Emergency Department Esketamine Trials: How the ASPIRE Studies Changed Acute Suicide Crisis Care
Quick Facts
How Were the ASPIRE Emergency Department Trials Designed?
The ASPIRE (Assessing Clinical Utility of Spravato for Patients at Imminent Risk of Suicide) program consisted of two pivotal Phase 3 trials. ASPIRE I (NCT03039192) and ASPIRE II (NCT03097133) together enrolled approximately 450 adults aged 18–64 who presented to emergency departments or inpatient psychiatric units with major depressive disorder and active suicidal ideation with intent.
Participants received two doses of either 84 mg intranasal esketamine or placebo nasal spray, administered on day 1 and day 25, in addition to comprehensive standard of care that included hospitalization, newly initiated or optimized antidepressant therapy, and psychotherapy as clinically indicated. The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after the first dose.
What Did the ASPIRE Trials Reveal About Speed of Symptom Relief?
In ASPIRE I, published by Fu and colleagues in the Journal of Clinical Psychiatry in 2020, esketamine-treated patients demonstrated a statistically significant reduction in MADRS total score compared to placebo at 24 hours (least-squares mean difference: −3.8, 95% CI: −6.56 to −1.11; P = 0.006). ASPIRE II confirmed these findings with a similar effect size, reinforcing the reproducibility of esketamine's rapid antidepressant action in acutely suicidal patients.
Notably, the Clinical Global Impression of Severity of Suicidality–Revised (CGI-SS-r) scale, a key secondary endpoint, also showed numerical improvements favoring esketamine, although statistical significance was not consistently achieved on this measure across both trials. Researchers have noted that this may reflect the inherent difficulty of measuring suicidality independently from depressive symptom burden.
What Monitoring Protocols Do Emergency Departments Follow After Esketamine Administration?
The Spravato Risk Evaluation and Mitigation Strategy (REMS) mandates that administration occur only in certified healthcare settings. In the emergency department context, clinical staff monitor patients for sedation, dissociation, and hemodynamic changes. Blood pressure is typically assessed at baseline, approximately 40 minutes post-dose, and prior to discharge from the monitoring period.
During the ASPIRE trials, the most frequently reported adverse events included dissociation (reported in approximately 26% of esketamine-treated patients versus 4% on placebo), dizziness, nausea, and vertigo. Most adverse events were mild to moderate in severity and resolved within 90 minutes. Serious adverse events were rare and occurred at similar rates in both treatment groups, supporting a favorable risk-benefit profile in this high-acuity population.
How Has the ASPIRE Evidence Influenced Emergency Psychiatric Protocols?
Before the ASPIRE results, emergency clinicians managing acute suicidal crises relied primarily on observation, safety planning, and initiation of conventional antidepressants with onset delays of two to four weeks. The FDA's August 2020 approval of esketamine for depressive symptoms in adults with MDD with acute suicidal ideation or behavior provided a pharmacological option specifically studied in this exact clinical scenario.
Health systems implementing esketamine in emergency departments have reported practical considerations including pharmacy storage requirements for a Schedule III controlled substance, dedicated monitoring space, nursing staff training, and insurance prior authorization challenges. A 2023 cost-effectiveness analysis published in the Journal of Medical Economics suggested esketamine was cost-effective at standard willingness-to-pay thresholds when accounting for potential reductions in inpatient psychiatric admissions and repeat ED visits.
Frequently Asked Questions
Esketamine is the S-enantiomer of ketamine, meaning it is one of two mirror-image molecular forms. It has approximately twice the binding affinity for the NMDA receptor compared to the R-enantiomer. The FDA-approved intranasal formulation (Spravato) delivers a standardized 84 mg dose, whereas racemic ketamine IV protocols used off-label for depression vary widely in dosing and lack the same regulatory oversight and standardized monitoring requirements.
The ASPIRE trials were powered to detect differences in depressive symptoms (MADRS scores), not suicide attempts or completed suicides, which are statistically rare events requiring much larger sample sizes. Patients with imminent risk requiring immediate intervention were excluded for ethical reasons. The trials did track suicidal behavior as a safety outcome, and rates were low and comparable between groups.
In the United States, call or text 988 to reach the Suicide and Crisis Lifeline, available 24 hours a day, 7 days a week. You can also go directly to any emergency department or call 911. In the UK, contact the Samaritans at 116 123. These services provide immediate support regardless of whether esketamine or any specific treatment is available locally.
References
- 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):19m13191.
- 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 Suicidal Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31.
- U.S. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available under a restricted distribution system. FDA News Release, March 5, 2019.
- Ross EL, Soeteman DI. Cost-effectiveness of Esketamine Nasal Spray for Patients With Treatment-Resistant Depression in the United States. Psychiatr Serv. 2020;71(10):988-997.