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Esketamine Nasal Spray for Treatment-Resistant Depression

27 Mar 2020 2:45 PM | Anonymous

By: Kathryn Renken, PharmD Candidate 2021, St. Louis College of Pharmacy

Mentor: Diane Klueppel, PharmD, SSM Health Rehabilitation Hospital

Depression Background 

Major depressive disorder is a condition “characterized by discrete episodes of at least 2 weeks’ duration … involving clear-cut changes in affect, cognition, and neurovegetative functions and inter-episode remissions,” distinct from normal sadness and grief.1 Symptoms include depressed mood, decreased interest or pleasure in activities, significant weight loss or gain in a short period of time, changes in sleep patterns, excessive fatigue, feelings of worthlessness, indecisiveness, and suicidal ideation. According to the National Institute of Mental Health’s 2017 National Survey on Drug Use and Health, an estimated that 17.3 million U.S. adults, or 7.1% of all adults in the United States, have experienced at least one major depressive episode.2 Out of these, it is estimated that 11 million, or 4.5% of all U.S. adults, have experienced severe impairment as a result, which can negatively affect an individual’s quality of life. Given that major depression can also lead to suicidal thoughts or behaviors, it is essential to identify and treat symptoms as quickly as possible. 

Treatment of depression often requires both pharmacologic and behavioral interventions. Pharmacologic interventions, including antidepressants, can take up to four weeks to reach full effect.3 First-line antidepressants typically include selective serotonin reuptake inhibitors (SSRIs) and, if unsuccessful, the patient may be switched to a different agent from the same or another class, requiring an additional four weeks to reach therapeutic effect. Due to the severe consequences of allowing depression to go untreated, it is crucial to find a medication that works for a patient as soon as possible. The longer a patient goes without proper treatment, the more likely that patient is to suffer severe consequences of the disease.4 

Esketamine (Spravato 

In March of 2019, the Food and Drug Administration approved esketamine nasal spray for use alongside a daily oral antidepressant for the treatment of resistant depression, defined as depression that has failed to respond to at least two other forms of antidepressants taken at appropriate doses and duration.1 During the induction period, patients receive an initial dose of 56 mg intranasally on day one, followed by 56 or 84mg twice weekly during weeks one through four based on efficacy and tolerability. Based on the results of this initial phase, patients go on to receive a maintenance dose during weeks five through eight of either 56 or 84 mg once weekly, followed by 56 or 84 mg every two weeks or once a week during week nine and thereafter.5 Patients using this medication can expect to experience its full effects within one month. 

The active ingredient of this nasal spray, esketamine, is a derivative of ketamine.5 It works by blocking the N-Methyl-D-Aspartate receptors in the brain to prolong the response of oral antidepressants, which necessitates the combination of the oral antidepressant and the nasal spray. Ketamine is currently a Schedule III drug, and the nasal spray is approved for use only in healthcare settings registered through the Spravato REMS program and under direct supervision of a healthcare professional.6 

Esketamine may cause an increase in blood pressure and should be used with caution in patients with underlying cardiovascular and cerebrovascular conditions. For this reason, prior to each dose, the patient’s blood pressure should be obtained, and if either the systolic pressure is greater than 140 mmHg or the diastolic pressure is greater than 90 mmHg, the physician must determine whether potential benefits of therapy outweigh the risks. If the patient is deemed appropriate for treatment, the first dose will be administered and the physician will monitor the patient’s blood pressure approximately forty minutes after administration and as clinically indicated over the next two hours to ensure that it remains at, or returns to, baseline prior to discharge. In addition to blood pressure, the healthcare professional will also monitor the patient for adverse events, such as extreme sedation or dissociation. Patients must remain at the clinic under observation for a minimum of two hours following nasal spray administration before they can be allowed to leave.6 

The FDA has issued black box warnings for sedation, dissociation, abuse, and misuse.7 Additional adverse effects include dizziness, nausea, reduced sensations, anxiety, lack of energy, increased blood pressure, vomiting, and feeling intoxicated.6 Patients and their family members or caregivers should be instructed to monitor for these effects and to contact their appropriate provider as indicated. 

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression: A Randomized Control Trial8 

From October of 2015 to February of 2018, researchers conducted a randomized controlled trial to investigate long-term efficacy of esketamine compared to placebo. Prior to randomization, all patients underwent screening, induction, and optimization with esketamine nasal spray. Those who achieved either stable response, defined as a steady improvement in depressive symptoms, or stable remission, defined as the cessation of depressive symptoms, by the end of the optimization phase were randomized to the control or experimental groups. These patients entered the maintenance phase of the study and were assessed for continued safety and efficacy of the drug. The experimental groups received treatment with their previously prescribed oral antidepressant and esketamine nasal spray, while the control groups received treatment with their previously prescribed oral antidepressant and placebo nasal spray. All randomized patients were included in the data analysis. 

This randomized control trial found that, compared with the placebo group, the esketamine group experienced significantly delayed relapse in depressive symptoms. The researchers found that the risk of relapse decreased by 51% among patients in stable remission following optimization and by 70% among patients in stable response following optimization. Further, safety data revealed that the most common adverse effects following esketamine administration included dysgeusia, vertigo, dissociation, somnolence, and dizziness, with the majority of these observed immediately after dose administration, recorded as mild to moderate, and resolved within the same day. No deaths occurred during the study. Serious adverse events included autonomic nervous system imbalance, disorientation, hypothermia, lacunar stroke, sedation, simple partial seizures, and suicidal ideation. These were reported in only six patients and occurred only during the induction phase, with no serious adverse effects noted during either optimization or maintenance phases of treatment.  


Esketamine (Spravato) nasal spray shows much promise in the treatment of resistant depression. Prior to its FDA approval for this indication, safety and efficacy data from clinical trials showed strong positive results in patients randomized to active treatment compared with placebo. Under close monitoring by a healthcare professional registered through the Spravato REMS program, more patients may soon find relief of their treatment-resistant depression through the use of this drug.


  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.
  2. National Institute of Mental Health. Major depression. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Updated February 2019. Accessed March 2, 2020.
  3. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. 2010. doi:10.1176/appi.books.9780890423363.48690
  4. Greden JF. The burden of recurrent depression: Causes, consequences, and future prospects. J Clin Psychiatry. 2001;62:5-9. Published January 8, 2001. Accessed March 2, 2020.
  5. SPRAVATO [package insert]. Titusville, NJ: Jannsen Pharmaceuticals, Inc; 2019.
  6. Janssen Pharmaceuticals, Inc. Nasal spray treatment for treatment-resistant depression. https://www.spravato.com/. Published 2019. Updated June 2019. Accessed March 2, 2020.
  7. United States Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; Available only at a certified doctor’s office or clinic. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Published March 5, 2019. Accessed March 2, 2020.
  8. Daly EJ, Trivedi MH, Janik K, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. Published June 5, 2019. Accessed March 2, 2020.

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