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

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 i...

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Bibliographic Details
Published in:CNS spectrums 2016-02, Vol.21 (1), p.12-22
Main Authors: Opler, Lewis A., Opler, Mark G. A., Arnsten, Amy F. T.
Format: Article
Language:English
Subjects:
Administration, Intranasal
Animals
Antidepressants
Cerebral Cortex - drug effects
Depressive Disorder, Treatment-Resistant - drug therapy
Depressive Disorder, Treatment-Resistant - physiopathology
Drug dosages
Excitatory Amino Acid Antagonists - pharmacology
Excitatory Amino Acid Antagonists - therapeutic use
FDA approval
Humans
Hypotheses
Ketamine
Ketamine - pharmacology
Ketamine - therapeutic use
Mental depression
Pain - physiopathology
Patients
Prefrontal Cortex - drug effects
Prefrontal Cortex - physiopathology
Ratings & rankings
Receptors, N-Methyl-D-Aspartate - drug effects
Review Article
Suicides & suicide attempts
Synapses - drug effects
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Summary: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.
ISSN:1092-8529
2165-6509
DOI:10.1017/S1092852914000686