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) (1), treatment
resistant depression (2, 3), and co-morbid occurrences of these
conditions (4). The (R,S), (R), and (S) stereoisomers of ketamine have
also demonstrated efficacy in attenuation of stress and depressive
symptoms (5), with (R)-ketamine demonstrating reduced abuse potential
and side effects (6). Although research on (R,S)-ketamine’s 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, hippocampal CA3, dorsal raphe nucleus, and the
prelimbic to dorsal raphe nucleus (PL-DRN) circuit. 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 therapeutic effects, NMDA receptor
antagonism may be unrelated to its antidepressant efficacy.