Targeting glutamate signalling in depression: progress and prospects

Nat Rev Drug Discov. 2017 Jul;16(7):472-486. doi: 10.1038/nrd.2017.16. Epub 2017 Mar 17.

Abstract

Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose-response relationships and therapeutic mechanisms.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Drug Design
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism
  • Humans
  • Ketamine / pharmacology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Signal Transduction / drug effects

Substances

  • Antidepressive Agents
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Ketamine