Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance

• Published in: European archives of psychiatry and clinical neuroscience Vol. 267; no. 8; pp. 723 - 735
• Main Authors: Fabbri, Chiara, Crisafulli, Concetta, Calati, Raffaella, Albani, Diego, Forloni, Gianluigi, Calabrò, Marco, Martines, Rosalba, Kasper, Siegfried, Zohar, Joseph, Juven-Wetzler, Alzbeta, Souery, Daniel, Montgomery, Stuart, Mendlewicz, Julien, Serretti, Alessandro
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2017; Springer Nature B.V
• Subjects: Adult; Antidepressants; Antidepressive Agents, Second-Generation - administration & dosage; Antidepressive Agents, Second-Generation - pharmacology; CHL1 protein; Circadian rhythms; Citalopram; Citalopram - administration & dosage; Citalopram - pharmacology; Databases, Genetic; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Depressive Disorder, Treatment-Resistant - drug therapy; Depressive Disorder, Treatment-Resistant - genetics; Endoplasmic reticulum; Female; Humans; Male; Medicine; Medicine & Public Health; Mental depression; Middle Aged; Molecular modelling; Neural networks; Neural plasticity; Neuromodulation; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Neurosciences; Original Paper; Pharmacogenetics - methods; Polymorphism, Single Nucleotide; Prospective Studies; Psychiatry; Remission; Remission Induction; Second Messenger Systems - drug effects; Second Messenger Systems - genetics; Single-nucleotide polymorphism; Studies; Synaptic plasticity; Treatment Outcome; Venlafaxine; Venlafaxine Hydrochloride - administration & dosage; Venlafaxine Hydrochloride - pharmacology; Antidepressant; Neuroplasticity; Pharmacogenetics; Gene; Treatment-resistant depression; Polymorphism
• ISSN: 0940-1334; 1433-8491
• DOI: 10.1007/s00406-017-0766-1

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.