Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression

with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esket-amine NS versus quetiapine XR further supports its use for TRD.


Introduction
Treatment resistant depression (TRD) is commonly defined as non-response to two or more pharmacological treatments of adequate duration and dose during the current major depressive episode (MDE) (European Medicines Agency, 2013), and affects approximately 30 % of patients with major depressive disorder (MDD) (McIntyre et al., 2023).While numerous therapeutic options are available to patients with MDD, few have good evidence or are approved specifically for the treatment of adults with TRD (McIntyre et al., 2023;Voineskos et al., 2020).The paucity of TRD-specific therapeutic options, alongside the high burden of illness in the TRD population, underscores the unmet clinical need of objective response for these patients (Heerlein et al., 2021).The likelihood of a patient continuing treatment is closely linked with the efficacy and safety profile of that treatment (Rosenblat et al., 2018(Rosenblat et al., , 2019)).Notably, the most common reason for changing treatment in patients with MDD is ineffectiveness, while both side effects and ineffectiveness are the most common reasons for discontinuing a medication (Rosenblat et al., 2018).Weight gain is the adverse event most commonly reported to lead to discontinuation (McIntyre et al., 2024).Thus, safe and effective TRD-specific therapeutic options that are well tolerated and acceptable to patients are needed (Rosenblat et al., 2018;Voineskos et al., 2020).
In clinical practice, pharmacologic treatments approved for major depressive disorder, including oral antidepressants and augmentation medications, are used in various treatment strategies (European Medicines Agency, 2013;Heerlein et al., 2021).Amongst these pharmacological options are augmentation with second-generation antipsychotics including aripiprazole, brexpiprazole, cariprazine and quetiapine extended release (XR), which have demonstrable efficacy when administered in conjunction with antidepressant treatments in partial responders (McIntyre et al., 2023).Quetiapine XR, an antipsychotic augmentation agent, is variously indicated for, and supported by guidelines for use in, the treatment of patients with TRD, being one of the most commonly utilised treatments in real-world practice (European Medicines Agency, 2014, 2019a;Heerlein et al., 2022; National Institute for Health and Care Excellence, 2022; Nationale Versorgungs Leitlinien, 2022; U.S. Food and Drug Administration, 2020).Commonly reported treatment-emergent adverse events (TEAEs) in patients receiving quetiapine XR include sedation, dizziness, hypotension and weight gain (European Medicines Agency, 2019a; Osborne et al., 2020;U.S. Food and Drug Administration, 2020).Esketamine nasal spray (NS) is approved specifically for TRD when given in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) (European Medicines Agency, 2019b; U.S. Food and Drug Administration, 2023).Common TEAEs include headache, dizziness, nausea, dissociation, somnolence and nasopharyngitis (Zaki et al., 2023).
ESCAPE-TRD was an open-label, 32-week, rater-blinded, randomised controlled trial that compared the efficacy and safety of flexibly-dosed esketamine NS with quetiapine XR, both in combination with an ongoing SSRI/SNRI, in patients with TRD (Reif et al., 2023).Of the few existing head-to-head studies in TRD, ESCAPE-TRD was the first comparison of esketamine NS with an augmentation strategy.ESCA-PE-TRD demonstrated the superiority of esketamine NS over quetiapine XR for treatment efficacy in both the short and long term (Reif et al., 2023).Specifically, esketamine NS significantly increased the odds of achieving remission at Week 8 (primary endpoint), and of being relapse-free through Week 32 after achieving remission at Week 8 (key secondary endpoint), versus quetiapine XR (Reif et al., 2023).Although the total number of TEAEs was higher in the esketamine NS arm, fewer patients reported TEAEs leading to treatment discontinuation with esketamine NS versus quetiapine XR (Reif et al., 2023).
Since TRD is associated with high rates of non-recovery, chronicity and recurrence, prolonged treatment is often considered beyond acute resolution of symptoms (Hirschfeld, 2001;McIntyre et al., 2014;Rush et al., 2006;Voineskos et al., 2020).The need for a longer-term treatment paradigm in patients with TRD thus invites the need to characterise not only the rate of reported TEAEs, but also the subjective experience and tolerability of a prescribed agent.Nevertheless, few studies have explored the long-term safety profile of antidepressant therapies in depth (Lunghi et al., 2020).Results from long-term studies have repeatedly documented the favourable long-term safety profile of esketamine NS, reporting that treatment-emergent dissociative symptoms were generally transient, with no reported events suggestive of abuse (Wajs et al., 2020;Young et al., 2023;Zaki et al., 2023).The present 32-week study, comparing esketamine NS to quetiapine XR in combination with conventional antidepressants, is to our awareness the longest comparative trial of its kind.This head-to-head design therefore provides a unique opportunity to characterise the long-term comparative effectiveness of esketamine NS versus quetiapine XR, which will be crucial in providing comprehensive information to both patients and clinicians in the context of shared decision-making processes.
To further extend our knowledge from what has been previously documented in the ESCAPE-TRD trial (Reif et al., 2023), in this secondary publication, we report key safety and tolerability findings, exploring the time course, burden and consequences of esketamine NS versus quetiapine XR treatment in patients with TRD.
ESCAPE-TRD was conducted in accordance with the Declaration of Helsinki (World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects, 2013), and approved by country-specific ethics review boards.All patients provided written informed consent and the study was registered at ClinicalTrials.gov.

Safety analysis
Safety analyses included patients who received ≥1 dose of study treatment.TEAEs were determined per investigators' clinical judgment and defined as events occurring or worsening at or after the first dose, and within 14 days (non-serious) or 30 days (serious) of the last dose of study treatment.Evaluation of TEAEs, clinical laboratory tests, pregnancy tests, vital signs (including blood pressure [BP] measurements), 12-lead electrocardiograms (ECGs), nasal examinations and body weight were performed throughout the study to monitor participant safety, as recorded by the treating physician.TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) versions 23-25 (MedDRA, 2024).In the esketamine NS arm, vital sign measurements (supine BP, pulse and respiratory rate) were recorded before and after each dose of study treatment; in the quetiapine XR arm they were recorded weekly (Weeks 1-4), every two weeks (Weeks 4-8), or every four weeks (Weeks 8-32).

Common TEAEs and TEAEs of special interest
Incidence of the most common TEAEs, defined as those occurring in ≥5 % of patients in either treatment arm, are reported.In a post-hoc analysis, odds ratios (with 95 % confidence intervals) of TEAE incidence summary data were calculated, and incidence rates were compared between treatment arms using chi-squared tests.In addition, pre-specified TEAEs of special interest (preferred terms) were grouped by the following MedDRA-based categories: sedation, dissociation, suicidality, suggestive of abuse potential, cystitis and hepatic impairment (see Supplementary Material S2 for a full list of TEAEs in each special interest category) and are reported by system organ class and preferred term.

Time course of TEAEs
In a post-hoc analysis, the median (95 % confidence interval [CI]) duration of each of the most common TEAEs (those occurring in ≥5 % of patients in either treatment arm) was calculated using the Kaplan-Meier method; missing or incomplete TEAE start/end dates were imputed (Supplementary Material S3).Proportions of TEAEs that resolved within the following windows of time are reported by treatment arm: ≤1 hour (h); >1 h to ≤2 h; >2 h to ≤3 h; >3 h to ≤8 h; >8 h but same day; unknown but same day; 2 days to ≤7 days; 8 days to ≤28 days; >28 days or AE ongoing.

Burden of TEAEs
In a post-hoc analysis, summary statistics were calculated for the number and proportion of days during study intervention on which a patient had any TEAE, where patients without a TEAE are counted with a duration of zero days.In a post-hoc analysis, a linear regression model with treatment arm as an independent variable was fitted to calculate the estimated mean difference between study arms in the proportion of days during study intervention on which a patient had any TEAE; 95 % CI and p value are reported.Frequencies of each event are reported by maximum severity (mild, moderate, or severe).The proportion of patients in each arm with a TEAE of weight change (increase or decrease), as considered clinically relevant and reportable by the attending physician, is reported.A post-hoc analysis of the proportion of patients with weight change of at least 7 % (increase or decrease) was also reported (described in Supplementary Material S4).Treatmentemergent abnormalities in vital sign measurements compared to baseline were calculated and their incidences are reported.Available data were used without imputation of missing values.

Consequences of TEAEs
Concomitant therapies were recorded and coded using the World Health Organization Drug Dictionary (WHO Collaborating Centre for International Drug Monitoring, 1992).The proportion of patients with at least one TEAE who received any concomitant medication as a result of a TEAE (post-hoc analysis) are reported by treatment arm.The proportion of TEAEs that led to dose reduction or interruption (post-hoc analysis), as well as the proportion of patients with a TEAE that led to treatment discontinuation, are also reported by treatment arm.

Statistical analysis
Odds ratios (ORs) and 95 % confidence intervals (CIs) between treatment arms are reported for the following TEAE summaries: incidence of TEAEs, TEAEs possibly related to treatment, TEAEs leading to death, incidence of ≥1 serious TEAE, TEAEs leading to treatment discontinuation, TEAEs leading to dose interruption or reduction and proportion of study intervention days with TEAEs.All p values reported were not adjusted for multiple testing.

Patient disposition and common TEAEs
Overall, 336 patients were randomised to esketamine NS and 340 patients to quetiapine XR; 334 and 336 patients, respectively, received ≥1 dose of study treatment.Baseline characteristics were comparable between arms, as reported previously (Reif et al., 2023).
TEAEs were reported in 307 (91.9 %) patients treated with esketamine NS and 262 (78.0 %) with quetiapine XR (OR: 3.211; 95 % CI: 2.006, 5.141; p < 0.001; Table 1).Serious TEAEs occurred in 19 (5.7 %) patients treated with esketamine NS, and 17 (5.1 %) of those treated with quetiapine XR (OR: 1.132; 95 % CI: 0.578, 2.218; p = 0.718; Table 1, Supplementary Table 1).The most common TEAE with esketamine NS was dizziness, occurring in 156 (46.7 %) esketamine NS-treated and 28 (8.3 %) quetiapine XR-treated patients (Table 2).The most common TEAE with quetiapine XR was somnolence, occurring in 78 (23.2 %) quetiapine XR-treated and 50 (15.0%) esketamine NStreated patients; other common TEAEs (occurring in ≥5 % of patients in either treatment arm) are reported in Table 2.No clinically relevant hepatic, renal, cardiac, or metabolic signals were identified from laboratory results or electrocardiograms in either arm.Treatment-emergent suicidal ideation was reported in 5 (1.5 %) and 7 (2.1 %) of patients treated with esketamine NS and quetiapine XR, respectively; treatmentemergent suicide attempts were reported in 2 (0.6 %) patients and 1 (0.3 %) patient, respectively.Safety analysis set (patients received ≥1 dose of study treatment).Adverse events were coded using MedDRA preferred terms.An adverse event was counted as treatment emergent if it started after taking first dose and on or before 14 days after last dose of study medication.A serious adverse event was also counted as TEAE if it started within 30 days of last dose.Esketamine NS and quetiapine XR were both dosed per label and taken in addition to an ongoing SSRI/SNRI (European Medicines Agency, 2019b, 2019a).P values are for row mean differences.a Mean difference between study arms in the proportion of days during study intervention on which a patient had any TEAE.CI: confidence interval; MedDRA: Medical Dictionary for Regulatory Activities; NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TEAE: treatment emergent adverse event; XR: extended release.

Time course of TEAEs
Although TEAEs were more common with esketamine NS than quetiapine XR, they were typically transient in nature: 92.0 % of all TEAEs resolved on the same day with esketamine NS, versus 12.1 % with quetiapine XR (Fig. 1).The duration of common TEAEs was generally shorter with esketamine NS versus quetiapine XR, with TEAEs experienced by esketamine NS-treated patients typically resolving within hours or 1 day (Fig. 1).Indeed, the majority of the most common TEAEs (occurring in ≥5 % of patients in either arm) most frequently resolved within ≤1 hour.For example, for dizziness, the most frequent TEAE reported with esketamine NS, 47.0 % of events resolved within 1 hour with esketamine NS versus 0.0 % of events with quetiapine XR, while 1.1 % and 93.1 %, respectively, lasted 2 days or more.Similarly for somnolence, the most frequent TEAE reported with quetiapine XR, 84.0 % of events resolved within 1 hour with esketamine NS, versus just 3.6 % of events with quetiapine XR.

Burden of TEAEs
TEAEs of special interest that occurred with both esketamine NS and quetiapine XR were typically mild or moderate in severity (Supplementary Table 2).The median number of study intervention days with TEAEs was lower with esketamine NS versus quetiapine XR: 16.0 versus 18.0 days, respectively (Table 3), culminating in a significantly lower overall proportion of study intervention days with TEAEs with esketamine NS versus quetiapine XR (median: 11.9 % versus 21.3 % of days, respectively; mean difference [95 % CI]: -13.9 [-19.2, -8.7]; p < 0.001).
Baseline weight and body mass index (BMI) were comparable between treatment arms (Table 3).Relative to patients who received esketamine NS, who generally maintained a stable weight and BMI over 32 weeks of treatment, patients treated with quetiapine XR more commonly experienced a TEAE of weight increased: 42 (12.5 %) versus 9 (2.7 %) patients, respectively (Table 3).Incidences of weight increase TEAEs were balanced across patients categorised as normal, overweight or obese by baseline BMI (Supplementary Figure 1).Weight gain led to treatment discontinuation in 6 (1.8 %) patients treated with quetiapine XR, versus 0 (0.0 %) patients treated with esketamine NS.The proportion of patients with weight change of at least 7 % (increase or decrease) is also reported in Supplementary Table 3.
With regards to abnormal vital sign measurements (Table 4), abnormally high systolic blood pressure relative to baseline was observed in 2 (0.6 %) patients treated with esketamine NS versus 0 (0.0 %) with quetiapine XR.Abnormally high diastolic blood pressure was observed in 15 (4.5 %) and 1 (0.3 %) patient, respectively; hypertension did not lead to discontinuation in either treatment arm.10 (3.0 %) patients in the esketamine NS arm versus 1 (0.3 %) patient in the quetiapine XR arm experienced an abnormally low respiratory rate; however no clinically significant decreases in respiratory rate were reported as TEAEs.6 (1.8 %) and 1 (0.3 %) patient in each arm, respectively, experienced an abnormal high respiratory rate.Safety analysis set (patients received ≥1 dose of study treatment).Adverse events were coded using MedDRA preferred terms.An adverse event was counted as treatment emergent if it started after taking first dose and on or before 14 days after last dose of study medication.A serious adverse event was also counted as TEAE if is started within 30 days of last dose.Median durations were not estimable when there were only two incidences of TEAEs and the TEAE with the longest duration was ongoing.CI limits were not estimable either due to a small sample size or because the majority of TEAEs had a duration of one day.Esketamine NS and quetiapine XR were both dosed per label and taken in addition to an ongoing SSRI/SNRI (European Medicines Agency, 2019a, 2019b).CI: confidence interval; COVID-19: coronavirus disease 2019; MedDRA: Medical Dictionary for Regulatory Activities; NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TEAE: treatment emergent adverse event; XR: extended release.

Consequences of TEAEs
Of patients who experienced at least one TEAE, a similar proportion of patients in each arm received medication for a TEAE: 127 (41.1 %) Data are reported as the proportions of most common TEAEs (occurring in ≥5 % of patients in either treatment arm) resolving over time, by duration of time to resolution.Adverse events were coded using MedDRA preferred terms.An adverse event was counted as treatment emergent if it started after taking the first dose and on or before 14 days after taking the last dose of study medication.A serious adverse event was also counted as a TEAE if it started within 30 days of taking the last dose.Esketamine NS and quetiapine XR were both dosed per label and taken in addition to an ongoing SSRI/SNRI (European Medicines Agency, 2019b, 2019a).COVID-19: coronavirus disease 2019; MedDRA: Medical Dictionary for Regulatory Activities; NS: nasal spray; TEAE: treatment emergent adverse event; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.ment).Patients without TEAE would be counted with duration=0.Adverse events were coded using MedDRA preferred terms.An adverse event was counted as treatment emergent if it started after taking first dose and on or before 14 days after last dose of study medication.A serious adverse event was also counted as a TEAE if it started within 30 days of taking the last dose.Esketamine NS and quetiapine XR were both dosed per label and taken in addition to an ongoing SSRI/SNRI (European Medicines Agency, 2019bAgency, , 2019a)).AE: adverse event; MedDRA: Medical Dictionary for Regulatory Activities; NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TEAE: treatment emergent adverse event; XR: extended release.Safety analysis set (patients received ≥1 dose of study treatment).Post-baseline vital sign values were considered treatment emergent if they met both the relevant value and change criteria reported in the table; for vital signs that did not include change from baseline criteria, treatment emergence was concluded if the post-baseline value was above the upper limit and the baseline value was below the upper limit (e.g. the value was normal or low) or if the post-baseline value was below the lower limit with the baseline value being above the lower limit (e.g. the value was normal or high); if the baseline value was missing, a post-baseline abnormality was always considered as treatment emergent.

Discussion
The long-term safety and tolerability profile of esketamine NS was investigated previously in the SUSTAIN-2 and SUSTAIN-3 studies (Wajs et al., 2020;Zaki et al., 2023).However, ESCAPE-TRD is, to our knowledge, the first randomised comparative study reporting the long-term safety and tolerability of esketamine NS versus quetiapine XR, in combination with an ongoing SSRI/SNRI, in patients with TRD.The safety and tolerability of esketamine NS and quetiapine XR were consistent with their established safety profiles, with no new safety signals identified (Reif et al., 2023;Zaki et al., 2023).Importantly, however, when considering the time course, burden and consequences of TEAEs with each treatment over the 32-week treatment phase, esketamine NS exhibited a generally more favourable safety profile versus quetiapine XR, with patient dispositional changes demonstrating greater tolerability of adverse events with esketamine NS.Indeed, although the odds of a patient experiencing a TEAE was significantly (three times) higher with esketamine NS versus quetiapine XR, the odds of a patient discontinuing treatment due to TEAEs was significantly (three times) lower with esketamine NS versus quetiapine XR.
Although TEAEs occurred significantly more frequently in patients treated with esketamine NS, they were typically of shorter duration than those in patients treated with quetiapine XR, which may be related to differences in the pharmacokinetic profiles of the two drugs and to the fact that esketamine does not require daily administration.Most TEAEs in esketamine NS-treated patients occurred under clinical supervision in the immediate post-dosing period, commonly resolving within a few hours, and almost always on the same day that they occurred.These rapidly resolving TEAEs commonly included dizziness, nausea, dissociation and vertigo.In contrast, sedation, occurring with similar frequency in each arm, typically persisted substantially longer with quetiapine XR than esketamine NS, and led to treatment discontinuation in seven patients treated with quetiapine XR versus none receiving esketamine NS; a full listing of the incidence of individual TEAEs that lead to treatment discontinuation in the ESCAPE-TRD trial has been previously reported (Reif et al., 2023).Other common TEAEs with quetiapine XR also tended to be chronic and more frequently led to treatment discontinuation than those occurring with esketamine NS, including fatigue and increase in weight.Overall, therefore, reflective of the disparate time courses of common TEAEs between arms, the proportion of days spent with TEAEs was substantially and significantly lower with esketamine NS than quetiapine XR.
Importantly, TEAEs of special interest, spanning categories of sedation, dissociation, suicidality, suggestive of abuse potential and cystitis were seldom severe in either arm, with no incidences of pre-specified TEAEs of special interest related to hepatic impairment reported.Consistent with previous studies, events indicative of abuse potential, cystitis and suicidality were comparably infrequent in both the esketamine NS and quetiapine XR arms (Reif et al., 2023;Zaki et al., 2023).Furthermore, abnormalities in vital sign measurements were infrequent and generally comparable between arms.As described in the primary publication (Reif et al., 2023), two deaths were reported during the trial: one occurred during Week 9 in an esketamine NS-treated patient (undetermined cause), and one occurred during Week 17 in a quetiapine XR-treated patient (cerebrovascular accident); neither was considered by the investigator to be related to the trial treatment.
Consistent with the time course of common TEAEs in each arm, the burdensome nature of TEAEs most often experienced with quetiapine XR may have more negatively impacted patients' quality of life and perception of treatment tolerability than those common to esketamine NS.Indeed, TEAEs reported with quetiapine XR resulted in dose reduction and/or subsequent treatment discontinuation significantly more often than those with esketamine NS.For instance, weight gain, being the adverse event that most commonly leads patients with MDD to discontinue a medication (Rosenblat et al., 2019), was relatively common with quetiapine XR and led to treatment discontinuation in 6 (1.8 %) patients.In contrast, fewer patients treated with esketamine NS experienced TEAEs of weight gain and no patients discontinued treatment due to TEAEs of weight gain.Sedation similarly occurred in a greater proportion of patients treated with quetiapine XR than esketamine NS.Given the potential for persistent sedation to substantially impact quality of life and productivity, its frequent occurrence in patients treated with quetiapine XR may have driven a ceiling effect of treatment effectiveness, since adequate doses may have been less tolerable to the patient than esketamine NS.Collectively, the temporal profile and nature of common TEAEs with esketamine NS are suggestive of greater tolerability and thus a reduced overall patient burden versus those experienced with quetiapine XR; this may have improved patients' perceptions of treatment favourability and their willingness to continue treatment (McIntyre et al., 2024;Reif et al., 2023).Since a recent consensus study reported that long-term maintenance of therapy is essential in patients with TRD, the apparent reduction in burden of continued esketamine NS versus quetiapine XR treatment over 32 weeks, as demonstrated here, further emphasises the preferentiality of esketamine NS as a therapeutic option in TRD (Maina et al., 2023).While approximately half of patients with depression report treatment side effects as one of the main reasons for changing an antidepressant therapy, almost two thirds cite a lack of perceived therapeutic efficacy (Rosenblat et al., 2018).Treatment acceptability, as evidenced by the patient's choice to continue treatment, is influenced by multiple factors, none of which singularly or comprehensively explain acceptability (Rosenblat et al., 2019).For example, treatments that are considered by patients as providing a significant and meaningful improvement in target psychopathology are often adhered to at a higher rate despite the presence of adverse events that for other treatments may prevent acceptability (Rosenblat et al., 2019).Therefore, the significantly lower rate of treatment discontinuation due to TEAEs experienced with esketamine NS relative to those experienced with quetiapine XR may also have been influenced by a more positive patient perception of treatment efficacy with esketamine NS, since patients were more likely to achieve remission and response with esketamine NS than quetiapine XR (Reif et al., 2023;Rosenblat et al., 2018).Together, these data are suggestive of both more favourable TEAE tolerability and benefit:risk profiles for esketamine NS than quetiapine XR, which may be indicative of a greater overall treatment acceptability and effectiveness.Thus, given the chronic and resistant nature of TRD, the long-term acceptability of esketamine NS further facilitates its use as an effective antidepressant therapy and addresses the need for a long-term treatment in this population (Heerlein et al., 2021).
Key strengths of ESCAPE-TRD were its large sample size, long (32week) duration and well-controlled head-to-head design, which facilitated direct comparison of the active compounds and provided improved generalisability and real-world relevance over a placebocontrolled study, which will be important for guiding future treatment recommendations (Vieta and Cruz, 2012).The visit schedule differed between patients receiving esketamine NS and quetiapine XR; since visits were conducted twice weekly in the esketamine NS arm and weekly in the quetiapine XR arm to Week 8, this increased frequency may have affected safety reporting.This difference, however, further supports the evidence of greater tolerability with esketamine NS, since increased visit frequency would likely increase sensitivity to detect TEAEs.Limitations include the open-label design, owing to the differing routes of administration between the two treatment arms, which was selected to eliminate the need for placebo in the trial and reduce visit frequency (Reif et al., 2023).In addition, since both esketamine NS and quetiapine XR were administered in addition to an oral SSRI/SNRI, the treatment combination may have affected the overall safety profile reported for each arm and added a layer of complexity to the comparisons drawn (Ilzarbe and Vieta, 2023).
In ESCAPE-TRD, although TEAEs were more frequent with esketamine NS, they were typically short-lived, mild in nature and significantly less likely to result in treatment discontinuation versus quetiapine XR, suggesting they may have been less burdensome.Building upon the rapid onset and superior efficacy of esketamine NS versus quetiapine XR demonstrated in ESCAPE-TRD (Reif et al., 2023), and in conjunction with its favourable acute and long-term safety profile, these data reinforce the superiority of esketamine NS over quetiapine XR.Indeed, esketamine NS presents a valuable and well-tolerated treatment option with a highly positive benefit-risk profile for many patients with TRD, for whom treatment outcomes are notoriously poor and positive changes are hard to achieve.These findings will support physicians in their undertaking of risk-benefit assessments when making treatment recommendations to their patients.

Fig. 1 .
Fig. 1.Time course profiles of the most common TEAEs with esketamine NS and quetiapine XR.Safety analysis set (patients received ≥1 dose of study treatment).Data are reported as the proportions of most common TEAEs (occurring in ≥5 % of patients in either treatment arm) resolving over time, by duration of time to resolution.Adverse events were coded using MedDRA preferred terms.An adverse event was counted as treatment emergent if it started after taking the first dose and on or before 14 days after taking the last dose of study medication.A serious adverse event was also counted as a TEAE if it started within 30 days of taking the last dose.Esketamine NS and quetiapine XR were both dosed per label and taken in addition to an ongoing SSRI/SNRI (European Medicines Agency, 2019b, 2019a).COVID-19: coronavirus disease 2019; MedDRA: Medical Dictionary for Regulatory Activities; NS: nasal spray; TEAE: treatment emergent adverse event; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

Table 1
Summary and consequences of TEAEs.

Table 2
Common TEAEs with esketamine NS and quetiapine XR (occurring in ≥5 % of patients in either treatment arm).

Table . 3
Burden of TEAEs with esketamine NS and quetiapine XR.

Table . 4
Patients who experienced treatment emergent abnormally low/high vital sign measurements.