The promise of ketamine for treatment-resistant depression: current evidence and future directions

Ann N Y Acad Sci. 2015 May;1345(1):47-58. doi: 10.1111/nyas.12646. Epub 2015 Feb 3.


Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants.

Keywords: antidepressant; bipolar disorder; ketamine; major depressive disorder; treatment resistant.

Publication types

  • Review

MeSH terms

  • Anhedonia / drug effects
  • Antidepressive Agents / therapeutic use*
  • Cognition / drug effects
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Depressive Disorder, Major / psychology
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / physiopathology
  • Depressive Disorder, Treatment-Resistant / psychology
  • Drug Resistance
  • Humans
  • Ketamine / therapeutic use*
  • Mood Disorders / drug therapy
  • Mood Disorders / physiopathology
  • Mood Disorders / psychology
  • Treatment Failure


  • Antidepressive Agents
  • Ketamine