MDD is associated with 8.3% of all US years lived with disability, and the disease imposes a substantial burden on the individual patient and on society.2,3 Depression, particularly if untreated, increases the risk for suicide, suicidal behavior, and self-harm.4,5 Despite the potentially devastating consequences of MDD, 35% of adults remain untreated.1 Among patients who receive treatment, approximately 30% have treatment-resistant depression (ie, an inadequate response to ≥2 different antidepressants at adequate dosing and duration during a depressive episode).6,7
Pharmacologic treatments for MDD include 1 or more antidepressants, including serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, tricyclics, tetracyclics, and monoamine oxidase inhibitors (MAOIs), among others.8
It can take several weeks for patients to respond to antidepressant therapy, leaving some patients at risk for serious symptoms, including suicidal behavior; furthermore, the risk for the relapse of MDD increases in patients who cycle through 3 or more treatment stages.5,6 Achieving and sustaining complete remission early in the treatment sequence is a crucial goal for patients with MDD.6,9 Novel, rapid-acting treatment options are needed for individuals with MDD, particularly those with treatment-resistant disease.5,10
Esketamine Nasal Spray Approved for Treatment-Resistant Depression
On March 5, 2019, esketamine CIII nasal spray (Spravato; Janssen Pharmaceuticals) was approved by the US Food and Drug Administration (FDA), in conjunction with an oral antidepressant, for the treatment of adults with treatment-resistant depression.7,11 Esketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, an ionotropic glutamate receptor in the brain, was granted fast track review and a breakthrough therapy designation by the FDA.7,11,12 This is the first NMDA receptor antagonist to receive FDA approval for treatment-resistant depression, with a new delivery system via a nasal spray.
Esketamine is available only through certified physicians’ offices or clinics under a Risk Evaluation and Mitigation Strategy (REMS) program, because of the risk for serious adverse outcomes resulting from sedation and dissociation caused by esketamine treatment and the potential for abuse and misuse.7 Esketamine is not an anesthetic.7
“Depression is a common and potentially debilitating illness that can have profound emotional, functional and economic impact on both those who suffer and their loved ones. The impact of depression is greatest for those who do not benefit from standard treatments,” said Michael E. Thase, MD, Professor of Psychiatry and Director of the Mood and Anxiety Disorders Treatment and Research Program, Perelman School of Medicine, University of Pennsylvania, and a principal investigator of esketamine. “In phase 3 clinical trials, we saw this therapy provide sustained improvement to patients with treatment-resistant depression.”12
Mechanism of Action
Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive antagonist of the NMDA receptor.7 The NMDA receptor is an ionotropic glutamate receptor.7 Abnormalities in the glutamatergic-signaling pathway, along with other synapses in neurocircuitry, play a role in the modulation of moods and emotions.5,13 The precise mechanism of action of esketamine and its effect as an antidepressant drug are unknown.7
Dosing and Administration
Esketamine is delivered through a nasal spray device. Each device delivers 2 sprays containing a total of 28 mg of esketamine.7
Esketamine should be administered intranasally under the supervision of a healthcare provider. The patient’s blood pressure should be monitored before and after the administration of esketamine. At the end of the induction phase (weeks 1-4), the evidence of therapeutic benefit should be assessed to establish whether continued esketamine treatment is needed.7
During the induction phase, esketamine is administered twice weekly: the starting dose on day 1 is 56 mg, and subsequent doses are 56 mg or 84 mg. During weeks 5 to 8 of the maintenance phase, esketamine 56 mg or 84 mg is administered once weekly. Starting in week 9, esketamine is administered every 2 weeks or once weekly at a dose of 56 mg or 84 mg. The dosing frequency should be tailored to the least frequent dose necessary to maintain remission or clinical response.7
Pivotal Clinical Trials: TRANSFORM-2 and SUSTAIN-1
Esketamine was evaluated in the phase 3 TRANSFORM-2 study, a 4-week randomized, placebo-controlled, double-blind clinical trial. The study included 223 adults (median age, 47 years; 62% female) with treatment-resistant depression, defined as an inadequate response to at least 2 different antidepressants of adequate dose and duration.5,7,14 The patients were randomized to esketamine nasal spray (flexible dose; 56 mg or 84 mg) twice weekly or to an intranasal placebo. All patients also received a daily concomitant oral antidepressant, as determined by the investigator based on the patient’s treatment history. An oral SSRI was newly initiated in 32% of patients and an oral SNRI was newly initiated in 68% of patients.7
At week 4, esketamine plus an oral antidepressant demonstrated statistically superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score compared with placebo plus an oral antidepressant (Table); the MADRS is a 10-item, clinician-rated scale designed to evaluate the severity of depressive symptoms.5,7 Moreover, esketamine showed a rapid onset of action, with most of this improvement occurring within 24 hours. Between day 2 and day 28, improvement in depressive symptoms continued in the esketamine and the placebo groups.7
SUSTAIN-1 was a long-term, randomized, double-blind, parallel-group phase 3 clinical trial that assessed the time to relapse with esketamine (56 mg or 84 mg) plus an oral antidepressant compared with placebo plus an oral antidepressant in 705 adults (median age, 48 years; 66% female) with treatment-resistant depression who achieved stable remission after an induction and optimization course of esketamine plus an oral antidepressant.7,15 Stable remission was defined as a MADRS total score of ≤12 for at least 3 of the last 4 weeks of treatment.7 The follow-up time frame was from randomization to the first relapse during the maintenance phase (up to 92 weeks).15
In this study, the time to depressive symptoms relapse was significantly longer in patients who continued treatment with the esketamine regimen versus those in the placebo group.7 The estimated hazard ratio (HR), based on weighted estimates, was 0.49 (95% confidence interval, 0.29-0.84); however, this HR did not remain constant throughout the study.7
The most common adverse reactions (incidence ≥5% and twice the incidence of placebo) associated with esketamine were dissociation (41%), dizziness (29%), nausea (28%), sedation (23%), vertigo (23%), hypoesthesia (18%), anxiety (13%), lethargy (11%), blood pressure increase (10%), vomiting (9%), and feeling drunk (5%).7
Esketamine is contraindicated in patients with aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation, in patients with a history of intracerebral hemorrhage, and in patients who are hypersensitive to esketamine, ketamine, or any of their excipients.7
The concomitant use of esketamine with central nervous system (CNS) depressants (eg, benzodiazepines, opioids, and alcohol) may increase the risk for sedation; patients receiving esketamine concomitantly with CNS depressants should be monitored closely.7
The concomitant use of esketamine with psychostimulants (eg, amphetamines, methylphenidate, modafinil, and armodafinil) or with MAOIs may increase blood pressure; patients receiving esketamine concomitantly with psychostimulants or MAOIs should be monitored closely.7
Use in Specific Populations
Data on the effects of esketamine on milk production or on the breastfed infant are not available. Given the potential for neurotoxicity, patients should be advised not to breastfeed during esketamine treatment. Esketamine may cause embryo-fetal harm; female patients of reproductive potential should consider pregnancy prevention during esketamine treatment.7
In phase 3 studies of esketamine, 12% of patients were aged ≥65 years. No overall differences in safety were reported in these patients versus younger patients.7
Patients with moderate hepatic impairment may require monitoring over a long period; treatment with esketamine is not recommended for patients with severe hepatic impairment.7
Warnings and Precautions
The prescribing information for esketamine includes a boxed warning about the risk for sedation and dissociation and the importance of monitoring patients for at least 2 hours after administration. The risks and benefits of esketamine should be considered before prescribing it for patients at risk for abuse; patients should be monitored for drug abuse and misuse. All patients receiving antidepressants should be monitored for clinical worsening and for suicidal thoughts and behaviors; esketamine is not approved for pediatric patients. The boxed warning also states that esketamine is only available through a restricted REMS program.7
Esketamine can cause increases in systolic and/or diastolic blood pressure at all recommended doses; patients with cardiovascular or cerebrovascular conditions may be at risk for associated adverse effects.7
Cognitive impairment can occur with the use of esketamine. Patients who receive esketamine treatment should not drive or operate machinery until the following day.7
Esketamine is not indicated for use as an anesthetic agent; the safety and efficacy of esketamine as an anesthetic drug have not been established.7
The FDA approval of esketamine nasal spray provides a novel, rapid-acting treatment option that may improve outcomes for appropriate patients with treatment-resistant depression.
Esketamine plus an oral antidepressant demonstrated significant improvement in the symptoms of depression at week 4 compared with placebo plus an oral antidepressant. In addition, patients who achieved stable remission with esketamine plus an oral antidepressant and continued to use that regimen during the long-term maintenance phase were significantly less likely to have a relapse than patients who continued to receive placebo plus an oral antidepressant.
- National Institute of Mental Health. Major depression. Updated February 2019. www.nimh.nih.gov/health/statistics/major-depression.shtml#part_155720. Accessed June 3, 2019.
- National Institute of Mental Health. U.S. YLDs contributed by mental and behavioral disorders. www.nimh.nih.gov/health/statistics/disability/us-ylds-contributed-by-mental-and-behavioral-disorders.shtml. Accessed June 11, 2019.
- Greenberg PE, Fournier AA, Sisitsky T, et al. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015;76:155-162.
- Department of Health & Human Services. Does depression increase the risk for suicide? www.hhs.gov/answers/mental-health-and-substance-abuse/does-depression-increase-risk-of-suicide/index.html. Accessed June 4, 2019.
- Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428-438.
- Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
- Spravato (esketamine) nasal spray, CIII [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals; May 2019.
- National Institute of Mental Health. Mental health medications. Revised October 2016. Accessed June 4, 2019.
- Trivedi MH, Daly EJ. Treatment strategies to improve and sustain remission in major depressive disorder. Dialogues Clin Neurosci. 2008;10:377-384.
- National Institute of Mental Health. Rapidly-acting treatments for treatment-resistant depression (RAPID). www.nimh.nih.gov/research/research-funded-by-nimh/research-initiatives/rapidly-acting-treatments-for-treatment-resistant-depression-rapid.shtml. Accessed June 3, 2019.
- US Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. March 6, 2019. www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed May 31, 2019.
- Janssen Pharmaceuticals. Janssen announces U.S. FDA approval of Spravato (esketamine) CIII nasal spray for adults with treatment-resistant depression (TRD) who have cycled through multiple treatments without relief. March 5, 2019. www.janssen.com/janssen-announces-us-fda-approval-spravato-esketamine-ciii-nasal-spray-adults-treatment-resistant. Accessed May 31, 2019.
- Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35:192-216.
- ClinicalTrials.gov. A study to evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression (TRANSFORM-2). https://clinicaltrials.gov/ct2/show/NCT02418585. Accessed June 5, 2019.
- ClinicalTrials.gov. A study of intranasal esketamine plus an oral antidepressant for relapse prevention in adult participants with treatment-resistant depression (SUSTAIN-1). https://clinicaltrials.gov/ct2/show/NCT02493868. Accessed June 5, 2019.