An Update on Glutamatergic System in Suicidal Depression and on the Role of Esketamine

Curr Top Med Chem. 2020;20(7):554-584. doi: 10.2174/1568026620666200131100316.


Background: A research on mood disorder pathophysiology has hypothesized abnormalities in glutamatergic neurotransmission, by suggesting further investigation on glutamatergic N-methyl-Daspartate (NMDA) receptor modulators in treating Major Depressive Disorder (MDD). Esketamine (ESK), an NMDA receptor antagonist able to modulate glutamatergic neurotransmission has been recently developed as an intranasal formulation for treatment-resistant depression (TRD) and for rapid reduction of depressive symptomatology, including suicidal ideation in MDD patients at imminent risk for suicide.

Objective: The present study aims at investigating recent clinical findings on research on the role of the glutamatergic system and ESK in treating suicidal depression in MDD and TRD.

Methods: A systematic review was here carried out on PubMed/Medline, Scopus and the database on U.S. N.I.H. Clinical Trials ( and the European Medical Agency (EMA) ( from inception until October 2019.

Results: Intravenous infusion of ESK is reported to elicit rapid-acting and sustained antidepressant activity in refractory patients with MDD and TRD. In phase II studies, intranasal ESK demonstrated a rapid onset and a persistent efficacy in patients with TRD as well as in MDD patients at imminent risk for suicide. However, some data discrepancies have emerged in phase III studies.

Conclusion: The U.S. Food and Drug Administration (FDA) granted fast track and Breakthrough Therapy Designation to Janssen Pharmaceuticals®, Inc. for intranasal ESK in 2013 for treatment-resistant depression (TRD) and in 2016 for the treatment of MDD with an imminent risk of suicide. However, further studies should be implemented to investigate the long-term efficacy and safety of intranasal ESK.

Keywords: Depression; Esketamine; Glutamate; Glutamatergic system; Ketamine; MDD; Suicide; Treatment-resistant depression..

Publication types

  • Systematic Review

MeSH terms

  • Administration, Intranasal
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacokinetics*
  • Clinical Trials as Topic
  • Databases, Factual
  • Depression / drug therapy*
  • Depressive Disorder, Major / drug therapy*
  • Drug Compounding
  • Glutamic Acid / pharmacology
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / pharmacokinetics*
  • Ketamine / pharmacology
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Suicide / prevention & control*
  • Synaptic Transmission / drug effects
  • Time Factors
  • Treatment Outcome
  • United States
  • United States Food and Drug Administration


  • Antidepressive Agents
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Esketamine
  • Ketamine