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)

Depression is a common, disabling disorder that carries substantial suicide-related morbidity and mortality. Patients with major depressive disorder (MDD) who have active suicidal ideation with intent represent a particularly severe subgroup, with more pronounced depressive symptoms and poorer treatment response than those without suicidal ideation. Current standard management for such patients typically includes initiation or optimisation of oral antidepressants and inpatient care, but conventional antidepressants often take four or more weeks to reach full effect and there were, until recently, no approved pharmacological treatments specifically for rapid reduction of depressive symptoms in this high-risk population. Ionescu and colleagues describe a global clinical development programme comprising two identically designed Phase III trials (ASPIRE I and ASPIRE II) intended to test whether adding esketamine nasal spray to comprehensive standard of care produces a more rapid reduction in depressive symptoms than placebo plus standard of care. The study reported in this paper (identified in the text as ASPIRE II) set out to determine if esketamine plus standard of care would significantly reduce Montgomery–Åsberg Depression Rating Scale (MADRS) total score at 24 hours post first dose compared with placebo plus standard of care, and to characterise safety in this acutely suicidal population.

This was a double-blind, randomised, placebo-controlled, multicentre study conducted between June 2017 and April 2019 at 47 sites across multiple countries. The study comprised a screening phase (within 48 hours before first dose), a 25-day double-blind treatment phase, and a 9-week follow-up phase (days 26–90). Eligible adults were 18–64 years old, met DSM‑5 criteria for MDD without psychosis based on the Mini International Neuropsychiatric Interview, had a baseline MADRS total score >28, and had active suicidal ideation with intent as determined by affirmative responses to MINI items assessing current suicidal thoughts and intent. Key exclusions included selected concurrent psychiatric diagnoses (for example bipolar disorder or psychotic disorders), recent moderate-to-severe substance/alcohol use disorder, and positive urine tests for certain illicit substances unless medically prescribed. Patients were randomised 1:1 by computer-generated permuted blocks and stratified by site and type of standard-of-care antidepressant (monotherapy or antidepressant plus augmentation). Blinding measures included addition of a bittering agent to placebo and identical nasal spray devices; efficacy raters were separate from safety raters and not involved in patient care. Intranasal study drug was self-administered under supervision twice weekly for 4 weeks: each nominal 84 mg dose comprised three devices delivering a total of 84 mg esketamine base (or matching placebo), with a protocol‑permitted one-time dose reduction to 56 mg for intolerance. Comprehensive standard of care was provided to all patients and consisted of recommended inpatient psychiatric hospitalisation (≥5 days; in some EU countries 14 days) and a newly initiated or optimised oral antidepressant regimen (monotherapy or antidepressant plus augmenting agent); antidepressant doses could be adjusted during the first 2 weeks. The primary efficacy endpoint was change in MADRS total score from baseline to 24 hours after the first dose (day 2). The key secondary endpoint was change in Clinical Global Impression‑Severity of Suicidality‑revised (CGI‑SS‑r) over the same interval. MADRS assessments were performed pre-dose and at 4 and 24 hours after the first dose, pre-dose at subsequent visits, and at multiple points during follow-up. Suicidality was assessed with a computerized Suicide Ideation and Behavior Assessment Tool including CGI‑SS‑r, CGI of Imminent Suicide Risk (CGI‑SR‑I), and Frequency of Suicidal Thinking (FoST). Safety monitoring included adverse events, vital signs, the Clinician Administered Dissociative States Scale (CADSS), and the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) at dosing visits. The primary analysis used ANCOVA on last observation carried forward (LOCF) data with factors for treatment, analysis centre, and standard‑of‑care antidepressant type, and baseline MADRS as a covariate; CGI‑SS‑r change was analysed with ANCOVA on ranks. A mixed model for repeated measures (MMRM) was used to assess treatment effect over time on observed cases. Multiplicity was controlled by a fixed-sequence testing procedure. The planned sample size (~112 per arm) was estimated to provide 90% power to detect a standardised effect size of 0.45 on the primary endpoint with a 2‑sided α=0.05.

Of 273 patients screened, 230 were randomised (115 per arm); 227 received at least one dose and were included in efficacy and safety analyses. Completion of the 4‑week double‑blind phase occurred in most patients (esketamine: 90/115, 78.3%; placebo: 94/115, 81.7%); 183 entered follow‑up and 166 completed day 90. Baseline clinical severity was high (mean MADRS 39.7, SD 5.48), 91.2% were rated moderately to extremely suicidal on CGI‑SS‑r, and 66.1% had a prior suicide attempt. A somewhat higher proportion randomised to esketamine had a recent (within 1 month) suicide attempt (31.6% vs 21.2%). Concomitant benzodiazepine use during double‑blind treatment occurred in 67.4% of patients. On the primary endpoint, MADRS total score decreased in both groups at 24 hours, with a significantly greater reduction in the esketamine plus standard‑of‑care group. Mean change from baseline to 24 hours was −15.7 (SD 11.56) with esketamine and −12.4 (SD 10.43) with placebo; the least‑squares mean difference was −3.9 (SE 1.39), 95% CI −6.60 to −1.11, 2‑sided P = .006. A significant advantage for esketamine was already evident at 4 hours (LS mean difference −4.2, 95% CI −6.38 to −1.94). The treatment benefit generally persisted across the double‑blind phase and was statistically significant at day 25 pre‑dose (LS mean difference −3.7, 95% CI −7.09 to −0.38). Remission (MADRS ≤12) rates were numerically higher with esketamine at most timepoints; the between‑group difference in remission was 11.3% (95% CI 1.83 to 20.80) at 24 hours. Response rates (≥50% MADRS improvement) generally favoured esketamine over placebo, except at the day 25 4‑hour post‑dose assessment. Subgroup analyses showed the primary treatment effect was observed in most subgroups, including patients with prior suicide attempts and those with more severe baseline depressive symptoms. Suicidality as measured by CGI‑SS‑r decreased rapidly in both groups (median change −1.0 at 24 hours), but the between‑group difference was not statistically significant (P = .379). Similar improvements in suicidality were observed by other indices and remained low during follow‑up; at day 90, among observed cases, 86.3% (69/80) of esketamine‑treated and 76.7% (66/86) of placebo‑treated patients had CGI‑SS‑r scores of 0 or 1. Adverse events commonly reported with esketamine during the double‑blind phase included dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. Most adverse events occurred on dosing days and resolved the same day. Thirteen (11.4%) esketamine‑treated patients required a dose reduction to 56 mg for intolerance. No deaths occurred. Events potentially related to suicidality during the double‑blind phase were balanced between groups (10 patients per group; 3 patients per group reported a suicide attempt). During follow‑up, nine patients in each group reported suicidality‑related events; four patients previously treated with esketamine and one previously treated with placebo attempted suicide in follow‑up. Dissociative symptoms (CADSS) and blood pressure increases began shortly after dosing, peaked at about 40 minutes, and generally resolved by 1.5 hours post‑dose; the highest mean CADSS post‑first dose was 15.9 (SD 12.8) with esketamine versus 1.9 in placebo. Sedation of moderate or greater severity (MOAA/S ≤3 at any time) occurred in 21/114 (18.4%) esketamine‑treated versus 3/113 (2.7%) placebo‑treated patients; none required medical intervention or showed respiratory depression.

Ionescu and colleagues report that, in this acutely suicidal MDD population, esketamine nasal spray added to comprehensive standard of care produced a statistically significant and clinically meaningful greater reduction in depressive symptoms at 24 hours compared with placebo plus standard of care. Rapid improvements were observed as early as 4 hours after the first dose, and the advantage for esketamine generally persisted throughout the 4‑week double‑blind treatment phase, with statistical significance at the final pre‑dose assessment. The authors note that these Phase III results confirm findings from the other identically designed trial in the programme. With respect to suicidality, severity decreased rapidly in both groups but the key secondary endpoint (CGI‑SS‑r at 24 hours) did not show a significant between‑group difference. The investigators suggest several possible explanations: the therapeutic effect of comprehensive standard‑of‑care interventions (including inpatient hospitalisation and initiation/optimisation of oral antidepressants), the intensive clinical contact inherent in trial participation, and concomitant benzodiazepine use may have mitigated suicidality in both arms. Safety findings were consistent with the known profile of esketamine; dissociation, transient sedation, and transient blood pressure elevations occurred primarily in the immediate post‑dose period and resolved within about 1.5 hours. No completed suicides were observed during the study period, and adverse events potentially related to suicidality were balanced between groups. The authors acknowledge methodological challenges inherent to trials in a high‑risk suicidal population. Conducting the study within comprehensive standard‑of‑care was necessary for safety and ethics but complicates attribution of effects solely to the investigational drug. Functional unblinding due to esketamine's acute dissociative effects could have biased clinical care decisions, although measures were implemented to separate efficacy raters from care providers. Additional limitations cited include the substantial placebo response seen in antidepressant trials, potential regional variation in standard‑of‑care practices (notably hospitalisation duration), and the influence of protocol‑specified hospitalisation requirements on outcomes. The investigators conclude that, while further research is warranted to understand real‑world implementation, these trials provide evidence that esketamine nasal spray may address an unmet need for a rapid‑acting antidepressant in adults with MDD and active suicidal ideation with intent.