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
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 (https://clinicaltrials.gov) and the European Medical Agency (EMA)
(https://clinicaltrialsregister.eu) 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