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Lack of Opioid System in the Antidepressant Actions of Ketamine

  • Kai Zhang
    Affiliations
    Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan

    Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
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  • Kenji Hashimoto
    Correspondence
    Address correspondence to Kenji Hashimoto, Ph.D., Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan.
    Affiliations
    Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan
    Search for articles by this author
Published:December 10, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.11.006
      The N-methyl-D-aspartate receptor antagonist ketamine can elicit rapid and sustained antidepressant effects in treatment-resistant patients with major depressive disorder. However, the precise molecular mechanisms underlying ketamine’s antidepressant actions are currently unknown. Recently, Williams et al. (
      • Williams N.
      • Heifets B.
      • Blasey C.
      • Sudheimer K.
      • Pannu J.
      • Pankow H.
      • et al.
      Attenuation of antidepressant effects of ketamine by opioid receptor antagonism.
      ) demonstrated the role of the opioid system in the rapid antidepressant effects of ketamine in patients with treatment-resistant major depressive disorder. In the small-sample, single-center crossover trial, the authors investigated the effects of pretreatment with the opioid receptor antagonist naltrexone (50 mg, 45 minutes before) on the antidepressant effects of ketamine (0.5 mg/kg, intravenous) in the patients. In ketamine-responsive patients with treatment-resistant depression, pretreatment with naltrexone profoundly attenuated ketamine’s antidepressant effects, with none of the ketamine responders meeting the response criterion at day 1. Furthermore, there were no differences in ketamine-induced dissociation between two conditions. The authors conclude that opioid receptor activation is required for ketamine’s acute antidepressant effects, although the dissociative effects of ketamine are not mediated by the opioid system (
      • Williams N.
      • Heifets B.
      • Blasey C.
      • Sudheimer K.
      • Pannu J.
      • Pankow H.
      • et al.
      Attenuation of antidepressant effects of ketamine by opioid receptor antagonism.
      ). However, the sample size (n = 7) of ketamine-responsive patients is too small. In addition, there are currently no reports showing the role of opioid receptors in the antidepressant effects of ketamine in rodent models of depression. Therefore, the present study was undertaken to examine whether naltrexone can block the antidepressant effects of ketamine in chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)-treated inflammation models of depression.
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