Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study

In the paper

“Research on mood disorder pathophysiology has implicated abnormalities in glutamatergic transmission, along with disrupted function and structure in neural circuits involved in mood regulation (4), findings that led to further investigation of glutamatergic N-methyl-D-aspartate (NMDA) receptor modulators in treating depression (5,6).”

What the sources say

• Supported

  The “Implications for Neurocircuitry-Based Models of Depression” section describes structural and functional abnormalities in a mood-related network and reports evidence of increased glutamatergic transmission in depression. “Recent Observations in Humans with Mood Disorders” likewise describes structural and functional alterations in implicated circuits. The later claim about investigating NMDA receptor modulators is attached to other citations, not this one. (LLM, conf=0.93)

  cites [4] source

In the paper

“The sample size planned for this study was calculated assuming a treatment difference for the double-blind treatment phase of 6.5 points in MADRS score between the esketamine plus antidepressant group and the antidepressant plus placebo group and a standard deviation of 12, based on the results of a phase 2 study of esketamine nasal spray for treatment-resistant depression (11) and clinical”

• Also stated in: § Sample size determination. · plain

  “Randomization of 98 individuals to each treatment group was required to achieve 90% power.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [11] source

In the paper

“Earlier studies of esketamine in patients with treatmentresistant depression (10,11) and major depression at imminent risk for suicide (12), which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [10] source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [11] sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [12] sourceExperimental — accuracy not yet measured

In the paper

“The magnitude of postdose blood pressure increases was lower compared with the previous phase 2 study of esketamine nasal spray (11), possibly because of the riskmitigation blood pressure guidelines initiated in phase 3 studies (see the online supplement).”

What the sources say

• Supported

  The cited paper is the earlier intranasal esketamine study, and its Safety section reports transient postdose blood-pressure increases, with maximum mean changes of 19.0 mm Hg systolic and 10.3 mm Hg diastolic. The citation is attached to that earlier study; the proposed explanation involving phase 3 risk-mitigation guidelines is attributed to the citing paper’s online supplement, not to this source. No page number is available in our copy. (LLM, conf=0.90)

  cites [11] source

In the paper

“Response was rapid in onset and increased over time during repeated dosing, with least square mean between-group differences, favoring esketamine, of 23.3 (95% CI=25.75, 20.85) 24 hours after dosing (i.e., at the day 2 visit), 22.9 (95% CI=25.17,20.59) at day 8, 22.0 (95% CI=24.78,0.82) at day 15, 23.8 (95% CI=26.87,20.65) at day 22, and, as noted above, 24.0 (95% CI=27.31,20.64) at day 28 (p=0.02”

In the paper

“Difference of LS | -4.0 | 1.69 | | |”

• Also stated in: § DISCUSSION · plain

  “95% CI on difference -7.31, -0.64”

• Also stated in: § DISCUSSION · plain

  “2-sided p value | 0.020”

In the paper

“Nine patients experienced one or more adverse events leading to discontinuation of intranasal study drug during the double-blind treatment phase, eight (of 115, 7.0%) in the esketamine plus antidepressant arm (single events of anxiety, depression, depressive symptoms, panic attack, drug intolerance, feeling drunk, dizziness, headache, vertigo, nausea, road traffic accident, and multiple injuries)”

• Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain

  “7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event.”

In the paper

“Generally, for patients who experienced sedation, this symptom started around 15 minutes into dosing and peaked at 30 to 45 minutes after dosing, and symptoms of sedation spontaneously resolved by 1 to 1.5 hours after dosing.”

In the paper

“Present-state dissociative symptoms and transient perceptual effects measured by the CADSS (see Figure S5 in the online supplement) began shortly after the start of esketamine dosing, peaked at 40 minutes, generally resolved by 1.5 hours, and attenuated with repeated dosing”

In the paper

“Most adverse events were of mild or moderate severity and were transient, with onset shortly after dosing and resolution by 1.5 hours after dosing, while patients were in the clinic.”

• Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · hedged

  “Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.”

In the paper

“At day 28, 53 of 101 (52.5%) and 31 of 100 (31.0%) patients in the respective treatment groups were in remission, with an NNT of 5 for remission.”

In the paper

“In post hoc analyses, the proportion of patients who at a given time point were responders and in remission in both treatment groups generally increased over time during the double-blind treatment phase, with 70 of 101 patients (69.3%) in the esketamine plus antidepressant arm and 52 of 100 patients (52.0%) in the antidepressant plus placebo arm being responders at day 28 (odds ratio=2.4,95% cred”

In the paper

“One patient in the esketamine plus antidepressant arm experienced multiple injuries in a road traffic (motorbike) accident (reported as serious adverse events) on day 16 of the double-blind treatment phase (approximately 28 hours after an esketamine dose) and subsequently died on day 55, 40 days after the last dose of esketamine (additional information is provided in the online supplement).The”

In the paper

“Transient blood pressure increases occurred after each dose of esketamine; the maximum value was reached at 40 minutes after dosing in most cases and typically returned to or near the predose range by 1.5-2 hours after dosing (see Figure S3 in the online supplement).”

In the paper

“During the double-blind treatment phase, the five most common treatment-emergent adverse events observed among patients in the esketamine plus antidepressant arm were dizziness, dissociation, dysgeusia, vertigo, and nausea (incidences ranging from 20.9% to 26.1%); the incidence of each was two to 10 times lower in the antidepressant plus placebo arm (Table 3).”

• Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain

  “The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm”

In the paper

“The proportion of responders at day 28 was comparable for patients who experienced dissociation (maximum CADSS score .4 on day 1) and those who did not (maximum CADSS score #4 on day 1), with response rates of 68.5% and 70.2%, respectively.”

In the paper

“No notable differences were observed between patients using concomitant benzodiazepines compared with those not using benzodiazepines.”

In the paper

“Median CGI-S scores improved from baseline to endpoint of the double-blind treatment phase in both groups, with a median change from baseline of 22.0 (range=25 to 1; interquartile range=2) in the esketamine plus antidepressant arm and 22.0 (range=25 to 1; interquartile range=3) in the antidepressant plus placebo arm (see Table S6 in the online supplement).”

• Also stated in: § RESULTS · hedged

  “The ANCOVA analysis based on the ranks of change showed a numerical difference favoring the esketamine arm over the comparator arm, with an odds ratio of 2.8 (95% credible interval=1.14, 7.68), suggesting that the odds of an improved CGI-S score at endpoint for patients in the esketamine arm were 2.8 times the odds for patients in the comparator arm.”

In the paper

“nocebo response (i.e., adverse effect following an”

In the paper

“The response and remission rates seen in the antidepressant plus placebo arm were higher than those reported in the Sequenced Treatment Alternatives to Relieve Depression trial for step 3 (response rate, 16.8%; remission rate, 13.7%) and in the olanzapine-fluoxetine study (33)”

What the sources say

• ?Not checked — no full text of the sourcecites [33] source

In the paper

“However, in post hoc analyses, the results from both patient-reported outcomes showed consistency with the primary clinicianbased outcome result (see Figure S6 in the online supplement), providing supportive evidence from patients' perspective of improvement in mood and function after 4 weeks of treatment.”

In the paper

“About 30% of patients with major depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (2).”

• Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain

  “About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants.”

What the sources say

• ?Not checked — no full text of the sourcecites [2] source

In the paper

“To maintain blinding, a bittering agent was added to the intranasal placebo to simulate the taste of the esketamine solution, and three devices were administered to all patients at all sessions”

In the paper

“A delta adjustment tipping point sensitivity analysis was performed to evaluate the robustness of the MMRM analysis to increasing deviations from the missing-at-random assumption (results are presented in the online supplement).”

In the paper

“Of 435 patients screened, nine (randomized at one site in Poland) were excluded from all analyses because of Good Clinical Practices violations (sensitivity analyses including this site confirmed no impact on the overall conclusions of the study), 227 underwent randomization to treatment; of these, three did not receive any study drug and one did not receive a dose of oral study antidepressant.”

• Also stated in: § RESULTS · plain

  “Most randomized patients (197/227, 86.8%) completed the 28-day double-blind treatment phase (see Figure S1 in the online supplement).”

In the paper

“Ketamine (an NMDA receptor antagonist) affects fast excitatory glutamate transmission, increases release of brain-derived neurotrophic factor, and stimulates synaptogenesis (7).”

What the sources say

• ?Not checked — no full text of the sourcecites [7] source

In the paper

“A serial gatekeeping (fixed sequence) approach was applied to adjust for multiplicity and to strongly control type I error across the primary and the three key secondary efficacy endpoints-namely, onset of clinical response by day 2, change in Sheehan Disability Scale score, and change in PHQ-9 score.”

In the paper

“Early clinical evidence suggested a potential role of ketamine in the treatment of depression, with mood-elevating effects observed in challenge studies (8).”

What the sources say

• ?Not checked — no full text of the sourcecites [8] source

In the paper

“In patients who respond to antidepressants, the time to onset of effect is typically several weeks, during which time patients remain symptomatic and at risk of suicidal behavior and self-harm (3).”

What the sources say

• ?Not checked — no full text of the sourcecites [3] source

In the paper

“In phase 2 studies, esketamine nasal spray demonstrated rapid onset and persistent efficacy in patients with treatment-resistant depression as well as in depressed patients at imminent risk for suicide (10)(11)(12).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites (10)(11)(12)

In the paper

“The only medication approved for the treatment of treatment-resistant depression is olanzapine plus fluoxetine, which has an NNT of 8 for response and 13 for remission (35).”

What the sources say

• ?Not checked — no full text of the sourcecites [35] source

In the paper

“which is considered a clinically meaningful treatment difference (26,27) suggesting rapid onset of antidepressant efficacy.”

What the sources say

• ?Not checked — no full text of the sourcecites [26] source
• ?Not checked — no full text of the sourcecites [27] source

In the paper

“it is noteworthy that the dissociation ratings (CADSS scores) increased in the control group who received placebo nasal spray, providing evidence of adequate blinding and supporting expectation of benefit as one of the contributing factors of the higher than anticipated placebo response observed in the control group.”

In the paper

“While eventual efficacy bias was mitigated by using independent remote MADRS raters, it is possible that the specific adverse event profile of esketamine affected the blind for the study patients.”

In the paper

“A number of factors may have contributed to the smaller than anticipated effect size finding, the lower treatment difference compared with our phase 2 work, and the higher response and remission rates observed for the oral antidepressant plus placebo group”

In the paper

“Because this trial was a flexible-dose study, dose-response relationships were not evaluated.”

In the paper

“Based on the predefined testing sequence, the other two key secondary endpoints (change in Sheehan Disability Scale and PHQ-9 scores) could not be formally evaluated.”

In the paper

“use of a newly initiated antidepressant (to which the patients had not shown a previous nonresponse) in the comparator arm (i.e., not a true placebo control)”