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

Chiara Fabbri, Concetta Crisafulli, Raffaella Calati, Diego Albani, Gianluigi Forloni, Marco Calabrò, Rosalba Martines, Siegfried Kasper, Joseph Zohar, Alzbeta Juven-Wetzler, Daniel Souery, Stuart Montgomery, Julien Mendlewicz, Alessandro Serretti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)723-735
Number of pages13
JournalEuropean Archives of Psychiatry and Clinical Neuroscience
Issue number8
StatePublished - 1 Dec 2017


  • Antidepressant
  • Gene
  • Neuroplasticity
  • Pharmacogenetics
  • Polymorphism
  • Treatment-resistant depression


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