Underlying mechanisms of ( R,S )-ketamine’s treatment efficacy for
post-traumatic stress disorder and depression: a review
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.