Psychiatry · Medical Literature
Trajectory of response to esketamine nasal spray for treatment resistant depression: Findings from ESCAPE-TRD.
Abstract
Previous research has demonstrated the positive impact of early remission on disease trajectory for patients with major depressive disorder. However, there is a paucity of literature assessing the response trajectory for patients with treatment resistant depression (TRD). These analyses investigated patient outcome trajectories to Week 32, including the relationship between short- and long-term outcomes with esketamine nasal spray (ESK-NS) treatment and symptom resolution. ESCAPE-TRD (NCT04338321), a randomized, open-label, phase IIIb study, evaluated the efficacy and safety of ESK-NS versus quetiapine extended release (QTP-XR) in patients with TRD. Rater-blinded Montgomery-Åsberg Depression Rating Scale (MADRS) total score was used to assess depressive symptoms and the trajectory of patient responses to Week 32. For ESK-NS versus QTP-XR, time to symptom resolution across MADRS items was evaluated using Kaplan-Meier analyses. Of 676 patients, 336 and 340 were randomized to ESK-NS and QTP-XR, respectively. Most ESK-NS-treated patients achieved continuously improved outcomes to Week 32; early response was associated with better long-term outcomes. Among patients who achieved Week 4 response, 89.6% achieved remission at any point from Week 4 to 32; 78.3% of Week 8 responders achieved remission at any point from Week 8 to 32. Greater and earlier symptom resolution was observed with ESK-NS versus QTP-XR across most MADRS items. Most ESK-NS-treated patients with TRD showed continuous improvements over time, with short-term response associated with better long-term outcomes. Long-term improvements were observed even among partial/minimal early responders, reinforcing the value of longer treatment. ESK-NS had a positive impact across the full spectrum of MADRS-assessed symptoms.
Clinical relevance
Among patients with treatment-resistant depression (TRD), does early response to esketamine nasal spray (ESK-NS) predict long-term outcomes through Week 32, and does ESK-NS achieve faster and broader symptom resolution across MADRS items compared with quetiapine extended release (QTP-XR)? __SNAPSHOT__ {"studyDesign":"Pre-specified secondary analysis of ESCAPE-TRD (NCT04338321): a randomized, open-label, rater-blinded, active-controlled, multicenter Phase IIIb trial. Outcome trajectory analysis using Kaplan–Meier methodology and alluvial (Sankey) diagrams for patient-level transitions.","setting":"171 sites across 24 countries (hospitals, inpatient and outpatient clinics, and research centers — multinational European/international trial).","sampleSize":"n=676 (ESK-NS: n=336; QTP-XR: n=340), randomized 1:1.","population":"Adults with TRD, defined as non-response to ≥2 consecutive adequate antidepressant treatments within the current major depressive episode, continuing an ongoing SSRI or SNRI at randomization.","intervention":"Esketamine nasal spray (ESK-NS; flexible dosing per label: 56 or 84 mg, administered twice weekly, weekly, or every 2 weeks) added to an ongoing SSRI or SNRI.","comparator":"Quetiapine extended release (QTP-XR; 150–300 mg daily) added to an ongoing SSRI or SNRI.","primaryOutcome":"Trajectory of patient outcomes (remission, response, partial response, minimal response, no remission) through Week 32, assessed by rater-blinded MADRS total score. Remission defined as MADRS ≤10. Secondary focus: time to symptom resolution across individual MADRS items (Kaplan–Meier analyses) and the relationship between short-term response (Week 4/8) and long-term outcomes (Week 32).","followUp":"32 weeks (acute phase: Weeks 0–8; maintenance phase: Weeks 8–32).","fundingSource":"Industry (Janssen EMEA)"}
Key findings
Most ESK-NS-treated patients demonstrated continuously improving outcomes across the 32-week study period. Early response was strongly associated with better long-term outcomes: among ESK-NS patients who achieved response at Week 4, 89.6% achieved remission at any point from Week 4 to 32; among those who achieved response at Week 8, 78.3% achieved remission at any point from Week 8 to 32. Importantly, long-term improvements were also observed among patients with only partial or minimal early responses, supporting the value of continued treatment even in the absence of full early response. ESK-NS demonstrated greater and earlier symptom resolution versus QTP-XR across most individual MADRS items, consistent with findings from the primary ESCAPE-TRD trial (in which remission at Week 8 was achieved by 27.1% of ESK-NS patients vs. 17.6% of QTP-XR patients; P=0.003, per the primary publication [Reif et al., NEJM 2023]). Sensitivity analyses from the same program demonstrated ESK-NS shortens time to first and confirmed remission vs. QTP-XR (HR: 1.711 [95% CI 1.402–2.087], p<0.001). Absolute remission rates continued to increase beyond Week 8 in both arms, with ESK-NS maintaining superiority at each timepoint through Week 32. Specific p-values, confidence intervals, and effect sizes for the primary trajectory analyses reported in the July 2026 European Psychiatry publication (PMID 42298878) are not fully available in the published abstract; exact figures from that paper beyond those noted above are not reported here. Treatment-emergent adverse events (TEAEs) from the parent trial were more frequent with ESK-NS (91.9%) than QTP-XR (78.0%), but were typically mild-to-moderate and transient; TEAE-related discontinuation was lower with ESK-NS (4.2% vs. 11.0%, p<0.001). Dissociation, dizziness, and vomiting were the most common TEAEs leading to ESK-NS discontinuation; sedation, weight gain, and somnolence most commonly led to QTP-XR discontinuation.
Practice implications
This secondary analysis of ESCAPE-TRD establishes that, in TRD patients treated with ESK-NS, early response at Weeks 4–8 is a meaningful prognostic signal for sustained long-term remission through Week 32 — a clinically useful framework for monitoring patients on this therapy. Crucially, the finding that partial or minimal early responders can still achieve meaningful long-term improvements suggests that premature discontinuation based solely on incomplete Week 4 or Week 8 response may not be warranted, provided the treatment is tolerated. ESK-NS demonstrated superior and faster resolution across the full spectrum of MADRS-assessed symptoms versus QTP-XR. These findings apply to adults with TRD (≥2 prior treatment failures) receiving ESK-NS alongside a background SSRI/SNRI; patients with ≥3 prior treatment failures showed even greater relative benefit from ESK-NS in other ESCAPE-TRD analyses. The population studied was predominantly European; generalizability to other healthcare systems and racial/ethnic groups requires caution. Only the abstract was available for this specific 2026 publication (PMID 42298878); quantitative trajectory data, alluvial diagram specifics, and precise Kaplan–Meier statistics for individual MADRS items from this paper are not independently verifiable and have not been reproduced here. This publication is a secondary/post-hoc analysis of a pre-existing RCT and does not alter the primary conclusions of ESCAPE-TRD but adds granularity regarding individual patient trajectories and the prognostic value of early response. Practice should be informed — not changed — by these trajectory data alone; the primary ESCAPE-TRD findings (Reif et al., NEJM 2023) remain the evidentiary basis for clinical decision-making. __LIMITATIONS__ Only the abstract was available for this 2026 European Psychiatry publication (PMID 42298878); complete methodology, exact statistics for trajectory analyses, and full alluvial diagram data could not be reviewed.,Secondary/post-hoc analysis of a pre-existing RCT: trajectory groupings and cut-points may have been selected after examining the data, introducing risk of spurious findings.,Open-label design for treating clinicians (though MADRS raters were blinded) introduces performance and ascertainment bias.,Industry-funded trial (Janssen EMEA); multiple secondary analyses from the same dataset increase risk of selective reporting.,Patients who discontinued treatment were classified as having unfavorable outcomes in the primary analysis, which may inflate apparent benefits for treatment continuers.,MADRS remission threshold (≤10) and response definition (≥50% reduction or MADRS ≤10) are clinician-defined surrogates; functional and quality-of-life outcomes as co-primary endpoints would strengthen clinical meaningfulness.,Trajectory analyses are inherently descriptive; the study does not establish a causal mechanism linking early response to sustained remission, nor identify predictors with sufficient power for individual clinical decision-making.,Generalizability is limited: the trial enrolled predominantly European patients at specialized centers, and findings may not apply to community settings, elderly patients (>65 excluded per USPI analysis), or populations with high comorbidity burden.,No adjustment for multiple comparisons across MADRS item analyses, raising the risk of Type I error for individual item findings.,Long-term safety beyond 32 weeks is not addressed in this publication; dissociation, abuse potential, and neurotoxicity concerns with chronic ketamine-class agents require ongoing surveillance. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This secondary analysis of ESCAPE-TRD demonstrates that early response to esketamine nasal spray at Weeks 4–8 is associated with higher rates of sustained remission through Week 32 in TRD patients, while even partial early responders show meaningful long-term gains — supporting continued treatment in tolerant patients who do not achieve full early response. ESK-NS achieved faster and broader symptom resolution across MADRS items compared with QTP-XR. These trajectory findings add prognostic granularity to the established superiority of ESK-NS over QTP-XR in TRD but are derived from a secondary/post-hoc analysis of an industry-funded open-label trial and should inform, not independently drive, clinical practice.