
authors.affiliation: 1 Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.|2 National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, Maudsley Hospital and King's College London, London, UK.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D002460:Cell Line; D015283:Citalopram / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D058492:Drug Repositioning / Q000379:methods; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009661:Nortriptyline / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D059467:Transcriptome / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D009661:Nortriptyline; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; C017967:W 7
keywords: Antidepressants; connectivity mapping; drug repositioning; major depression; neural stem cells