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Esketamine as an Antidepressant

Major depressive disorder (MDD) is a significant cause of disability worldwide and the most common illness preceding suicide. On March 5, 2019, the nasal spray drug, esketamine, also known as Spravato (by Janssen Pharmaceuticals), was approved by the FDA for treatment-resistant major depression.

Depression is a common and debilitating condition that is recognised as a leading cause of disability worldwide. A survey published in 2016 found that 3.3 out of every 100 UK adults had experienced depression in the week before being interviewed.

One of the key symptoms of depression is ‘Anhedonia‘ (the loss of pleasure). An important component of this symptom is an inability to feel excitement and also involves a lack of motivation.

A new study conducted on Marmosets, a type of non-human primate at the Wolfson Brain Imaging Centre and Translational Neuroimaging Laboratory in 2018 has shown that ketamine affect those brain regions thought to be responsible.

On 21st May, a trial which involved 227 patients who were randomly assigned to intranasal esketamine 56mg or 84mg twice-weekly or placebo, plus an antidepressant. Depressive symptoms were measured on the Montgomery–Åsberg Depression Rating Scale (MADRS), with a mean score of 37 out of 60 in both groups at baseline.

At 28 days, the change in MADRS score was significantly greater in the esketamine group than in the placebo group at –21.4 versus –17.0, respectively. Adverse events, such as dizziness, dissociation, vertigo and nausea, were more common in the active treatment group2.

Esketamine is the s-enantiomer of Ketamine. Ketamine is a mixture of two enantiomers (mirror-image molecules). This is the first time that the FDA has approved esketamine for any use. The FDA approved ketamine (Ketalar) in 1970.

Esketamine is contained within the standard pharmaceutical form of ketamine, which has traditionally been used at higher doses as an anaesthetic. The difference between Esketamine and Ketamine is that the latter contains the former. Pharmaceutical forms of ketamine contain two mirror-image molecules of itself called enantiomers (R-Ketamine and esKetamine – see below), the pharmaceutical industry has isolated one mirror image and shown some benefits (rapid onset whilst lower side effect profile) of using that “enantiomer” over the combination mixture¹.

Simply put, ketamine in its “natural” form is seen as “dirtier” than the pure form of esketamine as the original contains two enantiomers, one of which has been suggested by the pharmaceutical manufacturer as causing unwanted side effects.

esketamine enantiomer

Esketamine may prove to be a promising treatment for patients diagnosed with major depressive disorder who have not experienced an improvement in symptoms despite treatment with various medications and therapies. The intranasal route of administration for this drug allows for easy administration and a fast onset of action, which sets it apart from many other antidepressant agents that may take several weeks to take effect. This drug is indicated in conjunction with an oral antidepressant for the treatment of treatment-resistant depression (TRD) in adults.

Esketamine is not approved as an anaesthetic agent. The safety and effectiveness of esketamine as an anaesthetic agent have not been established to this date.

Other uses of Esketamine

Esketamine has shown some efficacy for Tinnitus and inner ear conditions. This is because it can work as an NMDA antagonist of receptors in the cochlea. Esketamine has been formulated as an intratympanic biodegradable gel, is manufactured by Auris Medical and can be accessed in the UK via secondary care.

Mechanism of action

Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The exact mechanism by which esketamine acts as an antidepressant is unknown. The primary circulating metabolite of esketamine (noresketamine) shows activity at the same receptor with a weaker affinity.

If you would like to watch a short video of how esketamine may work have a look at the video below:

Dosing: adult

Depression, treatment-resistant: Note: Administer in conjunction with an oral antidepressant. Must be administered under the direct supervision of a health care provider with patients monitored for adverse effects for at least 2 hours following administration.

Intranasal:

  • Induction: 56 mg twice weekly; may increase dose (after first dose) based on response and tolerability up to 84 mg twice weekly. After 4 weeks, evaluate for evidence of therapeutic benefit to determine need for continued treatment.
  • Maintenance: Beginning on week 5, using the previously established dose (56 or 84 mg) decrease the dosing frequency to once weekly. At week 9 and onward, adjust the dosing frequency to the least frequent interval to maintain remission/response; continue once weekly or decrease to every 2 weeks.
  • Missed treatment sessions or worsening of symptoms: Consider returning to patient’s previous dosing schedule (eg, every 2 weeks to once weekly or weekly to twice weekly).

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

  • Mild to moderate impairment (Child-Pugh classes A and B): There are no dosage adjustments provided in the manufacturer labeling (has not been studied); patients with moderate impairment may need to be monitored for adverse effects for a longer period of time.
  • Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

ALERT: US Boxed Warning

  • Sedation and dissociation: Patients are at risk for sedation and for dissociative or perceptual changes after administration of esketamine. Because of the risks of sedation and dissociation, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the health care setting.
  • Abuse and misuse: Esketamine has the potential to be abused and misused. Consider the risks and benefits of prescribing esketamine prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse.
  • REMS: Because of the risks of serious adverse outcomes resulting from sedation, dissociation, and abuse and misuse, esketamine is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS.
  • Suicidal thoughts and behaviors: Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for the emergence of suicidal thoughts and behaviors. Esketamine is not approved in pediatric patients.

Pharmacodynamics

  1. General effects: Esketamine is considered a central nervous system (CNS) depressant agent. It may cause sedation, dizziness, and lethargy, among other symptoms. This drug has dissociative and antidepressant properties. Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills. Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive. The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion.
  2. Effects on cardiac electrophysiology: The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers. A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine. Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine.
  3. Effects on blood pressure: Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses. Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours.
  4. Cognitive effects: In a study of healthy volunteers, one dose of this agent caused a decline in cognitive performance 40 minutes after administration. Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration. Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration.
Pharmacokinetics
Absorption   Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC.
Volume of distribution   The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L.  
Protein binding   The protein binding of esketamine is about 43% to 45%.  
Metabolism   Esketamine is mainly metabolized to the noresketamine metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19. Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites.  
Route of elimination   Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose).  
Half-life   The mean terminal half-life (t1/2) ranges from 7 to 12 hours.
Clearance   The average clearance of esketamine is approximately 89 L/hour following intravenous administration.   Elimination of the major esketamine metabolite, noresketamine, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours.

Patient-Reported Effects

The acute subjective effects of ketamine dosing can range from sub-perceptual disturbances in cognitive processing and body sensation to full dissociative states in which one feels separate from the body and thoughts dissolve fully. Research evidence suggests that some level of dissociation may be correlated with treatment response for depression.

These experiences are classified as non-ordinary states of consciousness and may represent novel experiences for patients. It is possible that some patient may experience a departure from their usual mind and physical state as challenging or unsettling in the moment. The treatment environment, supportive therapist stance and dosing protocol is designed to optimize the positive nature of the subjective experiences.

References