Mechanisms of ketamine action as an antidepressant

This review (2018) examines the neurobiological mechanisms underlying the antidepressant effects of ketamine. Whereas previous presumed that NMDA receptor inhibition is the principal mechanism, new evidence suggests that additional receptor-pathways that are specific to its downstream metabolite hydroxynorketamine are sufficient to improve depression (in animal studies) without blocking NMDA.

Abstract

“Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here we review hypotheses for the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary manner to exert acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.”

Authors: Panos Zanos & Todd D. Gould

Notes

This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘

Summary

INTRODUCTION

Major depressive disorder affects 16% of the world population and causes serious health and socio-economic consequences. Ketamine has been shown to have rapid-acting and sustained antidepressant effects in treatment-resistant depressed patients, but its routine clinical use is restricted due to its dissociative effects and abuse liability.

Ketamine was administered intravenously in 2000 and demonstrated rapid antidepressant effects in treatment-resistant major depressed patients. Ketamine also exerts antidepressant actions in patients suffering from bipolar depression, with a similar response rate.

Ketamine has been shown to induce rapid antidepressant effects, which are in sharp contrast with the delayed effect onset of currently approved antidepressant treatments.

Ketamine may act by inhibiting NMDARs, inhibiting GABAergic interneuron NMDARs, and by acting through the ketamine metabolite HNK.

NMDAR INHIBITION-MEDIATED MECHANISMS

NMDARs are glutamatergic, ligand-gated, ion channel receptors, which exist as heterotetramers. NMDARs are activated by L-glutamate and glycine/D-serine, and are voltage-dependent repulsion of magnesium (Mg2+) block at the ion channel pore via membrane depolarization, resulting in calcium influx.

Ketamine was shown to increase overall activity in the prefrontal cortex in healthy volunteers, which was hypothesized to be due to a preferential inhibition of NMDARs expressed on GABAergic interneurons. This action was supported by early findings showing that the NMDAR antagonist MK-801 initially inhibited firing of fast-spiking interneurons and subsequently increased firing of pyramidal neurons.

Ketamine, similar to negative allosteric modulators of benzodiazepine binding site of 5-containing GABAA receptors, promotes coherent network activity via disinhibition of excitatory neurotransmission and exerts rapid antidepressant actions in several animal tests.

Ketamine’s antidepressant effect may not be due to suppression of inhibitory GABAergic interneuron activity in the mPFC, as evidenced by the fact that ketamine administration to mice with a global reduction of GABAA receptor function reversed behavioral despair novelty-induced hyper-anxiety.

Ketamine and other NMDAR antagonists block spontaneous NMDAR-mediated neurotransmission at rest, thereby inducing synaptic potentiation and behavioral antidepressant actions in the CA1 region of the hippocampus. This mechanism involves eukaryotic elongation factor 2 kinase (eEF2K) and brain-derived neurotrophic factor (BDNF).

Ketamine inhibits extra-synaptic GluN2B-NMDARs, which are chronically activated by low-levels of ambient glutamate within the extracellular space. This inhibits protein synthesis, which maintains synaptic homeostasis, and therefore induces antidepressant actions via an mTOR-dependent mechanism.

Ketamine may act via inhibition of GluN2B-specific NMDARs on pyramidal neurons to exert its antidepressant effects, but it is unclear how ketamine, with no selectivity for GluN2B subunit inhibition, specifically acts at this site to induce its antidepressant actions.

Ketamine-selective antagonists exert rapid antidepressant actions in rodent models, and deletion of GluN2B-containing NMDARs from pyramidal cortical neurons in the brain of mice reduced behavioral despair. GluN2B-selective NMDAR blockers may exert antidepressant actions in humans, although these effects do not appear as rapidly as the effects of ketamine. However, a phase II clinical trial failed to identify significant antidepressant actions of MK-0657.

The lateral habenula (LHb) is a region of the epithalamus that acts as an intermediary between the forebrain, and midbrain monoaminergic systems. It has been recently demonstrated that LHb neurons show enhanced burst activity in rats characterized by congenital helpless behavior, and that ketamine decreases abnormally high NMDAR-dependent burst firing in LHb neurons.

NMDAR INHIBITION-INDEPENDENT MECHANISMS

Ketamine exerts rapid and sustained antidepressant actions in treatment-resistant depressed patients. However, clinical trials indicate that alternative NMDAR channel-blocking antagonists, such as memantine and AZD6765, lack the rapid, robust and/or long-lasting antidepressant actions of ketamine in humans.

Ketamine’s antidepressant mechanism of action is challenged by evidence that partial agonists at the NMDAR glycineB binding site, such as GLYX-13, can reduce ketamine-induced memory deficits in mice.

(R)-ketamine is superior to (S)-ketamine in rodent models of depression, but (S)-ketamine’s antidepressant behavioral actions require higher doses compared to those of (R)-ketamine. (R)-ketamine does not seem to exert its full antidepressant actions solely via inhibition of the NMDAR, at least in rodent models.

Ketamine, when administered intranasally, produced antidepressant effects in depressed patients. The effect lasted for at least 3 days, and in some cases, up to 2 weeks.

(2S,6S;2R,6R)-HNK is the major HNK metabolite found in the plasma and brain of mice, as well as plasma of humans. It is also 1.8-fold higher in humans compared with mice when given at antidepressant doses.

Early pharmacodynamic studies demonstrated that ketamine and norketamine induced anesthetic effects and hyper-locomotor activity in rats, whereas (2S,6S;2R,6R)-HNK had no effect on these outcomes.

There is evidence that metabolism of ketamine to (2S,6S;2R,6R)-HNK is necessary for its antidepressant action in rodent tests. Female rats and mice show greater antidepressant behavioral responses than male rats and mice.

Both (2S,6S)- and/2R,6R)-HNK enantiomers are sufficient on their own to exert dose-dependent antidepressant actions in several rodent tests, but Yang et al.128 failed to identify antidepressant-relevant actions of a single dose of (2R,6R)-HNK following chronic social defeat stress in mice.

At relevant concentrations, (2R,6R)-HNK does not appear to inhibit the NMDAR, and does not functionally inhibit NMDAR-mEPSCs at 10 M, compared with 50% inhibition by ketamine at this concentration. However, at high doses, (2R,6R)-HNK induces modest NMDAR inhibition-mediated side effects in mice.

Ketamine induces an increase in synaptic glutamatergic neurotransmission, which activates postsynaptic AMPARs and NMDARs, and is thought to be involved in the antidepressant actions of the drug.

Quantitative electroencephalography measurements revealed that ketamine induces increases in gamma-band power, which indicates activation of fast ionotropic excitatory receptors, including AMPARs. Pretreatment with the AMPAR antagonist NBQX prevents the antidepressant-like actions of ketamine in several tests, including the forced-swim test.

Ketamine upregulates AMPAR subunits in the hippocampus, and AMPAR-mediated synaptic potentiation is induced in the CA1 region by ketamine. NMDAR antagonists like MK-801 and AP-5148 can also induce synaptic plasticity changes, but MK-801 failed to induce long-lasting antidepressant actions in several animal tests.

Ketamine increases AMPAR-mediated excitatory post-synaptic potentials in the CA1 region of hippocampal slices, suggesting an enhancement of excitatory synaptic transmission. This effect appears independent of any possible NMDAR inhibition by (2R,6R)-HNK. (2R,6R)-HNK induces an acute and transient increase in high frequency gamma power in mice, and its rapid and sustained antidepressant actions require acute AMPAR activation. This activation is sustained 24 h post-injection, and blockade of the AMPAR abolishes these actions.

Ketamine increases BDNF levels in the hippocampus by activating the high-affinity BDNF receptor, tropomyosin receptor kinase B (TrkB). BDNF regulates neurite outgrowth, functional neuronal connections, synapse formation and synaptic plasticity in the central nervous system.

Ketamine’s antidepressant actions are dependent on BDNF signaling, and mice with the human BDNFVal66met (rs6265) single nucleotide polymorphism do not manifest ketamine’s antidepressant effects.

eEF2K is an atypical alpha-kinase that regulates protein synthesis and synaptic plasticity. Ketamine increases eEF2K activity, which in turn decreases eEF2 phosphorylation and thus reduces BDNF protein translation, resulting in long-term effects of ketamine via the induction of synaptic plasticity.

(2R,6R)-HNK administration induced a decrease in hippocampal eEF2 phosphorylation and increased BDNF levels, suggesting that protein synthesis through the eEF2 kinase/BDNF translation pathway might be involved in the antidepressant actions of this metabolite.

BDNF-mediated activation of TrkB receptors induces a translocation of Akt (protein kinase B) to the plasma membrane, which in turn activates the mTOR complex 1, which regulates neurogenesis, dendritic spine growth, protein translation initiation, and protein synthesis.

Ketamine administration induces a fast-onset induction of phospho-mTOR, phospho-p70S6 kinase and phospho-4EBP in the prefrontal cortex and hippocampus of mice and rats. This protein translation may be responsible for the prolonged effects of ketamine. Ketamine administration induces a rapid increase in phospho-Akt and phospho-ERK levels, which are upstream of mTOR signaling activation. MTOR activation is required for ketamine’s behavioral antidepressant actions, and its antidepressant actions are blocked by pretreatment with the AMPAR antagonist NBQX.

Ketamine activates mTOR signaling by deactivating glycogen synthase kinase-3 (GSK-3), and phosphorylation of GSK-3 induces mTOR activation, synaptoneurogenesis and enhanced antidepressant actions. Phosphorylation of GSK-3 might be caused by ketamine-induced activation of the mTOR upstream kinase Akt.

CONCLUSIONS

Ketamine’s mechanism of action as an antidepressant is likely to include additional mechanisms, in addition to NMDAR inhibition. These mechanisms may include ketamine metabolites, which exert electrophysiological, electroencephalographic, and molecular actions that might explain ketamine’s unique antidepressant actions.

Ketamine’s antidepressant actions are believed to be due to its activation of AMPARs, which in turn activates downstream neuroplasticity-related signaling pathways. Alternatively, eEF2 inactivation as a result of NMDAR inhibition at rest may regulate production of BDNF, resulting in an upregulation of AMPARs.

Ketamine’s antidepressant actions may be due to mechanisms independent of NMDAR inhibition, which may provide novel therapeutic targets for the long-term treatment of depression lacking undesirable side effects.