Mechanism of Action:
Esketamine’s specific mechanism for treating depression is unknown, but it is known to block NMDA receptors. One theory is that esketamine blocks a channel for a chemical in the brain called NMDA. This in turn increases the effects of another channel for a chemical called AMPA. This leads to increased effects of BDNF and mTOR. The increased effects of BDNF and mTOR helps the brain to rapidly form new connections between key brain cells in key areas. This all leads to a decrease in symptoms of depression!
Indication:
This is indicated in conjunction with an oral antidepressant for the treatment of treatment resistant depression in adults. Treatment resistant depression is defined as a trial of 2 prescription antidepressant medications at an adequate dose for an adequate amount of time.
Dosing and Administration:
This is an intranasal product that must be given under the supervision of a healthcare provider. Blood pressure will be assessed before and 40 minutes after administration.
Due to the potential of nausea and vomiting after administration, it is advised to avoid food for 2 hours and liquids for 30 minutes before the dose is administered. Patients on a nasal corticosteroid or nasal decongestant should administer at least 1 hour before administration
Dosing schedule:
| Induction Phase | Weeks 1 to 4: Administer twice weekly | Day 1 starting dose of 56mg Subsequent doses of 56 or 84mg |
| Maintenance phase | Weeks 5 to 8: Administer once weekly | 56mg or 84 mg |
| Week 9 or after: Administer every 2 weeks or once weekly | 56mg or 84 mg |
Steps for administration:
Esketamine is available as a 28mg nasal spray.
Do not prime the medication, 2 devices are used for the 56mg dose and 3 devices are used for the 84mg dose, with a 5-minute rest between use of each device.
Each device contains 2 sprays (one for each nostril). There are 2 green dots and 1 dot will go away with each spray.
- Blow nose before first device only
- The healthcare professional will check expiration date, peel blister to remove device, check for 2 green dots and hand to the patient
- The patient will hold their thumb on the plunger and recline head 45 degrees backwards
- The patient will insert the tip into the first nostril, close the opposite nostril and breathe in through the nose while pressing the plunger. Then sniff gently to keep the medication inside the nose. Then the process is repeated with the second nostril.
- The device is checked to make sure the green dots are gone. Do not blow nose, dap nasal drip and wait 5 minutes to repeat doses.
Post-Administration Observation is at least 2 hours and patients are instructed to not drive until the next day.
Contraindications:
Aneurysmal vascular disease, intracerebral hemorrhage, and hypersensitivity
Precautions:
Increase in blood pressure: 8 to 17% of Spravato treated patients had an increase of more than 40 in systolic blood pressure and 25 in diastolic blood pressure and 3% of Spravato patients had a systolic blood pressure increase past 180.
Cognitive impairment – short term impairment was seen between 40 minutes and 2 hours post dose. Long term impairment has been noted with Ketamine use but was not seen in 1 year of Spravato use. Long term effects past 1 year have not been evaluated
Impaired ability to drive: The effects of Spravato on driving were comparable to placebo 6 hours post dose
Ulcerative or Interstitial Cystitis: This has been seen with ketamine. Spravato showed higher rates of lower urinary tract symptoms. Monitor for urinary and bladder symptoms
Embryo-fetal toxicity: This is based on animal trials of Ketamine. Esketamine can also be found in human milk the implications of this are unknown because it hasn’t been studied in pediatric patients.
Drug interactions:
CNS depressants such as benzodiazepines, opioids and alcohol may increase sedation
Stimulants such as amphetamine, methylphenidate, and modafinil and MAOI antidepressants may all increase blood pressure.
Adverse Effects:
The most commonly observed adverse reactions (incidence ≥5% and at least twice that of placebo plus oral antidepressant) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.
Full prescribing information:
Black box warning: Sedation (49 to 61%), Dissociation (61 to 75%), abuse and misuse (schedule III product), and suicidal thoughts and behaviors (all antidepressants have this final black box warning)
REMS drug – healthcare setting must be certified, and patients must be monitored by a healthcare professional for at least 2 hours after administration
Safety and abuse trials:
Spravato was evaluated for safety in 1709 patients from five Phase 3 studies (3 short-term and 2 long-term) and one Phase 2 study.
4.6% of patients who received Spravato discontinued treatment due to an adverse event due to 1.4% in the placebo group. In adults older than 65, the proportions were 5.6% vs 3.1% in the placebo group.
Abuse potential study
A cross-over, double-blind abuse potential study of Spravato and ketamine was conducted in 34 recreational polydrug users. Spravato “drug likability” scores and “take drug again” scores were similar to scores in the IV ketamine score and higher than placebo scores.
Dependence has been reported to ketamine. There were no withdrawal symptoms of esketamine after 4 weeks, but withdrawal symptoms are likely if esketamine was abused. Tolerance has also been reported with ketamine. Similar tolerance is expected with prolonged use of esketamine. There is no specific antidote for esketamine in the case of overdose.
Clinical Studies:
Short-term study
Spravato was evaluated in a randomized, placebo-controlled, double-blind trial in adults with treatment resistant depression. Patients discontinued antidepressant treatment and then were randomized to receive twice weekly dosing of Spravato (56 or 84mg) or intranasal placebo. All patients also received an open-label treatment with an oral antidepressant (duloxetine, escitalopram, sertraline, venlafaxine XR). MADRS depression scale was used to assess change in depression. The average decrease was 19.8 points in the Spravato plus oral antidepressant group as compared to 15.8 points in the placebo and oral antidepressant group.
Long-term study
Spravato was evaluated in a randomized, placebo-controlled, double-blind trial in adults with treatment resistant depression. Patients recruited for the long-term study were previous responders to Spravato in a short-term trial. After 16 weeks of treatment with Spravato and an oral antidepressant, patients were then randomized to continue Spravato or switch to a placebo nasal spray. Remission was defined as a MADRS score of ≤12 and response was defined as a MADRS score reduction of ≥50%. Patients in remission who continued treatment with Spravato plus and antidepressant had a longer time to relapse of depression symptoms than patients on placebo. Patients with a response also had a longer time to relapse. Still around 35-40% of Spravato treated patients relapsed with depression as compared to around 70% of placebo patients.
References:
Spravato Package Insert. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf
Depression Toolbox 