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Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism

Molecular Psychiatry volume 24, pages 1779–1786 (2019)Cite this article

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Abstract

We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine’s antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery–Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

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Funding

This work was supported by the Stanford Clinical and Translational Science Award to Spectrum [NIH UL1 TR 001085] (NRW + AFS); the 2016 and 2018 NARSAD Young Investigator Grant program (NRW); the Avy L. and Robert L. Miller Foundation (NRW); NIMH K08MH110610 (BDH) and the Pritzker Family Fund (AFS).

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  1. These Co-first authors contributed equally: Nolan R. Williams, Boris D. Heifets

  2. These Co-second authors contributed equally: Brandon S. Bentzley, Christine Blasey

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Nolan R. Williams, Brandon S. Bentzley, Christine Blasey, Keith D. Sudheimer, Jessica Hawkins, David M. Lyons & Alan F. Schatzberg

  2. Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA

    Boris D. Heifets

  3. Department of Psychology, Palo Alto University, Palo Alto, CA, USA

    Christine Blasey

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AFS reports Consulting: Bracket/Clintara; Alkermes; Neuronetics; McKinsey; GLG Consulting; Avanir. Equity: Xhale; Corcept; Merck; Seattle Genetics; Gilead; Titan; Incyte Genetics; Intersect. Grants; Janssen. The remaining authors declare that they have no conflict of interest.

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Williams, N.R., Heifets, B.D., Bentzley, B.S. et al. Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Mol Psychiatry 24, 1779–1786 (2019). https://doi.org/10.1038/s41380-019-0503-4

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