Glutamate-based antidepressants: 20 years on

Trends Pharmacol Sci. 2009 Nov;30(11):563-9. doi: 10.1016/


Depression is a chronic recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires > or =2-4 weeks of treatment and a first course of therapy provides symptom relief to only 60-65% of patients. Roche and Evotec recently announced plans to develop N-methyl-D-aspartate (NMDA) receptor antagonists targeting the NR2B subtype for treatment-resistant depression. This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101 606), has antidepressant effects in patients unresponsive to a serotonin selective reuptake inhibitor, as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist ketamine. Here we describe evidence that glutamate-based therapies might represent an effective alternative to biogenic-amine-based agents for depression and provide perspectives on the development of these agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Clinical Trials as Topic
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Drug Delivery Systems*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Drug Resistance
  • Excitatory Amino Acid Antagonists / pharmacology
  • Humans
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors


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