title: Transcriptomics and the mechanisms of antidepressant efficacy.
abstract: The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: karen.hodgson@kcl.ac.uk.
authors.forename: Karen
authors.initials: K
authors.lastname: Hodgson
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: katherine.tansey@kcl.ac.uk.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: timothy.powell@kcl.ac.uk.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Powell
authors.affiliation: Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: gcoppola@ucla.edu.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. Electronic address: rudolf.uher@kcl.ac.uk.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.affiliation: University Psychiatric Clinic, Ljubljana, Slovenia. Electronic address: mojca-zvezdana.dernovsek@guest.arnes.si.
authors.forename: Mojca
authors.initials: M
authors.lastname: Zvezdana Dernovšek
authors.affiliation: Research Department P, Aarhus University Hospital, Risskov, Denmark; The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus and Copenhagen, Denmark. Electronic address: nielmors@rm.dk.
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poland. Electronic address: jhauser@ump.edu.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hauser
authors.affiliation: Laboratoire de Psychologie Médicale, Université Libre de Bruxelles; Psy Pluriel - Centre Européen de Psychologie Médicale, Belgium. Electronic address: dsouery@ulb.ac.be.
authors.forename: Daniel
authors.initials: D
authors.lastname: Souery
authors.affiliation: Department of Psychiatry, University of Bonn, Germany. Electronic address: Wolfgang.Maier@ukb.uni-bonn.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Croatian Institute for Brain Research, Medical School, University of Zagreb, Croatia. Electronic address: Neven.henigsberg@zg.t-com.hr.
authors.forename: Neven
authors.initials: N
authors.lastname: Henigsberg
authors.affiliation: Central Institute of Mental Health, Division of Genetic Epidemiology in Psychiatry, Mannheim, Germany. Electronic address: marcella.rietschel@zi-mannheim.de.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Psychiatric Unit (UOP 23), Department of Mental Health,Spedali Civili Hospital of Brescia; Biological Psychiatry Unit, IRCCS-FBF, Brescia. Electronic address: anna.placentino@spedalicivili.brescia.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Placentino
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, AB, Canada; MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: kaitchis@ualberta.ca.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: ian.craig@kcl.ac.uk.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Craig
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: anne.farmer@kcl.ac.uk.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: gerome.breen@kcl.ac.uk.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College London, UK. Electronic address: peter.mcguffin@kcl.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: King׳s College London, Institute of Psychiatry, King׳s Health Partners Centre for Neurodegeneration Research, London, UK; NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King׳s College London, London, UK. Electronic address: richard.j.dobson@kcl.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Dobson
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D015283:Citalopram / Q000627:therapeutic use*; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005060:Europe; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D046228:Microarray Analysis; D009661:Nortriptyline / Q000627:therapeutic use*; D059467:Transcriptome / Q000187:drug effects*; D016896:Treatment Outcome; D044465:White People
chemical_list: D000928:Antidepressive Agents; D002352:Carrier Proteins; C576215:KXD1 protein, human; D015283:Citalopram; D009661:Nortriptyline; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted
keywords: Antidepressants; Gene expression; Genetics; Major Depressive Disorder; Pharmacogenetics; Transcriptomics