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Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior

  • Rebecca A. Brachman
    Affiliations
    Departments of Neuroscience, Columbia University, New York.
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  • Josephine C. McGowan
    Affiliations
    Departments of Psychiatry, Columbia University, New York.

    Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., New York, New York.
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  • Jennifer N. Perusini
    Affiliations
    Departments of Psychiatry, Columbia University, New York.

    Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., New York, New York.
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  • Sean C. Lim
    Affiliations
    Departments of Psychiatry, Columbia University, New York.

    Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., New York, New York.
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  • Thu Ha Pham
    Affiliations
    Institut National de la Santé et de la Recherche Médicale UMR-S 1178 Santé Publique, Santé Mentale, Université Paris-Sud, Fac Pharmacie, Université Paris Saclay, France.
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  • Charlene Faye
    Affiliations
    Institut National de la Santé et de la Recherche Médicale UMR-S 1178 Santé Publique, Santé Mentale, Université Paris-Sud, Fac Pharmacie, Université Paris Saclay, France.
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  • Alain M. Gardier
    Affiliations
    Institut National de la Santé et de la Recherche Médicale UMR-S 1178 Santé Publique, Santé Mentale, Université Paris-Sud, Fac Pharmacie, Université Paris Saclay, France.
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  • Indira Mendez-David
    Affiliations
    Institut National de la Santé et de la Recherche Médicale UMR-S 1178 Santé Publique, Santé Mentale, Université Paris-Sud, Fac Pharmacie, Université Paris Saclay, France.
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  • Denis J. David
    Affiliations
    Institut National de la Santé et de la Recherche Médicale UMR-S 1178 Santé Publique, Santé Mentale, Université Paris-Sud, Fac Pharmacie, Université Paris Saclay, France.
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  • René Hen
    Affiliations
    Departments of Psychiatry, Columbia University, New York.

    Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., New York, New York.

    Department of Pharmacology, Columbia University, New York, New York.
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  • Christine A. Denny
    Correspondence
    Address correspondence to Christine Ann Denny, Ph.D., Columbia University/Research Foundation for Mental Hygiene, Inc., Psychiatry, NYSPI Kolb Research Annex, Room 777, 1051 Riverside Drive, Unit 87, New York, NY 10032-2695.
    Affiliations
    Departments of Psychiatry, Columbia University, New York.

    Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., New York, New York.
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      Abstract

      Background

      Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified.

      Methods

      Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine could protect against depressive-like behavior. Mice were administered a single dose of saline or ketamine and then 1 week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT.

      Results

      SD robustly and reliably induced depressive-like behavior in control mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test and in the dominant interaction test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training, and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the forced swim test, novelty suppressed feeding paradigm, and the sucrose splash test.

      Conclusions

      These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.

      Keywords

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      Linked Article

      • From Mice to Men: Can Ketamine Enhance Resilience to Stress?
        Biological PsychiatryVol. 79Issue 9
        • Preview
          The rapid antidepressant properties of intravenous ketamine have ignited high hopes from researchers, clinicians, and patients alike. Although bottom-up patient demand has led some clinicians to offer repeated ketamine infusions directly to patients, academic commentators have warned against premature clinical adoption (1), at times likening the field’s enthusiasm to the misguided use of stimulants or opiates to induce short-term depression relief. The rapidity of the antidepressant onset of ketamine (2 hours after infusion) is impressive, but effects also dissipate rapidly (3–7 days).
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