Long-term treatment with esketamine nasal spray in patients with treatment resistant depression: Results from the ESCAPE-LTE study

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.