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Annu Rev Pharmacol Toxicol. 2014;54:119-39. doi: 10.1146/annurev-pharmtox-011613-135950.

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

Author information

1
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institutes of Health/National Institute of Mental Health, Bethesda, Maryland 20814-9692; email: mark.niciu@nih.gov.

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.

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