title: Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance.
abstract: Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4-6 weeks and in case of non-response with escitalopram for 4-6 weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity.
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fabbri
authors.affiliation: Department of Biomedical Science, Odontoiatric and Morphological and Functional Images, University of Messina, Messina, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.affiliation: INSERM U1061, France and FondaMental Foundation, University of Montpellier UM1, Montpellier, France.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Calati
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Albani
authors.affiliation: Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: Department of Biomedical Science, Odontoiatric and Morphological and Functional Images, University of Messina, Messina, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Calabrò
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.|Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Martines
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zohar
authors.affiliation: Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Juven-Wetzler
authors.affiliation: Laboratoire de Psychologie Medicale, Centre Européen de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Brussels, Belgium.
authors.forename: Daniel
authors.initials: D
authors.lastname: Souery
authors.affiliation: lmperial College School of Medicine, London, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Montgomery
authors.affiliation: Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Julien
authors.initials: J
authors.lastname: Mendlewicz
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy. alessandro.serretti@unibo.it.
authors.forename: Alessandro
authors.identifier: http://orcid.org/0000-0003-4363-3759
authors.initials: A
authors.lastname: Serretti
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology*; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D030541:Databases, Genetic; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012074:Remission Induction; D015290:Second Messenger Systems / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D000069470:Venlafaxine Hydrochloride
keywords: Antidepressant; Gene; Neuroplasticity; Pharmacogenetics; Polymorphism; Treatment-resistant depression