What evidence is available for intranasal esketamine as a treatment for acute depression/suicidal ideation in the emergency department?

Introduction

Major depressive disorder (MDD) is a common and frequently disabling psychiatric disorder that affects an estimated 17.3 million adults in the United States and an estimated 264 million people worldwide.1-3 Signs and symptoms of depression can include persistent sad or “empty” mood, loss of interest in usual activities, fatigue, difficulty concentrating, insomnia, irritability, feelings of worthlessness or guilt, feelings of hopelessness, and thoughts of death or suicide.4 The Centers for Disease Control and Prevention (CDC) estimates that in 2019, 12 million American adults seriously thought about suicide, 3.5 million planned a suicide attempt, and 1.4 million made a suicide attempt.5 Over 47,500 suicide deaths occurred in 2019, making suicide the 10th leading cause of death in the United States.

Patients experiencing acute suicidal ideation often present to the emergency department, where prompt intervention is required to prevent self-harm.6 In 2017, suicidal ideation or suicide attempt accounted for nearly 1.5 million emergency department visits in the United States.7 Emergency department management of suicidal patients has typically focused on nonpharmacologic measures that keep patients safe until the suicidal crisis has passed and they can be referred for appropriate inpatient or outpatient psychiatric care.8,9 Pharmacologic options for the rapid treatment of depression and suicidal ideation are limited, since conventional antidepressants typically require weeks or months to take effect.10 If acute symptoms (eg, anxiety, panic, agitation, insomnia, pain) are contributing to suicidal ideation, these symptoms may be treated with anxiolytics, sedative-hypnotics, antipsychotics, and/or analgesics.9

Esketamine and depression

In 2019, intranasal esketamine was approved for use in treatment-resistant depression alongside oral antidepressants.11 Esketamine is the S-enantiomer of ketamine; it acts as a nonselective, noncompetitive antagonist at N-methyl-D-aspartate (NMDA) receptors.1 Compared to racemic ketamine and the R-enantiomer of ketamine, esketamine has greater anesthetic/analgesic activity and decreased psychomimetic activity.11  Esketamine binding at NMDA receptors leads to increased glutamate in the central nervous system. However, the exact mechanism of esketamine’s antidepressant effect remains unknown.

Intravenous ketamine has demonstrated rapid antidepressant effects, including improvements in suicidal ideation as soon as 40 minutes after a single dose.12 However, intravenous ketamine may be inconvenient to administer, and alternative routes of administration have not been well-explored in the treatment of active suicidal ideation. Several recent studies have examined the utility of intranasal esketamine in the setting of acute suicidal ideation, and in August 2020, the U.S. Food and Drug Administration (FDA) approved intranasal esketamine for the treatment of depressive symptoms in adults with MDD and acute suicidal ideation or behavior.12,13

Evidence for intranasal esketamine in patients with active suicidal ideation

To date, 3 randomized, double-blind, placebo-controlled trials, summarized in Table 1, have been performed to examine the effects of intranasal esketamine on acute depressive symptoms and active suicidal ideation.6,14,15 Two of these trials, ASPIRE I and ASPIRE II, formed the basis for intranasal esketamine’s approval in MDD with acute suicidal ideation.13 All 3 trials used a primary endpoint of reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score.6,14,15 Improvement in MADRS score was examined 4 hours and 24 hours after a single dose of intranasal esketamine. All 3 trials found significant improvements in MADRS score from baseline that were greater with esketamine compared to placebo at both of these early time points.

Suicidal ideation was measured with the Suicide Ideation Behavior and Assessment Tool, a recently-developed computerized instrument that includes clinical global impression measures specific to suicidality and suicide risk.6,14,15 Improvements in clinical global impression measures of suicidality and suicide risk were not significantly different between esketamine and placebo groups in any trial. However, several confounding factors may have contributed to this finding. The clinical global impression measures were clinician-reported, rather than patient-reported like MADRS scores; previous studies have reported discrepancies between patient and clinician ratings of suicidal ideation.16 In all 3 trials, the suicidal ideation-specific items on MADRS were significantly improved with esketamine versus placebo at 4 hours post-dose, although differences became insignificant at 24 hours post-dose.6,14,15 Another possible confounding factor was the high degree of clinician contact and follow-up associated with trial enrollment.16 In general, care, attention, and social support have been shown to reduce suicidal ideation. The ASPIRE trials also allowed for the concomitant use of benzodiazepines during the trial, which may have further contributed to the rapid reductions in suicidality that were observed in both esketamine and placebo treatment groups.6,14

A limitation common to all 3 trials was the exclusion of patients with certain comorbid psychiatric conditions (eg, history of psychotic symptoms/disorder, bipolar disorder) and patients with moderate to severe substance use disorder.6,14,15 Since depression commonly co-occurs with these disorders, the exclusion of patients with these disorders may limit the applicability of trial results in clinical practice. Additionally, although the placebo formulations included a bittering agent to mask treatment assignment, the authors note that the distinctive side effects of esketamine may have led to patient unblinding.

Table 1. Overview of randomized controlled trials for intranasal esketamine in active suicidal ideation.6,14,15 
Study design and durationSubjectsInterventionsResultsConclusions
Ionescu 20216
 
ASPIRE II
 
Phase 3, DB, PC, MC, RCT
 
Treatment for 4 weeks; follow-up for 90 days		N=227 patients aged 18 to 64 years meeting DSM-V criteria for MDD with MADRS score >28 and suicidal ideation with intent
 
Mean age: 40.8 years
 
Mean MADRS score at baseline: 39.7
 
91.2% were moderately to extremely suicidal according to CGI-SS-r scores; 66.1% reported prior suicide attempts		Esketamine 84 mg IN twice weekly for 4 weeks (n=114)
 
Placebo IN twice weekly for 4 weeks (n=113)
 
First dose of study drug administered in the ED or inpatient psychiatric unit
 
A dose reduction to 56 mg esketamine was permitted if patients were intolerant to 84 mg
 
Standard of care oral antidepressants (with or without augmenting therapies) were initiated or optimized at randomization; doses of these agents could be titrated during the first 2 weeks of DB treatment. Most patients (61.2%) received antidepressants in conjunction with augmenting therapies
 
Benzodiazepines equivalent to ≤6 mg/day lorazepam were permitted during the study but prohibited within 8 hours before study drug doses		Primary:
Mean change in MADRS total score from baseline to 24 hours after the first dose of study drug: -15.7 vs. ‑12.4 for esketamine vs. placebo (LSMD, ‑3.9; 95% CI, ‑6.60 to ‑1.11; p=0.006)
 
Secondary:
Decrease in MADRS score from baseline to 4 hours after the first dose of study drug was significantly greater in the esketamine group (LSMD between groups at 4 hours, -4.2; 95% CI, ‑6.38 to -1.94)
 
More patients in the esketamine group attained remission (MADRS ≤12) at 24 hours after the first dose (22% vs. 11%; treatment difference, 11.3%; 95% CI, 1.83 to 20.80)
 
Both groups experienced similar changes in CGI-SS-r score from baseline to 24 hours after the first dose of study drug (median change from baseline, ‑1.0 point in both groups; p=0.379)
 
MADRS suicidal thoughts item scores improved more in the esketamine group vs. placebo at 4 hours (LSMD, -0.57; 95% CI, ‑0.97 to ‑0.17), but differences were not significant at 24 hours
 
Safety:
No deaths were reported, and serious AEs were similar between groups (4.4% with esketamine and 5.3% with placebo)
 
Frequent AEs (≥20%) that were more common in the esketamine group were dizziness (41.2% vs. 18.6%), dissociation (38.6% vs. 8.0%), nausea (33.3% vs. 14.2%), dysgeusia (25.4% vs. 15.9%), somnolence (22.8% vs. 10.6%), and paresthesia (20.2% vs. 6.2%)		Esketamine nasal spray decreased depressive symptoms vs. placebo in patients with MDD and active suicidal ideation. Between-group differences were observed as soon as 4 hours after the first dose of esketamine.
Fu 202014
 
ASPIRE I
 
Phase 3, DB, PC, MC, RCT
 
Treatment for 4 weeks; follow-up for 90 days		N=224 patients aged 18 to 64 years presenting to the ED or inpatient psychiatric unit and meeting DSM-V criteria for MDD with MADRS score >28 and suicidal ideation with intent
 
Mean age: 39.3 years
 
Mean MADRS score at baseline: 41.1
 
88.8% were moderately to extremely suicidal according to CGI-SS-r scores; 60.1% reported prior suicide attempts, 28.1% within the last month		Esketamine 84 mg IN twice weekly for 4 weeks (n=112)
 
Placebo IN twice weekly for 4 weeks (n=112)
 
A dose reduction to 56 mg esketamine was permitted if patients were intolerant to 84 mg
 
Standard of care oral antidepressants (with or without augmenting therapies) were initiated or optimized at randomization; doses of these agents could be titrated during the first 2 weeks of DB treatment. Most patients (55.4%) received antidepressants without augmenting therapies
 
Benzodiazepines were permitted during the study		Primary:
Mean change in MADRS total score from baseline to 24 hours after the first dose of study drug: ‑16.4 vs. ‑12.8 for esketamine vs. placebo (LSMD, ‑3.8; 95% CI, ‑6.56 to ‑1.09; p=0.006)
 
Secondary:
Esketamine treatment effect was observed from 4 hours after the first dose (values not provided)
 
More patients in the esketamine group attained remission (MADRS ≤12) at 24 hours after the first dose (19% vs. 9%; treatment difference, 10%; 95% CI, 0.87 to 18.77)
 
Both groups experienced similar changes in CGI-SS-r score from baseline to 24 hours after first dose of study drug (p=0.107)
 
MADRS suicidal thoughts item scores improved more in the esketamine group vs. placebo at 4 hours (LSMD, -0.53; 95% CI, ‑0.94 to ‑0.12), but differences were not significant at 24 hours
 
Safety:
No deaths were reported, and serious AEs were similar between groups (3.5% with esketamine and 5.4% with placebo)
 
Frequent AEs (≥15%) that were more common in the esketamine group were dizziness (35.4% vs. 8.9%), dissociation (29.2% vs. 3.6%), nausea (20.4% vs. 13.4%), headache (18.6% vs. 17.9%), somnolence (18.6% vs. 9.8%), and increased blood pressure (16.8% vs. 5.4%)		Esketamine improved depressive symptoms compared to placebo; these improvements were seen as soon as 4 hours after the first dose of esketamine.
Canuso 201815
 
DB, PC, MC, RCT
 
Treatment for 4 weeks; follow-up for 81 days		N=66 patients aged 19 to 64 years presenting to the ED or inpatient psychiatric unit and meeting DSM-V criteria for MDD with MADRS score ≥22 and active suicidal ideation
 
Mean age: 35.8 years
 
Mean MADRS score at baseline: 38.6
 
Mean Beck Scale for Suicidal Ideation score at baseline: 22.8		Esketamine 84 mg IN twice weekly for 4 weeks (n=35)
 
Placebo IN twice weekly for 4 weeks (n=31)
 
A dose reduction to 56 mg esketamine was permitted if patients were intolerant to 84 mg
 
Standard of care oral antidepressants (with or without augmenting therapies) were initiated or optimized at randomization; doses of these agents could be titrated during the first 2 weeks of DB treatment. Most patients (75.8%) received antidepressants without augmenting therapies		Primary:
Mean change in MADRS total score from baseline to 4 hours after the first dose of study drug: ‑13.4 vs. ‑9.1 for esketamine vs. placebo (LSMD, ‑5.3; p=0.015)
 
Secondary:
Decrease in MADRS score from baseline to 24 hours after the first dose of study drug was significantly greater in the esketamine group (LSMD between groups at 24 hours, -7.2; p=0.015)
 
MADRS suicidal thoughts item scores improved more in the esketamine group at 4 hours (p=0.002 vs. placebo), but between-group differences were not significant at 24 hours
 
Both groups experienced similar changes in CGI-SR-I score from baseline at 4 hours (p=0.112) and 24 hours (p=0.150) after the first dose of study drug
 
More patients receiving esketamine achieved resolution of suicide risk at 4 hours (21.2% vs. 9.7%) and 24 hours (40.0% vs. 6.5%) after the first dose
 
Safety:
Discontinuation due to AEs occurred in 5 esketamine-treated patients and 1 placebo-treated patient
 
Frequent AEs (≥20%) that were more common in the esketamine group were nausea (37.1% vs. 3.2%), dizziness (34.3% vs. 12.9%), dysgeusia (31.4% vs. 16.1%), dissociation (31.4% vs. 12.9%), headache (31.4% vs. 25.8%), and vomiting (20.0% vs. 0%)		Esketamine improved depressive symptoms compared to placebo, with significant differences seen as soon as 4 hours after the first dose.
Abbreviations: AE=adverse event; CGI-SR-I=Clinical Global Impression-Imminent Suicide Risk; CGI-SS-r=Clinical Global Impression-Severity of Suicidality-revised; CI=confidence interval; DB=double-blind; DSM-V=Diagnostic and Statistical Manual of Mental Disorders, 5th edition; ED=emergency department; IN=intranasal; LSMD=least squares mean difference; MADRS=Montgomery-Asberg Depression Rating Scale; MC=multicenter; MDD=major depressive disorder; PC=placebo-controlled; RCT=randomized controlled trial.

Practical considerations with intranasal esketamine

Administration and monitoring requirements may be important to consider for emergency department use of intranasal esketamine. Each nasal spray device for intranasal esketamine contains 28 mg of esketamine; therefore, in order to administer a full 84 mg dose, 3 nasal spray devices are required.17 The manufacturer recommends waiting 5 minutes between each nasal spray device, so the full 84 mg dose will take approximately 15 minutes to administer. Intranasal esketamine is only available through a restricted distribution program known as the Spravato Risk Evaluation and Mitigation Strategy (REMS).18 This REMS program was established to mitigate the risk of serious adverse outcomes due to esketamine’s side effects of sedation and dissociation. Intranasal esketamine must be administered under the direct supervision of a healthcare provider, and patients must be monitored for at least 2 hours after each dose.

Intranasal esketamine is not appropriate for certain groups of patients.17 Esketamine typically increases blood pressure, so it is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral hemorrhage. It is also not recommended for use in pregnant women, due to risk of embryofetal toxicity.

Conclusion and ongoing trials

In August 2020, intranasal esketamine was approved for the treatment of depressive symptoms in adults with MDD and acute suicidal ideation or behavior. This approval was based on the results of 2 phase 3 trials, ASPIRE I and ASPIRE II. In these trials, a single dose of intranasal esketamine reduced depressive symptoms at 4 hours post-dose; intranasal esketamine may therefore be useful in the emergency department management of select patients with MDD and acute suicidal ideation. However, its specific efficacy in preventing suicide or reducing suicidal ideation has not yet been demonstrated, as clinical trials found no significant differences in clinician-assessed suicidality between intranasal esketamine and placebo. Of note, intranasal esketamine is only available through a restricted distribution program, and patients must be monitored for at least 2 hours after administration.

References

  1. Khorassani F, Talreja O. Intranasal esketamine: a novel drug for treatment-resistant depression. Am J Health Syst Pharm. 2020;77(17):1382-1388. doi:10.1093/ajhp/zxaa191
  2. Depression. World Health Organization. Updated January 30, 2020. Accessed March 26, 2021. https://www.who.int/news-room/fact-sheets/detail/depression
  3. Major depression. National Institute of Mental Health. Updated February 2019. Accessed March 26, 2021. https://www.nimh.nih.gov/health/statistics/major-depression.shtml
  4. Depression. National Institute of Mental Health. Updated February 2018. Accessed March 25, 2021. https://www.nimh.nih.gov/health/topics/depression/index.shtml
  5. Suicide prevention: fast facts. Centers for Disease Control and Prevention. Updated March 23, 2021. Accessed March 26, 2021. https://www.cdc.gov/suicide/facts/index.html
  6. Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31. doi:10.1093/ijnp/pyaa068
  7. Owens PL, McDermott KW, Lipari RN, Hambrick MM. Emergency department visits related to suicidal ideation or suicide attempt, 2008-2017. Agency for Healthcare Research and Quality. Published September 2020. Accessed March 26, 2021. https://hcup-us.ahrq.gov/reports/statbriefs/sb263-Suicide-ED-Visits-2008-2017.jsp
  8. Betz ME, Boudreaux ED. Managing suicidal patients in the emergency department. Ann Emerg Med. 2016;67(2):276-282. doi:10.1016/j.annemergmed.2015.09.001
  9. Coshal S, Saunders J, Matorin AA, Shah AA. Evaluation of depression and suicidal patients in the emergency room. Psychiatr Clin North Am. 2017;40(3):363-377. doi:10.1016/j.psc.2017.05.008
  10. Pompili M. Intranasal esketamine and current suicidal ideation with intent in major depression disorder: beat the clock, save a life, start a strategy. Front Psychiatry. 2020;11:325. doi:10.3389/fpsyt.2020.00325
  11. Bozymski KM, Crouse EL, Titus-Lay EN, Ott CA, Nofziger JL, Kirkwood CK. Esketamine: a novel option for treatment-resistant depression. Ann Pharmacother. 2020;54(6):567-576. doi:10.1177/1060028019892644
  12. Xiong J, Lipsitz O, Chen-Li D, et al. The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. J Psychiatr Res. 2021;134:57-68. doi:10.1016/j.jpsychires.2020.12.038
  13. Janssen announces U.S. FDA approval of Spravato® (esketamine) CIII nasal spray to treat depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Biospace. Published August 3, 2020. Accessed March 26, 2021. https://www.biospace.com/article/releases/janssen-announces-u-s-fda-approval-of-spravato-esketamine-ciii-nasal-spray-to-treat-depressive-symptoms-in-adults-with-major-depressive-disorder-with-acute-suicidal-ideation-or-behavior/
  14. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3). doi:10.4088/JCP.19m13191
  15. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620-630. doi:10.1176/appi.ajp.2018.17060720
  16. Olié E, Nobile B, Courtet P. The antisuicidal effect of esketamine should be further investigated. J Clin Psychiatry. 2020;81(6). doi:10.4088/JCP.20l13482
  17. Spravato. Package insert. Janssen Pharmaceuticals Inc.; 2020.
  18. Spravato® REMS. Janssen Pharmaceuticals, Inc. Accessed March 26, 2021. https://www.spravatorems.com/

Prepared by:

Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2021

The information presented is current as of March 11, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.