Ketamine/esketamine: Putative mechanisms of action

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Looking at the extensive published data over the past 20 years, a consistent model has emerged whereby glutamate agonism of the AMPA-glutamate receptor, both with and without antagonism of the NMDA-glutamate receptor, appears to set in motion a molecular cascade involving BDNF and VEGF, and ultimately increasing the activity of mTOR, with resulting synaptogenicity that increases global brain connectivity in the human prefrontal cortex. As we continue to understand the complexities and additional circuitries that are involved in the RAAD effect of K/ESK, the hope is that novel molecular targets for future drug development will emerge.

Bottom Line

Extensive published data over the past 20 years has produced a consistent model to explain the putative mechanisms of action for the rapid antidepressant effects of ketamine and esketamine. We must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our patients with treatment-resistant depression.

Related Resources

Drug Brand Names

Esketamine nasal spray • Spravato
Imipramine • Tofranil
Ketamine • Ketalar
Naltrexone • Vivitrol, ReVia
Rapamycin • Rapamune
Remifentanil • Ultiva


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