Esketamine for Treatment-Resistant Depression (TRD)

Lee Pravder, MD
      February 26, 2019

It’s finally happening. The first new class of antidepressant medication in 30 years. On February 12, the FDA advisory committee gave it’s approval to esketamine to be marketed under the trade name SpravatoTM by Janssen Pharmaceutical Companies of Johnson & Johnson for TRD and for MDD with an imminent risk of suicide.1

Here is a summary of what you need to know:

  • Approximately 30% of people with MDD are “treatment resistant”
  • The main hypothesis for the underlying pathophysiology of MDD had been the monoamine theory
  • New lines of research are finding that synaptic connectivity is diminished in key areas in pts with MDD
  • Glutamate which is the main excitatory neurotransmitter in the brain is involved with numerous second messenger systems that enhance synaptic connectivity.
  • The FDA granted Breakthrough Therapy designation both for TRD as well as MDD with imminent risk of suicide. This was based on 5 studies for pts with TRD: 3 short-term studies, one withdrawal maintenance of effect and on long-term safety study.1
  • Data from both a short-term Phase 3 study and a long-term Phase 3 study demonstrated that esketamine nasal spray plus a newly initiated oral antidepressant provided statistically significant, clinically meaningful, rapid, and sustained improvement of depressive symptoms in this difficult-to-treat population.1
  • However, a controlled study of patients with TRD comparing IV Ketamine + Naltrexone to IV Ketamine plus placebo showed the Naltrexone group did not experience the antidepressant effect, whereas the placebo group did.2 This is suggestive that the primary mechanism of action for Ketamine is via opiate receptors . . . stay tuned!
  1. Johnson & Johnson. FDA Advisory Committee Recommends Approval of SPRAVATOTM (esketamine) Nasal Spray CIII for Adults with Treatment-Resistant Depression. accessed February 25, 2019.
  2. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psych. 2018;175(12):1205-1215.
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