The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects

Curr Psychiatry Rep. 2007 Dec;9(6):467-74. doi: 10.1007/s11920-007-0063-1.


In this article, we first review a study showing that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine leads to rapid, robust, and relatively sustained antidepressant effects in patients with treatment-resistant major depression. We then discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine may be mediated by increased AMPA-to-NMDA glutamate receptor throughput in critical neuronal circuits. We hypothesize that ketamine directly mediates this throughput, whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the lag of onset of several weeks to months that is observed with traditional antidepressants.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Amantadine / pharmacology
  • Amantadine / therapeutic use
  • Depressive Disorder, Major / psychology*
  • Dopamine Agents / pharmacology
  • Dopamine Agents / therapeutic use
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use*
  • Memantine / pharmacology
  • Memantine / therapeutic use
  • Mood Disorders / drug therapy*
  • Mood Disorders / metabolism*
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, Glutamate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors


  • Dopamine Agents
  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Amantadine
  • Memantine