Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds.

Abstract

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.

• Authors: Mark J Niciu, Ioline D Henter, David A Luckenbaugh, Carlos A Zarate Jr, Dennis S Charney
• Journal: Annual review of pharmacology and toxicology (Annu Rev Pharmacol Toxicol) Vol. 54 Pg. 119-39 ( 2014) ISSN: 1545-4304 [Electronic] United States
• PMID: 24392693 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Antidepressive Agents
• Excitatory Amino Acid Antagonists
• Peptide Elongation Factor 2
• Ketamine
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Glycogen Synthase Kinase 3

Topics

• Antidepressive Agents (pharmacology)
• Depression (drug therapy)
• Excitatory Amino Acid Antagonists (pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• Humans
• Ketamine (pharmacology)
• Peptide Elongation Factor 2 (metabolism)
• Randomized Controlled Trials as Topic
• TOR Serine-Threonine Kinases (metabolism)