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Underlying mechanisms of ( R,S )-ketamine’s treatment efficacy for post-traumatic stress disorder and depression: a review
  • Richard Hartman ,
  • Thomas Cutting
Richard Hartman
Loma Linda University School of Behavioral Health

Corresponding Author:rhartman@llu.edu

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Thomas Cutting
Loma Linda University School of Behavioral Health
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Abstract

Numerous studies have demonstrated the efficacy of (R,S)-ketamine as a treatment for posttraumatic stress disorder (PTSD), treatment resistant depression, and co-morbid occurrences of these conditions. The (R) and (S) stereoisomers of ketamine have also demonstrated efficacy in attenuation of stress and depressive symptoms, with (R)-ketamine demonstrating reduced abuse potential and side effects. Although research on (R,S)-ketamine and its metabolites’ efficacy has been promising, less is known about the mechanisms by which these compounds elicit their therapeutic effects. Here, we review the research literature concerning the hypothesized mechanisms of (R,S)-ketamine and its metabolites. The pharmacodynamics of (R,S)-ketamine’s effects on depression involve the dentate gyrus, prefrontal cortex, the CA3 region of the ventral hippocampus (vCA3), dorsal raphe nucleus, and the prelimbic to dorsal raphe nucleus (PL-DRN) circuit. Concerning PTSD, The pharmacodynamics of (R,S)-ketamine include attenuation of the 5-HT dorsal raphe nucleus and activation of the PL-DRN circuit. Additionally, (R,S)-ketamine administration prior to stress exposure is associated with increased metabolism of purine and pyrimidine after stress, as well as potentiation of inhibitory neurotransmitters and dampening of excitatory neurotransmitters, with the exception of glutamic acid. The current evidence suggests that, although brain-derived neurotropic factor (BDNF) expression through activation of tropomyosin-related kinase B (TrkB) is likely necessary for (R,S)-ketamine’s remedial effects, NMDA receptor antagonism may be unrelated to its therapeutic efficacy.
17 Sep 2024Submitted to European Journal of Neuroscience
30 Oct 2024Submission Checks Completed
30 Oct 2024Assigned to Editor
30 Oct 2024Review(s) Completed, Editorial Evaluation Pending
30 Oct 2024Reviewer(s) Assigned