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

Classified as probably not a substantial claim. May combine two claims.

Research on mood disorder pathophysiology has implicated abnormalities in glutamatergic transmission, along with disrupted function and structure in neural circuits involved in mood regulation.

“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).”

• cites [4] sourceSupported

Classified as probably not a substantial claim. May combine two claims.

The sample size was planned assuming a treatment difference of 6.5 points in MADRS score, a standard deviation of 12, a two-sided significance level of 0.05, and a dropout rate of 25%; 98 individuals per treatment group were required for 90% power.

“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.”

• cites [11] sourceSupported

May combine two claims.

Earlier studies of esketamine in patients with treatment-resistant depression and major depression at imminent risk for suicide, which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.

“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.”

• cites [10] sourceSupported
• cites [11] sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [12] sourcePartly supported

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

  Experimental — accuracy not yet measured

May combine two claims.

The magnitude of postdose blood pressure increases was lower compared with the previous phase 2 study of esketamine nasal spray, possibly because of the risk-mitigation blood pressure guidelines initiated in phase 3 studies.

“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).”

• cites [11] sourceSupported

May combine two claims.

Response was rapid in onset and increased over time during repeated dosing, with least square mean between-group differences favoring esketamine at day 2, day 8, day 15, day 22, and day 28.

“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”

The quote only partly states this claim.

The least-squares mean difference in change in MADRS score from baseline to day 28 between esketamine plus antidepressant and antidepressant plus placebo was -4.0 (95% CI -7.31 to -0.64; two-sided p=0.020).

“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”

The quote only partly states this claim.

Nine patients experienced adverse events leading to discontinuation of intranasal study drug during the double-blind treatment phase: eight (7.0%) in the esketamine plus antidepressant arm and one (0.9%) in the antidepressant plus placebo arm.

“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.”

May combine two claims.

For patients who experienced sedation, the symptom started around 15 minutes into dosing, peaked at 30 to 45 minutes after dosing, and spontaneously resolved by 1 to 1.5 hours after dosing.

“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.”

May combine two claims.

Present-state dissociative symptoms and transient perceptual effects measured by the CADSS began shortly after the start of esketamine dosing and peaked at 40 minutes.

“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”

May combine two claims.

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.

“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.”

May combine two claims.

At day 28, the proportion of patients in remission was higher in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm, with an NNT of 5 for remission.

“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.”

May combine two claims.

In post hoc analyses, the proportion of responders at day 28 was higher in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm, with an NNT for response of 6.

“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”

May combine two claims.

One patient in the esketamine plus antidepressant arm experienced multiple injuries in a road traffic accident on day 16 and subsequently died on day 55; the investigator considered the events as doubtfully related to esketamine or to antidepressant.

“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”

May combine two claims.

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.

“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).”

May combine two claims.

The five most common treatment-emergent adverse events in the esketamine plus antidepressant arm were dizziness, dissociation, dysgeusia, vertigo, and nausea, and the incidence of each was two to 10 times lower in the antidepressant plus placebo arm.

“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”

May combine two claims.

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.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

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

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

May combine two claims. The quote only partly states this claim.

Median CGI-S scores improved from baseline to endpoint in both groups, with a numerical difference favoring esketamine.

“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.”

The quote only partly states this claim.

Nocebo response was noted by an increase in CADSS scores after placebo nasal spray administration to which a bittering agent was added for blinding.

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

May combine two claims.

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 and in the olanzapine-fluoxetine study.

“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)”

• cites [33] sourceNot checked — no full text of the source

May combine two claims.

In post hoc analyses, results from both patient-reported outcomes (Sheehan Disability Scale and PHQ-9) showed consistency with the primary clinician-based outcome result, providing supportive evidence from patients' perspective of improvement in mood and function after 4 weeks of treatment.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

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

“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.”

• cites [2] sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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.

“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”

Probably not a substantial claim: may not pass S3 (load-bearing).

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.

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase.

“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).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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

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

• cites [7] sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

A serial gatekeeping (fixed sequence) approach was applied to adjust for multiplicity and to strongly control type I error across the primary and three key secondary efficacy endpoints.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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

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

• cites [8] sourceNot checked — no full text of the source

May combine two claims.

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.

“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).”

• cites [3] sourceNot checked — no full text of the source

May combine two claims.

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.

“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).”

• cites (10)(11)(12)Not matched

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

May combine two claims.

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.

“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).”

• cites [35] sourceNot checked — no full text of the source

May combine two claims.

The day 2 difference of 23.3 points is considered a clinically meaningful treatment difference, suggesting rapid onset of antidepressant efficacy.

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

• cites [26] sourceNot checked — no full text of the source
• cites [27] sourceNot checked — no full text of the source

May combine two claims.

The increase in dissociation ratings (CADSS scores) in the control group who received placebo nasal spray provides evidence of adequate blinding and supports expectation of benefit as one of the contributing factors of the higher than anticipated placebo response observed in the control group.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

It is possible that the specific adverse event profile of esketamine affected the blind for the study patients.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A number of factors may have contributed to the smaller than anticipated effect size, the lower treatment difference compared with phase 2 work, and the higher response and remission rates observed for the oral antidepressant plus placebo group: newly initiated antidepressant in comparator, high frequency of patient interaction, nasal spray delivery system, high patient expectation due to media, и

“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”

Probably not a substantial claim: may not pass S3 (load-bearing).

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

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

Probably not a substantial claim: may not pass S3 (load-bearing).

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.

“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.”

May combine two claims.

The comparator arm used a newly initiated antidepressant, not a true placebo control.

“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)”