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

Major depressive disorder (MDD) is a common, disabling condition frequently associated with suicidal ideation and attempts. Patients with active suicidal ideation and intent represent a particularly severe and vulnerable subgroup, with greater symptom burden, comorbidity, functional impairment and prior suicide attempts than patients with MDD who are not suicidal. Standard management in this crisis context typically includes hospitalisation and initiation or optimisation of oral antidepressant therapy, but conventional antidepressants have a delayed onset of effect (often 4–6 weeks) and patients remain at high risk of self-harm in the immediate period following discharge. Canuso and colleagues note a clear unmet need for treatments that produce rapid reductions in depressive symptoms for adults with MDD and acute suicidal ideation or behaviour. A small proof-of-concept study had suggested that esketamine nasal spray, an N-methyl-D-aspartate receptor antagonist, combined with an oral antidepressant, may act rapidly in this population. The present paper reports post hoc pooled analyses of two identically designed Phase III, double-blind, randomised trials (ASPIRE I and ASPIRE II) to better characterise efficacy and safety of esketamine plus comprehensive standard of care in a larger cohort, with additional subgroup analyses emphasising patients with a history of suicide attempt.

The pooled analyses draw on ASPIRE I and ASPIRE II, two global, multicentre, double-blind, randomised, placebo-controlled Phase III trials conducted between June 2017 and April 2019. Eligible adults were aged 18–64 years, met DSM-5 criteria for MDD, presented to an emergency department or inpatient psychiatric unit with affirmative responses on MINI suicide screening items (including intent to act in the past 24 hours), warranted acute psychiatric hospitalisation, and had a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score >28 before the first dose. Patients with current or past psychotic disorder, certain other psychiatric diagnoses, or recent moderate-to-severe substance use disorder were excluded. All participants agreed to comprehensive standard-of-care treatment comprising initial hospitalisation and initiation or optimisation of oral antidepressant therapy, with the choice of antidepressant or augmentation (second antidepressant, atypical antipsychotic, or mood stabiliser) left to investigator discretion. Within each trial, patients were randomised 1:1 to receive 84 mg esketamine nasal spray or matching placebo twice weekly for 4 weeks (eight administration days: days 1, 4, 8, 11, 15, 18, 22, 25), self-administered under supervision. The first dose was given in the emergency department or after admission, with a recommended hospital stay of about 5 days (longer in some EU countries). Benzodiazepines and psychotherapy were permitted with prespecified timing restrictions around dosing. To preserve blinding, separate raters conducted efficacy assessments and safety/care duties. Primary efficacy assessments included the MADRS (a 10-item clinician-rated depression scale, 0–6 per item) measured at baseline, 4 and 24 hours after the first dose, and at subsequent visits. Suicidality was assessed with the Suicide Ideation and Behavior Assessment Tool (SIBAT), the principal clinician-reported measure being the Clinical Global Impression—Severity of Suicidality—revised (CGI-SS-r, 0–6 scale). Other SIBAT outcomes included clinician-rated imminent suicide risk and frequency of suicidal thinking, plus patient-rated frequency. Adverse events were collected throughout. For the pooled post hoc analyses, the primary end point was change in MADRS total score from baseline to 24 hours after the first dose. Analyses used analysis of covariance (ANCOVA) on last observation carried forward (LOCF) data with study, treatment, analysis centre, and standard-of-care antidepressant strategy as factors and baseline score as a covariate. Time-course analyses used mixed models for repeated measures. Subgroup analyses (including by baseline severity and history of suicide attempt) employed similar ANCOVA models. The safety set comprised all randomised patients who received at least one dose; the efficacy set required baseline plus at least one postbaseline assessment.

Across the two trials, 543 patients were screened and 456 randomised (ASPIRE I: 226; ASPIRE II: 230 allocated to study treatments), with four randomised patients excluded from safety analyses because they did not receive any intranasal study drug and one further patient excluded from efficacy analyses for having no postbaseline data. Most randomised patients completed the 4-week double-blind phase (esketamine: 192/229, 83.8%; placebo: 187/227, 82.4%). The pooled sample had a mean age of 40.1 years, was 60.8% female and predominantly White (73.2%). Baseline mean MADRS total score was 40.4, indicating severe depression; 90.0% were rated moderately to extremely suicidal on the CGI-SS-r and 63.1% reported a prior lifetime suicide attempt. For the primary outcome, MADRS total score decreased in both groups at 24 hours after the first dose, with greater improvement in the esketamine-plus-standard-of-care group: mean change −16.1 (SD 11.73) versus −12.6 (SD 10.56) for placebo, yielding an ANCOVA least squares mean difference of −3.8 (SE 0.98; 95% CI −5.75 to −1.89). A treatment benefit was evident as early as 4 hours post-dose (LS mean difference −3.4; 95% CI −5.05 to −1.71) and persisted at later time points including day 25 (LS mean difference −3.4; 95% CI −5.36 to −1.36). Subgroup analyses showed consistent benefit across groups, notably among patients with higher baseline MADRS (>median 41) and among those with prior suicide attempts. Remission (MADRS ≤12) rates were higher with esketamine at most time points. At 24 hours after the first dose, remission was 20.4% with esketamine versus 9.8% with placebo (difference 10.6%; 95% CI 4.05 to 17.10). By day 25 (4 hours post-dose) remission rates were 50.4% versus 37.3% (difference 13.1%; 95% CI 4.03 to 22.19). Response (≥50% MADRS reduction) at 24 hours favoured esketamine (34.5% vs 25.3%; difference 9.2%; 95% CI 0.77 to 17.59) and remained numerically higher thereafter. Analyses of individual MADRS items found esketamine-treated patients more likely to achieve clinically meaningful improvement (≥2-point decrease) across symptoms. At 4 hours, significant early effects (lower bound of 95% CI >1.0 for odds ratio) were seen for reported sadness (OR 2.29), apparent sadness (OR 1.99), inner tension (OR 1.92), suicidal thoughts (OR 1.91), inability to feel (OR 1.75), and pessimistic thoughts (OR 1.63). At 24 hours, notable item-level ORs included concentration difficulties (OR 2.47) and apparent sadness (OR 2.13). Suicidality measured by CGI-SS-r declined rapidly in both arms. The between-group difference at 24 hours was not statistically significant (LS mean difference −0.20; 95% CI −0.43 to 0.04), though a significant between-group difference was observed at 4 hours (−0.41; 95% CI −0.63 to −0.18). In the subgroup with prior suicide attempts, CGI-SS-r change favoured esketamine at both 24 hours (LS mean difference −0.31; 95% CI −0.61 to −0.01) and 4 hours (−0.40; 95% CI −0.68 to −0.11). Resolution of suicidality (CGI-SS-r 0–1) occurred in higher proportions with esketamine at 4 hours after the first dose (33.2% vs 20.0%; difference 13.2%; 95% CI 5.12 to 21.25), but differences were smaller and not statistically significant at 24 hours and at day 25. Adverse events were more frequent with esketamine and typically occurred on dosing days and resolved the same day. The most common (≥20%) events with esketamine 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%). Dose reductions or interruptions for adverse events occurred in 15.4% of esketamine-treated patients versus 1.8% with placebo; discontinuations due to adverse events were 6.2% versus 3.6%. Four patients in each treatment group attempted suicide during the double-blind phase. During the follow-up (when only standard-of-care antidepressant therapy continued), seven patients previously treated with esketamine and three previously treated with placebo attempted suicide; one patient died by suicide three days after the last esketamine dose. The authors report no treatment-emergent psychosis or withdrawal/abuse signals during follow-up.

Canuso and colleagues emphasise that the ASPIRE trials enrolled adults with MDD at imminent risk of suicide, a population largely excluded from prior antidepressant registration studies. Pooling the two identically designed trials produced a cohort of 451 adults with acute suicidal ideation or behaviour, which the authors state is, to their knowledge, the largest such sample studied in an antidepressant trial. The pooled results demonstrate that esketamine plus comprehensive standard of care produced greater and more rapid reductions in depressive symptoms than placebo plus standard of care, with benefits evident as early as 4 hours and sustained through the 4-week double-blind period. The authors highlight that rapid symptom reduction is particularly important in the acutely suicidal population and that effect sizes were notable among patients with greater baseline severity and those with prior suicide attempts, groups at higher risk of poor response. Although both treatment groups showed rapid reductions in clinician-rated suicidality (CGI-SS-r), the between-group difference at 24 hours did not reach statistical significance in the full cohort; the investigators suggest this may reflect the therapeutic effects of hospitalisation and intensive clinical contact, the high quality of standard-of-care interventions provided, and methodological challenges in measuring rapid fluctuations in suicidal ideation. They also note that traditional once-daily or single-timepoint assessments may inadequately capture short-term variability in suicidal thinking. Regarding safety, the adverse event profile observed in ASPIRE trials aligns with the established safety profile of esketamine: most events occurred on dosing days and resolved within the same day. Suicide-related events occurred in this highly vulnerable population, as expected given baseline risk; the authors observe that the greater number of attempts in the esketamine group may partially reflect a 5% higher rate of recent suicide attempts at randomisation in that arm. The single completed suicide occurred in the follow-up phase and involved a patient with multiple prior attempts. The authors acknowledge important limitations: all patients received comprehensive standard of care including hospitalisation and optimised oral antidepressants, which may have raised placebo response and limited ability to detect between-group differences for suicidality. Regional differences in standard-of-care practices and the frequent study contacts may also limit generalisability. They conclude that rapid reduction of depressive symptoms with esketamine, when used alongside standard care, may provide a clinically useful option to bridge an urgent symptom control gap while longer-acting treatments take effect.

The pooled analyses of ASPIRE I and ASPIRE II reinforce the individual trial findings: esketamine nasal spray, administered with comprehensive standard of care, rapidly reduces depressive symptoms in adults with MDD and acute suicidal ideation or behaviour, with particularly marked benefit among those with a history of prior suicide attempts. The authors present esketamine plus standard of care as a therapeutic option for urgent symptom control in this severely ill and vulnerable population.