Intranasal Esketamine – Psychopharmacology, Side effects and Clinical Application
Antidepressants such as SSRIs and SNRIs can be limited by their 3-6 weeks delay before a therapeutic effect is observed that can result in the need for multiple medication trials.
Research suggests that approximately 30% of patients are resistant to antidepressant treatment. [Rush et al. 2006]; [Trivedi et al. 2006]
Treatment resistant depression (TRD) is defined as the failure of at least two trials and is characterised by severe morbidity in addition to higher rates of hospitalisation, suicidal ideation, and serious medical complications.
We had previously covered ketamine and esketamine.
The U.S. Food and Drug Administration in 2019 approved esketamine nasal spray (Spravato) in conjunction with an oral antidepressant, for TRD. [Kim et al. 2019]
In 2020, the FDA approved Esketamine nasal spray to treat depressive symptoms in adults with major depressive disorder (MDD) and acute suicidal ideation or behaviour.
The Australian TGA approved intranasal Esketamine (SPRAVATO) for TRD in 2021. According to the TGA:
Spravato is indicated for treatment resistant depression (Major Depressive Disorder in adults who have not responded adequately to at least two different antidepressants of adequate dose and duration to treat the current moderate to severe depressive episode).
Spravato is to be initiated in conjunction with a newly initiated oral antidepressant.
Esketamine, the S-enantiomer of racemic ketamine, is a non-selective and non-competitive N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist that enhances glutamate release in the cortex and limbic systems.
The NMDA receptor is an ionotropic glutamate receptor that is suggested to play a central role in cognition and memory. [[Malhotra et al. 1996]; [Newcomer et al. 1999]; [Krystal et al. 2000]
1.NMDA receptor antagonism by esketamine at GABA-ergic interneurons (inhibitory) results in GABA-ergic inhibition leading to a surge of glutamate (excitatory) release. [Sattar Y et al., 2018]
2. Glutamate activates the postsynaptic AMPA receptors, which are postulated to mediate the rapid antidepressant effects of ketamine. [Sanacora G & Schatzberg A et al., 2015]
3. Other mechanisms include improved brain plasticity via the stimulation of brain-derived neurotropic factor (BDNF) production and activation of the mammalian target of rapamycin (mTOR). [Ignacio M et al., 2016]
4. Downstream modulation of mTOR is thought to stimulate additional BDNF production, resulting in increased brain plasticity through dendritic growth and improved synaptic transmission.
5. Attenuation of excessive NMDAR-dependent burst firing of neurons in the lateral habenula which is associated with overactivity in depression. [Zanos & Gould, 2018]
6. Decrease in the functional connectivity between dorsal and pregenual ACC (anterior consulate cortex) AND between default mode network (DMN) and Executive control network (ECN) in PFC which is linked to ruminations. [Li et al, 2020]
Read more about the DMN, ECN and Salience network (SN) in the neurobiology of depression. This is relevant to the treatment of depression as SSRIs do not target the ECN in treatment and melancholic and severe depression involved the ECN. Furthermore, the different areas are correlated with specific depressive symptoms.
7. Anti-inflammatory effects via modulation of astrocytes and microglia. Ketamine reduces glutamate excitotoxicity via inhibiting overactivated microglia and inhibits excessive NMDAR activity in astrocytes. Acting on the kynurenine pathway reduces the conversion of kynurenine to quinolinic acid, which again reduces glutamate excitotoxicity. Ketamine also rapid inhibits pro-inflammatory cytokines which may contribute to the rapid antidepressant effect of ketamine. [Nikkheslat, 2021].
Read more on Inflammation and Depression – A Simplified Guide
8. The monoaminergic system is partly involved in the acute and sustained antidepressant-like effects of ketamine. (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism while (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. [Ago et al, 2019]
9. Animal studies have shown that the antidepressant effect of ketamine may be partially mediated by the modification of gut microbiota. This area is underexplored in humans currently. [Wilkowska et al, 2021]
The majority of studies evaluating the mechanism of action of ketamine have used racemic ketamine (R-Ketamine).
Esketamine, the S-enantiomer has a higher affinity (3- to 4-fold) for the NMDA receptor than the R-ketamine enantiomer and is thought to produce fewer significant psychotomimetic effects, drowsiness, lethargy, or cognitive impairment than the R-ketamine enantiomer.
Data shows that esketamine pharmacokinetics are not dose-dependent between 28 mg, 56 mg, or 84 mg esketamine.
- Bioavailability is approximately 48%, and in healthy subjects, 78% of absorbed esketamine is metabolised to norketamine. Some of these losses could be from aerosolised ketamine being left behind in the container or mouthpiece or the drug being swallowed into the gastrointestinal tract. [Jonkman et al. 2017]
- Esketamine particles range in size from 0.4 to 4.4 µm. Particles that are greater than 5 µm are trapped in the oropharynx, whereas particles that are less than 1 µm are usually exhaled. Therefore the smaller esketamine particles are likely to be exhaled.
- Esketamine absorption was shown to fit two models: fast absorption (directly absorbed in the alveoli) and a slower absorption with a half-life of 13 minutes (possibly via the gastrointestinal tract after swallowing).
- Esketamine has a much higher viscosity than water, and therefore some esketamine particles may be retained in some areas of the pulmonary system before slowly being released over time.
- Esketamine plasma concentrations reach a Cmax in 20 to 40 minutes. However, there is a large intersubject variability for both Cmax and AUC calculations.
- Population data suggest no gender or BMI specific reason behind variations in esketamine absorption and distribution.
- Following administration, there is a rapid decline in plasma concentrations as esketamine and its major metabolite, esnorketamine, are quickly metabolised.
- Esketamine is primarily metabolised by CYP2B6 and CYP3A4 enzymes followed by glucuronidation of metabolites and generally, less than 1% of unmetabolised esketamine can be detected in the urine.
SIDE EFFECTS AND SAFETY
Esketamine is a Schedule III controlled substance and therefore has restricted availability due to the potential for misuse. Patients require a full drug history assessment as well as the ongoing assessment of drug-seeking behaviours or drug diversion.
- Adverse events – The most commonly reported adverse events are dissociation, dizziness/vertigo, nausea/vomiting, sedation, paresthesia, hypoaesthesia, and blood pressure increases. (See trial data below)
- Neuropsychiatric effects: The most common psychological effects of IN esketamine were dissociative or perceptual changes (including distortion of time, space and illusions), derealisation and depersonalisation (61% to 75% of SPRAVATO-treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative Symptoms Scale)
- Dissociation measured using the Clinician-Administered Dissociative States Scale (CADSS), has been shown to begin shortly after the start of dosing, peaking at approximately 40 minutes post-dose and resolving at approximately two hours post-dose. [Bahr R et al., 2019]
- Recommendations are that patients should be monitored 2 hrs post-dose.
- Adverse reactions – Cognitive impairment due to sedation and dissociation will cause an impaired ability to drive or operate machinery. Other known adverse reactions include an increased risk of ulcerative/interstitial cystitis and embryo-foetal toxicity.
- Special precautions – An increase in the incidence of suicidal thoughts and behaviours in adolescents and adults under the age of 24 years was observed in clinical trials when compared to adults aged 25 years and older.
- Drug interactions – Concomitant CNS depressants such as benzodiazepines and opioids can increase sedation and therefore, their use requires close monitoring. Psychostimulants (e.g. amphetamines and methylphenidate) and MAOIs also come with a precaution as these can also increase blood pressure.
- Read the FDA document.
Esketamine package insert comes with the following information [[Package insert: Spravato, Janssen]]:
- A single-use nasal spray that is indicated in conjunction with an oral antidepressant. Each inhaler contains 28 mg esketamine and is delivered across two sprays.
- The recommended starting dosage is 56 mg esketamine, which is to be administered twice per week for 4 weeks.
- Dosage can be increased to 84 mg esketamine if necessary, and after 4 weeks, evidence of a therapeutic benefit should be thoroughly assessed.
- A maintenance phase of one dose per week (week 5 to week 8) is then initiated, however, after week 9 the dosing frequency can be scaled between once per week or once every two weeks depending on efficacy and tolerability.
- Starting dose for patients ≥65 years is 28 mg.
Esketamine’s efficacy and safety in TRD have been assessed in 5 phase III studies:
- Three 4-week, double-blind placebo-controlled studies (Short term): TRANSFORM 1,2 and 3
- One maintenance of effect: SUSTAIN-1
- One Long Term Open-Label Safety: SUSTAIN-2
The primary endpoint in three of these studies was the change from baseline in MADRS Total Score after 4 weeks. [Kim et al. 2019]
In the other two studies, the time to relapse for stable remitters was the primary endpoint.
Due to the ethical nature of starting TRD patients on a new as-of-yet unapproved therapy, all patients were also required to initiate treatment with either duloxetine, venlafaxine XR, escitalopram, or sertraline.
TRANSFORM-1 and 3 did not reach statistical significance.
Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. [Fedgchin M et al., 2019]
- This pivotal trial showed a statistically significant effect.
- Enrolled patients aged 18 to 64 years old with TRD were switched from a prior oral AD to which they had not responded to a new oral AD, plus either 56-mg or 84-mg flexible-dosing Intranasal (IN) esketamine or IN placebo. Both the IN esketamine and IN placebo were administered twice weekly.
Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points.
The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event.
Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing. [Popova V et al., 2019]
- After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.
Among the 121 who achieved a stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4).
Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment.
The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%) each reported in fewer patients (<7%) treated with an antidepressant and placebo. [Daly E et al., 2019]
- This study enrolled geriatric TRD patients aged 65 years and older. Patients were administered a flexible dose of 28 mg, 56 mg, or 84 mg esketamine twice weekly for 4 weeks plus new oral AD followed by a 24-week open-label phase.
- Esketamine/antidepressant did not achieve statistical significance for the primary endpoint in this study of patients with TRD ≥65 years.
- From a clinical perspective, Esketamine patients were 5.3 times more likely than placebo patients to show improved Clinical Global Impression-Severity scale (CGI–S) scores.
Additional analyses suggested improvement for esketamine/antidepressant versus antidepressant/placebo in younger patients (65–74 years) and in patients with earlier onset of depression (<55 years).
Overall, the adverse event profile in older patients was similar to that seen in esketamine studies of younger patients; no new safety concerns were identified. [Ochs-Ross R et al., 2020]
- The aim was to evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant in patients with TRD.
Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%).
Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs.
Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day.
Two deaths were reported; neither was considered related to esketamine.
Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression.
Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose.
Montgomery-Åsberg Depression Rating Scale total score decreased during the induction phase, and this reduction persisted during the optimisation/maintenance phase (48 week). [Wajs E et al., 2020]
- 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment.
Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point.
These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide. [Canuso C et al., 2018]
- Esketamine, or S-ketamine, is a ketamine enantiomer that has a higher affinity for the NMDA receptor.
- Esketamine is a glutamatergic modulator and therefore has a novel and mechanistically distinct antidepressant effect.
- Esketamine shows robust, rapid, and sustained antidepressant effects as well as rapidly reducing suicidal ideation [Ionescu et al. 2016],[Canuso C et al., 2018]
- The ASPIRE-II study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. [Ionescu et al, 2021]
- Efficacy of esketamine 56 and 84 mg for TRD shows a rapid reduction of symptoms as early as 24 hours post-dose
- Studies have shown high rates of response and remission after induction.
- Studies have also shown maintenance of effect with individualised reduced dosing frequency.
- The new FDA approval applies only to the intranasal form.
- IN esketamine costs could range from $5,664 to $8,142 ($US ) in the first month of induction-phase treatment, $2,832 to $4,248 in the second month, and possibly $1,416 to $4,248 each month thereafter, depending on whether dosing is weekly or bi-weekly. [Bahr R et al., 2019]
A Cautious but Welcoming Approach:
Ketamine and esketamine are much needed options for people with treatment resistant depression. As with other psychotropics reserved for major mental illness (lithium, clozapine), use should be monitored stringently. Potential licensing represents an opportunity to deliver, and carefully monitor, probably the first truly new and effective psychiatric therapeutic agent of the 21st century and should be cautiously welcomed. [Jauhar S & Morrison P, 2019]
So, where are we? Intranasal esketamine represents an easier method of administration than intravenous administration of ketamine. Do we have clear evidence of efficacy? Maybe? How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear. If patients lose response, should we increase the frequency of administration? This could be problematic. Can coming off the drug be problematic? Data suggest that it could be an issue. Taken together, there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice. Only time will tell how useful it will be. Still, the agent could be helpful to many patients with refractory depression, and efforts to develop rapidly acting agents for severely depressed patients need to be applauded. [Schatzberg, 2019]
A real world observational, retrospective and multicentric study (REAL-ESK) showed the following: [Martinotti et al, 2022]
- REAL-ESK study comprised 116 TRD patients from several Italian real-world settings.
- 3-month response (64.2 %) and remission (40.6 %) were similar to RCTs reports.
- Only 3/116 subjects (2.58 %) dropped out for side effects.
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Fedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R., Lim, P., … & Ravindran, A. (2019). Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). International Journal of Neuropsychopharmacology, 22(10), 616-630.
Wajs, E., Aluisio, L., Holder, R., Daly, E. J., Lane, R., Lim, P., … & Kasper, S. (2020). Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). The Journal of clinical psychiatry, 81(3).
Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., … & Drevets, W. C. (2018). Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. American Journal of Psychiatry, 175(7), 620-630.
Ionescu DF, Fu DJ, Qiu X, Lane R, Lim P, Kasper S, Hough D, Drevets WC, Manji H, Canuso CM. Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). Int J Neuropsychopharmacol. 2021 Jan 20;24(1):22-31.