A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder (NCT04338321), a randomized phase 3 study. The primary outcome is Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8.

2. Clinical Question

The central statistical comparison is between the Week 8 remission percentages in the two treatment strategies, each used with a continuing SSRI/SNRI. The endpoint is a binary classification: each participant either met the stated remission definition or did not. The registry reports the outcome as a percentage of participants and also records a sponsor analysis designated as a superiority analysis.

The question is specific to remission at Week 8, not to every aspect of depressive symptoms or longer-term outcome. A separate secondary outcome concerns participants who had remission at Week 8 and remained relapse-free until Week 32. That later measure is related to, but does not replace, the primary endpoint. The trial also posted symptom-scale and safety outcomes.

3. Trial Design

The registry describes a randomized, open-label, rater-blinded, active-controlled, international, multicenter, parallel-group Phase 3 study. Enrollment was 676, and the record lists the study as completed. The study began on 2020-08-21, with primary completion on 2022-01-20. Those dates describe the registry record and do not by themselves establish when every analysis was conducted.

The two strategies paired an antidepressant that participants continued taking with either esketamine nasal spray or quetiapine extended-release. The esketamine arm used flexible dosing, and the intervention list includes 28 mg, 56 mg, and 84 mg. The quetiapine arm included 50 mg, 100 mg, and 150 mg. The complete dosing and adjustment schedules are not reported in the registry record.

Open-label describes the treatment assignment as not masked, while rater-blinded indicates that outcome raters were blinded according to the study title. The registry does not report further details about which personnel were blinded or how blinding was maintained. Randomization and a parallel-group design support a direct comparison of assigned strategies, while the active comparator means the study compared two treatment approaches rather than a treatment with no active comparator.

The primary endpoint was assessed at Week 8 in the full analysis set, which the registry defines as all randomized participants. The primary outcome was the percentage meeting the specified MADRS remission definition. The registry also lists a Week 32 outcome combining Week 8 remission with being relapse-free until Week 32. Details of the randomization procedure, allocation concealment, and the protocol’s original sample-size justification are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Participants who discontinued the treatment early still remained in the study and were followed up until the end of study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The full analysis set (FAS) included all randomized participants.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8, measured over Week 8.

The primary endpoint is the percentage of participants with remission, assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) at Week 8. The MADRS is a clinician-rated measure designed to assess depression severity and changes during antidepressant treatment. It covers apparent and reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest, pessimistic thoughts, and suicidal thoughts. Its total possible score is 60, with higher scores indicating more severe symptoms.

The registry defines remission as a MADRS total score less than or equal to 10, with no treatment or study discontinuation before Week 8. This definition therefore combines a symptom-score threshold with a continuation condition. A participant who discontinued before Week 8 did not meet the stated remission definition, regardless of the reason for discontinuation.

A binary endpoint can be useful because it expresses the proportion of participants reaching a defined clinical state rather than only the average change in a symptom score. It is also straightforward to compare between randomized groups. However, reducing a score to a remission classification does not retain all information about symptom levels: participants on either side of the threshold may have relatively similar scores. The record also lists clinician-rated and participant-reported symptom outcomes among secondary measures, offering different views of change beyond the primary remission classification.

7. Results Posted in the Registry

• Quetiapine Extended Release (XR) + Oral AD: 17.6% (60/340) versus 27.1% (91/336) on control; risk difference -9.4 percentage points (95% CI -15.7 to -3.2), risk ratio 0.65 (0.49–0.87); unadjusted two-proportion z-test p = 0.003.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Quetiapine Extended Release (XR) + Oral AD: 14.1% (48/340) versus 21.7% (73/336) on control; risk difference -7.6 percentage points (95% CI -13.4 to -1.9), risk ratio 0.65 (0.47–0.91); unadjusted two-proportion z-test p = 0.010.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Quetiapine Extended Release (XR) + Oral AD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Number of Participants With TEAEs of Special Interest

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Quetiapine Extended Release (XR) + Oral AD: 41.7% (140/336) versus 66.8% (223/334) on control; risk difference -25.1 percentage points (95% CI -32.4 to -17.8), risk ratio 0.62 (0.54–0.72); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Quetiapine Extended Release (XR) + Oral AD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes extend the primary question to longer follow-up, symptom scales, clinician assessments, participant reports, and safety. The Week 32 remission-and-relapse-free outcome is conceptually closest to the primary endpoint because it begins with Week 8 remission and adds a later relapse-free condition. Other listed measures assess related but distinct aspects of depressive illness, including MADRS, CGI-S, CGI-C, and PHQ scores.

The posted pattern includes a numerical difference between groups on the Week 32 combined outcome, but secondary endpoints should be treated as supportive context rather than as repeated versions of the primary test. Different outcomes have different definitions, timeframes, measurement scales, and analysis populations. A result on a symptom scale does not directly answer the same question as whether a participant met the remission threshold.

The registry lists 24 secondary outcomes, while the available results include several types of measures. When many outcomes are tested, the chance of at least one apparently notable result can increase. Unless the analysis plan controls for multiplicity, an isolated unadjusted p-value generally carries less confirmatory weight than a prespecified primary result. Whether multiplicity was controlled, and how the secondary analyses were prioritized, are not reported in the registry record.

Accordingly, secondary results can help characterize consistency and breadth, but they should not be counted as independent confirmations without considering their relationships and the analysis plan. The primary result remains a Week 8 remission comparison; the secondary outcomes address additional questions rather than expanding that endpoint’s definition.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32
• Change From Baseline in Clinician-rated Overall MADRS Score
• Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF)
• Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score
• Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF
• Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score
• Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF
• Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score

9. Statistical Interpretation

10. Statistical Methods Explained

Statistical methods help distinguish the observed group percentages from the uncertainty around their comparison. The primary endpoint is binary: remission was either recorded according to the registry definition or was not. The analysis therefore compares proportions, rather than comparing average MADRS scores as the primary outcome.

What does the risk difference express?

The recalculated risk difference is the proportion in the quetiapine group minus the proportion in the esketamine group. Its estimate is -0.094. The negative direction reflects the ordering of groups in that calculation; it is not a negative remission rate. Reversing the group order would reverse the sign, while leaving the underlying comparison unchanged. The result is an unadjusted calculation from posted group summaries, rather than a substitute for the sponsor’s own analysis.

A risk difference describes an absolute difference in proportions on the probability scale. It can be read as a direct contrast between the chance of meeting the endpoint in the two groups, subject to the analysis definition and study population. Other measures, such as a risk ratio or odds ratio, express the same binary comparison on different scales. Their numerical values are not directly interchangeable with a risk difference, and each can convey a different sense of relative versus absolute contrast.

What does the p-value address?

The unadjusted p-value is 0.003. In general, a p-value assesses how compatible the observed data are with a specified null hypothesis under the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of the difference. A small p-value does not remove concerns about bias, outcome definitions, missing data, or multiple testing.

The sponsor reports a Cochran-Mantel-Haenszel analysis. In general, this method can compare categorical outcomes while accounting for strata. The registry record does not report the strata or other details needed to describe the exact adjustment. Its reported parameter is Mean Difference (Final Values), with a value of 9.44 and a 95% confidence interval from 3.19 to 15.68. Because that parameter is not the recalculated risk difference, the estimates use different reported scales and should be read separately.

Why does the analysis population matter?

The full analysis set is defined in the registry as all randomized participants. An analysis population determines which participants contribute to the reported outcome and can affect the interpretation of a randomized comparison. The remission definition also counts treatment or study discontinuation before Week 8 as not meeting remission. Further details about other missing measurements, imputation, or sensitivity analyses are not reported in the registry record.

Why can binary outcomes lose information?

A threshold-based endpoint gives a clear classification, but it compresses a range of MADRS scores into two categories. Participants close to the threshold may be classified differently despite similar scores, while score changes that do not cross the threshold do not change remission status. For that reason, the posted continuous symptom outcomes can provide complementary context, although they answer different questions.

The study’s title identifies it as randomized, open-label, and rater-blinded. Randomization is intended to make assigned groups comparable on average, while blinding outcome raters can reduce some forms of assessment influence. Open-label treatment assignment may still affect experience, behavior, or other processes. The registry does not report enough operational detail to assess those possibilities or the exact analysis model beyond the named sponsor method.

11. Confidence Intervals and Precision

The recalculated risk-difference estimate is -0.094, with a 95% confidence interval from -0.157 to -0.032. The interval gives a range of values compatible with the data and the assumptions of that calculation. In general, a confidence interval reflects both the estimated contrast and its sampling uncertainty; it is not a guarantee that the true value lies within the interval.

Because both endpoints of this interval are below zero, the unadjusted interval does not include a zero difference on the stated comparison scale. That is consistent with the unadjusted p-value of 0.003. The interval also shows that the estimate is not known with unlimited precision: a range of contrasts remains compatible with the data. The direction depends on the stated ordering, quetiapine minus esketamine.

The sponsor reports a separate 95% confidence interval, from 3.19 to 15.68, for its Mean Difference (Final Values) estimate of 9.44. This is a different reported parameter and scale from the recalculated risk difference. It should not be combined with, or interpreted as a narrower version of, that risk-difference interval.

Confidence intervals address sampling uncertainty under an analysis; they do not cover every source of uncertainty. They do not correct for possible selection, measurement, or missing-data problems, and they do not account for multiple testing unless the analysis specifically does so. The registry does not report a multiplicity adjustment for the primary result. The width of the intervals should therefore be read as one aspect of precision, alongside the study design and the limitations of the registry record.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations are planning calculations based on fractions of the observed effect, not the trial’s own original design assumptions. For these binary outcomes, the figures are participants per arm. The stated calculation assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect equal to the specified fraction of the observed effect. The trial’s original sample-size justification and assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect and assumptions were correct. The 90% power column uses a higher target chance of detection, so its planning figure is larger. These are design-planning concepts, not probabilities that the observed trial result is correct.

Rows for planning at 100%, 75%, and 50% of the observed effect illustrate how assumed effect size changes the planning requirement. A smaller effect is harder to distinguish from random variation, so it generally requires more participants to reach the same target power. These figures are not observed power and do not show how much power the completed trial achieved.

The sample-size display should be read as a sensitivity illustration: it asks what planning numbers follow if the assumed effect is a stated fraction of the observed contrast, while holding the listed calculation assumptions in place. It does not establish that the effect will recur in a future study. The display’s figures should not be confused with enrollment in this completed trial or with the number of participants contributing to a particular safety outcome.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.271; treatment proportion p₁ = 0.176; average p̄ = 0.224.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5893 = 1.1550.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5855 = 0.4928.
4. n = (1.1550 + 0.4928)² / (-0.0944)² = 304.9, rounded up to 305 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.270833333333333                          # control proportion
p1 <- 0.176470588235294                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(4338321)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 305 (80% power), 408 (90% power)
 75% of observed effect: n per arm = 563 (80% power), 754 (90% power)
 50% of observed effect: n per arm = 1,312 (80% power), 1,755 (90% power)
power.prop.test: 304.9 
Simulated power at n = 305 per arm: 0.804 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis uses the Cochran-Mantel-Haenszel method and identifies its parameter as Mean Difference (Final Values). It reports a value of 9.44, a 95% confidence interval from 3.19 to 15.68, and p=0.003, with the analysis designated as superiority. The registry’s unadjusted recalculation instead compares the posted remission proportions as a risk difference, with an estimate of -0.094, a 95% confidence interval from -0.157 to -0.032, and p=0.003.

These analyses report different parameter scales, so their estimates should not be compared as though they were two versions of one number. The recalculation is a simple unadjusted contrast from the posted summaries; the sponsor analysis is the analysis reported by the study record. The record does not provide full detail about the sponsor analysis specification or any strata used in the Cochran-Mantel-Haenszel method.

The registry does not flag a discrepancy between the reported analysis and recalculation. The sponsor’s analysis remains the study’s reported analysis, while the recalculation offers a transparent, unadjusted summary of the posted group proportions. Both reported p-values are 0.003, but matching p-values do not make the estimates or methods equivalent.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and 24 secondary outcomes. Testing multiple outcomes can increase the chance of a nominally notable result even when no true differences exist. Statistical plans often address this issue through a prespecified testing hierarchy or an adjustment to the inference, but whether either approach was used for the secondary outcomes is not reported in the registry record. The record also does not report a multiplicity procedure for the primary and secondary outcomes together.

The primary remission endpoint has a stated definition and a full analysis set comprising all randomized participants. It also explicitly treats treatment or study discontinuation before Week 8 as not meeting remission. That definition clarifies one aspect of outcome classification, but it does not tell readers how other missing MADRS assessments were handled. Imputation methods, sensitivity analyses, and assumptions about missing data are not reported in the registry record.

Missing data can affect a binary outcome when some participants lack an assessment or leave the study. The consequences depend on why data are missing and on the analysis rules. A complete-case analysis, an imputation approach, and treating missing outcomes as non-remission can answer different effective questions. The registry’s remission definition specifies discontinuation but does not report a full missing-data strategy for every circumstance.

The sponsor’s reported analysis is identified as Cochran-Mantel-Haenszel, but the registry record does not report the detailed model specification, strata, or sensitivity analyses needed to assess robustness. It also does not report interim analyses or the protocol’s complete statistical analysis plan. These absences do not establish that such procedures were not used; they mean the registry record does not permit their evaluation.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: depression (0.9%), suicidal ideation (0.9%), somatic symptom disorder (0.6%), suicide attempt (0.6%), anxiety (0.6%).

The adverse-event record reports serious adverse events among 19 participants at risk in the esketamine nasal spray plus oral antidepressant group and 17 participants at risk in the quetiapine extended-release plus oral antidepressant group. The corresponding serious-event risk denominators are 334 and 336. The record also reports one death in each group. These counts describe events recorded during the study and do not establish that treatment caused them.

The listed leading serious adverse-event terms and percentages include depression at 0.9%, suicidal ideation at 0.9%, somatic symptom disorder at 0.6%, suicide attempt at 0.6%, anxiety at 0.6%, and acute coronary syndrome at 0.3%. The registry’s record of these terms should not be interpreted as a complete account of all possible risks or as a comparison adjusted for differences in exposure.

Other adverse events were recorded for 289 participants at risk in the esketamine group and 216 participants at risk in the quetiapine group. The event categories and denominators differ from the primary endpoint analysis. A safety comparison requires attention to event definitions, exposure duration, severity, and whether events were judged related to treatment; those details are not reported in the registry record.

17. What the Result Does, and Does Not, Mean

The primary result describes observed Week 8 remission percentages in two randomized treatment strategies for participants with treatment-resistant major depressive disorder who continued an SSRI/SNRI. The esketamine group had a reported remission percentage of 27.1%, and the quetiapine group had a reported percentage of 17.6%. The unadjusted comparison has a confidence interval that does not include zero on its stated risk-difference scale, alongside an unadjusted p-value of 0.003.

This finding does not establish that every participant will respond in the same way, nor does it determine the best treatment for an individual. It does not show what either study drug would do without the continuing antidepressant, because both strategies included one. It also does not directly answer questions about outcomes beyond the measured follow-up, all symptoms, functioning, or comparative safety in populations not represented by the study.

The Week 8 outcome is a threshold-based remission classification, with a condition concerning discontinuation. It is not identical to average symptom improvement, and a group-level percentage cannot describe the full range of individual experiences. The Week 32 secondary measure adds a relapse-free condition, but it remains a separate outcome with its own definition.

Statistical evidence should be considered alongside uncertainty, study design, missing-data handling, multiplicity, and the registry’s reporting detail. The open-label design and incomplete information about analysis procedures are relevant limitations. The results are a comparison of the recorded outcomes under this study’s conditions, not a universal conclusion about treatment effects or a substitute for clinical judgment.

18. Why This Trial Matters Statistically

This trial is statistically informative because it compares two active treatment strategies in a randomized parallel-group design and defines a binary primary outcome that can be interpreted as a remission proportion. The comparison concerns clinically recognizable remission at Week 8, while both groups continued an SSRI/SNRI. The registry also reports a sponsor analysis and enough group-level information to permit an unadjusted risk-difference recalculation.

The distinction between an adjusted or stratified sponsor analysis and a simple unadjusted comparison matters. They can use different methods and express effects on different scales. Reporting both makes it possible to see the observed proportions and to distinguish those from the sponsor’s stated analysis, without treating the recalculation as a replacement for the trial analysis.

The study also illustrates why endpoint definitions and analysis populations matter. Remission is defined by a MADRS threshold plus no treatment or study discontinuation before Week 8, and the full analysis set includes all randomized participants. Those choices shape the meaning of the result. A later remission-and-relapse-free endpoint, symptom scales, and safety outcomes provide additional perspectives but do not answer the primary question in the same way.

Finally, the registry’s incomplete reporting on multiplicity, missing-data methods, and the original sample-size justification illustrates the limits of interpreting a result from summary information alone. Confidence intervals, p-values, and planning illustrations are useful, but they do not resolve unreported design or analysis details. Keeping those distinctions visible supports a more precise reading of both the result and its limits.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The study is described as open-label, although raters were blinded according to the title. The registry record does not explain how rater blinding was implemented or maintained. Awareness of treatment assignment can influence participant experience and reporting, even when outcome raters are blinded; the extent of any such influence cannot be assessed from the record.

The primary outcome combines a MADRS threshold with no treatment or study discontinuation before Week 8. This is a clear operational definition, but it means discontinuation is part of endpoint classification rather than merely an issue of missing measurement. The record does not report how other missing assessments were handled, why participants discontinued, or sensitivity analyses for alternative missing-data assumptions.

The sponsor’s reported analysis is identified as Cochran-Mantel-Haenszel, but the registry does not report its full specification or the strata used. The recalculated risk difference is unadjusted and should not be treated as a replacement for that analysis. The record does not report a multiplicity strategy for the many secondary outcomes, which limits the confirmatory interpretation of secondary findings.

The complete treatment schedules are not reported in the registry record, and the original sample-size justification is not reported. The record also does not provide enough information to assess adherence, exposure duration by group, or the circumstances surrounding the safety events. These are limitations of what can be concluded from the registry record, rather than evidence that a particular procedure or analysis was absent from the full study documentation.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder — NCT04338321.
• Registry record last updated 2025-04-29; status last verified 2025-04.
• Results first posted 2023-02-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

The registry describes a completed randomized, open-label, rater-blinded, active-controlled, parallel-group Phase 3 study of esketamine nasal spray versus quetiapine extended-release, with both strategies paired with a continuing SSRI/SNRI. Enrollment was 676.

The primary endpoint was the percentage meeting the MADRS remission definition at Week 8. Posted remission percentages were 27.1% for esketamine plus oral antidepressant and 17.6% for quetiapine extended-release plus oral antidepressant. The unadjusted risk-difference recalculation was -0.094 for quetiapine minus esketamine, with a 95% confidence interval from -0.157 to -0.032 and p=0.003. The sponsor reported a separate Cochran-Mantel-Haenszel analysis with a Mean Difference (Final Values) of 9.44 and a 95% confidence interval from 3.19 to 15.68.

The registry also lists secondary symptom, remission, relapse-free, and safety outcomes. Details about multiplicity, missing-data methods, and the original sample-size justification are not reported in the registry record.