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HelixTalk Episode #96 - Abra Cadabra, SPRA-VATO!!! Is Esketamine a New “Magic” Cure for Depression?

Date posted: May 28, 2019, 6:00 am

In this episode we discuss the recent FDA approval of esketamine (Spravato) for the management of treatment resistant depression as an add on to oral antidepressant therapy. The agent is novel though so, too, may be its adverse effect profile and logistics of administration.


Key Concepts

  1. Esketamine represents, to a large degree, the culmination of many years of research into the role of glutamate receptor antagonists in depression management. However, even now we do not fully know how it works though it is likely a combination of NMDA antagonism and consequential agonism at AMPA which facilitates better neuronal communication.
  2. Data showing day 2 separation from placebo in terms of improvement in MADRS scores is something that just doesn't occur in depression studies (which usually need a number of weeks to demonstrate efficacy), and this is what is likely driving a lot of the optimism behind treatment.
  3. That being said, it is surprising that some of the phase III studies did not show any benefit and that the FDA allowed for a withdrawal study to count as the second efficacy study needed for approval, particularly given the FDA concerns that patients in the enriched sample who were randomized to placebo were now aware (due to lack of active control and to the known dissociative effects of esketamine) that they were no longer getting the medication which had worked so well for them, potentially resulting in a negative expectancy bias.
  4. Side effects such as hypertension, sedation, and dissociation which require a strict monitoring protocol, along with the need to present twice weekly for administration during the induction phase, may limit patient acceptance of treatment.