Effects of esketamine on patient-reported outcomes in major depressive disorder with active suicidal ideation and intent: a pooled analysis of two randomized phase 3 trials (ASPIRE I and ASPIRE II)

The authors note that major depressive disorder (MDD) is a leading cause of disability worldwide and that a substantial subset of people with MDD experience suicidal ideation; this subgroup has been associated with poorer health-related quality of life (HRQoL), greater work and activity impairment, and elevated suicide risk. Standard of care (SOC) in acute suicidal risk usually comprises psychiatric hospitalisation and initiation or optimisation of oral antidepressant therapy, but oral antidepressants can take several weeks to show effect and suicide risk often remains high following discharge. Esketamine nasal spray plus comprehensive SOC has regulatory approval for depressive symptoms in patients with MDD who have active suicidal ideation with intent, based on two identically designed Phase III trials (ASPIRE I and ASPIRE II) that demonstrated rapid clinician-rated reductions in depressive symptoms and an expected safety profile in this high-risk population. To broaden understanding of treatment impact from the patient perspective, the authors conducted a pooled post hoc analysis of patient-reported outcomes (PROs) collected in ASPIRE I and ASPIRE II. The pooled analysis aimed to evaluate self-reported hopelessness, depression-specific quality of life, general HRQoL, and medication satisfaction over the 4-week double-blind treatment phase, comparing esketamine plus SOC with placebo plus SOC.

This post hoc pooled analysis used patient-level data from two identically designed, randomised, double-blind, placebo-controlled, multicentre Phase III trials (ASPIRE I and ASPIRE II). In both trials adults aged 18–64 years with DSM-5 major depressive disorder without psychosis, active suicidal ideation with intent within 24 hours prior to randomisation, need for acute psychiatric hospitalisation because of imminent suicide risk, and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score >28 at pre-dose on day 1 were enrolled. After screening within 48 hours prior to day 1, patients were randomised 1:1 to receive esketamine 84 mg nasal spray or matched placebo nasal spray plus comprehensive SOC, which included initial hospitalisation and a newly optimised oral antidepressant regimen; study medication was administered twice weekly over a 4-week double-blind phase. Patient-reported instruments included the Beck Hopelessness Scale (BHS), the Quality of Life in Depression Scale (QLDS), the EQ-5D-5L (descriptive system producing a health status index [HSI] plus an overall visual analogue scale [EQ-VAS]), and the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). All PROs were self-completed on an electronic tablet and were evaluated from baseline through day 25; TSQM-9 was collected at day 25 only. Prespecified meaningful change thresholds cited by the authors were: QLDS change ≥8 points, HSI change ≥0.03 to 0.07, and EQ-VAS change of ~7–10 points; a BHS score <9 was used to indicate minimal or mild hopelessness. For the principal analyses, the authors used a mixed-effects model for repeated measures (MMRM) on observed cases to estimate least-squares mean changes from baseline to day 25 for BHS and QLDS, with baseline score as a covariate and fixed effects for day, treatment, analysis centre, type of randomised SOC antidepressant treatment, and day-by-treatment interaction, plus a random subject effect. Missing data were assumed to be missing at random. Relative risks with 95% confidence intervals compared the proportions reporting any perceived problems (EQ-5D-5L levels 2–5) at day 25 between treatment groups. Proportions of patients achieving the predefined meaningful change thresholds were summarised and between-group differences with 95% CIs were estimated. The authors note that the original trials were powered on the primary clinician-rated MADRS endpoint and that PROs were not primary endpoints.

The pooled full efficacy analysis set comprised 451 patients: 226 randomised to esketamine plus SOC and 225 to placebo plus SOC. Baseline demographic and clinical characteristics were reported as similar between groups; mean ages were approximately 40 years and roughly 60% of participants were female. Baseline PRO scores were comparable across treatment arms. Beck Hopelessness Scale (BHS): At baseline mean BHS total scores indicated severe hopelessness (15.4 for esketamine + SOC and 15.8 for placebo + SOC). By day 25 mean BHS scores fell to 8.2 (SD 6.6) with esketamine + SOC and 8.9 (SD 6.6) with placebo + SOC. The mean change from baseline to day 25 was −7.4 (6.7) for esketamine + SOC versus −6.8 (6.5) for placebo + SOC; the least-squares mean difference was −1.0 (95% CI −2.23, 0.21), as estimated by the MMRM. Quality of Life in Depression Scale (QLDS): Baseline mean QLDS scores were 27.0 in both arms. At day 25 the extracted text reports mean (SD) QLDS scores of 12.6 (11.3) for esketamine + SOC and 14.7 (10.8) for placebo + SOC. In the pooled analysis the mean change from baseline to day 25 was reported in the abstract as −14.4 (11.5) for esketamine + SOC versus −12.2 (10.8) for placebo + SOC, with an LS mean difference of −3.1 (95% CI −5.21, −1.02), favouring esketamine. EQ-5D-5L descriptive system, health status index (HSI), and EQ-VAS: Relative risks (95% CI) for reporting any perceived problems (levels 2–5) at day 25 with esketamine + SOC versus placebo + SOC were: mobility 0.78 (0.50, 1.20); self-care 0.83 (0.55, 1.27); usual activities 0.87 (0.72, 1.05); pain/discomfort 0.85 (0.69, 1.04); and anxiety/depression 0.90 (0.80, 1.00). Baseline HSI was 0.56 (0.20) in both arms. At day 25 mean (SD) HSI was 0.79 (0.17) with esketamine + SOC and 0.76 (0.18) with placebo + SOC; mean change from baseline was 0.23 (0.21) versus 0.19 (0.22). Proportions achieving HSI changes ≥0.03 were 168/226 (74.3%) for esketamine and 147/225 (65.3%) for placebo; proportions achieving ≥0.07 were 152/226 (67.3%) and 134/225 (59.6%), respectively. EQ-VAS baseline means were ≈40 in both groups. At day 25 mean (SD) EQ-VAS values were reported as 64.3 for esketamine + SOC and 60.5 for placebo + SOC, with mean changes from baseline of 24.0 (27.2) versus 19.3 (24.4). The proportion achieving EQ-VAS change ≥7 was 139/226 (61.5%) with esketamine and 126/225 (56.0%) with placebo; the proportion achieving ≥10 was 137/226 (60.6%) versus 121/225 (53.8%). Treatment Satisfaction Questionnaire for Medication (TSQM-9): At day 25, mean (SD) domain scores reported in the abstract were effectiveness 67.2 (25.3) with esketamine + SOC versus 56.2 (26.8) with placebo + SOC; global satisfaction 69.9 (25.2) versus 56.3 (27.8); and convenience 74.0 (19.4) versus 75.4 (18.7). The extracted text indicates numerically higher satisfaction for effectiveness and global satisfaction with esketamine, with little difference in convenience. The authors state that improvements were seen in both treatment groups across several PROs, with numerically greater improvements for esketamine + SOC on measures of hopelessness, depression-specific QoL, HRQoL indices, and patient-reported effectiveness and global satisfaction. The extracted text does not consistently present formal p-values for all PRO comparisons; the QLDS LS mean difference reported above has a 95% CI excluding zero, while the BHS LS mean difference CI crosses zero.

The authors interpret the pooled PRO findings as supplementary evidence to clinician-rated efficacy results from ASPIRE I and ASPIRE II, indicating that patients treated with esketamine plus SOC reported numerically greater improvement than those receiving placebo plus SOC across several patient-centred measures. They highlight greater reductions in self-reported hopelessness (BHS), larger improvements in depression-specific quality of life (QLDS), improvements in general HRQoL (EQ-5D-5L HSI and EQ-VAS), and higher patient-reported effectiveness and global satisfaction (TSQM-9) with esketamine. The authors note that both groups improved on PROs, but that esketamine-treated patients showed numerically larger changes and higher proportions reaching predefined thresholds for meaningful change on several measures. The discussion places these observations alongside earlier clinician-rated findings of rapid reduction in depressive symptoms with esketamine at 24 hours post-first dose, and aligns the PRO results with the growing emphasis—per recent regulatory guidance—on collecting patient experience data to inform regulatory decision-making and treatment choice. The authors also reference external patient-reported data that link hopelessness and other symptoms to suicidal ideation, noting that reductions in hopelessness are therefore clinically relevant. Key limitations acknowledged by the authors include limited generalisability because trial participants received comprehensive and optimised clinical care (including hospitalisation and frequent assessments) that may differ from routine clinical practice and that such care could have influenced PRO responses. The authors also acknowledge that the post hoc nature of the pooled PRO analysis is a limitation and that they did not investigate relationships with sociodemographic variables (age, gender, race, ethnicity). They further note that PROs were not primary endpoints and that the original sample size calculations were powered for the clinician-rated MADRS primary outcome rather than the PROs reported here. In sum, the authors conclude that these PRO data support a patient-perspective benefit associated with esketamine plus SOC in improving HRQoL and related patient-reported domains among adults with MDD and active suicidal ideation and intent, while recognising the stated limitations and the supplementary (rather than definitive) nature of these findings for informing practice and policy.