Underlying Mechanisms of the Treatment Efficacy of ( <i>R, S</i> )‐Ketamine for Post‐Traumatic Stress Disorder and Depression: A Review

ABSTRACT Numerous studies have demonstrated the efficacy of ( R, S )‐ketamine as a treatment for post‐traumatic stress disorder (PTSD), treatment‐resistant depression, and comorbid occurrences of these conditions. The ( R ) and ( S ) stereoisomers of ketamine have also demonstrated efficacy in attenuating stress and depressive symptoms, with ( R )‐ketamine demonstrating reduced abuse potential and side effects. Although research on the efficacy of ( R, S )‐ketamine and its metabolites has revealed promising results, less is known about the mechanisms by which these compounds elicit their therapeutic effects. Here, we review the literature concerning the hypothesized mechanisms of ( R, S )‐ketamine and its metabolites. The pharmacodynamics of the effects of ( R, S )‐ketamine on depression involve the dentate gyrus, prefrontal cortex, CA3 region of the ventral hippocampus, dorsal raphe nucleus, and prelimbic–dorsal raphe nucleus circuit. When treating PTSD, the pharmacodynamics of ( R, S )‐ketamine include attenuated serotonin signaling in the dorsal raphe nucleus and activation of the prelimbic–dorsal raphe nucleus circuit. Additionally, in PTSD, ( R, S )‐ketamine administration prior to stress exposure is associated with the increased metabolism of purine and pyrimidine after stress, the potentiation of inhibitory neurotransmitters, and the dampening of excitatory neurotransmitters (except for glutamic acid). Together, the current evidence suggests that, although brain‐derived neurotrophic factor expression through the activation of tropomyosin‐related kinase B is likely necessary for the treatment effects of ( R, S )‐ketamine, N ‐methyl‐D‐aspartate receptor antagonism may be unrelated to its therapeutic efficacy.