Treatment resistant depression is a common and burdensome condition with poor outcomes and few treatment options. Approximately one third of patients with major depressive disorder are treatment resistant to the current antidepressants. In addition, depression in patients with bipolar disorder is typically poorly responsive to antidepressants. And so, there is an unmet need for rapidly acting antidepressants in those treatment-resistant patients with either major depressive disorder or bipolar disorder. Currently, the most commonly used oral antidepressants are thought to treat depression by increasing levels of neurotransmitters (serotonin, norepinephrine, and dopamine) in areas of the brain that affect mood. Research evidence suggests that N-methyl-D-aspartate (NMDA) receptor antagonism produces antidepressant effects (Stahl, 2013). Ketamine, an NMDA antagonist, is a racemic mixture comprising equal parts of R-ketamine (arketamine) and S-ketamine (esketamine). Because S-ketamine has a higher affinity for the NMDA receptor, esketamine was developed as an antidepressant, and in March 2019, esketamine nasal spray was approved by the U.S. Food and Drug Administration for use in conjunction with an oral antidepressant for the treatment of treatment-resistant depression in adults (Hashimoto, 2019).

Esketamine is marketed by Janssen under the trade name Spravato. It is a Schedule III medication and is formulated as a nasal spray. There are multiple restrictions that may affect time management for the provider. The medication must be administered under the direct supervision of a healthcare provider, and postadministration observation is also required. Before administration, blood pressure must be assessed. After dosing, blood pressure is reassessed at approximately 40 minutes and subsequently as clinically warranted. If blood pressure is decreasing and the patient appears clinically stable for at least 2 hours, the patient may be discharged at the end of the postdose monitoring period. Because some patients may experience nausea and vomiting after administration of Spravato, the patient should be advised to avoid food for at least 2 hours and avoid liquids for at least 30 minutes prior to administration.

Regarding recommended dosage, there is an induction phase and a maintenance phase. The induction phase covers Weeks 1-4, and the medication is administered twice a week. Day 1 starting dose is 56 mg; subsequent doses are either 56 or 84 mg. The maintenance phase is covered in two subphases. During Weeks 5-8, 56 or 84 mg is administered once weekly. During Week 9 and thereafter, 56 or 84 mg is administered every 2 weeks (but may be individualized to once weekly, depending on response). Each nasal spray device delivers 28 mg of esketamine. If a 56-mg dose is administered, two devices are used. For 84 mg doses, three devices are used, with a 5-minute rest between use of each device. Each device contains two sprays-one spray for each nostril. Each package provides detailed instructions on use of the device in delivering the medication and includes preparing the device, preparing the patient, and confirming delivery.

In clinical trials, over half of those patients treated with Spravato developed sedation. Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider 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 healthcare setting. The most common psychological effects of Spravato were dissociative or perceptual changes, including distortion of time, space and illusions, derealization, and depersonalization. If the patient has a preexisting psychotic disorder, treatment with Spravato should be initiated only if the benefit outweighs the risks.

Since Spravato contains esketamine, a Schedule III-controlled substance, it may be subject to abuse and diversion. Each patient should be assessed for risk of abuse or misuse, and all patients should be monitored for the development of these behaviors, including drug-seeking behavior. Know how to access referrals for specialized addiction treatment if warranted.

Spravato is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Spravato REMS, because of the risks of serious adverse outcomes from sedation, dissociation, and abuse/misuse. Requirements include the following: (a) healthcare settings must be certified in the program and ensure that Spravato is only dispensed in healthcare settings and administered to patients who are enrolled in the program, (b) the medication is administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration, and (3) pharmacies must be certified in the REMS and must only dispense Spravato to healthcare settings that are certified in the program (Jannsen Pharmaceuticals, 2019).

The search for better acting agents is a continuous process, and the clinical efficacy of various NMDA antagonists and their mechanisms of action are now in the spotlight. However, risks should be equally evaluated when assessing the benefits of this product. As a Schedule III medication, Spravato stimulates areas of the nucleus accumbens in the brain, which may produce cravings for drugs of abuse should the patient be either in an active addiction or in recovery. Providers should obtain a thorough alcohol and other drug history and include the procurement of collateral information from credible sources. Spravato has merit and may be a lifesaver if properly managed. This new medication gives hope to patients who do not respond to currently available pharmacotherapy (Pochwat, Nowak, & Szewczyk, 2019).

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