Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior

This pooled analysis (n=456) of the two ASPIRE studies (comparing ketamine to placebo, both with standard care) finds significant improvements in depression scores immediately (4 & 24 hours) up to 25 days later (all similar reductions). The study also showed improvements on suicidal ideation (which all patients had), most for those with a history of suicide attempt.

Abstract

“Purpose/Background Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies.”

Methods/Procedures Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression–Severity of Suicidality–Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance.

Findings/Results Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], −3.8 [−5.75 to −1.89]) and at earlier (4 hours: −3.4 [−5.05 to −1.71]) and later time points (day 25: −3.4 [−5.36 to −1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression–Severity of Suicidality–Revised at 24 hours was −0.20 (−0.43 to 0.04) for all patients and −0.31 (−0.61 to −0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache.

Implications/Conclusions Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.

Authors: Carla M. Canuso, Dawn F. Ionescu, Xiang Li, Xin Qiu, Rosanne Lane, Ibrahim Turkoz, Abigail I. Nash, Tricia J. Lopena & Dong-Jing Fu

Notes

This study is a follow-up to earlier analyses of the ASPIRE studies (e.g. Ionescu et al, 2020)

Summary

from http://journals.lww.com/psychopharmacology

Esketamine nasal spray was approved by several health authorities for the treatment of depression.

(J Clin Psychopharmacol 2021;00: 00–00)

Major depression is a common, serious, and burdensome psy-chiatric illness that affects relationships, parental functioning, work performance, and various other aspects of role performance, as well as health and disability years.

Patients with MDD who have active suicidal ideation with intent manifest more severe depressive symptoms, greater psychiatric comorbidities, worse functioning and quality of life, and more prior suicide attempts than patients without suicidal ideation.

Patients with MDD who have suicidal ideation with intent require immediate and comprehensive intervention to avert self-harm. However, the utility of standard antidepressants is limited in such situations.

Patients with MDD who have suicidal ideation are less likely to respond to treatment than patients with MDD without suicidal ideation. Esketamine nasal spray may be a promising treatment for patients with MDD who have suicidal ideation.

In 2 identically designed, phase 3 global studies of adults with MDD who had active suicidal ideation with intent, esketamine was shown to provide rapid relief of depressive symptoms and suicidality. The product is approved in the EU for the treatment of depressive symptoms in adults with MDD.

MATERIALS AND METHODS

The ASPIRE I and ASPIRE II trials enrolled patients aged between 18 and 64 years with a diagnosis of MDD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). They were treated with standard-of-care treatment, including hospitalization and initiation or optimization of antidepressant(s) during double-blind treatment.

The ASPIRE I and ASPIRE II studies were double-blind, randomized, placebo-controlled, multicenter, multicountry trials conducted between June 2017 and April 2019. All patients provided written informed consent before their study participation commenced. Within each ASPIRE trial, eligible patients were randomized to self-administer 84 mg of esketamine nasal spray or matching placebo nasal spray twiceweekly for 4 weeks under the supervision of a study site healthcare professional.

Patients were allowed to take benzodiazepines during the study, except during the 12 hours around the first intranasal study drug dose, and the 8 hours before the day 2 assessments.

Efficacy and Safety Assessments

To prevent functional unblinding, 28 trained and certified raters assessed patients’ depressive symptoms at baseline, 4 and 24 hours after the first dose of intranasal study drug, and 4 hours after the final dose on day 25.

Existing scales were not sensitive to rapid changes in suicidality, so a computerized instrument, the Suicide Ideation and Behavior Assessment Tool, was developed. This instrument assessed clinician-reported Clinical Global Impression – Severity of Suicidality – revised, patient-reported Clinical Global Impression of Imminent Suicide Risk, and adverse events.

Statistical Methods

Post hoc analyses were conducted on pooled data from the identically designed ASPIRE I and ASPIRE II trials. Point estimates of treatment differences and 95% CIs are reported.

All patients who received at least 1 dose of study drug were included in the safety analysis and efficacy analysis.

In both ASPIRE studies, patients had a change in MADRS total score from baseline to 24 hours after the first dose. The change in MADRS total score was analyzed using analysis of covariance (ANCOVA) and subgroup analyses were performed using an ANCOVA model.

A mixed model for repeated measures was used to analyze data from the double-blind phase of a study. The treatment effect over time for MADRS total score was determined using observed case data and generalized estimation equations of logistic regression models.

A subgroup analysis was performed on change in CGI-SS-r from baseline to 24 hours after the first dose, and on change in CGI-SS-r from 4 hours after the first dose to 24 hours after the first dose.

RESULTS

There were 543 patients screened, 456 patients randomized, and 4 patients were excluded from safety analyses because they did not receive a dose of study drug. Most patients completed the 4-week double-blind treatment phase.

The treatment groups were similar based on demographics, baseline clinical characteristics, and baseline psychiatric history. Most patients were moderately to extremely suicidal.

At randomization, patients received antidepressant monotherapy or antidepressant plus augmentation therapy as standard-of-care treatment. Venlafaxine, quetiapine, escitalopram, duloxetine, and mirtazapine were the most frequently used antidepressants during the double-blind phase.

Efficacy Results

Patients who received esketamine had greater improvement of depressive symptoms than those who received placebo, and the improvement was sustained throughout the follow-up phase.

At all time points during double-blind treatment, patients in the esketamine plus standard-of-care group achieved a greater percentage of remission than those in the placebo plus standard-of-care group.

Esketamine treated patients had a greater likelihood of achieving clinically meaningful improvement on all symptoms of depression, as measured by the MADRS, at 4 hours and at 24 hours after the first dose.

Patients in both treatment groups experienced rapid reduction in suicidality as measured by the CGI-SS-r. The difference between groups was not statistically significant, but patients in both treatment groups experienced improvement from baseline to 24 hours after the first dose.

The resolution of suicidality was achieved by 33.2% of patients in the esketamine plus standard-of-care group and 20.0% of patients in the placebo plus standard-of-care group at 4 hours, 24 hours, and day 25 before dose.

Safety Results

The most frequently reported adverse events during the double-blind treatment phase are listed in Table 2 and during the follow-up phase in Table S1. No symptoms or adverse events consistent with withdrawal or abuse were reported during treatment with intranasal study drug.

In the esketamine plus standard-of-care group, 15.4% of patients experienced 1 or more adverse events leading to dose reduction or interruption, compared with 1.8% of patients in the placebo plus standard-of-care group.

Seven patients previously treated with esketamine plus standard of care attempted suicide in the follow-up phase, and one patient died by suicide in the follow-up phase.

DISCUSSION

The ASPIRE trials were among the first to enroll patients with MDD at imminent risk of suicide. Esketamine plus standard of care resulted in greater improvement of depressive symptoms in patients with acute suicidal ideation or behavior compared with placebo plus standard of care.

Esketamine improved depressive symptoms in patients with severe depression who were acutely suicidal, and improved across all symptoms of depression throughout 4-week double-blind treatment.

Results of the pooled analyses are consistent with the findings of the individual trials on the key secondary end point, and suggest that hospitalization, intensive clinical contact, and/or the method used to assess suicidality may have contributed to the results.

Esketamine nasal spray is approved to treat depressive symptoms in adults with MDD and acute suicidal ideation or behavior, but not for reducing suicidal ideation or behavior.

The adverse events observed in the ASPIRE studies are consistent with the established safety profile of esketamine nasal spray. Although tragic, there was only one suicide among more than 500 patients with MDD who had active suicidal ideation with intent, a high rate of prior suicide attempts, and moderate to severe depressive symptoms at baseline.

Limitations

Patients in the control arm of the ASPIRE studies received comprehensive standard of care, including initial psychiatric hospitalization and optimized oral antidepressant therapy.

CONCLUSIONS

The pooled results from the ASPIRE trials confirm that esketamine nasal spray provides rapid relief of depressive symptoms in patients with MDD and acute suicidal ideation or behavior.

Study details

Compounds studied
Ketamine

Topics studied
Depression

Study characteristics
Placebo-Controlled Double-Blind Randomized

Participants
456

Institutes

Institutes associated with this publication

Johnson & Johnson
One of the largest pharmaceutical companies in the world, Johnson & Johnson are responsible for bringing esketamine to market in the form of Spravato.

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression: A Randomized, Double-Blind, Multicenter, Active-Controlled Study Conducted in China and USA
This double-blind, randomized Phase III trial (n=227) finds no significant difference between esketamine plus a new antidepressant versus only the antidepressant (and a placebo) at day 28 on depression scores (MADRS). The study reports one death in the esketamine group. It also states esketamine to be "effective and safe" though only the first claim could be credibly made if one only looks at the immediate (24-hour) effects.

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