Ketamine: A tale of two enantiomers

Abstract

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

Keywords: (R)-ketamine; (S)-ketamine; 5-HT; AMPA receptor; BDNF; ERK; GSK-3; Ketamine; NMDA receptor; TrkB; depression; dopamine; mTORC1; opioid receptor.

Figure 1.

Chemical structure of ketamine enantiomers. (S)-ketamine and (R)-ketamine are a pair of stereoisomers that are non-superimposable mirror images of each other. An example of familiar objects that are related in such a way are the left and right hand.

Figure 2.

Major metabolites of (S)-ketamine and (R)-ketamine. (S)-ketamine or (R)-ketamine are initially metabolised to (S)-norketamine or (R)-norketamine via CYP3A4 or CYP2B6. (S)-norketamine or (R)-norketamine are further metabolised to (S)-dehydronorketamine (DHNK) or (R)-DHNK. (S)-norketamine or (R)-norketamine are metabolised to (2S,6S)-hydroxynorketamine (HNK) or (2R,6R)-HNK via CYP2A6. (S)-ketamine or (R)-ketamine may also be metabolised to (2S,6S)-HK or (2R,6R)-hydroxyketamine (HK) via CYP2A6 before transformation to (2S,6S)-HNK or (2R,6R)-HNK. Metabolites identified as candidate antidepressants are highlighted in dashed boxes.

Figure 3.

Proposed signalling pathways underlying the antidepressant actions of ketamine enantiomers and metabolites. Top: (S)-ketamine causes glutamate release via disinhibition of γ-aminobutyric acid (GABA) interneurons. Resulting glutamate surge stimulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors leading to release of brain-derived neurotrophic factor (BDNF) with resulting activation of tropomyosin kinase B (TrkB)-Akt-mammalian target of rapamycin complex 1 (mTORC1) signalling. This leads to increased synthesis of proteins required for synaptogenesis. (S)-ketamine and (S)-norketamine suppress resting N-Methyl-D-Aspartate (NMDA) receptor activity, deactivating eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation, augmentation of BDNF synthesis and TrkB-mTORC1 activation. Bottom: (R)-ketamine causes glutamate release via disinhibition of GABA interneurons with activation of AMPA receptors and BDNF release but there may be an alternative pathway by which (R)-ketamine stimulates AMPA receptor transmission that still needs to be elucidated. (R)-ketamine may cause preferential activation of TrkB-MEK-ERK signalling pathway leading to synaptogenesis. (2R,6R)-HNK directly activates AMPA receptors and inhibition of group II metabotropic glutamate (mGlu2) receptors may also be involved in this metabolite’s antidepressant actions.

Figure 4.

Hypothesised monoamine and opioid mechanisms and potential convergences with signalling pathways implicated in the antidepressant actions of ketamine. (a) (R,S)-ketamine inhibits lateral habenula (LHb) bursting via actions on N-Methyl-D-Aspartate (NMDA)/low voltage sensitive t-type channels (T-VSCC)/mu-opioid receptors (MOR). This results in disinhibition of monoamine release via γ-aminobutyric acid (GABA)-ergic interneurons in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) to projections including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). Action of (R,S)-ketamine on NMDA/MOR on GABAergic interneurons in the DRN and VTA may be a further mechanism of disinhibition of 5-HT and dopamine release. 5-HT release in mPFC may also occur via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor stimulation in DRN for (R,S)-ketamine and (S)-ketamine but might not be as relevant for (R)-ketamine. (b) Stimulation of postsynaptic 5-HT_1A receptors via 5-HT in mPFC results in activation of Akt/mammalian target of rapamycin complex 1 (mTORC1) and potentially ERK signalling. Stimulation of postsynaptic D1 receptor via dopamine may result in activation of mTORC1/ERK and inactivation of eukaryotic elongation factor 2 (eEF2) kinase. Postsynaptic MOR activation may also potentiate the ERK signalling pathway.

Figure 5.

Outstanding questions.