Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: A perspective review

Nicolas D. Iadarola, Mark J. Niciu, Erica M. Richards, Jennifer L. Vande Voort, Elizabeth D. Ballard, Nancy B. Lundin, Allison C. Nugent, Rodrigo Machado Vieira, Carlos A. Zarate

Research output: Contribution to journalReview article

113 Scopus citations

Abstract

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Original languageEnglish (US)
Pages (from-to)97-114
Number of pages18
JournalTherapeutic Advances in Chronic Disease
Volume6
Issue number3
DOIs
StatePublished - May 2015

Keywords

  • Antagonist
  • Bipolar depression
  • Bipolar disorder
  • Glutamate
  • Ketamine
  • Major depressive disorder
  • N-methyl-D-aspartate receptor
  • NR2B
  • Treatment-resistant depression

ASJC Scopus subject areas

  • Medicine (miscellaneous)

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  • Cite this

    Iadarola, N. D., Niciu, M. J., Richards, E. M., Vande Voort, J. L., Ballard, E. D., Lundin, N. B., Nugent, A. C., Machado Vieira, R., & Zarate, C. A. (2015). Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: A perspective review. Therapeutic Advances in Chronic Disease, 6(3), 97-114. https://doi.org/10.1177/2040622315579059