Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression: A Randomized, Double-Blind, Multicenter, Active-Controlled Study Conducted in China and USA

Major depressive disorder (MDD) is a leading contributor to global disease burden and in China affects an estimated 12-month prevalence of 2.1% and a lifetime prevalence of 3.4%. A substantial minority of patients—commonly described as treatment-resistant depression (TRD)—fail to achieve clinically meaningful benefit after at least two antidepressant trials in the current episode; this group represents an important unmet need because standard oral antidepressants typically take 4–7 weeks to achieve full effect and patients remain at risk during that period. Esketamine nasal spray, the S‑enantiomer of ketamine, is approved in combination with an oral antidepressant for TRD in several regions and has shown rapid onset of antidepressant effect in prior global Phase III studies, including TRANSFORM‑2, which demonstrated statistically significant improvement versus oral antidepressant plus placebo at Day 28 and clinically meaningful benefit at 24 hours. Chen and colleagues therefore conducted a Phase III, randomised, double‑blind, active‑controlled study (NCT03434041) with a design largely mirroring TRANSFORM‑2 to evaluate the efficacy and safety of flexibly dosed intranasal esketamine (56 or 84 mg) plus a newly initiated oral antidepressant over a 4‑week double‑blind period in predominantly Chinese adults with TRD. The trial aimed to support registration of esketamine in China and to characterise both short‑term efficacy (primary endpoint: change in MADRS at Day 28) and rapid onset effects (key secondary: change in MADRS at 24 hours), together with safety and pharmacokinetic data in the China population.

This Phase III, multicentre, randomised, double‑blind, active‑controlled study was carried out from June 2018 to April 2021 at 22 sites in China and 5 in the United States. The protocol comprised a prospective 4‑week screening/observation phase (with an optional up to 3‑week taper of existing antidepressants), a 4‑week double‑blind treatment phase with intranasal study drug administered twice weekly (Days 1, 4, 8, 11, 15, 18, 22, 25) plus a newly initiated oral antidepressant, and an 8‑week post‑treatment follow‑up phase. US participants could enter an open‑label long‑term extension after the double‑blind phase. Eligible adults were 18–64 years old with DSM‑5 MDD (single or recurrent episode) without psychotic features and met TRD criteria of nonresponse to at least two antidepressants at adequate dose and duration in the current episode. Nonresponse during the screening period was defined as ≤25% MADRS improvement and MADRS ≥28 at Weeks 2 and 4. Key exclusions included prior nonresponse to esketamine/ketamine, recent electroconvulsive therapy nonresponse, psychotic or bipolar disorders, recent suicidal intent/behaviour, and recent substance use disorders. All participants provided written informed consent and the study was approved by relevant ethics committees and institutional review boards. Randomisation was central and stratified by country (China or US), oral antidepressant class (SNRI or SSRI), and consent to biomarker evaluation, with 1:1 allocation to intranasal esketamine or matching placebo, each combined with a newly initiated open‑label oral antidepressant chosen from duloxetine, escitalopram, sertraline, or venlafaxine XR. Blinding was maintained for investigators, patients, raters and analytic teams. Intranasal devices delivered 28 mg per two sprays; initial esketamine dosing was 56 mg on Day 1 with investigator‑guided optional escalation to 84 mg on subsequent dosing days based on tolerability and efficacy. Oral antidepressant dosing began Day 1 following a protocol titration schedule. Efficacy assessments were centred on the clinician‑rated Montgomery‑Åsberg Depression Rating Scale (MADRS; primary endpoint: change from baseline to Day 28), with independent, remote, blinded MADRS raters conducting telephone assessments. Key secondary endpoints were MADRS change at 24 hours post first dose and change in Sheehan Disability Scale (SDS) at Day 28. Additional measures included CGI‑S, GAD‑7, and EQ‑5D‑5L. Pharmacokinetic sampling was performed in the China population at predose, 40 minutes, 2 hours and 6 hours postdose on Day 25. Safety evaluations included adverse event reporting, vital signs, laboratory tests, ECGs, C‑SSRS for suicidality, CADSS for dissociation, and PWC‑20 for withdrawal. The planned sample size assumed a 6.5‑point MADRS difference with SD 12, yielding approximately 117 patients per arm to achieve >90% power; the final plan targeted ~210 Chinese and ~24 non‑Chinese patients. The primary efficacy analysis used a mixed‑effects model for repeated measures (MMRM) on observed cases with baseline MADRS as covariate and fixed effects for treatment, country, AD class, day, and day-by-treatment interaction. A serial gatekeeping hierarchy controlled multiplicity between the primary and two key secondary endpoints. Safety and PK analyses were descriptive.

A total of 252 patients were randomised (224 China; 28 US)—126 to esketamine plus oral antidepressant and 126 to oral antidepressant plus placebo—and 214 (84.9%) completed the double‑blind phase. Most patients received intranasal medication on all eight dosing days and ≥85% were exposed to study drug for at least 22 days. Dose escalation occurred in 40.2% of esketamine patients by Day 4 and by Day 25, 85.2% of esketamine patients were on 84 mg. Baseline MADRS means were 36.5 (SD 5.21) in the esketamine group and 35.9 (SD 4.50) in the placebo group. At Day 28 mean MADRS scores were 26.5 (SD 10.33) and 27.9 (SD 10.04), respectively. Mean change from baseline at Day 28 was −10.1 (SD 10.80) for esketamine plus AD and −8.1 (SD 10.26) for AD plus placebo. The MMRM least‑squares mean difference at Day 28 was −2.0 (95% CI −4.64, 0.55), which did not reach statistical significance (two‑sided p = 0.123). In the China subgroup (n = 222) the LS mean difference was −0.7 (95% CI −3.35, 1.94). Although the primary endpoint was not significant, the prespecified rapid‑onset secondary endpoint (MADRS change at 24 hours) numerically favoured esketamine: LS mean difference −3.3 (95% CI −5.33, −1.33) in the overall population and −2.6 (95% CI −4.64, −0.60) in the China subgroup. Because the primary endpoint was not met, the key secondary endpoints were not formally tested per the hierarchical procedure. SDS change at Day 28 showed an LS mean difference of −1.0 (95% CI −2.96, 0.97) overall and −0.1 (95% CI −2.09, 1.93) in China. Other secondary measures showed modest differences: CGI‑S LS mean difference at Day 28 was −0.2 (95% CI −0.46, 0.10), and GAD‑7 change favoured esketamine with an ANCOVA LS mean difference −1.6 (95% CI −2.78, −0.36). EQ‑5D‑5L dimensions improved in both groups. Pharmacokinetic sampling in Chinese patients showed peak mean esketamine concentrations at 40 minutes postdose, with mean values of approximately 101 ng/mL for the 56 mg group (n = 13) and 108 ng/mL for the 84 mg group (n = 75); concentrations declined at later timepoints and dose‑related differences were more apparent at 2 and 6 hours. Regarding safety, 95.2% (n = 120) of esketamine‑treated patients experienced one or more treatment‑emergent adverse events (TEAEs) versus 70.6% (n = 89) in the placebo group. Events judged at least possibly related to intranasal drug occurred in 92.9% of esketamine patients and 43.7% of placebo patients. The most common TEAEs (≥10% in esketamine group) were dizziness (77.0%), dissociation (59.5%), nausea (42.1%), increased blood pressure (30.2%), hypoesthesia (19.8%), vomiting (18.3%), blurred vision (18.3%), somnolence (15.9%), headache (12.7%), and dysgeusia (11.1%); corresponding common TEAEs in the placebo group included dizziness (19.8%), nausea (13.5%), headache (11.1%) and increased blood pressure (10.3%). Most TEAEs were mild or moderate and generally occurred on dosing days with resolution the same day. There was one death in the esketamine arm: a patient completed suicide on Day 4 after the first dose. The investigator considered the event possibly related to esketamine, whereas the sponsor assessed it as not related citing multiple contributing factors including prior high suicidal risk. One additional oesketamine‑arm patient had an aborted suicide attempt deemed doubtfully related to treatment. During the double‑blind phase, four patients (1 in the esketamine group, 3 in placebo) experienced serious adverse events related to underlying depression. TEAEs leading to discontinuation occurred in 7 (5.6%) esketamine patients and 2 (1.6%) placebo patients; nausea, vomiting, dissociation and dizziness were among the most frequent causes. Physiological effects included transient blood pressure increases peaking at 40 minutes postdose and returning near baseline by 1.5 hours; mean maximal systolic increase was 13.2 (SD 11.14) mmHg with esketamine versus 5.4 (SD 9.29) mmHg with placebo, and mean maximal diastolic increases were 10.2 (SD 8.35) mmHg versus 4.7 (SD 6.62) mmHg. Dissociative effects measured by CADSS peaked at 40 minutes and largely resolved by 1.5 hours; 72.8% of esketamine patients had an increase >4 in CADSS total score at any time versus 4.8% of placebo patients. PWC‑20 assessments showed no clear evidence of withdrawal two weeks after cessation. C‑SSRS ratings indicated an increase in the proportion of patients with no suicidal ideation from baseline to endpoint in both groups; treatment‑emergent suicidal ideation occurred in 12 esketamine and 14 placebo patients, and one esketamine patient had treatment‑emergent suicidal behaviour.

Chen and colleagues report that the trial did not meet its primary efficacy endpoint: esketamine plus a newly initiated oral antidepressant was not statistically superior to oral antidepressant plus placebo for change in MADRS at Day 28, with an observed LS mean difference of −2.0 (95% CI −4.64, 0.55). Nonetheless, a clinically meaningful and rapid reduction in depressive symptoms was observed 24 hours after the first dose (LS mean difference −3.3 overall and −2.6 in the China subgroup), consistent with esketamine's prior characterisation as a rapid‑acting antidepressant. The authors note that the failure to replicate the global Phase III therapeutic effect at Day 28 in this predominantly Chinese sample contrasts with earlier global findings, and they explored several potential explanations without identifying a definitive cause. Pharmacokinetic measures were in expected ranges and showed dose‑dependent differences similar to global studies. Potential contributors discussed include the use of independent remote MADRS raters assessing by telephone—an approach adopted to reduce observer bias given esketamine's recognisable transient effects—and possible cultural or communication differences that could reduce sensitivity of remote clinician ratings in a Chinese population. Post‑hoc comparisons suggested that patient‑reported outcomes sometimes favoured esketamine while clinician remote ratings did not, implying some improvement may not have been captured by remote assessment. Site heterogeneity was also considered: higher‑enrolling, more experienced sites in China showed numerically greater treatment differences than lower‑enrolling sites. Safety findings were in line with the established esketamine profile. The transient dissociative and blood pressure effects observed typically peaked shortly after dosing and resolved within hours. The authors discuss limitations including the inherent difficulty of blinding transient dissociative effects—hence the choice of remote blinded raters—which itself may have reduced sensitivity for detecting change; the flexible‑dose design precluded formal dose‑response evaluation; and other standard constraints of the study population and duration. Overall, the investigators conclude that while rapid symptom reduction was observed, the primary 4‑week efficacy outcome did not demonstrate statistical superiority, and no new safety signals emerged.

In this Phase III, randomised, double‑blind study in predominantly Chinese adults with TRD, esketamine nasal spray plus a newly initiated oral antidepressant did not show statistical superiority over oral antidepressant plus placebo for improvement in depressive symptoms at Day 28. A rapid reduction in depressive symptoms within 24 hours after the first intranasal dose was observed in the overall and China populations, and safety results were consistent with the known esketamine profile with no new safety signals identified.