madman
Super Moderator
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 the 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.
Introduction
There are significant limitations to current widely prescribed antidepressant treatments. These include a significant delay in the onset of therapeutic action (weeks to months) and approximately one-third of patients with major depressive disorder (MDD) failing to demonstrate an adequate response (Al-Harbi, 2012). For individuals with depression, particularly if suffering from suicidal ideation, these time lags and resistance to standard treatments can be extremely harmful (Hantouche et al., 2010). Increasing evidence has revealed that the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist has the potential to overcome such limitations, demonstrating rapid antidepressant and anti-suicidal effects, even in treatment-resistant patients (Coyle and Laws, 2015; Kishimoto et al., 2016). It has been proposed that ketamine’s antidepressant effects are primarily mediated through NMDA receptor antagonism, resulting in disinhibition of pyramidal cells and an acute cortical glutamate surge, with downstream effects on synaptogenesis and neuroplastic pathways (Lener et al., 2017). However, the precise molecular and cellular processes underlying ketamine’s antidepressant effects are still not clear and evidence suggests that mechanisms other than NMDA receptor inhibition play a more crucial role in the antidepressant effects of ketamine, it's component enantiomers and metabolites (Jelen et al., 2018; Zanos et al., 2016). In this review, we summarise findings on the antidepressant effects of ketamine and its enantiomers. We then discuss underlying therapeutic mechanisms, exploring the case that ketamine’s enantiomers and metabolites may produce complementary antidepressant effects via distinct mechanisms, before considering future directions of enquiry.
Ketamine enantiomers and metabolites
Ketamine as an antidepressant
(R,S)-ketamine:
(S)-ketamine:
(R)-ketamine:
Mechanistic considerations
*NMDA receptor antagonism and α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation
*GABAergic interneuron inhibition
*BDNF-TrkB signalling
*Mammalian target of rapamycin complex and extracellular signal-regulated kinase
*Glycogen synthase kinase 3
*Translocation of Gs alpha subunit from lipid rafts
*Monoaminergic systems
*Inhibition of lateral habenula bursting
*Opioid receptor system
Conclusion
The discovery of the rapid antidepressant effects of (R,S)- ketamine, including in treatment-resistant patients, has appropriately been hailed ‘the most important discovery in half a century in depression research (Duman and Aghajanian, 2012). Through the drug development and clinical trials process, the (S)-ketamine nasal spray, SpravatoTM, has been approved in both the United States and Europe, although some concerns remain regarding the efficacy and side effects. The first pilot study of (R)-ketamine in TRD has demonstrated encouraging results and, considering preclinical findings, it appears (R)-ketamine may have a more favourable safety profile than (S)-ketamine. Accumulating preclinical evidence also suggests (R)-ketamine to have more potent and longer-lasting antidepressant effects than both (R,S)-ketamine and (S)-ketamine. As studies of (R)-ketamine progress through Phase I and Phase II, results from direct comparison studies of the safety and efficacy of (R)-ketamine and (S)-ketamine in TRD will be crucial. Other key outstanding questions are outlined in Figure 5
Although NMDA receptor inhibition and subsequent AMPA receptor activation has a role in the antidepressant effects of ketamine, further mechanistic work is building a more nuanced understanding of the distinct molecular and cellular mechanisms of ketamine, its enantiomers and metabolites, including BDNF-TrkB, mTORC1 and ERK signalling. Although there may be a role for monoaminergic and opioid receptor systems in the antidepressant effects or detrimental side effects of ketamine, further work examining the effects of each of the component enantiomers on these systems are required. All the while, new pieces of the ketamine puzzle are being discovered and other potential future directions of enquiry include examining the role of the transforming growth factor β1 system (Zhang et al., 2020b) and the brain-gut-microbiome axis (Huang et al., 2019; Yang et al., 2017b) in the antidepressant effects of ketamine and its enantiomers.
As we further our understanding of the similarities and differences in the signalling pathways associated with (S)-ketamine, (R)-ketamine and their metabolites, we should bear in mind potential complementary or synergistic antidepressant effects that might arise via distinct mechanisms. A deeper understanding of the precise molecular and cellular mechanisms underlying the antidepressant effects and negative side effects of (R,S)-ketamine, (S)-ketamine and (R)-ketamine will be invaluable as we seek to develop future rapid-acting antidepressants with favourable safety profiles, alongside treatment strategies to maintain adequate response.
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 the 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.
Introduction
There are significant limitations to current widely prescribed antidepressant treatments. These include a significant delay in the onset of therapeutic action (weeks to months) and approximately one-third of patients with major depressive disorder (MDD) failing to demonstrate an adequate response (Al-Harbi, 2012). For individuals with depression, particularly if suffering from suicidal ideation, these time lags and resistance to standard treatments can be extremely harmful (Hantouche et al., 2010). Increasing evidence has revealed that the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist has the potential to overcome such limitations, demonstrating rapid antidepressant and anti-suicidal effects, even in treatment-resistant patients (Coyle and Laws, 2015; Kishimoto et al., 2016). It has been proposed that ketamine’s antidepressant effects are primarily mediated through NMDA receptor antagonism, resulting in disinhibition of pyramidal cells and an acute cortical glutamate surge, with downstream effects on synaptogenesis and neuroplastic pathways (Lener et al., 2017). However, the precise molecular and cellular processes underlying ketamine’s antidepressant effects are still not clear and evidence suggests that mechanisms other than NMDA receptor inhibition play a more crucial role in the antidepressant effects of ketamine, it's component enantiomers and metabolites (Jelen et al., 2018; Zanos et al., 2016). In this review, we summarise findings on the antidepressant effects of ketamine and its enantiomers. We then discuss underlying therapeutic mechanisms, exploring the case that ketamine’s enantiomers and metabolites may produce complementary antidepressant effects via distinct mechanisms, before considering future directions of enquiry.
Ketamine enantiomers and metabolites
Ketamine as an antidepressant
(R,S)-ketamine:
(S)-ketamine:
(R)-ketamine:
Mechanistic considerations
*NMDA receptor antagonism and α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation
*GABAergic interneuron inhibition
*BDNF-TrkB signalling
*Mammalian target of rapamycin complex and extracellular signal-regulated kinase
*Glycogen synthase kinase 3
*Translocation of Gs alpha subunit from lipid rafts
*Monoaminergic systems
*Inhibition of lateral habenula bursting
*Opioid receptor system
Conclusion
The discovery of the rapid antidepressant effects of (R,S)- ketamine, including in treatment-resistant patients, has appropriately been hailed ‘the most important discovery in half a century in depression research (Duman and Aghajanian, 2012). Through the drug development and clinical trials process, the (S)-ketamine nasal spray, SpravatoTM, has been approved in both the United States and Europe, although some concerns remain regarding the efficacy and side effects. The first pilot study of (R)-ketamine in TRD has demonstrated encouraging results and, considering preclinical findings, it appears (R)-ketamine may have a more favourable safety profile than (S)-ketamine. Accumulating preclinical evidence also suggests (R)-ketamine to have more potent and longer-lasting antidepressant effects than both (R,S)-ketamine and (S)-ketamine. As studies of (R)-ketamine progress through Phase I and Phase II, results from direct comparison studies of the safety and efficacy of (R)-ketamine and (S)-ketamine in TRD will be crucial. Other key outstanding questions are outlined in Figure 5
Although NMDA receptor inhibition and subsequent AMPA receptor activation has a role in the antidepressant effects of ketamine, further mechanistic work is building a more nuanced understanding of the distinct molecular and cellular mechanisms of ketamine, its enantiomers and metabolites, including BDNF-TrkB, mTORC1 and ERK signalling. Although there may be a role for monoaminergic and opioid receptor systems in the antidepressant effects or detrimental side effects of ketamine, further work examining the effects of each of the component enantiomers on these systems are required. All the while, new pieces of the ketamine puzzle are being discovered and other potential future directions of enquiry include examining the role of the transforming growth factor β1 system (Zhang et al., 2020b) and the brain-gut-microbiome axis (Huang et al., 2019; Yang et al., 2017b) in the antidepressant effects of ketamine and its enantiomers.
As we further our understanding of the similarities and differences in the signalling pathways associated with (S)-ketamine, (R)-ketamine and their metabolites, we should bear in mind potential complementary or synergistic antidepressant effects that might arise via distinct mechanisms. A deeper understanding of the precise molecular and cellular mechanisms underlying the antidepressant effects and negative side effects of (R,S)-ketamine, (S)-ketamine and (R)-ketamine will be invaluable as we seek to develop future rapid-acting antidepressants with favourable safety profiles, alongside treatment strategies to maintain adequate response.
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