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)

Canuso and colleagues frame major depressive disorder (MDD) as a common, severe condition that frequently co-occurs with suicidal thoughts and behaviours, and they emphasise that people with active suicidal ideation with intent represent an especially ill subgroup with greater symptom severity, comorbidity, functional impairment and prior suicide attempts. Earlier research and clinical practice rely on hospitalisation and initiation or optimisation of oral antidepressants, but these traditional approaches have a delayed onset of full therapeutic effect (typically 4–6 weeks) and may be less effective in patients who present with suicidal intent. A small proof-of-concept trial suggested that esketamine nasal spray, an N-methyl-D-aspartate receptor antagonist, given with an oral antidepressant could produce rapid relief of depressive symptoms and suicidality, motivating larger confirmatory studies.

The primary efficacy measure in each trial, and in the pooled analysis, was change in MADRS total score from baseline (predose day 1) to 24 hours post-first dose (day 2). MADRS evaluates core depressive symptoms on ten items rated 0–6. Because existing suicidality scales were not designed to detect rapid change, the Suicide Ideation and Behavior Assessment Tool (SIBAT) was used; its principal clinician-reported measure was the Clinical Global Impression–Severity of Suicidality–revised (CGI-SS-r, 0–6). Other SIBAT outcomes included clinician-rated imminent suicide risk and frequency of suicidal thinking and patient-rated frequency of suicidal thinking. Primary and key secondary end points were analysed by analysis of covariance (ANCOVA) on last observation carried forward (LOCF) data with factors for study, treatment, centre within study, and standard-of-care antidepressant strategy, plus baseline score as a covariate. Mixed models for repeated measures analysed change over time, and subgroup and item-level analyses used ANCOVA or generalized estimating equations as appropriate. Safety analyses included all randomised patients who received at least one dose; efficacy analyses required baseline and at least one postbaseline assessment.

Adverse events that occurred in ≥20% of esketamine-treated patients were dizziness (38.3% vs 13.8% placebo), dissociation (33.9% vs 5.8%), nausea (26.9% vs 13.8%), somnolence (20.7% vs 10.2%) and headache (20.3% vs 20.4%). Most adverse events occurred on dosing days and resolved the same day. No treatment-emergent psychosis or withdrawal/abuse phenomena were reported during follow-up in the extracted text. Dose reductions or interruptions due to adverse events occurred in 15.4% of esketamine patients versus 1.8% of placebo patients; discontinuations for adverse events were 6.2% and 3.6%, respectively. Four patients in each group attempted suicide during the double-blind phase; during follow-up seven patients previously treated with esketamine and three previously treated with placebo attempted suicide. One patient who had received esketamine died by suicide in the follow-up phase; this patient had multiple prior attempts including one within the month before randomisation. The authors note that the slight imbalance in recent suicide attempts at baseline may partly explain differences in suicide attempts between groups.

The authors position their pooled findings as consistent with the individual trials while providing greater precision for subgroup estimates. They restate that esketamine is approved to provide rapid reduction of depressive symptoms in this clinical context but is not approved specifically for reducing suicidal ideation or behaviour. Safety observations were consistent with the established profile of esketamine: most adverse events were transient and occurred on dosing days. Key limitations acknowledged include the comprehensive standard-of-care received by control participants, which may have increased placebo response; the intensive visit schedule that could have influenced outcomes; and potential variability in standard-of-care practices across regions, which may limit generalisability. The investigators also note the methodological challenge of measuring rapid changes in suicidality and reference ecological momentary assessment evidence showing high short-term variability in suicidal thoughts.

The pooled results from ASPIRE I and ASPIRE II confirm and strengthen the individual trial findings: when administered in the context of comprehensive standard of care, esketamine nasal spray produces a rapid reduction in depressive symptoms in adults with MDD and acute suicidal ideation or behaviour, with particularly notable effects in patients who have a history of prior suicide attempt.