The antidepressant actions of ketamine and its enantiomers

Abstract

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist first developed as an anesthetic, has shown significant promise as a medication with rapid antidepressant properties in treatment-resistant depression. However, concerns such as adverse side effects and potential misuse liability have limited its widespread use. Racemic ketamine has two enantiomers-(S)- and (R)-ketamine-that appear to have disparate underlying mechanisms. This brief review summarizes some of the most recent preclinical and clinical research regarding the convergent and divergent prophylactic, immediate, and sustained antidepressant effects of (S)- and (R)-ketamine while addressing potential differences in their side effect and misuse liability profiles. Preclinical research suggests divergent mechanisms underlying (S)- and (R)-ketamine, with (S)-ketamine more directly affecting mechanistic target of rapamycin complex 1 (mTORC1) signaling and (R)-ketamine more directly affecting extracellular signal-related kinase (ERK) signaling. Clinical research suggests that (R)-ketamine has a milder side effect profile than (S)-ketamine and decreases depression rating scale scores, but recent randomized, controlled trials found that it had no significant antidepressant efficacy compared to placebo, suggesting that caution is warranted in interpreting its therapeutic potential. Future preclinical and clinical research is needed to maximize the efficacy of each enantiomer, either by optimizing dose, route of administration, or administration paradigm.

Keywords: Antidepressant; Depression; Ketamine; R-ketamine (arketamine); S-ketamine (esketamine).

Figure 1.. Chemical structure of (S)- and (R)-ketamine and their metabolic pathways.

(S)-ketamine and (R)-ketamine are metabolized in a stereoselective manner by P450 liver enzymes. The enantiomers are first metabolized to their norketamine counterparts through nitrogen-mediated demethylation. Subsequent metabolism leads to dehydroxynorketamine (DHNK) or hydroxylation to hydroxynorketamine (HNK). Each enantiomer can also be metabolized to hydroxyketamine, another intermediary step for HNK.

Figure 2.. Hypothesized convergent/divergent mechanisms between (S)- and (R)-ketamine.

Both (S)- and (R)-ketamine increase the probability of glutamate release into the synaptic cleft, increasing AMPAR throughput and activating downstream cellular signaling mechanisms, as well as increasing synaptic protein translation of AMPAR subunits and PSD-95, contributing to further synaptogenesis and dendritogenesis. The actions of (S)-ketamine appear to be primarily facilitated through preferential binding to NMDARs expressed in GABAergic interneurons, leading to a depolarization of cortical excitatory neurons. This depolarization causes the observed glutamate release, as well as a release of neurotrophic factors such as BDNF, which binds to TrkB receptors. This, in turn, activates the mTORC1 signaling pathway, leading to the upregulation of synaptogenesis and dendritogenesis discussed earlier. In addition, (S)-ketamine binds to extrasynaptic NMDARs, disinhibiting mTORC1 signaling by deactivating eEFK2 (not pictured here). Binding to mu-opioid receptors may facilitate antidepressant effects but may also contribute to increased adverse events. In contrast, (R)-ketamine seems to primarily facilitate immune modulation by affecting microglial signaling and increasing BDNF release. This BDNF release binds to TrkB and activates the ERK signaling pathway, upregulating synaptogenesis and dendritogenesis. While displayed as distinct mechanisms here, please note that there may be overlap and other potential mechanisms not noted in this figure. Figure is approximate for illustrative purposes. Abbreviations: AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF: brain-derived neurotrophic factor; CREB: cyclic adenosine monophosphate response element-binding protein; eEFK2: eukaryotic elongation factor-2 kinase; ERK: extracellular signal-related kinase; GABA: gamma aminobutyric acid; mTORC1: mechanistic target of rapamycin complex 1; NFATc4: nuclear factor of activated T cells 4; NMDAR: N-methyl-D-aspartate receptor; PSD-95: postsynaptic density protein 95; TrkB: tropomyosin receptor kinase B.