This historic review (2019) examines cellular mechanisms underlying the antidepressant effects of the R(-) and S(+) ketamine enantiomers and their norketamine and hydroxynorketamine metabolites. Although S(+) ketamine exhibits greater affinity to the NMDAR, which is believed to be the mediator of its antidepressant effect, preclinical evidence from animal models suggests that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects with less detrimental side‐effects. Given that the phase I clinical studies on R(-)ketamine and hydroxynorketamine are now underway, future studies will be able to perform a direct comparison of their efficacy to treat patients with depression.
Abstract
“Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)‐ketamine (or arketamine) and (S)‐ketamine (or esketamine). Because (S)‐ketamine has higher affinity for NMDAR than (R)‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects than (S)‐ketamine in animal models of depression and that (R)‐ketamine has less detrimental side‐effects than (R,S)‐ketamine or (S)‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABAA] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.”
Author: Kenji Hashimoto
Summary
Major depressive disorder (MDD) affects approximately 320 million people worldwide and is increasing in incidence. Approximately 30% of MDD patients are refractory to the current antidepressants.
Bipolar disorder (BD) is a major psychiatric disorder that exhibits extreme mood swings. Bipolar depression is typically poorly responsive to antidepressants, and there is an unmet medical need for treatment options.
Ketamine, an NMDAR antagonist, has been shown to have robust antidepressant effects in treatment-resistant patients with MDD or BD. The author discusses the history, molecular mechanisms, and antidepressant actions of ketamine and its major metabolites.
Brief history of phencyclidine and ketamine
Phencyclidine (PCP) was synthesized in 1956 and used as an anesthetic compound in humans undergoing surgery. However, some patients treated with PCP exhibited severe and prolonged post-surgery delirium, and PCP was found to be an excellent drug model of schizophrenia.
Scientists at Park Davis synthesized a series of short-acting derivatives of PCP, including CI-581 (ketamine), which was studied in humans in 1964. Ketamine produced certain side-effects, including psychotomimetic effects and dissociation.
Ketamine is a racemic mixture of equal amounts of the two enantiomers: (R)-enantiomer and (S)-enantiomer. (S)-ketamine has a three- to fourfold greater affinity for the NMDAR than (R)-ketamine.
Ketamine’s antidepressant effects in humans MDD
Domino described his experience of a patient who took PCP and ketamine repeatedly.
In 2000, Berman and colleagues reported that ketamine had rapid acting antidepressant effects in patients with MDD. Subsequent studies replicated the robust antidepressant effects of ketamine in refractory MDD patients, and ketamine showed greater improvement in depressive symptoms than midazolam.
Ketamine showed good response rates in treatment-resistant MDD patients. It was tolerated well and maintained antidepressant efficacy.
Ketamine can be administered via intramuscular, nasal, oral, rectal, subcutaneous, and sublingual routes. However, the bioavailability of ketamine via intranasal administration is low, which causes lower efficacy compared to intravenous and intramuscular administrations.
Ketamine improved depressive symptoms in depressed patients receiving hospice care, but its effects were slow to develop. Ketamine might have a lower oral bioavailability than intravenous and intramuscular administrations.
Bipolar depression
Ketamine showed rapid antidepressant actions in refractory BD patients, and had antidepressant and anti-suicidal effects in Chinese patients with MDD and BD.
Although ketamine might produce adverse reactions in bipolar depression patients, two case reports showed ketamine-induced switch from depression to mania in treatment-resistant patients.
Comparison of ketamine enantiomers in healthy control subjects
Mathisen et al.55 reported that (S)-ketamine (0.45 mg/kg) caused psychotic reactions in patients with oral pain, whereas (R)-ketamine (1.8 mg/kg) did not.56 Furthermore, it is well known that experiencing illusion and alterations in hearing, vision, and proprioception is attributable to (S)-ketamine’s actions.57
(S)-ketamine
The (S)-enantiomer of ketamine was selected as an antidepressant candidate because NMDAR inhibition was believed to play a crucial role in ketamine’s robust antidepressant effects in MDD patients. The (S)-ketamine intranasal injection showed good efficacy for the rapid reduction in the depressive symptoms in treatment-resistant MDD patients.
The Janssen Pharmaceutical Company presented five phase 3 trials of (S)-ketamine in treatment-resistant patients. Two of the five trials demonstrated positive results, and the US FDA approved (S)-ketamine nasal spray for treatment-resistant patients on 5 March 2019.
Predictable biomarkers of ketamine’s antidepressant effects in MDD patients
Ketamine can produce antidepressant effects in approximately two-thirds of refractory MDD patients, but has detrimental side-effects. The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may be a potential genetic biomarker for ketamine’s responder.
Ketamine’s rapid anti-inflammatory actions might contribute to its rapid antidepressant effects. However, baseline levels of IL-6 and tumor necrosis factor- were not associated with the antidepressant response.
Ketamine increases blood levels of osteoprotegerin/receptor activator of nuclear factor kB Ligand (OPG/RANKL) ratio and osteopontin after ketamine infusion, suggesting that the OPG/RANK/L system might be involved in ketamine’s antidepressant effects.
Ketamine increased amplitudes, decreased peak frequency, and amplified band amplitudes in the visual cortex of healthy control subjects, and increased amplitudes in the visual cortex of MDD patients. Higher amplitudes at baseline were related to better antidepressant response in MDD patients with lower baseline .
Enantiomers of ketamine and its metabolites Antidepressant effects of (R)-ketamine and (S)-ketamine in rodents
Several drugs inhibiting NMDAR have been developed as new antidepressants, but ketamine’s antidepressant effects are more potent than those of non-ketamine NMDAR antagonists. In 2010, we hypothesized that (R)-ketamine would produce more potent antidepressant actions compared to (S)-ketamine. In 2015, Zanos and colleagues confirmed our findings, and in 2016, Fukumoto and colleagues reported that (R)-ketamine and (R,S)-ketamine significantly reversed depression-like behavior in rats after repeated corticosterone treatments.
Brain regions for the antidepressant actions of ketamine
Ketamine could attenuate the decreased levels of BDNF and PSD-95 in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from CSDS-susceptible mice, but not in the nucleus accumbens.
Ketamine infusion into the infralimbic region of the medial prefrontal cortex (mPFC) reproduced the antidepressant-like effects of systemic ketamine administration, and optogenetic stimulation of the infralimbic region of mPFC showed ketamine-like antidepressant-like effects in control-naive rats.
Ketamine restored dopamine neuron population activity and synaptic plasticity in the NAc and hippocampus pathway in Wistar-Kyoto rats exposed to inescapable, uncontrollable footshocks, but it is unclear whether ketamine-induced LTP loss in the NAc is associated with its antidepressant actions.
Yang et al.99 demonstrated that ketamine-induced blockade of NMDAR-dependent bursting activity in the lateral habenula mediates its rapid-acting antidepressant effects in rodents with depression-like phenotype.100 It may be of interest to investigate this further.
Side-effects of ketamine
Although the psychotomimetic effects of ketamine and dissociative symptoms in humans after ketamine infusion are well known, off-label ketamine treatment for depression has become popular in the USA.
(S)-ketamine increased locomotor activity in mice and caused prepulse inhibition deficits, but (R)-ketamine did not. The positron emission tomography study suggests that (S)-ketamine may contribute to acute side-effects (i.e., psychotomimetic and dissociation) in humans.
In 1989, Olney and colleagues reported that NMDAR antagonists caused neuropathological changes in the retrosplenial cortex of rats. These compounds also produced heat shock protein HSP-70 protein in the retrosplenial cortex.
The reduction of parvalbumin (PV)-immunoreactivity in the PFC is associated with psychosis. A single dose of (S)-ketamine causes the reduction of PV-immunoreactivity in the PFC, but a repeated dose of (R)-ketamine does not.
We compared antidepressant effects and side-effects in mice after intranasal administration of (R,S)-ketamine and its two enantiomers. (R)-ketamine was found to be a safer antidepressant than (S)-ketamine and (R,S)-ketamine.
(2R,6R)-hydroxynorketamine
In 2016, Zanos and colleagues demonstrated that (2R,6R)-HNK was essential for (R,S)-ketamine’s antidepressant actions in rodents. Additional research has shown that (2R,6R)-HNK can reverse depression-like behaviors in rats and mice.
(2R,6R)-HNK inhibits long-term potentiation in the NAc97 similarly to ketamine, and promotes structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPA receptor (AMPAR)-dependent BDNF. However, it is unknown whether these actions of (2R,6R)-HNK are associated with its antidepressant actions.
Intracerebroventricular injection of (R)-ketamine revealed rapid and long-lasting antidepressant actions in a CSDS model. In addition, direct injection of (R)-ketamine into the brain regions demonstrated long-lasting antidepressant actions in a rat LH model.
(R,S)-ketamine and (R,d2-ketamine) produced similar rapid and long-lasting antidepressant effects in CSDS-susceptible mice, suggesting no deuterium isotope effect in the antidepressant actions of (R)-ketamine.
Ketamine is metabolized by CYP enzymes in the liver, and CYP inhibitors increase the blood levels of (R)-ketamine, whereas (2R,6R)-HNK is not. The presence of CYP inhibitors does not affect the antidepressant effects of (R)-ketamine in an LPS-induced mouse model of depression.
Although the reasons underlying these discrepancies remain unclear, it is possible that variations in the strain, species, or experimental conditions contribute to these discrepancies. Furthermore, (2R,6R)-HNK is a final metabolite of (R)-ketamine, but its antidepressant action as a compound independent from (R)-ketamine needs to be studied.
(S)-norketamine
Ketamine-induced side-effects are suggested to be associated with NMDAR inhibition. Norketamine, a prodrug of ketamine, shows rapid and sustained antidepressant actions in CSDS and LPS models of depression, and has less potent antidepressant actions than ketamine.
Other NMDAR antagonists and modulators
Ketamine has been studied for its antidepressant effects, but other NMDAR antagonists have not. Memantine is a low-to-moderate-affinity NMDAR antagonist that is currently used in the treatment of Alzheimer’s disease.
Lanicemine, a low-trapping NMDAR antagonist, did not show antidepressant actions in treatment-resistant MDD patients. Furthermore, lanicemine did not increase PFC global brain connectivity with global signal regression, suggesting differences between ketamine and lanicemine.
Rapastinel (formerly GLYX-13) had antidepressant-like actions in rodents and may be associated with the lack of psychotomimetic side-effects. AGN-241751 (a positive modulator of NMDAR) is being developed as a rapid and sustained antidepressant, but three acute pivotal phase 3 studies of rapastinel in MDD patients did not meet their primary endpoint.
and potassium channel Kir4.1 inhibitor
Yang and colleagues demonstrated that ketamine promotes rapid-acting antidepressant effects in rodents by blocking NMDAR-dependent bursting activity. Furthermore, ketamine requires both NMDAR and low-voltage-sensitive T-type calcium channels (T-VSCC), and ethosuximide might not exert ketamine-like robust antidepressant actions in patients with depression.
Inwardly rectifying potassium channel Kir4.1 in astroglia is reportedly responsible for potassium buffering. However, non-specific Kir4.1 inhibitors did not produce any antidepressant action in CSDS-susceptible mice, suggesting that Kir4.1 in the LHb may be a therapeutic target for depression.
Negative modulators of α5 GABAA receptors
Two negative allosteric modulators of 5 GABAA receptors showed rapid-acting antidepressant actions in chronic-restraint and chronic unpredictable mild stress (CUMS) models, but did not produce an antidepressant effect in a chronic social disorganization stress (CSDS) model.
AMPAR activation
Ketamine can increase extracellular levels of glutamate in the rat PFC, suggesting that ketamine might stimulate glutamatergic neurotransmission in the PFC. AMPAR is required for ketamine’s antidepressant effects.
Although the molecular and cellular mechanisms underlying robust antidepressant actions of ketamine remain unclear, NMDAR blockade causes the disinhibition of pyramidal cells, thereby resulting in a burst of glutamatergic transmission.
Mammalian target of the rapamycin complex 1 signaling
The mammalian target of the rapamycin complex 1 (mTORC1) is a ubiquitous protein kinase involved in protein synthesis and synaptic plasticity. Ketamine activates the mTORC1 signaling, which increases the numbers of synaptic proteins and increases the numbers and functions of new spine synapses. The role of mTORC1 in the antidepressant actions of ketamine remains controversial. However, rapamycin improved social interaction deficits in mouse models of tuberous sclerosis complex, indicating that the dose (10 mg/kg, i.p.) is effective in the brain disorders.
Interestingly, (S)-ketamine increased the phosphorylated mTOR protein in the blood from MDD patients, and (R)-ketamine can influence the ERK and their phosphorylation in the blood from BD patients.
Abdallah and colleagues demonstrated that rapamycin prolonged the sustained antidepressant effects of ketamine in treatment-resistant MDD patients. These data do not support the previous preclinical report180 from the same university.
BDNF–TrkB signaling
Multiple lines of evidence suggest that BDNF and its receptor TrkB play a crucial role in depression and in the mechanisms of antidepressants. Ketamine and its enantiomers may exert long-lasting antidepressant effects through the activation of BDNF – TrkB cascade.
Vascular endothelial growth factor
Viral-mediated hippocampal knockdown of VEGF produced depressive-like behaviors and decreased hippocampal neurogenesis in rats, which partially recovered after injection of ketamine.
Ketamine’s antidepressant-like effects were blocked by forebrain excitatory neuron-specific deletion of either VEGF or its receptor Flk-1 or by intra-mPFC injection of a VEGF neutralizing antibody. Furthermore, inhibition of neuronal VEGF signaling blocked the neurotrophic and synaptogenic effects of ketamine.
Hyperpolarization-activated cyclic nucleotide-gated channel
The inhibition of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) by ketamine obstructs the synaptic and behavioral actions of ketamine. Furthermore, the lentiviral-mediated knockdown of HCN1 protein prevented depression-like behaviors after CUMS.
Glycogen synthase kinase-3
Ketamine is reported to increase the serine phosphorylation of glycogen synthase kinase-3 and GSK-3 in the cerebral cortex and hippocampus, and this may be the reason why ketamine has antidepressant effects.
Ketamine could improve the decreased expressions of BDNF and p11 in the hippocampus of CUMS rats, but not sustain antidepressant effects.
Opioid receptor system
Ketamine interacts with opioid receptors. However, a study by Williams and colleagues demonstrated that pretreatment with naltrexone did not affect the antidepressant effects of ketamine in treatment-resistant MDD patients, and a study by Yale University demonstrated that naltrexone did not affect the antidepressant effects of ketamine in patients with depression and alcohol use disorder.
microRNA
The microRNA (miRNA) regulate the translation of mRNA by binding to the 30 untranslated region of mRNA in a sequence-specific manner. Ketamine and repeated electroconvulsive shock therapy share a common target, miRNA-598-5p, which may play a role in the antidepressant effects.
Role of gut microbiota
Multiple lines of evidence suggest that gut microbiota might be involved in the pathophysiology of depression and in the antidepressant-like effects of certain potential candidates. (R)-ketamine, for example, may be able to affect the gut microbiota in CSDS-susceptible mice through the gut-brain axis.
Concluding remarks and future directions
Ketamine’s antidepressant and anti-suicidal effects in treatment-resistant patients with MDD or BD are serendipity in the field of mood disorders. A phase 1 study of (R)-ketamine and (2R,6R)-HNK was initiated in early 2019.
Considering the high attrition rates, substantial costs, and the slow pace of development of novel drugs, old drug repurposing is increasingly becoming an attractive approach. (R)-ketamine may be a good candidate for drug repurposing in the field of psychiatric disorders.
Acknowledgments
This study was supported by the Japan Agency for Medical Research and Development.