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Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish

Published online by Cambridge University Press:  26 January 2015

Lewis A. Opler ,
Mark G. A. Opler  and
Amy F. T. Arnsten
Lewis A. Opler
Affiliation:
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA
Mark G. A. Opler
Affiliation:
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA Department of Psychiatry, New York University School of Medicine, New York, New York, USA ProPhase LLC, New York, New York, USA
Amy F. T. Arnsten*
Affiliation:
Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA
*
*Address for correspondence: Amy F. T. Arnsten, PhD, Dept. Neurobiology, Yale Medical School, 333 Cedar St., New Haven, CT 06510, USA. (Email: amy.arnsten@yale.edu)
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Abstract

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine’s ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Keywords

Antidepressantarea 25glutamateprefrontal cortexrTMS
Type
Review Article
Information
CNS Spectrums , Volume 21 , Issue 1 , February 2016 , pp. 12 - 22
Copyright
© Cambridge University Press 2015 

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Footnotes

This work is dedicated to the memory of Daniel Friedland, with the hope that we may discover more effective treatments to alleviate suffering. This work was funded in part by NIH Pioneer Award DP1AG047744 to AFTA. The authors would like to thank Drs. G. Aghajanian, R. Duman, J. Krystal, H. Mayberg, J. Murrough, G. Sanacora, and J. Singh for informative and inspiring discussions.

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