SUMMARY

• Esketamine (ESK), the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.^1-3 However, the precise mechanism of action of ESK nasal spray in major depressive disorder (MDD) is unknown. The antidepressant pharmacologic action of ESK is thought to be similar to ketamine.^1-5
  • The major circulating metabolite of ESK (noresketamine) demonstrated activity at the same NMDA receptor with less affinity.⁶
  • The predominant hypothesis on the antidepressant mechanism of action is described below and a video illustration can be accessed at: https://players.brightcove.net/1421910869001/default_default/index.html?videoId=6022469928001 [copy and paste URL to browser].
• At the doses used, ESK’s primary antidepressant activity is not believed to directly involve inhibition of serotonin, norepinephrine, or dopamine reuptake,^1-3 nor is it believed to directly involve mu-opioid receptor (MOR) stimulation.^7-10

BACKGROUND

In depression, there are structural and functional impairments of synapses in brain regions involved with mood and emotional behavior. In addition to the well-established role of monoamines (such as serotonin, norepinephrine, and dopamine), glutamate has also been shown to have an important role in regulating synaptic connectivity.^1-3 A growing body of evidence points to altered glutamate signaling in the pathophysiology of MDD.^2,11 Glutamate is the major excitatory neurotransmitter that plays a critical role in maintaining synaptic connections.^1-3,12 Glutamate binds to 2 major types of receptors in the brain, the NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, both of which are potential targets for drug development in glutamatergic neurotransmission.^1,3 In the brain, glutamate neurons outnumber monoaminergic neurons and play a leading role in mediating learning, memory, and mood regulation.¹³ Activation of glutamate receptors triggers multiple pathways that may influence synaptic connectivity in mood-related circuitry implicated in depression.^2,11

MECHANISM OF ACTION

The precise mechanism of action of ESK in MDD is unknown, but the prevailing theory is that it preferentially blocks NMDA receptors on inhibitory γ-amino-butyric acid (GABA)-ergic interneurons.^1-3 ESK is a noncompetitive, subtype nonselective, activity-dependent NMDA receptor antagonist. Evidence within the literature suggests that this blockade transiently enhances the activity of glutamatergic neurons, including increasing the presynaptic release of glutamate, and stimulation of postsynaptic AMPA receptors. These, in turn, result in activation of downstream neurotrophic intracellular signaling pathways, leading to increased synaptic protein synthesis, synaptogenesis, and ultimately improving synaptic connectivity. Evidence from a placebo-controlled neuroimaging trial in patients with treatment-resistant depression suggests that increased connectivity occurs, at least in part, in the prefrontal cortex and limbic seed (e.g., amygdala and hippocampus) regions of the brain.¹⁴

Unlike existing pharmacotherapies for depression, ESK’s primary antidepressant activity is not believed to directly involve inhibition of serotonin, norepinephrine, or dopamine reuptake.^1-3

Antidepressant Effect And Relationship to Opioid Receptors

Esketamine Data

Research with ESK has demonstrated that at antidepressant doses, ESK does not sufficiently occupy opiate receptors to exert a clear functional effect on these receptors.^7-9,15,16 In preclinical models, the binding affinities of ESK and ketamine were 10 to 20-fold weaker at the MORs (ESK Ki range, 11-28 µM; ketamine Ki, 42 µM)^7-9 than at the NMDA receptors (ESK Ki range, 0.30-1.1 µM; ketamine Ki range, 0.53-1.06 µM).^9,15,16 Binding affinities to the kappa and delta opioid receptors were generally weaker than at the mu receptors.^8,9

Saad et al (2019)⁷ conducted a post hoc analysis of 2 short-term acute studies in patients with treatment-resistant depression (TRD)^17,18 to explore the role of MOR function on the antidepressant effect of ESK. The single nucleotide polymorphism (SNP) of interest, rs1799971, was directly genotyped. This SNP has been shown to affect response to endogenous opioids. Results showed that this variant in the opioid receptor mu 1 (OPRM1) did not significantly alter Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 2 or day 28 in patients who received ESK; however, patients who received an antidepressant plus placebo showed significant improvements in their MADRS scores on day 2 with those trending in the same direction on day 28 (see Table: Effect of OPRM1 Missense Variants on MADRS Response in Two Short-Term Clinical Trials (Trials 3001 and 3002) Combined Data Sets). Based on these findings, MOR did not affect the antidepressant action of ESK but did impact the placebo effect.

Ketamine Data

Williams et al (2018 and 2019)^19,20 reported interim results of an analysis of 12 patients with TRD who completed a double-blind, crossover study that evaluated whether opioid receptors play a role in the antidepressant effect of ketamine. Patients received oral naltrexone 50 mg or placebo 45 minutes prior to intravenous (IV) ketamine 0.5 mg/kg over 40 minutes. In the 7 patients who met the prespecified response criterion (defined as a ≥50% reduction in the 17-item HAM-D score from baseline to day 1 with ketamine + placebo), reductions in the 17-item HAM-D score were significantly attenuated in the ketamine + naltrexone arms compared with the ketamine + placebo arm on day 1 (primary endpoint) and day 3, but not at days 5, 7, or 14.¹⁹ In a secondary endpoint analysis, the authors found that changes in suicidality, based on item 3 of the Hamilton Depression Rating Scale, item 10 of the MADRS, and the Columbia Suicide Severity Rating Scale, were also significantly attenuated with the addition of naltrexone.²⁰ The authors suggested that ketamine’s acute antidepressant effect requires opioid system activation.^19,20

The interpretability of these findings is limited by the study design, including a lack of a control arm necessary to assess the effects of naltrexone alone or placebo alone (which is considered relevant since endogenous opioid peptide signaling of MOR has been associated with positive mood responses to placebo),²¹ possible carryover effects resulting from the crossover design, and a small final sample size due to early termination of the study resulting from ineffectiveness and “noxious” side effects (severe nausea and vomiting) for many patients receiving ketamine + naltrexone. In addition, the study did not specifically recruit for suicidal patients. The authors acknowledged a need to replicate the findings.^19,20

The subsequent publications did not find evidence of direct MOR activation^10,22-24; however one study in rodents suggests that interactions between NMDA and MOR may be necessary for an antidepressant effect, but that ketamine does not act as an opioid to produce this effect.²⁴

Yoon et al (2019)¹⁰ evaluated the use of naltrexone pretreatment with ketamine in patients with MDD and alcohol use disorder. This 8-week, open-label, pilot study included 5 patients who received injectable naltrexone (380 mg once as an extended release formulation, 2-6 days prior to the first ketamine infusion) and repeated IV ketamine infusions (0.5 mg/kg once a week for 4 weeks for a total of 4 treatments). Clinical response, defined as a ≥50% improvement in the Montgomery Asberg Depression Rating Scale scores from baseline to 4 hours post infusion, was met by 60% of patients after the initial ketamine dose and by 100% by the fourth dose. No serious side effects were reported. The authors concluded that naltrexone pretreatment does not appear to interfere with the antidepressant effects of ketamine.

Marton et al (2019)²² conducted a retrospective analysis of treatment outcome data of 40 veterans with TRD who were treated with up to 6 infusions of ketamine (0.5 mg/kg over 40 minutes) twice weekly for 3 weeks. During the treatment period, 7 patients received MOR agonists (buprenorphine [n=5], methadone [n=2]) for >12 months, 1 patient received long-acting injectable naltrexone, and 27 patients were not on opioidergic drugs. While the results demonstrated significant reductions (P<0.001) in Beck Depression Inventory-II scores over the 6 infusions of ketamine treatment, no difference was found between the MOR agonist and non-MOR agonist groups pre- and post-treatment. A similar antidepressant response was seen in the one patient receiving naltrexone.

Grunebaum et al (2020)²³ explored whether ketamine’s antisuicidal ideation and antidepressant effects were related to MOR-1 by comparing patients with and without a common A118G OPRM1 gene SNP that has a functional association with opioid therapy. They hypothesized that the patients without the OPRM1 allele would have a diminished response to ketamine. A total of 80 patients with MDD (based on DSM-IV) and a Beck Scale for Suicidal Ideation (SSI) of ≥4 were randomized to receive IV ketamine 0.5 mg/kg over 40 minutes or midazolam 0.02 mg/kg over 40 minutes. SSI was measured at 24 hours after infusion. Patients provided a blood sample at baseline and the OPRM1 A118G polymorphism was genotyped. Adjusting for baseline, results did not indicate that a loss of function of the OPRM1 SNP affected ketamine’s therapeutic effects (t=0.59, df=66; P=0.554), The author acknowledged that this was an underpowered sample size and that more research was needed.

Animal Data

Klein et al (2020)²⁴ used Sprague-Dawley rats to conduct behavioral and cellular assays in the lateral habenula brain nucleus to examine whether the antidepressant effect of low-dose ketamine is mediated by the opioid system. Their observations suggest that ketamine does not directly act on opiate receptors to produce its antidepressant effects, but that some signaling or interaction between the opioid system and NMDA receptors may be needed. Another animal study using increasingly higher doses of S-ketamine in Sprague-Dawley rats found decreases in MOR density and MOR desensitization in the nucleus accumbens without producing changes in NMDA receptor density.²⁵ According to Hess et al, the interaction between ketamine and the opioid system in depression is complex and controversial.²⁶

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 December 2023. This response excludes case reports but are cited in the References section.²⁷