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)

This double-blind, placebo-controlled, randomized study (n=230) evaluated esketamine nasal spray (84 mg) for rapid reduction of depressive symptoms in patients with major depressive disorder (MDD) who have active suicide ideation with intent. It found that patients in both treatment categories demonstrated a very significant decrease in depressive symptoms over placebo and confirmed that esketamine nasal spray could play a role in helping critically ill patients with MDD who have suicidal intent.

Abstract

“Background: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment.

Methods: This double-blind study (ASPIRE II) randomized adults (aged 18–64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression–Severity of Suicidality–revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change.

Results: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: –15.7 [11.56]) vs placebo (–12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: –3.9 [1.39], 95% CI: –6.60, –1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference –4.2, 95% CI: –6.38, –1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression–Severity of Suicidality–revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.

Conclusion: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent.”

Authors: Dawn F. Ionescu, Dong-Jing Fu, Xin Qiu, Rosanne Lane, Pilar Lim, Siegfried Kasper, David Hough, Wayne C. Drevets, Husseini Manji & Carla M. Canuso

Summary

Suicidal ideation is a serious problem.

Introduction

Depression is a common and disabling psychiatric illness that can have a devastating impact on all aspects of life. Moreover, suicide is a major public health concern in patients with major depressive disorder.

Depression with suicidal ideation is a particularly severe form of MDD, and the current standard of care includes initiation or optimization of oral antidepressants and, frequently, hospitalization. However, there are no approved pharmacological treatments for the rapid reduction of depressive symptoms in this patient population.

Esketamine nasal spray was approved in 2019 for treatment-resistant depression in adults and in a phase 2/3 study of depressed patients at imminent risk for suicide. It is also being studied for the treatment of depressive symptoms in adult MDD patients with acute suicidal ideation or behavior.

Ethical Practices

The study protocol and amendments were approved by an independent review board or ethics committee. Written informed consent was secured from all patients.

Patients

Eligible patients had a MADRS total score >28 at baseline, met DSM-5 criteria for MDD, and agreed to undergo comprehensive standard-of-care treatment, including initial hospitalization and antidepressant(s) initiated or optimized during double-blind treatment.

Key exclusion criteria included concurrent psychiatric illnesses, moderate to severe substance use disorders, current or prior diagnosis of psychotic disorder, and positive urine test results for phencyclidine, cocaine, or amphetamines.

Intranasal Study Drug and Standard-of-Care Oral Antidepressant Therapy

Patients self-administered intranasal study drugs twice weekly for 4 weeks. After the first dose, a 1-time dose reduction from 84 mg to 56 mg was allowed for patients who experienced intolerance.

Standard-of-care oral antidepressant(s) were initiated at randomization and could be titrated/ adjusted if needed during the first 2 weeks of double-blind treatment but not thereafter.

Intranasal study drug was administered in an emergency department or inpatient psychiatric unit, and patients were to remain for a recommended 5 days. Benzodiazepines were allowed, but not within 8 hours of each intranasal study drug dose.

Efficacy and Safety Assessments

Efficacy raters assessed depressive symptoms before and 4 and 24 hours after the first dose of intranasal study drug, and at all post-treatment follow-up phase visits.

Suicidal ideation and behavior were assessed using a computerized instrument at all in-person visits during the double-blind treatment phase and follow-up phase. Safety assessments included monitoring of vital signs, CADSS, and MOAA/S at all dosing visits.

Statistical Methods

The safety analysis set included all patients who received at least 1 dose of study drug, and the efficacy analysis set included all patients who had baseline and post-baseline evaluations.

Efficacy Endpoints and Analyses

Statistical analyses were conducted at a 2-sided .05. Multiplicity was controlled by a fixed sequence testing procedure.

The primary efficacy endpoint was change in MADRS total score from baseline to 24 hours after the first dose. Five patients had missing data for day 2, so the MADRS total score from 4 hours post-first dose was carried forward to day 2.

Treatment effect over time for MADRS total score was analyzed using a mixed model for repeated measures based on observed case data.

The key secondary efficacy endpoint was analyzed using an ANCOVA model with unranked baseline score as a covariate. Subgroup analyses were performed according to the ANCOVA model.

Patients in remission and response rate were summarized, and treatment difference in proportions and 95% CIs were calculated. Adverse events were summarized, including vital signs, CADSS, and MOAA/S.

Sample Size Determination

The sample size was calculated based on a standardized effect size of 0.45 and a 2-sided significance level of 0.05.

Patients and Treatment

Of 273 patients screened, 230 were randomized (115 to each treatment arm), and 183 entered the follow-up phase. 166 completed the day 90 follow-up visit.

The treatment groups were similar, in general, based on demographics, baseline clinical ratings, psychiatric histories, and standard-of-care antidepressant use. Most patients were moderately to extremely suicidal, and two-thirds reported a prior suicide attempt.

The mean (SD) length of hospitalization was 21.6 days for patients receiving esketamine plus standard-of-care and 19.1 days for patients receiving placebo plus standard-of-care. Two-thirds of patients received concomitant benzodiazepine(s) during the double-blind treatment.

Efficacy Results

Esketamine significantly decreased MADRS total score from baseline to 24 hours after the first dose in both the esketamine plus standard-of-care group and the placebo plus standard-of-care group, and the difference between treatment groups remained evident over the double-blind treatment phase.

The percentage of patients who achieved remission was numerically greater for the esketamine plus standard-of-care group than the placebo plus standard-of-care group at all time points during double-blind treatment, except on day 18.

Patients in both treatment groups experienced rapid reduction in suicidality as measured by the CGI-SS-r. Most patients in both treatment groups had a CGI-SS-r score of 0 or 1 at day 90, indicating they were normal/ questionably suicidal.

Safety Results

The most frequently reported adverse events during the double-blind treatment phase and follow-up phase were listed in Table 2 and Supplementary Table 3. No deaths were reported during the study.

Patients who received esketamine had a balanced number of adverse events potentially related to suicidality during the double-blind treatment phase. Six of the 11 patients who attempted suicide during the study had a history of a prior suicide attempt.

Esketamine-induced dissociative symptoms and transient perceptual effects peaked at 40 minutes post-dose and generally resolved by 1.5 hours post-dose. No symptoms or adverse events consistent with withdrawal or abuse were reported during the follow-up period.

Discussion

In a study of patients with MDD and suicidal ideation and intent, esketamine nasal spray significantly improved depressive symptoms compared with placebo plus standard of care at the primary endpoint. The advantage with esketamine continued until the end of 4-week double-blind treatment.

The difference in the key secondary outcome did not reach statistical significance between the 2 treatment groups, perhaps because of the increased clinical contact and use of benzodiazepines in both treatment arms.

The adverse events observed in this study are consistent with the established safety profile of esketamine nasal spray, and were generally confined to the immediate (1.5 hour) post-dosing period. No completed suicides were observed in either treatment group during the duration of the double-blind and follow-up phases.

During the double-blind treatment phase, 3 patients in each treatment group attempted suicide. During the follow-up phase, 4 patients previously treated with esketamine attempted suicide, 3 had a recent prior attempt, and 1 patient previously treated with placebo attempted suicide.

A population-based retrospective cohort study of US health claims found that the rate of suicide attempts in the period immediately following a psychiatric hospitalization is relatively low in this high-risk population and consistent with the literature.

This study was conducted in the context of comprehensive standard of care for patients with MDD who have active suicidal ideation and intent. Potential bias on efficacy outcomes was mitigated by the protocol requirements that efficacy raters could not be involved in patient care.

Esketamine nasal spray may fulfill the unmet need for a rapid-acting antidepressant in patients with MDD who have active suicidal ideation and intent, addressing the limitation of delayed onset of antidepressant efficacy observed with existing pharmacological treatments.

Acknowledgments

We acknowledge Sandra Norris, PharmD, Ellen Baum, PhD, and the study patients for their participation in this study.

Statement of Interest

Drs Ionescu, Fu, Qiu, Lim, Hough, Drevets, Manji, and Canuso are employees of Janssen Research & Development, LLC, and Dr Kasper received grants and consulting fees from several pharmaceutical companies.