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Ketamine Mechanism of Action: Separating the Wheat from the Chaff
Abstract
(R,S)-ketamine (ketamine) exerts rapid (within hours) and robust (>60% response) antidepressant effects in severely ill-depressed patients who have failed conventional treatments (Zarate et al, 2006). This clinical finding has been paradigm-shifting as there is now tremendous hope that very ill-depressed patients can be treated in a matter of hours, rather than many weeks or months required for standard therapies to take effect (if they do at all).
... 12,13 A subsequent surge of preclinical studies attempted to back-translate clinical findings in order to identify the cellular and molecular mechanisms of action underlying ketamine's unique antidepressant effects and to develop other glutamatergic modulators that lacked the undesirable side effects induced by NMDAR antagonism (including psychotomimetic or dissociative symptoms, possible abuse liability, and evidence of brain lesions associated with chronic abuse). 8,[14][15][16] Much is still unknown about the cellular actions of ketamine, but growing evidence suggests that its antidepressant effects are associated with rapid improvements in synaptic plasticity in executive areas of the brain. [17][18][19] For instance, one of the striking effects of acute ketamine administration in rodents is its ability to rapidly restore (within 24 hours of administration) dendritic arborization and the density of synaptic spines reduced by chronic stress, an effect observed only after several weeks of treatment with traditional antidepressants 20,21 ; it should be noted, however, that some of these effects appear to be sexdependent. ...
... 20,25 In addition, the antidepressant-like effects of ketamine in rodents were abolished in the presence of NBQX (2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f] quinoxaline), an AMPAR antagonist. 14,15,26 Further confirming the key role of AMPAR activation in inducing rapid antidepressant effects, preclinical studies demonstrated that the ketamine metabolite (2R,6R)hydroxynorketamine (HNK) exerts AMPAR-dependent sustained antidepressant effects without displaying significant binding affinity for NMDARs. 15 Furthermore, the antidepressant actions of (2R,6R)-HNK appear to be related to acute increases in excitatory neurotransmission resulting by AMPAR activation followed by long-term adaptation characterized by increased levels of GluA1 and GluA2 AMPAR synaptic subunits. ...
Teaser
The development of AMPA receptor (AMPAR) modulators as therapeutics has been fraught with challenges. However, recent advances, such as novel chemokines and modulators and high-throughput screening approaches to drug discovery, hold considerable promise for advancing the field.
Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Although the preclinical research has been positive, not many direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may be developed eventually.
... However, the authors assert that the effects of ketamine are unlikely to be fully explained by NMDARs in PV interneurons; a perspective that is gaining support. Effects of ketamine outside of NMDARs are further highlighted by advancements that demonstrate HNKs, which also have antidepressantlike effects in preclinical models, may not require NMDARs for their long-lasting effects on behavior or synaptic plasticity in the hippocampus [75,165,206]. ...
Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.
... Given the timescale required to observe tangible effects with immunomodulation in general, it is probably not surprising that many studies fail to correlate rapid antidepressant onset with immediate reductions in cytokine activity. Indeed, ketamine (and its metabolites) espouse numerous non-inflammatory mechanisms which can account for their immediate antidepressant effects [184]. ...
Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.
... Investigations on connectivity patterns, including input and output circuits, can help dissect the diverse functions of the NAc subregions. The output patterns of the NAc have been well identified, including both the direct and indirect pathways (Kupchik et al., 2015;Gould et al., 2017). Furthermore, previous studies on afferent connections to the NAc subregions have primarily focused on the hippocampus, basal amygdala, and ventral mesencephalon (Zahm and Brog, 1992). ...
The nucleus accumbens (NAc) is the ventral part of the striatum and the interface between cognition, emotion, and action. It is composed of three major subnuclei: i.e., NAc core (NAcC), lateral shell (NAcLS), and medial shell (NAcMS), which exhibit functional heterogeneity. Thus, determining the synaptic inputs of the subregions of the NAc is important for understanding the circuit mechanisms involved in regulating different functions. Here, we simultaneously labeled subregions of the NAc with cholera toxin subunit B conjugated with multicolor Alexa Fluor, then imaged serial sections of the whole brain with a fully automated slide scanning system. Using the interactive WholeBrain framework, we characterized brain-wide inputs to the NAcC subdomains, including the rostral, caudal, dorsal, and ventral subdomains (i.e., rNAcC, cNAcC, dNAcC, and vNAcC, respectively) and the NAc subnuclei. We found diverse brain regions, distributed from the cerebrum to brain stem, projecting to the NAc. Of the 57 brain regions projecting to the NAcC, the anterior olfactory nucleus (AON) exhibited the greatest inputs. The input neurons of rNAcC and cNAcC are two distinct populations but share similar distribution over the same upstream brain regions, whereas the input neurons of dNAcC and vNAcC exhibit slightly different distributions over the same upstream regions. Of the 55 brain regions projecting to the NAcLS, the piriform area contributed most of the inputs. Of the 72 brain regions projecting to the NAcMS, the lateral septal nucleus contributed most of the inputs. The input neurons of NAcC and NAcLS share similar distributions, whereas the NAcMS exhibited brain-wide distinct distribution. Thus, the NAcC subdomains appeared to share the same upstream brain regions, although with distinct input neuron populations and slight differences in the input proportions, whereas the NAcMS subnuclei received distinct inputs from multiple upstream brain regions. These results lay an anatomical foundation for understanding the different functions of NAcC subdomains and NAc subnuclei.
... Thus, the serotonergic system might not be involved mainly in the antidepressant-like effects of ketamine metabolites, except for (2R,6R)-HNK. Interestingly, like (R,S)-ketamine, both systemic and local injection of (2R,6R)-HNK caused an increase in baseline 5-HT release in the PFC 24 hours after injection (Pham et al., 2018), although (2R,6R)-HNK does not bind to NMDA receptors at antidepressant-relevant concentrations (Gould et al., 2017). In this study, (R)-ketamine, (S)-ketamine, (S)-NK, and (2R,6R)-HNK increased prefrontal NA release. ...
Background:
Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites are not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex (PFC) of mice.
Methods:
The extracellular monoamine levels in the PFC were measured by in vivo microdialysis.
Results:
(R)-ketamine and (S)-ketamine acutely increased serotonin (5-HT) release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine (DA) release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in 5-HT and noradrenaline, but not DA, release. (S)-NK increased DA and noradrenaline, but not 5-HT, release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist NBQX attenuated (S)-ketamine-induced, but not (R)-ketamine-induced 5-HT release, whereas NBQX blocked DA release induced by both enantiomers. Local application of (R)-ketamine into the PFC caused a greater increase in prefrontal 5-HT release than that of (S)-ketamine.
Conclusions:
(R)-ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-ketamine-induced 5-HT and DA release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.
... It has reported that (2R,6R)-hydroxynorketamine (HNK) as the major active metabolite of ketamine is essential for the antidepressant-like activity of ketamine and involves early activation of AMPA receptor in mPFC and hippocampus (Zanos et al., 2016). Unlike ketamine, (2R,6R)-HNK at antidepressant-relevant concentrations does not bind to NMDAR (Gould et al., 2017), but could increase mPFC glutamatergic AMPA-R activity and mPFC glutamate release by pyramidal neurons without affecting its reuptake (Pham et al., 2018). In addition, it has suggested that activation of AMPA receptor is required for antidepressant effects of ketamine (Pham et al., 2018). ...
There is accumulating evidence demonstrating that dysfunction of glutamatergic neurotransmission, particularly via N-methyl-d-aspartate (NMDA) receptors, is involved in the pathophysiology of major depressive disorder (MDD). Several studies have revealed an altered expression of NMDA receptor subtypes and impaired NMDA receptor-mediated intracellular signaling pathways in brain circuits of patients with MDD. Clinical studies have demonstrated that NMDA receptor antagonists, particularly ketamine, have rapid antidepressant effects in treatment-resistant depression, however, neurobiological mechanisms are not completely understood. Growing body of evidence suggest that signal transduction pathways involved in synaptic plasticity play critical role in molecular mechanisms underlying rapidly acting antidepressant properties of ketamine and other NMDAR antagonists in MDD. Discovering the molecular mechanisms underlying the unique antidepressant actions of ketamine will facilitate the development of novel fast acting antidepressants which lack undesirable effects of ketamine. This review provides a critical examination of the NMDA receptor involvement in the neurobiology of MDD including analyses of alterations in NMDA receptor subtypes and their interactive signaling cascades revealed by postmortem studies. Furthermore, to elucidate mechanisms underlying rapid-acting antidepressant properties of NMDA receptor antagonists we discussed their effects on the neuroplasticity, mostly based on signaling systems involved in synaptic plasticity of mood-related neurocircuitries.
... Debido a que una gran mayoría de las neuronas y de sus sinapsis en estas áreas cerebrales usan el glutamato como su neurotransmisor, se debe reconocer que este sistema (glutamatérgico) es un mediador primario de la patología depresiva y, potencialmente, también una vía final común para la acción terapéutica de los agentes antidepresivos (148). La evidencia convincente de estos estudios clínicos sugiere que la transmisión de glutamato es anormalmente regulada en las áreas límbicas y corticales en el cerebro de los individuos deprimidos (149). ...
Resumen
La depresión mayor representa un problema de salud pública debido a su alta prevalencia. La etiología de la depresión es compleja, en ella intervienen factores psicosociales, genéticos, y biológicos. Entre los factores psicosociales, se ha observado que los primeros episodios depresivos aparecen después de algún evento estresante, y el estrés que acompaña al primer episodio produce cambios a largo plazo en la fisiología cerebral. Estos cambios de larga duración pueden producir variaciones a nivel estructural y en el funcionamiento de diferentes áreas cerebrales. Entre los factores genéticos que intervienen en la enfermedad depresiva, se ha reportado que alrededor de 200 genes están relacionados con el trastorno depresivo mayor. Dentro de los factores biológicos, existen evidencias de alteraciones a nivel de neurotransmisores, citosinas y hormonas, cuyas acciones inducen modificaciones estructurales y funcionales en el sistema nervioso central, en el sistema inmunológico y en el sistema endocrino, que incrementan el riesgo de padecer la depresión mayor. A pesar de años de estudio, las bases biológicas de la depresión mayor y el mecanismo preciso de la eficacia antidepresiva siguen siendo poco claras. Los objetivos de la presente revisión son el resumir las principales conclusiones de la literatura clínica y experimental en relación con la etiología del trastorno depresivo mayor.
Palabras clave
Depresión mayor, neurotransmisores, neuroplasticidad, serotonina, norepinefrina, sistema inmune.
Abstract
Major depression represents a public health problem due to its high prevalence. The etiology of major depression is complex because involves psychosocial, genetic, and biological factors. Among psychosocial factors, different studies report that the first depressive episode appear after some stressful event and produces long-term changes in brain physiology. These long-lasting changes produce variations at the structural level and in the functioning of different brain areas. Among the genetic factors involved in depressive illness, it has been reported that about 200 genes are related to major depressive disorder. Within the biological factors, there is an evidence of alterations in the level of neurotransmitters, cytosine’s and hormones, whose actions induces structural and functional modifications in the central nervous system, the immune system and the endocrine system, which increases the risk of suffering major depression. Despite years of study, the biological basis of major depression and precise mechanisms of antidepressant efficacy remain unclear. The objective of the present review is to summarize the main conclusions of the clinical and experimental literature regarding to the etiology of major depressive disorder.
Key words
Major depression, neurotransmitters, neuroplasticity, serotonin, norepinephrine, immune system.
... Brain tissue concentration of (2R,6R)-HNK was about 25% of that of (R,S)-ketamine (9). Unlike (R,S)-ketamine, (2R,6R)-HNK does not bind to NMDAR at antidepressant-relevant concentrations (13), but rather increases mPFC glutamatergic AMPAR activity. Here, activation of the mPFC results in an excitatory effect and increased Glu release by pyramidal cells ( Figure 1F, N, O), without affecting its reuptake ( Figure 1G): various 5-HT receptor subtypes on pyramidal neurons and GABA interneurons are known to modulate mPFC neuronal activity (14,15). ...
... Brain tissue concentration of (2R,6R)-HNK was about 25% of that of (R,S)-ketamine (9). Unlike (R)-ketamine, (2R,6R)-HNK does not bind to NMDA-R at antidepressant-relevant concentrations (13), but increases mPFC glutamatergic AMPA-R activity. Here, activation of the mPFC results in an excitatory effect and increased glutamate release by pyramidal cells (Fig.1F-1N-1O), without affecting its reuptake (Fig.1G) interneurons are known to modulate mPFC neuronal activity (14,15). ...
Racemic (R,S)-ketamine, a non-competitive antagonist of NMDA receptor, at sub-anesthetic doses, exhibits a rapid and persistent antidepressant (AD) activity in treatment-resistant depressed patients and in preclinical studies in rodents. However, the mechanism mediating these activities is unknown. We recently reported that (R,S)-ketamine-induced increases in presynaptic serotonin (5-HT) release in the medial prefrontal cortex (mPFC) correlated with its AD-like activity in mice. The control exerted by the mPFC is important in regulating stress processing and AD-like activity. However, little is known about the regulation of synaptic excitatory/inhibitory balance in glutamate/GABA neurotransmission induced by these compounds.
Recently, it was shown that (R,S)-ketamine metabolism to (2R,6R)-hydroxynorketamine (HNK) is essential for its AD-like activity, and involves early activation of AMPA receptor in mice hippocampus and mPFC. However, (R)-ketamine displays greater potency and longer lasting AD effects than (2R,6R)-HNK.
Here, we compared the sustained AD-like activity and neurotransmitters’ changes between (R,S)-ketamine and (2R,6R)-HNK in BALB/cJ mice, using the forced swim test (FST), a model to screen AD-like activity of drug, coupled to in vivo microdialysis in the same mice. Cortical extracellular 5-HT, GABA, glutamate and glutamine levels were measured by HPLC.
A single dose of (R,S)-ketamine and (2R,6R)-HNK (either 10 mg/kg intraperitoneal, or 1 nmol/side intra-mPFC) administered 24hr prior testing showed comparable AD-like activity in the FST and serotonergic effects. Interestingly, (2R,6R)-HNK displayed a more glutamatergic, but less GABA-ergic potency than (R,S)-ketamine.
Our results confirmed the sustained AD-like activity in mice of both drugs, which required presynaptic cortical release of various excitatory and inhibitory neurotransmitters. We also found that (2R,6R)-HNK, via AMPA receptor activation, increased excitatory synaptic transmission in the mPFC by enhancing presynaptic glutamate release. It is therefore of great interest to make direct comparisons of these compounds in future clinical studies in depressed patients.
... Ketamine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor, a major type of glutamate receptor in the brain (Gould et al, 2017). Ketamine is routinely used for anesthetic induction because of its dissociative properties. ...
Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate (NMDA) receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-hours post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time*Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time*Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first two weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety. ClinicalTrials.gov Identifier: NCT02083926
Major depressive disorder is a common psychiatric disorder, with ∼30% of patients suffering from treatment-resistant depression. Based on preclinical studies on ketamine, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation may be a promising therapeutic approach. In this study, we synthesized a series of novel 3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs and analyzed their potential as AMPAR potentiators. Compounds 5aa and 7k exhibited high potentiation with little agonist activity in a high-throughput screen using a calcium influx assay in cultured hippocampal primary neurons. In rats, compound 7k had better pharmacokinetic properties and oral bioavailability (F = 67.19%); it also exhibited an acceptable safety profile in vital internal organs based on hematoxylin and eosin staining. We found that 7k produced a rapid antidepressant-like effect in chronic restraint stress-induced mice 1 h after intraperitoneal administration. Our study presented a series of novel AMPAR potentiators and identified 7k as a promising drug-like candidate against major depressive disorders.
Major depression (MDD) is a serious neuropsychiatric disorder afflicting around 16-17 % of the global population and is accompanied by recurrent episodes of sadness and suicidal thoughts. Current pharmacological interventions take several weeks to even months for an improvement in depressive symptoms to emerge, with a significant percentage of individuals not responding to these medications at all, thus highlighting the need for rapid and effective next-generation treatments for MDD. Pre-clinical studies in animals have demonstrated that antagonists of the metabotropic glutamate receptor subtype 2/3 (mGlu2/3 receptor) exert rapid antidepressant-like effects, comparable to the actions of ketamine. Therefore, it is possible that mGlu2 or mGlu3 receptors to have a regulatory role on the unique antidepressant properties of ketamine, or that convergent intracellular mechanisms exist between mGlu2/3 receptor signaling and ketamine's effects. Here, we provide a comprehensive and critical evaluation of the literature on these convergent processes underlying the antidepressant action of mGlu2/3 receptor inhibitors and ketamine. Importantly, combining sub-threshold doses of mGlu2/3 receptor inhibitors with sub-antidepressant ketamine doses induce synergistic antidepressant-relevant behavioral effects. We review the evidence supporting these combinatorial effects since sub-effective dosages of mGlu2/3 receptor antagonists and ketamine could reduce the risk for the emergence of significant adverse events compared with taking normal dosages. Overall, deconvolution of ketamine's pharmacological targets will give critical insights to influence the development of next-generation antidepressant treatments with rapid actions.
While the molecular target of (R,S)-ketamine (ketamine) is thought to be the NMDA receptor, subanesthetic doses of ketamine have been known to modulate monoaminergic neurotransmission in the central nervous system. Although the involvement of the serotonergic system in the antidepressant effects of ketamine has been reported in most studies of this topic, some recent studies have reported that the dopaminergic system plays a key role in the effects of ketamine. Additionally, several lines of evidence suggest that the antidepressant-like effects of (R)-ketamine might be independent of the monoaminergic system. Ketamine metabolites also differ considerably in their ability to regulate monoamine neurotransmitters relative to (S)-ketamine and (R)-ketamine, while (2R,6R)-hydroxynorketamine might share common serotonergic signaling mechanisms with ketamine. In the current review, we summarize the effects of ketamine and its metabolites on monoamine neurotransmission in the brain and discuss the potential roles of the monoaminergic system in the mechanism of action of ketamine.
Treatment refractory depression (TRD) causes more burden although newer antidepressants have been introduced in last decades. In this chapter, the authors will discuss the novel treatment approaches based upon new neurobiological models and review the evidence-based treatments. Special consideration will be given to the inflammation hypothesis, ketamine, ECT, and deep brain stimulation.
The in vitro metabolic fate of the anesthetic agent ketamine [(+)2-o-chlorophenyl-2-methylaminocyclohexanone] has been evaluated using microsomal preparations from rat liver. With the aid of a rapid, nonselective metabolite extraction procedure and sample analysis by combined glass capillary gas chromatography low (and high) resolution mass spectrometry, eight metabolites of the drug were identified, six of which have not been reported previously. The novel metabolites were products of alicyclic ring hydroxylation of ketamine and of N-desmethylketamine (norketamine). Semi-quantitative analysis of metabolites produced during microsomal incubation was achieved using glass capillary gas chromatography. The results from this study indicate that 5,6-dehydronorketamine, previously considered to be a major biotransformation product of ketamine in mammalian systems, is almost certainly a methodological artefact.
Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.
To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression.
A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005.
Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant).
After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.
Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.
Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
Objective:
The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression.
Method:
Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes.
Results:
Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37-22.29) and 14.47 (2.67-78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges' g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.
Conclusions:
The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine's mechanism of action. The fleeting nature of ketamine's therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.
(R,S)-Ketamine was initially developed as an anesthetic agent and its pharmacological properties were determined on the basis of this clinical use. However, pharmacological studies in rat led to the development of the ‘Ketamine Paradigm’, whereby (R,S)-ketamine and its N-demethylated metabolite (R,S)-norketamine were deemed the active compounds whereas the other ketamine metabolites were considered inactive. Recent in vivo and in vitro studies with (2S,6S)-hydroxynorketamine, a previously identified ‘inactive’ metabolite, have demonstrated that this compound is an active and selective inhibitor of the α7 subtype of the nicotinic acetylcholine receptor and that this activity contributes to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. Thus, it appears that it is necessary to reassess the ‘Ketamine Paradigm’ in regards to the use of sub-anesthetic doses of (R,S)-ketamine in the treatment of treatment-resistant depression.
The in vitro metabolic fate of the anesthetic agent ketamine [(±)2-0-chlorophenyl-2-methylaminocyclohexanone] has been evaluated using microsomal preparations from rat liver. With the aid of a rapid, nonselective metabolite extraction procedure and sample analysis by combined glass capillary gas chromatography low (and high) resolution mass spectrometry, eight metabolites of the drug were identified, six of which have not been reported previously. The novel metabolites were products of alicyclic ring hydroxylation of ketamine and of N-desmethylketamine (norketamine). Semi-quantitative analysis of metabolites produced during microsomal incubation was achieved using glass capillary gas chromatography. The results from this study indicate that 5,6-dehydronorketamine, previously considered to be a major biotransformation product of ketamine in mammalian systems, is almost certainly a methodological artefact.
• The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f).
• The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis–Menten, Hill or substrate inhibition equation.
• 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates.
• 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.
Stereoselective and regiospecific hydroxylation of ketamine and norketamine
- Z Desta
- R Moaddel
- Et Ogburn
- C Xu
- A Ramamoorthy
- Sl Venkata
Desta Z, Moaddel R, Ogburn ET, Xu C, Ramamoorthy A,
Venkata SL et al (2012). Stereoselective and regiospecific hydroxylation of ketamine and norketamine.
Xenobiotica 42: 1076-1087.
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression
- Ca Zarate
- Jr
- Jb Singh
- Pj Carlson
- Ne Brutsche
- R Ameli
- Da Luckenbaugh
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE,
Ameli R, Luckenbaugh DA et al (2006). A randomized trial of an N-methyl-D-aspartate antagonist in
treatment-resistant major depression. Arch Gen
Psychiatry 63: 856-864.