Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning

J Psychopharmacol. 2017 Mar;31(3):338-345. doi: 10.1177/0269881117691467. Epub 2017 Feb 16.

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.

Keywords: Antidepressants; connectivity mapping; drug repositioning; major depression; neural stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / pharmacology*
  • Cell Line
  • Citalopram / therapeutic use
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Drug Repositioning / methods
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Humans
  • Nortriptyline / pharmacology
  • RNA, Messenger / metabolism
  • Serotonin Uptake Inhibitors / therapeutic use
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Sulfonamides / pharmacology
  • Transcriptome / genetics

Substances

  • Antidepressive Agents
  • RNA, Messenger
  • Serotonin Uptake Inhibitors
  • Sulfonamides
  • Citalopram
  • W 7
  • Nortriptyline