Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Biol Psychiatry. 2017 May 15;81(10):886-897. doi: 10.1016/j.biopsych.2016.05.005. Epub 2016 May 12.


In patients with major depressive disorder or bipolar disorder, abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate and gamma-aminobutyric acid have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic-dose ketamine has led to a collection of studies that have examined neurochemical (e.g., glutamatergic and gamma-aminobutyric acidergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.

Keywords: Bipolar disorder; Glutamate; Ketamine; Major depressive disorder; Mood disorder; NMDA receptor antagonist.

Publication types

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

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Major* / metabolism
  • Depressive Disorder, Major* / physiopathology
  • Glutamic Acid / metabolism*
  • Humans
  • Ketamine / therapeutic use*
  • gamma-Aminobutyric Acid / metabolism*


  • Antidepressive Agents
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Ketamine