This Phase IV single-arm long-term extension trial (n=183) found that the vast majority of patients with treatment-resistant depression who achieved remission with esketamine nasal spray (plus an antidepressant) did not relapse over 136 weeks of treatment, with side effects largely resolving the same day and no new safety concerns identified.
Papers cited by this study that are also in Blossom
Optimising patient outcomes in treatment resistant depression (TRD) requires treatments which provide sustained remission, without relapse, and tolerability in the long term. ESCAPE-LTE (NCT04829318) was a phase IV, single-arm, 2-year (104 weeks) long-term extension of ESCAPE-TRD (NCT04338321; 32 weeks), a rater-blinded, randomised, active-controlled trial, which evaluated the safety, tolerability and efficacy of esketamine nasal spray (NS), alongside an ongoing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, in patients with TRD. The primary endpoints were the proportion of patients who reported treatment-emergent adverse events (TEAEs) or suicidal ideation and behaviour (using the Columbia-Suicide Severity Rating Scale). Effectiveness was assessed using the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impression-Severity scale, Patient Health Questionnaire-9 and EuroQol 5-Dimension 5-Level questionnaire. Outcomes are reported from ESCAPE-TRD baseline to the end of ESCAPE-LTE (136 weeks of treatment, 138 weeks including safety follow-up). In patients who entered ESCAPE-LTE (N = 183), TEAEs and serious TEAEs were observed in 96.7% and 8.2%, respectively. 98.3% of TEAEs occurring on dosing days resolved same-day; few patients discontinued due to TEAEs during ESCAPE-LTE (3.3%). 151/160 (94.4%) patients who were non-suicidal at baseline remained non-suicidal to the end of ESCAPE-LTE. In the subgroup with remission in ESCAPE-TRD, 79.2% did not relapse or discontinue treatment throughout ESCAPE-LTE; the overall relapse rate for patients achieving remission across both studies was 6.9%. The vast majority of patients with TRD who achieved remission with esketamine NS did not relapse over 136 weeks of treatment; no new safety concerns were identified, and the safety profile was consistent with short-term studies.
Major depressive disorder (MDD) causes pervasive affective, cognitive and somatic symptoms and a substantial subset of patients do not respond to standard antidepressant treatments. Treatment resistant depression (TRD) is commonly defined as non-response to two or more adequate pharmacological trials and affects an estimated one-third of people with MDD. Patients with TRD have lower chances of achieving remission with successive treatment steps and face high relapse rates even after remission; consequently, durable treatments that induce remission and maintain it with acceptable tolerability are clinically important. A. and colleagues report results from ESCAPE-LTE, a 2-year, single-arm, open-label long-term extension (LTE) of the ESCAPE-TRD trial, designed to evaluate the long-term safety, tolerability and effectiveness of esketamine nasal spray (NS) administered with a concurrent SSRI or SNRI in adults with TRD. The paper presents outcomes across ESCAPE-TRD plus ESCAPE-LTE (up to 136 weeks of treatment; 138 weeks including safety follow-up), focusing on treatment-emergent adverse events (TEAEs), suicidality (Columbia‑Suicide Severity Rating Scale, C‑SSRS), and clinical effectiveness measured by scales including the Montgomery‑Åsberg Depression Rating Scale (MADRS).
ESCAPE-LTE was a Phase IV, single-arm, open-label extension conducted in 14 countries from April 2021 to July 2024 that enrolled patients who completed 32 weeks of ESCAPE-TRD (a randomised, rater‑blinded, active‑controlled Phase IIIb study comparing esketamine NS with quetiapine XR, both with an SSRI/SNRI). Entry to ESCAPE-LTE required completion of ESCAPE-TRD on esketamine NS plus an SSRI/SNRI and investigator judgement that continued treatment could be beneficial; achieving response or remission in the parent study was not required for entry. Patients were not eligible to enter the LTE if continuation was judged to have no prospect of long-term benefit, if they had clinically relevant adverse events, unstable cardiovascular risk for blood/intracranial pressure increase, or suicidal intent (C-SSRS items 4 or 5), though the extraction indicates no patients met these exclusion criteria prior to LTE entry. If commercial esketamine became available in a participant's country, those patients were discontinued from the study and offered commercial treatment. In ESCAPE-LTE patients continued esketamine NS (28, 56 or 84 mg) administered weekly or every two weeks in combination with an SSRI/SNRI; starting dose/frequency in the LTE reflected the patient’s dose at completion of ESCAPE-TRD and investigators could adjust dose and frequency within label recommendations. The SSRI/SNRI dose was maintained or optimised at investigator discretion. The planned LTE treatment duration was up to 104 weeks (maximum total treatment 136 weeks including ESCAPE-TRD). The primary objective was long-term safety and tolerability, assessed by frequency of TEAEs and suicidality (change from ESCAPE-TRD baseline to maximum recorded C-SSRS). TEAEs of special interest were predefined (sedation, dissociation, suicidality, signs suggestive of abuse potential, cystitis, hepatic impairment). Secondary objectives included long-term effectiveness, principally the proportion of patients who remained relapse-free to Week 104 of ESCAPE-LTE (i.e. through 136 weeks total). Remission was defined as MADRS ≤10. Relapse was defined as MADRS ≥22 at two consecutive assessments within 5–31 days, hospitalisation for worsening depression or suicide prevention/attempt, or other investigator-determined relapse events. Other effectiveness measures included CGI‑S, PHQ‑9 and EQ‑5D‑5L. Given the exploratory, single-arm design, no formal hypothesis testing or sample size calculation was performed. Safety and effectiveness analyses included all patients who received at least one dose of esketamine in ESCAPE-LTE. Safety was analysed pooled across ESCAPE-TRD and ESCAPE-LTE (Week 0–138 including safety follow-up) and for ESCAPE-LTE alone (Week 32–138). Any adverse event occurring after the first esketamine dose in ESCAPE-TRD through the 2‑week safety follow-up in ESCAPE-LTE was considered treatment-emergent. Efficacy outcomes were analysed across ESCAPE-TRD and ESCAPE-LTE (Week 0–136) using observed‑case analyses; no imputation was performed for missing data, and LOCF was reported only in supplementary materials for remission/response by visit. Proportions were reported with 95% Clopper‑Pearson confidence intervals where indicated.
Patient disposition and baseline characteristics: Of 336 patients randomised to esketamine in ESCAPE-TRD, 258 (76.8%) completed ESCAPE-TRD and 183 (54.5% of the original 336) entered ESCAPE-LTE. The analysis population comprised those who received at least one LTE dose (N = 183). Baseline characteristics (reported from ESCAPE-TRD baseline) were typical of TRD: 30.1% male, 31.7% had ≥3 treatment failures in the current episode, mean age 44.6 (SD 13.1) years, and mean duration of current episode 52.4 (SD 51.9) weeks. Of the 183 LTE entrants, 35 (19.1%) discontinued esketamine during ESCAPE-LTE; the most common reason was patient withdrawal (n = 19; 10.4%). If commercial esketamine became available locally, patients were discontinued; this applied to 17 (9.3%) patients during the trial. Mean exposure across both studies was 853.2 days (SD 185.1; range 269–970). Dosing: At ESCAPE-TRD baseline most patients (95.6%) started on 56 mg; at entry to ESCAPE-LTE dosing distribution was 1.1% on 28 mg, 37.2% on 56 mg and 61.7% on 84 mg. For final doses during the study 54.6% received 84 mg, 42.6% 56 mg and 2.7% 28 mg. During ESCAPE-LTE, 19 (10.4%) patients had a decrease in dose frequency and 30 (16.4%) experienced both an increase and a decrease; no patients had only an increase. Safety and tolerability: TEAEs were common but typically transient and of mild or moderate intensity. Across patients entering ESCAPE-LTE, 96.7% experienced at least one TEAE (as reported in the abstract); serious TEAEs occurred in 11 patients during ESCAPE-LTE (6.0% [95% CI 3.0, 10.5]) and 15 patients across ESCAPE-TRD plus ESCAPE-LTE (8.2% [4.7, 13.2]). Serious TEAEs occurring during ESCAPE-LTE included one report each of alcohol poisoning, multiple injuries, brain neoplasm, invasive ductal breast carcinoma, worsening depression, suicidal ideation, acute coronary syndrome, goitre, macular hole, back pain and psychomotor hyperactivity. Few patients discontinued due to TEAEs during ESCAPE-LTE (n = 6; 3.3% [1.2, 7.0]), most commonly for depressive symptoms/disorders (n = 4; 2.2%). TEAEs led to dose interruption or modification in 24 patients (13.1% [8.6, 18.9]) over the course of both studies; in ESCAPE-LTE the most common reason for dose interruption/modification was COVID-19 infection. The most common TEAEs across both studies were headache (n = 95; 51.9%), dizziness (n = 89; 48.6%) and nausea (n = 74; 40.4%). TEAEs of special interest were reported in 126 patients (68.9%), most frequently dizziness (48.6%), dissociation (23.5%) and somnolence (18.6%). Almost all TEAEs that occurred on dosing days resolved the same day (98.5% in ESCAPE-LTE alone and 98.3% across both studies), and the median number of study intervention days with a TEAE was 22.0 during ESCAPE-LTE and 54.0 across both studies. No new signals for abuse potential, renal disorders or lower urinary tract symptoms were identified with longer exposure. Suicidality and vital signs: Of 160 patients who were non‑suicidal at ESCAPE-TRD baseline per C‑SSRS, 151 (94.4%) remained non‑suicidal to study end; 8 (5.0%) reported suicidal ideation at any point and 1 (0.6%) reported suicidal behaviour. Among 23 patients with suicidal ideation at baseline, 16 (69.6%) had ideation at least once subsequently while 7 (30.4%) improved to no ideation. No patients had abnormally high systolic blood pressure compared with baseline; abnormally high diastolic pressure was observed in 10 patients (5.5%). Four patients (2.2%) had abnormally low respiratory rate without coincident respiratory‑depression TEAEs. Clinically significant weight increase occurred in 34 patients (18.6%) and a clinically significant weight decrease occurred in 26 patients (14.2%). Effectiveness: Of 149 patients who had achieved remission at any time during ESCAPE-TRD, 118 (79.2% [95% CI 71.8, 85.4]) did not relapse or discontinue treatment during ESCAPE-LTE; 9 (6.0%) relapsed and 22 (14.8%) discontinued treatment without experiencing relapse from the point of remission. Twenty-four patients (13.1%) did not remit in ESCAPE-TRD but achieved remission during ESCAPE-LTE (mean time to remission for these late remitters 60.2 weeks); of these late remitters 21 (87.5%) did not relapse and 3 (12.5%) relapsed. The overall relapse rate across both studies was 6.9%. Symptom scores: Patients showed rapid reductions in MADRS mean score from 31.5 (SE 0.4) at baseline to 14.7 (SE 0.6) at Week 8 (mean change −16.8 [SE 0.6]). The extraction contains partial data indicating continuous improvement thereafter (for example a value reported at Week 32 and a later value that is truncated), but the full series of later MADRS means and exact end‑of‑study values are not clearly reported in the extracted text. CGI‑S, PHQ‑9 and EQ‑5D‑5L measures were also reported to show maintenance or further improvement over long‑term treatment in the full text.
A. and colleagues interpret these findings as evidence that long‑term esketamine NS administered with an SSRI/SNRI is generally well tolerated and maintains clinical benefits in many patients with TRD over a prolonged treatment period (up to 136 weeks). They highlight that most TEAEs were mild or moderate, transient and occurred in the supervised post‑dosing period, with almost all dosing‑day TEAEs resolving the same day. No new long‑term safety signals were identified for concerns historically associated with ketamine (abuse potential, renal or lower urinary tract disorders), and serious TEAEs and discontinuations due to TEAEs were relatively infrequent. The authors position these long‑term results alongside prior shorter‑term trials and real‑world data, noting concordance with the SUSTAIN programme and other evidence that esketamine produces durable antidepressant effects and a stable safety profile. They emphasise the clinical importance of achieving and maintaining remission in TRD and note that a subset of patients achieved later remission during extended treatment, suggesting value in continuing treatment for patients who tolerate and may eventually respond to esketamine NS. Key limitations acknowledged by the authors include the open‑label, single‑arm design without a comparator, and potential survivor bias because only patients who completed ESCAPE‑TRD could enter the LTE, which may over‑represent patients who tolerated and benefited from initial treatment. The authors also note that patients were discontinued if commercial esketamine became available locally (n = 17) and that missing data were not imputed. They acknowledge that the mandatory concomitant SSRI/SNRI (per the European label) was not analysed as a contributor to outcomes, and that conducting the LTE only in countries where commercial esketamine was unavailable at enrolment may limit generalisability to settings where esketamine is routinely available. Despite these limitations, the authors cite the prolonged duration of follow‑up and trial population characteristics resembling clinical practice as strengths. They suggest the observed safety, tolerability and sustained effectiveness over 136 weeks support esketamine NS as a long‑term treatment option for patients with TRD and could inform shared decision‑making between clinicians and patients, including consideration of long‑term adherence and quality‑of‑life benefits.
Long‑term exposure to esketamine nasal spray in combination with an SSRI/SNRI over 136 weeks did not reveal new safety signals and showed a safety and tolerability profile consistent with prior, shorter‑term studies. Clinical and patient‑reported improvements in depressive symptoms and quality of life achieved in the parent trial were largely maintained long term, and relapse rates among those who achieved remission were low. The authors conclude these data support the long‑term safety and effectiveness of esketamine NS in the treatment of patients with TRD and may aid clinician–patient decision‑making about treatment options.
ESCAPE-TRD (NCT04338321) was a 32-week randomised, openlabel, rater-blinded, active-controlled phase IIIb study comparing the efficacy and safety of esketamine NS versus quetiapine XR, both in combination with an SSRI/SNRI, in patients with TRD.ESCAPE-LTE (NCT04829318) was a phase IV, single-arm, 2-year open-label extension study conducted in 14 countries between April 2021 and July 2024 to evaluate the long-term safety, tolerability and effectiveness of esketamine NS in combination with an SSRI/SNRI in patients who completed ESCAPE-TRD. Eligible patients were those who completed esketamine NS treatment in combination with an SSRI/SNRI through to the end of the primary study (Week 32 of ESCAPE-TRD) and who were considered to benefit from continuing treatment with esketamine NS in the opinion of the investigator, and for whom commercial esketamine NS was not accessible in their country. Fulfilling the criteria for response or remission was therefore not a precondition for transitioning from ESCAPE-TRD to ESCAPE-LTE. Patients who completed ESCAPE-TRD were not eligible to enter ESCAPE-LTE if: 1) continuation of esketamine NS would bear no benefit in the opinion of the investigator and/or patient (e.g. no prospect of a long-term response and pessimism of the patient), 2) they completed ESCAPE-TRD while presenting adverse events deemed clinically relevant by the investigator, 3) they had developed cardiovascular conditions where an increase in blood or intracranial pressure posed a serious risk, or 4) they had suicidal ideation with some intent to act (defined as an answer of "Yes" on the Columbia-Suicide Severity Rating Scale [C-SSRS] item 4 or 5). However, no such instances of patients meeting any of these four criteria prior to entry to ESCAPE-LTE occurred. If commercial esketamine NS became accessible in a given country, all patients from that country were discontinued from the study and offered commercial esketamine NS. This criterion was fulfilled for 17 (9.3%) patients during the trial. ESCAPE-TRD and ESCAPE-LTE were conducted in accordance with the Declaration of Helsinki; country-specific ethics review boards provided approval and all patients provided written informed consent.
In ESCAPE-TRD, patients were administered esketamine NS or quetiapine XR, both flexibly dosed per label. (Spravato Summary of Product Characteristics 2019; Spravato US Prescribing Information 2019) In ESCAPE-LTE, patients continued to receive esketamine NS 28, 56, or 84 mg weekly or every 2 weeks in combination with an SSRI/SNRI; the starting dose of esketamine NS was based on the patients' dose and frequency at completion of the maintenance phase of ESCAPE-TRD (Week 32; Fig.). The SSRI/SNRI dose was maintained at an optimal stable dose or optimised throughout the study (and the SSRI/SNRI switched if needed for tolerability reasons), at the investigator's discretion. Investigators changed the dose and frequency of esketamine NS within label recommendations during ESCAPE-LTE based on clinical judgment. Patients continued in the study for a maximum of 2 further years of treatment (104 weeks; 136 weeks' total treatment from baseline of ESCAPE-TRD) or when esketamine NS became accessible in the participant's local country, whichever came first.
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Reif, A., Bitter, I., Buyze, J. et al. · New England Journal of Medicine (2023)
Rhee, T. G., Shim, S. R., Forester, B. P. et al. · JAMA Psychiatry (2022)
Sanacora, G., Ahmed, M., Brown, B. et al. · American Journal of Psychiatry (2025)
Zaki, N., Chen, N. )., Lane, R. et al. · International Journal of Neuropsychopharmacology (2025)
The primary objective was to assess the long-term safety and tolerability of esketamine NS in combination with an ongoing SSRI/SNRI, through the number of patients who developed treatment-emergent adverse events (TEAEs) or suicidal ideation and behaviour, as assessed by change from baseline of ESCAPE-TRD to the maximum recorded C-SSRS score. Clinically relevant TEAEs of special interest were predefined and based on the following MedDRA-based categories: sedation, dissociation, suicidality, suggestive of abuse potential, cystitis and hepatic impairment. The secondary objectives evaluated the long-term effectiveness of esketamine NS. This was assessed by the proportion of patients who were relapse-free to Week 104 of ESCAPE-LTE (end of study; 136 weeks' total treatment). Remission was defined as a score of ≤10 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Relapse was defined as worsening of depressive symptoms, as assessed by total MADRS score of ≥22 at two consecutive assessments within 5-31 days, hospitalisation for worsening depression or suicide prevention or attempt, or any other event indicative of relapse as determined by the investigator. Effectiveness was also assessed by change from baseline of ESCAPE-TRD in the clinician-rated severity of depressive illness (using the MADRS and the Clinical Global Impression-Severity scale [CGI-S]), patient-reported depressive symptoms (using the Patient Health Questionnaire-9 [PHQ-9]) and patient-reported health-related quality of life (using the EuroQol 5-Dimension 5-Level questionnaire [EQ-5D-5L]).
Given the single-arm, exploratory nature of this study, no statistical hypothesis, nor sample size estimation were performed. The safety and effectiveness analysis sets comprised all patients who received at least one dose of esketamine NS during ESCAPE-LTE, making them a subset of patients from ESCAPE-TRD. Safety data were analysed using data pooled across both ESCA-PE-TRD and ESCAPE-LTE (Week 0-138 [including safety follow-up]), and from ESCAPE-LTE alone (Week 32-138). Any AE occurring at or after the initial administration of esketamine NS in ESCAPE-TRD through completion of the 2-week safety follow-up visit in ESCAPE-LTE was considered to be treatment emergent. Serious AEs reported within 30 days after the last dose of esketamine NS in ESCAPE-LTE were also regarded as treatment emergent. For patients with post-baseline C-SSRS assessments, change from baseline of ESCAPE-TRD to the maximum (highest) recorded C-SSRS score is reported. The proportion of patients with a TEAE was estimated with a 95% Clopper-Pearson confidence interval (CI). Efficacy data were analysed across both ESCAPE-TRD and ESCAPE-LTE (Week 0-136). Overall proportions of patients experiencing remission and relapse, as well as mean MADRS, CGI-S, PHQ-9 and EQ-5D-5L over time, are reported using observed case (OC). Data for patients who discontinued treatment during the trial were therefore included in the analysis up to their point of discontinuation only; no imputation was performed for missing data. Overall relapse assessment was conducted from the point the patient first achieved remission in ESCAPE-TRD; patients who did not achieve remission in ESCAPE-TRD, but went on to achieve remission in ESCAPE-LTE, were also analysed as observed. The overall proportion of patients without relapse or treatment discontinuation was estimated with a 95% Clopper-Pearson CI. Proportions of patients with remission and response by visit are reported using last observation carried forward (LOCF; Supplementary Material only).
Of the 336 patients randomised to esketamine NS at baseline in ESCAPE-TRD, 258 (76.8%) completed ESCAPE-TRD and 183 (54.5%) entered ESCAPE-LTE. Patient characteristics for those who received at least one dose of esketamine NS in ESCAPE-LTE are reported in Tablefrom the baseline of ESCAPE-TRD and were typical of patients with TRD (male: 30.1%; ≥3 treatment failures in current episode: 31.7%; mean [standard deviation; SD] age: 44.6 [13.1]; mean [SD] duration of current episode: 52.4 [51.9] weeks). Of all included patients, 35 (19.1%) discontinued esketamine NS treatment during ESCAPE-LTE; the most common reason for discontinuation was withdrawal by the patient (n = 19 [10.4%]; other reasons included in Supplementary Table). At baseline in ESCAPE-TRD, most patients (95.6%) received 56 mg as the starting dose of esketamine NS whilst 4.4% of patients received 28 mg. On entry to ESCAPE-LTE, two patients (1.1%) received 28 mg of esketamine NS, 37.2% received 56 mg and 61.7% received 84 mg; 100 (54.6%) patients received 84 mg of esketamine NS for their final dose, 78 (42.6%) received 56 mg and 5 (2.7%) received 28 mg (Supplementary Figure). Overall, 19 (10.4%) patients had a dose frequency decrease during ESCAPE-LTE and 30 (16.4%) patients had both a dose frequency increase and decrease during ESCAPE-LTE; no patients only had a dose frequency increase in the long term. Across both studies, the mean (SD; range) number of days patients were exposed to esketamine NS was 853.2 (185.1; 269-970). In ESCAPE-LTE alone and over the course of ESCAPE-TRD and ESCAPE-LTE, almost all TEAEs that occurred on dosing days resolved on the same day (98.5% and 98.3%, respectively). Indeed, the majority of the most common TEAEs (occurring in ≥5% of patients) typically resolved within ≤1 hour (Fig.). The median number of study intervention days with TEAEs was 22.0 during ESCAPE-LTE and 54.0 over the course of ESCAPE-TRD and ESCAPE-LTE (Table).
Low proportions of patients experienced serious TEAEs (ESCAPE-LTE: n = 11; 6.0% [3.0, 10.5]; ESCAPE-TRD and ESCAPE-LTE: n = 15; 8.2% [4.7, 13.2]; Table). Serious TEAEs reported during ESCAPE-LTE only included alcohol poisoning, multiple injuries, brain neoplasm, invasive ductal breast carcinoma, worsening of depression, suicidal ideation, acute coronary syndrome, goitre, macular hole, back pain and psychomotor hyperactivity (reported by one patient each). Few patients reported TEAEs that led to treatment discontinuation (n = 6; 3.3% [1.2, 7.0]) during ESCAPE-LTE (Table), with the most common being due to depressive symptoms/disorders (aggression, depression, depression suicidal, irritability, mood swings and suicidal ideation; n = 4 [2.2%]). TEAEs leading to esketamine NS dose interruption or modification occurred in 24 (13.1% [8.6, 18.9]) patients in) patients over the course of both ESCAPE-TRD and ESCAPE-LTE (Table). The most common TEAE that led to dose interruption or modification of esketamine NS, in ESCAPE-LTE alone (4.9% of patients) and in both studies combined (6.6% of patients), was COVID-19 infection. Over the course of both ESCAPE-TRD and ESCAPE-LTE, the most common TEAEs reported by patients included headaches (n = 95; 51.9%), dizziness (n = 89; 48.6%) and nausea (n = 74; 40.4%; Fig.). TEAEs of special interest were reported in 126 (68.9%) patients; the most common being dizziness (n = 89; 48.6%), dissociation (n = 43; 23.5%) and somnolence (n = 34; 18.6%; Fig.). Importantly, no new signals of abuse potential, renal disorders and lower urinary tract symptoms were identified with longer exposure to esketamine NS. Of the 160 patients who were non-suicidal at baseline of ESCAPE-TRD according to the C-SSRS, 151 (94.4%) remained non-suicidal to the end of ESCAPE-LTE, 8 (5.0%) presented suicidal ideation at any point during the studies and 1 (0.6%) patient presented suicidal behaviour (preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt or suicide). Of the 23 patients who presented suicidal ideation at baseline, 16 (69.6%) presented suicidal ideation at least once during the studies, whilst 7 (30.4%) showed improvement and no longer presented suicidal ideation or behaviour. Over the course of ESCAPE-TRD and ESCAPE-LTE, no patient had abnormally high systolic blood pressure compared with baseline; abnormally high diastolic blood pressure was observed in 10 (5.5%) patients. A total of 4 (2.2%) patients experienced an abnormally low respiratory rate, but no coincident TEAEs of respiratory depression were reported in these patients (reported TEAEs included throat irritation, asthma, pharyngeal hypoaesthesia and cough). Overall, 34 (18.6%) patients had a clinically significant increase in weight from baseline whilst 26 (14.2%) patients had a clinically significant decrease in weight (Supplementary
Of 149 patients who experienced remission at any timepoint during ESCAPE-TRD, 118 (79.2% [95% CI: 71.8, 85.4]) patients did not relapse or discontinue study treatment; 9 (6.0%) patients experienced relapse, and 22 (14.8%) patients did not experience relapse but discontinued treatment, from the point of remission and throughout ESCAPE-LTE (Fig.). A total of 24 (13.1%) patients did not experience remission during ESCAPE-TRD, but went on to achieve remission during ESCAPE-LTE. The mean time to remission in these late remitters was 60.2 weeks from the start of treatment. Of these, 21 (87.5%) patients did not relapse and 3 (12.5%) experienced relapse. The overall relapse rate across the course of both ESCAPE-TRD and ESCAPE-LTE was 6.9%. The proportions of patients with remission and response by visit are presented in Supplementary Figuresand. Patients showed rapid reductions in mean (standard error [SE]) MADRS score from 31.5 (0.4) at baseline to 14.7 (0.6) at Week 8 (mean change from baseline: -16.8 [0.6]; Fig.). Continuous improvements were observed over the long-term, from 9.3 (0.5) at Week 32 to 6.8 (0. remission after 2 years and improvements in depressive symptoms generally sustained during maintenance therapy, for up to 6.5 years.These studies, alongside real-world data up to 5 years,) also demonstrated the durable safety profile of esketamine NS in the long term, with most adverse events being mild or moderate, transient and resolving on the same day. The enduring safety profile and treatment response demonstrated in ESCAPE-LTE further supports the findings from the SUSTAIN trial programme and reinforces the evidence for the long-term treatment of patients with TRD with esketamine NS. In line with these studies, here, esketamine NS was well tolerated over 138 weeks. The majority of patients reported TEAEs with a maximum intensity of mild or moderate; most occurred under clinical supervision and were resolved in the immediate post-dosing period of the weekly or biweekly administration visits. This represents a beneficial change in treatment paradigm for patients with TRD relative to oral antidepressants, which are taken daily and thus may be more likely to result in continuous side effects.The demonstrated short duration and mild or moderate severity of TEAEs are most beneficial when considering patient preferences for long-term treatments that are highly tolerable.In line with previous analyses over shorter periods,although a relatively high proportion of patients reported TEAEs in this study (96.7%), they were typically mild or moderate and can largely be attributed to expected esketamine-associated transient side effects in the immediate post-administration supervision period (such as dissociation, dizziness and somnolence). Whilst the dissociative effects of ketamine are well documented, they can be well managed in informed patients.The majority of TEAEs that occurred on dosing days also resolved same-day (98.3%), leading to a low median proportion of overall study days with a TEAE (6.4%). Additionally, no sequelae, nor new safety or tolerability concerns, were identified with longer exposure to esketamine NS beyond those characterised in previous analyses over shorter time periods. This included no new trends related to suicidality, abuse potential, increased blood pressure, renal disorders or lower urinary tract symptoms. Such outcomes are recognised as longstanding concerns rooted in historical ketamine abuse data;however, evidence from the clinical use of esketamine NS demonstrates that these concerns have not materialised into clinical issues within the context of approved use.Taken together, these findings indicate that esketamine NS could improve patient acceptability and long-term adherence to treatment, by minimising the time course, burden and consequences of TEAEs on their daily lives, which is critical to maintain relapse prevention.The relatively low impact of TEAEs is also reflected in few patients discontinuing esketamine NS, or requiring dose interruptions/modifications due to TEAEs, during ESCAPE-LTE. Given the scarcity of comparable long-term studies with continued follow-up in TRD, the high retention rate observed here, with 80.3% of patients entering ESCAPE-LTE completing 136 weeks' treatment (and 9.3% discontinuing to receive commercially available esketamine NS), holds particular value for supporting esketamine NS as a long-term treatment option. (AJSelecting a treatment with high acceptability from the onset of therapeutic intervention may reduce unnecessary exposure of patients to consecutive lines of therapy, each with their own side-effect profiles. (AJSo far, other therapeutic options have not demonstrated equivalent levels of tolerability from a patient perspective. Notably, use of electroconvulsive therapy as a treatment for depression has been linked to side effects that are prolonged during the acute series, including headaches, muscle pain and amnesia, whilst quetiapine XR and other atypical antipsychotics are associated with weight gain and metabolic syndrome.) Such chronic effects were not observed with long-term esketamine NS treatment. Overall, the high retention rates reported in ESCAPE-LTE thus support esketamine NS as a first-line treatment in TRD that patients are willing to use for sufficient time periods to achieve and maintain long-term remission and avoid unnecessary exposure to ineffective or poorly tolerated treatments. Attaining remission is difficult for patients with TRD and, even once remission has been achieved, relapse rates are high in the long term. (AJThis is supported by the LQD study, comparing quetiapine XR with lithium, in which long-term remission rates at Week 52 were 11.2% with quetiapine XR and 8.6% for lithium.In the STAR-D trial, among patients who entered a 52-week follow-up period after achieving remission with citalopram over 12 weeks as a first-line treatment, 33.5% experienced relapse.Also in STAR-D, relapse rates significantly worsened with each subsequent treatment step (p < 0.0001). (AJFurther, a non-interventional European cohort study reported that 19.2% of patients with TRD achieved remission and 69.2% showed no response at Month 12 in clinical practice, while 33.3% of those in remission at Month 6 were no longer in remission, and patients remaining on treatments for substantial periods of time despite these low rates.The significance of achieving sustained remission is paramount in light of the reported severity of long-term prognosis in patients with depressive disorders.Here, over 136 weeks, patients treated with esketamine NS experienced substantial and continuous clinical improvements in measures of depressive symptoms, disease severity and health-related The uniquely long assessment period in ESCAPE-LTE as compared with the LQD or STAR-D studies also allowed additional analysis of late remission. (AJInterestingly, the proportion of patients in remission continued to increase throughout long-term treatment and 13.1% of patients (n = 24) who continued into the LTE phase achieved late remission, on average 60 weeks after treatment initiation. Variability in time to remission may be observed due to the heterogeneous population of patients with TRD, as well as the requirement to achieve a threshold to meet MADRS-defined remission in clinical trials. This finding suggests that, in patients with TRD who both tolerate and respond to treatment, sustained therapy may in time lead to remission, underscoring the potential value of continuing treatment even when full clinical benefits are not immediately observed. Overall, these observations reflect sustained long-term effectiveness regardless of when remission was achieved, which may have clinical implications of improved function and prognosis for patients. (AJThe results reported here demonstrate that multiple measures of effectiveness, both clinician-and patient-reported, attained during the ESCAPE-TRD trial, were largely maintained or improved throughout ESCAPE-LTE, further supporting the prolonged effectiveness of esketamine NS. The continued improvement in CGI-S score is particularly important from a clinical perspective, since changes in pre-defined CGI-S reflect the transition from a state of severe illness to one of normality or near-normality more intuitively than mean scores with other measures (e.g. MADRS).The high number of patients continuing treatment over the duration of the study, and the subsequent study results themselves, suggest that participants found the treatment both tolerable and effective over the long term. This is further supported by a recent report indicating that >70% of patients with TRD were satisfied or very satisfied with esketamine NS treatment.Moreover, the increased frequency and length of interaction with healthcare personnel, due to the need for healthcare professional supervision during administration of esketamine NS, may also influence patient adherence and result in maintenance of efficacy in the long term. Additionally, the alignment of clinical efficacy outcomes with improvement in health-related quality of life places esketamine NS as a desirable treatment option from the perspective of both patients and physicians, which may support shared decision-making for, and adherence to, long-term treatment plans for patients with TRD. Key strengths of this study include the prolonged duration of treatment (136 weeks' total treatment including ESCAPE-TRD) and the study design and trial population reflecting real-world clinical practice as closely as possible, within the constraints of a clinical trial.However, due to the interventional nature of the study, it may not be completely reflective of observations made in real-world treatment. In patients with TRD a high level of chronicity is observed and so the extended total duration of this study better reflects the treatment experience in clinical practice compared with other trials of a shorter duration. (AJA limitation of this long-term extension study was that the treatment was open-label and single-arm with no comparator group. The analysis also only included patients who had completed ESCAPE-TRD (a subgroup of the patients who started esketamine NS treatment at ESCAPE-TRD baseline), which may influence the interpretation of some of the results presented here due to survivor bias, since patients were more likely to continue with treatment if they experienced more favourable effectiveness and safety. However, given that ESCAPE-LTE was openlabel, this population may represent real-world patients who benefit from and tolerate esketamine NS treatment sufficiently to warrant treatment continuation. Furthermore, patients entering ESCAPE-LTE generally had similar baseline characteristics to those in the original randomised trial population, with the exception of fewer previous treatment failures and a shorter duration of current depressive episode.Patients were also discontinued if commercial esketamine NS became available in their country and missing data from these patients were not imputed, although the number of patients for which this applied was low (n = 17; 9.3%). Additionally, it was not analysed whether the concomitant SSRI/SNRI administration, which was mandatory and aligns with the requirements of the European label, (Spravato Summary of Product Characteristics 2019) contributed to esketamine NS treatment success. Finally, the ESCAPE-LTE study was only conducted in countries where esketamine NS was not yet available at the time of enrolment, which may limit the generalisability of findings to real-world clinical settings where esketamine NS treatment can currently be offered.
Long-term exposure to esketamine NS yielded no new safety signals or concerns over 136 weeks and demonstrated an overall safety and tolerability profile consistent with the existing, well-characterised safety profile of esketamine NS. Low proportions of patients experienced relapse and substantial clinical and patient-reported improvements in depressive symptoms and quality of life achieved during ESCAPE-TRD were maintained long-term. These data provide evidence to support the safety and effectiveness of esketamine NS in the long term for the treatment of patients with TRD, which may aid in shared decisionmaking between clinicians and patients regarding treatment options in TRD.
ESCAPE-TRD and ESCAPE-LTE were conducted in accordance with the Declaration of Helsinki; country-specific ethics review boards provided approval. All patients provided written informed consent and the studies were registered at ClinicalTrials.gov.