Glutamate and depression: clinical and preclinical studies

Ann N Y Acad Sci. 2003 Nov;1003:250-72. doi: 10.1196/annals.1300.016.


The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical models. Moreover, antidepressant-like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants.

Publication types

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

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Aspartic Acid / physiology
  • Calcium / metabolism
  • Clinical Trials as Topic
  • Depressive Disorder / drug therapy
  • Depressive Disorder / physiopathology*
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / physiopathology
  • Excitatory Amino Acids / physiology
  • Glutamates / physiology*
  • Humans
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / physiology
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Antidepressive Agents
  • Excitatory Amino Acids
  • Glutamates
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Aspartic Acid
  • Calcium