Trajectory of response to esketamine nasal spray for treatment resistant depression: findings from ESCAPE-TRD

Major depressive disorder can cause broad and persistent symptoms, including anhedonia, suicidal thinking, sleep disturbance and appetite change, and treatment resistant depression (TRD) is associated with an even heavier burden and lower likelihood of remission. The authors note that, although earlier research in major depressive disorder has shown that early symptom improvement can shape later outcomes, there is still limited evidence on how treatment response evolves over time in TRD and whether early changes can help predict longer-term prognosis. They also frame the Montgomery-Åsberg Depression Rating Scale (MADRS) as a useful way to examine symptom-by-symptom recovery rather than relying only on overall depression scores. The purpose of these secondary analyses was to examine the trajectory of response to esketamine nasal spray in ESCAPE-TRD and to compare the time to symptom resolution between esketamine nasal spray and quetiapine extended release. The paper focuses on whether early response or remission is linked to better outcomes by Week 32, and whether continuing treatment may still be beneficial even when early improvement is only minimal or partial. It is presented as an individual-patient trajectory analysis from a Phase IIIb randomised trial.

The analyses used data from ESCAPE-TRD (NCT04338321), a randomised, open-label, active-controlled Phase IIIb study in patients with TRD. Participants received esketamine nasal spray or quetiapine extended release, each in combination with an ongoing SSRI or SNRI. The extracted text does not clearly report the full inclusion and exclusion criteria in this section, although it notes that the trial population was representative of TRD and that baseline suicidal thoughts were less common because of the study’s exclusion criteria. Depressive symptoms were assessed with the MADRS, which has 10 items and a total score ranging from 0 to 60. In these analyses, remission was defined as a total score of 10 or less. Minimal response, partial response and response were defined as less than 25%, 25% to less than 50%, and at least 50% reduction from baseline, respectively. Outcomes were treated as mutually exclusive at each visit, and patients were categorised by their highest achieved outcome while on treatment. The investigators also reported the proportion of patients who were off treatment at each visit. For the esketamine nasal spray group, the authors examined whether short-term outcomes at Week 4 or Week 8 predicted longer-term outcomes through Week 32. They assessed the proportions who achieved response or remission at any point from Week 4 to Week 32 and from Week 8 to Week 32, and they examined transitions between outcome categories over time, including stable remission. Missing on-treatment visits were handled with last observation carried forward, while patients who discontinued were classed as off treatment and were not included in short-term to long-term outcome linkage after discontinuation. To compare symptom resolution at the item level, the authors used Kaplan-Meier analyses and Cox proportional hazards models for each MADRS item. Individual item scores were dichotomised among patients who had a baseline item score of at least 2, with 0 to 1 defined as symptom resolution. Patients who stopped treatment before symptom resolution were censored. Hazard ratios and 95% confidence intervals were reported, and p values were nominal and not adjusted for multiple testing. For proportions of symptom resolution, discontinuations were imputed as negative outcomes using non-responder imputation.

A total of 676 patients were randomised, with 336 assigned to esketamine nasal spray and 340 to quetiapine extended release. Baseline characteristics were similar across groups, and most MADRS symptoms were common at study entry. Reduced appetite and suicidal thoughts were less prevalent than the other symptoms reported. The authors state that the baseline profile was broadly representative of the TRD population in the trial. Among patients treated with esketamine nasal spray, outcomes generally improved over time, although individual trajectories fluctuated. At Week 8, 27.1% of patients had achieved remission, 24.7% had response, and 24.7% had partial response. By Week 32, 49.7% had achieved remission and 16.4% had response; minimal response fell to 3.0% and partial response to 7.7%. The authors describe a continuing shift towards better outcomes over the 32 weeks. Short-term improvement was strongly associated with later benefit in the esketamine group. Among Week 4 responders, 89.6% went on to achieve remission at some point from Week 4 to Week 32. Among Week 8 responders, 78.3% later achieved remission. Among Week 4 partial responders, 66.1% later achieved remission and 88.1% later achieved response. Even some minimal responders improved over time: of the Week 4 minimal responders who stayed on treatment, 69.6% later achieved response and 49.4% later achieved remission; among Week 8 minimal responders, 51.1% later achieved response and 33.3% later achieved remission. The number of patients in stable remission increased steadily across the study period. Compared with quetiapine extended release, esketamine nasal spray showed earlier symptom resolution across most MADRS items. This was most pronounced for apparent sadness, reported sadness, lassitude and inability to feel, with hazard ratios of 1.94, 1.96, 2.06 and 1.84, respectively, all with p<0.0001. Additional benefits were reported for inner tension (HR 1.49), concentration difficulties (HR 1.64), pessimistic thoughts (HR 1.58) and suicidal thoughts (HR 1.44; p<0.05). Sleep improved at similar rates in both groups up to Week 20, and appetite resolution did not differ significantly overall (HR 1.11; p=0.3465). The authors also note that the proportional hazards assumption was violated for reduced sleep, so a hazard ratio was not estimated for that symptom. The paper states that patients receiving quetiapine extended release also improved over time, but esketamine nasal spray produced higher rates of response and remission and fewer treatment discontinuations.

The authors interpret these findings as showing that patients with TRD treated with esketamine nasal spray generally moved towards better outcomes over 32 weeks, with most transitions reflecting improvement rather than deterioration. They argue that the high symptom burden at baseline highlights the need for treatments that can address the full symptom spectrum and support sustained remission. In their view, the data suggest that early symptom change can be clinically informative when deciding whether to continue or modify treatment. They place the results in the context of the ESCAPE-TRD primary findings, which had already shown superior efficacy for esketamine nasal spray versus quetiapine extended release. The secondary analyses are presented as extending that message by showing that even patients with minimal or partial early response may still improve with continued treatment. The authors emphasise that Week 4 and Week 8 are meaningful assessment points in practice, and they explicitly link Week 4 assessment to the end of the esketamine induction phase recommended in the product information. They also argue that earlier response was associated with better long-term remission, and that small early gains may still be prognostically useful. For symptom-level analyses, the authors state that esketamine nasal spray appeared to resolve a broad range of MADRS symptoms faster than quetiapine extended release, including several core depressive symptoms such as sadness, anhedonia-related symptoms and suicidal thoughts. They describe the sleep and appetite findings as more comparable between groups, and they suggest that some apparent early sleep benefit with quetiapine may reflect sedation rather than antidepressant action. They caution, however, that these symptom-level p values were not adjusted for multiplicity, so those analyses should be considered exploratory. The main limitations they acknowledge are the lack of adjustment for potential confounders such as benzodiazepine use or time spent with healthcare professionals, and the smaller suicidal-thoughts subgroup because of trial exclusion criteria, which reduced power for that domain. They also note that item-level maintenance of symptom resolution was not directly assessed, although overall stability and stable remission were reported. The authors suggest that further research should identify predictors of long-term outcomes and examine treatment effects on suicidal ideation more robustly.

The authors conclude that most patients treated with esketamine nasal spray showed continuous improvement over 32 weeks, and that short-term response was associated with more favourable and sustained long-term outcomes. They suggest that these findings may help clinicians decide when to continue treatment rather than stopping too early.