Esketamine (Spravato) is a CIII nasal spray that is indicated for treatment-resistant depression in adults in conjunction with oral antidepressant therapy. Esketamine, an S-enantiomer of racemic ketamine, is a non-selective and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, an inotropic glutamate receptor. The precise mechanism of action of esketamine in depression is currently unknown.1

Esketamine shows promise for adults suffering from treatment-resistant depression. A recent study showed that approximately 30% of patients meet the criteria for treatment-resistant depression (TRD), having no positive therapeutic response even after trying 2 or more antidepressant medications.

Esketamine also has recently received attention as an effective and fast acting treatment for depression and suicidal ideation. Traditionally, oral anti-depressant therapy may take weeks for an individual to observe full therapeutic effects.

In contrast, esketamine nasal spray has been reported to rapid onset of full anti-depressant effects within 2 to 24 hours of administration of nasal esketamine spray.3 When compared with Midazolam in the treatment of patients with depression and suicidal ideations, ketamine was observed to produce a greater reduction in suicidal ideations within 24 hours.4

Indications
Esketamine is a CIII nasal spray indicated for the treatment of treatment resistant depression in adults in combination with oral anti-depressant therapy. Esketamine is currently not approved as an anesthetic agent. The safety and efficacy of esketamine as an anesthetic agent has not been established.

Mechanism of action
Esketamine, the S-enantiomer of racemic ketamine. It is a non-selective, non-competitive antagonist of the NMDA receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.1

Dosing and administration
Esketamine is administered via single use nasal spray devices and to be used in combination with oral anti-depressant therapy. Each single-use device delivers 28 mg of esketamine. The dosing schedule of esketamine is broken up into 2 phases: the induction phase (weeks 1-4), and the maintenance phase (weeks 4 to 8, then weeks 9-plus).

In the induction phase (weeks 1 to 4), on day 1, the initiation dose is 56 mg (2 devices). Subsequent doses in the induction phase may be 56 mg or 84 mg twice weekly based on efficacy and tolerability. In weeks 5 to 8 of the maintenance phase, either 56 mg or 84 mg may be administered once weekly. In the ninth week and thereafter, either 56 mg or 84 mg may be administered once weekly or once every 2 weeks. The frequency in weeks 9-plus is determined by the patient response and clinical judgment of the remission/response to treatment.

Important considerations
Esketamine is to be administered under supervision of a healthcare provider. After esketamine is administered, the patient must retain in a post-administration observation period of at least 2 hours at each treatment session due to sedative and dissociative adverse effects. 

Prior to each treatment of esketamine, a baseline blood pressure assessment must be obtained. After the administration of the medication, blood pressure must be re-evaluated after 40 minutes and when clinically indicated. Providers must consider short-term increases in blood pressure when administering esketamine. If an increase in blood pressure poses a serious risk treatment should be delayed.

Clinical Studies
Rapid reduction of depression symptoms at risk for imminent suicide
In a double blind, multi-proof of concept study, patients were administered esketamine 84 mg twice weekly for 4 weeks in addition to comprehensive care and compared with a placebo. The primary endpoint was to measure the change from baseline to 4 hours using the Montgomery-Åsberg Depression Rating Scale (MADRS).

Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. The trial concluded that in in addition to comprehensive standard-of-care treatment, esketamine may result in significant rapid improvement of depressive symptoms and suicidal ideations in patients at risk for suicide.5

Treatment resistant depression
In a randomized, double-blind clinical trial of 67 adults with treatment-resistant depression, patients were assessed at baseline using the MADRS scale and 1 week after administration of intranasal esketamine 24 mg to 84 mg twice weekly in adjunct with oral antidepressant therapy. The results of the study concluded that there were measurable improvements of depressive symptoms and scores using the MADRS scale persisted despite esketamine cessation and reduced dose frequency.6

Contraindications
Esketamine is contraindicated in patient populations who have aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage or hypersensitivity to esketamine, ketamine, or any excipients in the medication.1

Drug interaction studies
Monoamine oxidase inhibitors: Administration of esketamine alongside monoamine oxidase inhibitors may result in increased blood pressure.1

Psychostimulants: Administration of esketamine alongside psychostimulants (eg, methylphenidate, amphetamines etc) may result in increased blood pressure.1

Central nervous system (CNS) depressants: CNS depressants (alcohol, benzodiazepines, etc) may result in increased sedation if administered with esketamine. 1

Special Populations
Pregnancy: Esketamine is not recommended in pregnancy due to insufficient data supporting its usage.1

Lactation: Esketamine is present in human breast milk. Breast feeding is not recommended during treatment of this medication.1

Geriatric patients: Increased peak plasma concentrations and area under the curve (AUC) have been observed in the elderly when compared with younger adult patients.1

Hepatic impairment: Mild/moderate hepatic impairment (Child-Pugh class A & B): the AUC and t1/2 values were higher in comparison to patients with normal liver function.1

Severe hepatic impairment (Child-Pugh class C): Usage of esketamine in severe hepatic impairment has not been studied at this time and its usage is recommended against.1

Abuse and dependence
Under the Federal Controlled Substances Act, esketamine is registered as a CIII. Patients with a history of substance abuse may be at an increased risk to abuse and become dependent on the use of esketamine.

Prolonged use of ketamine has been found to warrant physiological dependence on the drug along with tolerance to treatment. Health care providers must evaluate signs and symptoms of dependence upon discontinuing therapy.

Adverse events (AEs)
Sedation and dissociation are largely the most common and notable AEs. Other AEs that have been reported are hypertension, cognitive impairment, inability to operate machinery/drive, ulcerative/intestinal cystitis, and embryo-fetal toxicity.1

Storage and handling
As esketamine is a Schedule III controlled substance, it must be stored in accordance to state and federal regulations regarding controlled substances. It can be stored in room temperature in accordance to USP standards. Esketamine must be disposed of in accordance to local, state, and federal regulations.

About the Authors
Nick Longhi is a PharmD candidate at Marshall University School of Pharmacy, anticipated to graduate in Spring 2021.

Jonathan Ogurchak, PharmD, CSP, is the founder and CEO of STACK, a pharmacy compliance management software, and serves as preceptor for a virtual Advanced Pharmacy Practice Experiential Rotation for specialty pharmacy, during which this article was composed.

Citations
1.  SPRAVATO® [Package Insert] Titusville, NJ. Janssen Pharmaceuticals Inc; 2020.
 https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf

2. Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report [published online May 22, 2009] Psychological Medicine. 2010;40(1):41–50. doi: 10.1017/S0033291709006011

3. Daly EJ, Singh JB, FedgchinM, et al: Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatmentresistant depression: a randomized clinical trial. JAMA 2018; 75: 139–148

4. Grunebaum MF, Galfalvy HC, Choo TH, et al: Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolamcontrolled randomized clinical trial. Am J Psychiatry (Epub ahead of print, Dec 5, 2017)

5. Canuso C, et al. "Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Subjects Assessed to be at Imminent Risk for Suicide." Society of Biological Psychiatry 71st Annual Scientific Meeting. May 12-14, 2016.

6. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75(2):139‐148. doi:10.1001/jamapsychiatry.2017.3739