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      Rethinking ketamine and esketamine action: Are they antidepressants with mood-stabilizing properties?

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          Abstract

          Ketamine and esketamine, the S-enantiomer of the racemic mixture, have recently generated considerable interest as potential therapeutic agents for Treatment-Resistant Depression (TRD), a complex disorder that includes various psychopathological dimensions and distinct clinical profiles (e.g., comorbid personality disorder, bipolar spectrum, dysthymic disorder). This perspective article provides a comprehensive overview of the action of ketamine/esketamine from a dimensional point of view, taking into account the high prevalence of bipolarity in TRD and the evidence of the efficacy of these substances on mixed features, anxiety, dysphoric mood, and, generally, bipolar traits. Additionally, the article underscores the complexity of the pharmacodynamic mechanisms of action of ketamine/esketamine, which goes beyond the non-competitive antagonism of NMDA-R. The need for further research and evidence is highlighted, mainly to evaluate the efficacy of esketamine nasal spray in bipolar depression, the presence of bipolar elements as a predictor of response, and the potential role of these substances as mood stabilizers. The article implies that, in the future, ketamine/esketamine could be used with fewer limitations, not only as antidepressants for the most severe form of depression but also as valuable tools to stabilize subjects with mixed symptoms or bipolar spectrum.

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          Author and article information

          Journal
          Eur Neuropsychopharmacol
          European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
          Elsevier BV
          1873-7862
          0924-977X
          May 2023
          : 70
          Affiliations
          [1 ] Department of Neurosciences, Imaging and Clinical Sciences, Università degli Studi G. D'Annunzio, Chieti, Italy.
          [2 ] Department of Neurosciences, Imaging and Clinical Sciences, Università degli Studi G. D'Annunzio, Chieti, Italy. Electronic address: mauro.pettorruso@hotmail.it.
          [3 ] Chair of Psychiatry, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.
          [4 ] Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
          [5 ] Department of Neurosciences, Imaging and Clinical Sciences, Università degli Studi G. D'Annunzio, Chieti, Italy; Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.
          Article
          S0924-977X(23)00037-8
          10.1016/j.euroneuro.2023.02.010
          36867895
          415f28ce-5150-4d61-be37-f38928ba03fd
          History

          Rapid-acting therapies,Bipolar depression,Esketamine,Ketamine,Mood stabilizers,TRD

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