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Cited by 795Treatment of Major DepressionElectroconvulsive Therapy StudiesTryptophan and brain disorders

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial

Open access
Daly, Ella J., Trivedi, Madhukar H., Janik, Adam, Li, Honglan, Zhang, Yun, Li, Xiang, Lane, Rosanne, Lim, Pilar +15 more·2019·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2019.1189PMC PMC6551577
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Abstract

Importance Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results Among the 297 adults (mean age [SD]…

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Crossref · 10.1001/jamapsychiatry.2019.1189

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

1 of 11 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The safety results were consistent with previous findings from completed short-term (4-week) phase 2 and 3 studies.

    “Results were consistent with previous findings from completed short-term (4-week) phase 2 and 3 studies.10,12,15”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [10] 10. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: results of a double-blind, doubly-randomized, placebo-controlled study. JAMA Psychiatry. 2018;75(2):139-148. doi:10.1001/ jamapsychiatry.2017.3739 source

      The Discussion (page unavailable) says the esketamine doses appeared safe, with no new or unexpected safety concerns. But the Design describes this as a phase 2 study with two one-week double-blind periods; the paper does not compare its safety results with completed four-week phase 2 and 3 studies. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [12] 12. Popova V, Daly E, Trivedi M, et al. Randomized, double-blind study of flexibly-dosed intranasal esketamine plus oral antidepressant vs active control in treatment-resistant depression. Paper presented at: 2018 American Society for Clinical Pathology Annual Meeting; May 30, 2018; source
    • cites [15] 15. Fedgchin M, Trivedi M, Daly EJ, et al. Randomized, double-blind study of fixed-dose intranasal esketamine plus oral antidepressant vs. active control in treatment-resistant depression (abstract 18). Presented at the 9th Biennial Conference of the International Society for Affective Disorders (ISAD) and the Houston Mood Disorders Conference; September 21, 2018; source
  • Findingnone given

    No clinically significant change in electrocardiographic findings was observed during the study.

    “No clinically significant change in electrocardiographic findings was observed during the study.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among patients who achieved stable remission, the hazard ratio for time to relapse was 0.45 (95% CI, 0.17-1.18) for transfer-entry patients.

    “The HRs were 0.49 (95% CI, 0.27-0.90)for direct-entry patients and 0.45 (95% CI, 0.17-1.18)for transfer-entry patients.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among patients who achieved stable remission, 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse.

    “Overall, among patients who achieved stable remission, 24 patients (26.7%) in the esketamine and antidepressant group and 39 patients (45.3%) in the antidepressant and placebo group experienced a relapse event during the maintenance phase”
    Quote in the paperSubstantial claim
  • Findingown data

    In a post hoc analysis, esketamine plus antidepressant delayed relapse compared with antidepressant plus placebo among patients who achieved stable remission and patients who achieved stable response combined (HR, 0.38; 95% CI, 0.26-0.57; P<.001).

    “In addition, in a post hoc analysis, esketamine and antidepressant delayed relapse compared with antidepressant and placebo among patients who achieved stable remission and patients who achieved stable response combined (HR, 0.38; 95% CI, 0.26-0.57;P < .001).”
    Quote in the paperSubstantial claim
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    Among patients who achieved stable remission, esketamine plus oral antidepressant treatment decreased the risk of relapse by 51% and significantly delayed relapse compared with oral antidepressant plus placebo (HR, 0.49; 95% CI, 0.29-0.84; P=.003; NNT, 6).

    “Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84)among patients who achieved stable remission”
    • Also stated in: § Efficacy Results · plain
      “Continued treatment with esketamine and antidepressant significantly delayed relapse compared with treatment with antidepressant and placebo (patients who achieved stable remission: HR, 0.49; 95% CI, 0.29-0.84;P = .003,number needed to treat [NNT], 6;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No cases of respiratory depression or interstitial cystitis were observed.

    “No cases of respiratory depression or interstitial cystitis were observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer than 7% of patients treated with antidepressant and placebo.

    “The most common adverse events reported for esketamine-treated patients after randomization weretransientdysgeusia,vertigo,dissociation,somnolence,anddizziness(incidence,20.4%-27.0%),each reported in fewer patients (<7%) treated with an antidepressant and placebo.”
    • Also stated in: § Safety Results · plain
      “The 5 most common AEs reported in the esketamine and antidepressant group during the maintenance phase were dysgeusia, vertigo, dissociation, somnolence, and dizziness (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Seven patients experienced one or more adverse events during the maintenance phase leading to discontinuation of the intranasal study drug; 4 (2.6%) were in the esketamine and antidepressant group and 3 (2.1%) were in the antidepressant and placebo group.

    “Seven patients experienced 1 or more AEs during the maintenance phase, leading to discontinuation of the intranasal study drug; 4 (2.6%) of 152 were in the esketamine and antidepressant group (worsening depression, 3 patients; anxiety and confusional state [transient], 1 patient) and 3 (2.1%) of 145 were in the antidepressant and placebo group (worsening depression for each).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among patients who achieved stable response, esketamine plus oral antidepressant treatment decreased the risk of relapse by 70% and significantly delayed relapse compared with oral antidepressant plus placebo (HR, 0.30; 95% CI, 0.16-0.55; P<.001; NNT, 4).

    “Continued treatment with esketamine and antidepressant significantly delayed relapse compared with treatment with antidepressant and placebo (patients who achieved stable remission: HR, 0.49; 95% CI, 0.29-0.84;P = .003,number needed to treat [NNT], 6; patients who achieved stable response: HR, 0.30; 95% CI, 0.16-0.55:P < .001,NNT, 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a post hoc sensitivity analysis excluding one site at a time, the hazard ratio was estimated to range from 0.42 to 0.57, consistent with the overall HR of 0.47 (unweighted).

    “On the basis of this analysis, the HR was estimated to range from 0.42 to 0.57, which is consistent with the overall HR of 0.47 (unweighted).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of esketamine and oral antidepressant-treated patients who reported no suicidal ideation or behavior at baseline, 42 (11.6%) had a higher postbaseline C-SSRS score in the optimization phase, and 3 (2.4%) had a higher postbaseline score in the maintenance phase compared with 6 patients (4.5%) receiving antidepressant and placebo.

    “Of those patients treated with esketamine and oral antidepressant who reported no suicidal ideation or behavior at baseline, 42 (11.6%)had a higher postbaseline score (maximum C-SSRS score of 1 ) in the optimization phase; and 3 (2.4%) had a higher postbaseline score (maximum C-SSRS score of 1 [n = 2] and 4 [n = 1]) compared with 6 patients (4.5%) receiving antidepressant and placebo (maximum C-SS”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Few patients experienced treatment-emergent transient hypertension during the maintenance phase: systolic hypertension occurred in 1 (0.7%) esketamine-treated patient and 0 antidepressant-and-placebo-treated patients; diastolic hypertension occurred in 2 (1.3%) esketamine-treated patients and 0 antidepressant-and-placebo-treated patients.

    “Few patients experienced treatment-emergent transient hypertension, defined 0 100 80 Patients Without Relapse, % 60 40 20 0 100 80 Patients Without Relapse, % 60 40 20 B Patients who achieved stable response No. at risk Esketamine nasal spray and oral antidepressant Oral antidepressant and placebo nasal spray 0 90 86 84 69 74 52 58 41 53 34 39 28 31 22 25 19 20 12 14 10 10 7 8 4 7 3 7 3 6 3 5 3 2”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Most direct-entry patients (362 [85.4%]) had baseline C-SSRS scores of 0, indicating no suicidal ideation or behavior.

    “Most direct-entry patients (362 [85.4%]) had baseline C-SSRS scores of 0, indicating no suicidal ideation or behavior.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After completing induction and optimization treatment, MADRS total scores separated between patients randomized to continue versus discontinue esketamine, with lower scores over time for esketamine-treated patients, and this separation was maintained in both stable remission and stable response patients.

    “After completing induction and optimization treatment (16 weeks total), in patients who achieved stable remission and those who achieved stable response, there was separation in MADRS total scores between patients randomized to continue vs discontinue esketamine treatment, each in the presence of antidepressant therapy, with MADRS total scores being lower over time for esketamine-treated patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nineteen of the 39 relapses in patients who achieved stable remission and were switched to placebo nasal spray occurred in the first month after discontinuation of esketamine treatment, with 11 of these 19 early relapses occurring in patients who had required weekly treatment administration in the last 4 weeks of the optimization phase before randomization.

    “Nineteen of the 39 relapses in patients who achieved stable remission and who were switched to placebo nasal spray occurred in the first month after discontinuation of esketamine treatment (6 by week 2 and the remainder by week 4), with 11 of these 19 early relapses occurring in patients who had required weekly treatment administration in the last 4 weeks of the optimization phase before randomiz”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No deaths were reported during the study.

    “No deaths were reported during the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most adverse events were mild to moderate, observed after dosing, and generally resolved the same day.

    “Most AEs were mild to moderate, observed after dosing, and generally resolved in the same day.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Transient blood pressure increases were observed with esketamine on treatment days; the maximum value was reached at 40 minutes after administration in most cases and typically returned to the predose range by 1.5 hours after administration.

    “Transient blood pressure increases were observed with esketamine on treatment days; the maximum value was reached at 40 minutes after the start of administration in most cases and typically returned to the predose range by 1.5 hours after administration”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No symptoms or adverse events of psychosis were observed.

    “No symptoms or AEs of psychosis were observed.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Present-state dissociative symptoms generally resolved by 1.5 hours after the start of esketamine treatment.

    “Present-state dissociative symptoms, as measured by CADSS (eFigure 4 in Supplement 2), began shortly after the start of esketamine treatment, peaked at 40 minutes, and generally resolved by 1.5 hours.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Present-state dissociative symptoms peaked at 40 minutes after the start of esketamine treatment.

    “Present-state dissociative symptoms, as measured by CADSS (eFigure 4 in Supplement 2), began shortly after the start of esketamine treatment, peaked at 40 minutes, and generally resolved by 1.5 hours.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Randomization was balanced using randomly permuted blocks and stratified by country.

    “Randomization was balanced using randomly permuted blocks and stratified by country.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Patients who achieved stable remission and those who achieved stable response were separately randomized 1:1 according to a computer-generated schedule to continue esketamine or switch to placebo, with oral antidepressant continued in each group.

    “Patients who achieved stable remission and those who achieved stable response (without remission) were separately randomized 1:1 according to a computer-generated schedule to continue esketamine treatment or discontinue esketamine treatment and switch to placebo nasal spray, each in addition to oral antidepressant treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Even when patients with treatment-resistant depression respond to treatment, the overall relapse rate while continuing treatment with the same antidepressant is high after 2 failed trials (65%; within 3.1 months) and 3 failed trials (71.1%; within 3.3 months).

    “Even when patients with TRD respond to treatment, the overall relapse rate while continuing treatment with the same antidepressant is high after 2 (65%; within 3.1 months) and 3 failed trials (71.1%; within 3.3 months).3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163 (11):1905-1917. doi:10.1176/ajp.2006.163.11.1905 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Patients with treatment resistance who achieve remission have lower relapse rates compared with those who respond but do not experience remission.

    “Because patients with treatment resistance who achieve remission reportedly have lower relapse rates compared with those who respond but do not experience remission, 3 the prespecified primary analysis was conducted using the analysis of patients who achieved stable remission.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163 (11):1905-1917. doi:10.1176/ajp.2006.163.11.1905 source

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

    Study design and conductnone given

    One patient who did not meet stable remission or stable response criteria at the end of the optimization phase was incorrectly randomized in the group with stable response.

    “One patient who did not meet stable remission or stable response criteria at the end of the optimization phase was incorrectly randomized in the group with stable response.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The placebo solution contained a bittering agent (denatonium benzoate) to simulate the taste of esketamine solution and maintain the blinding.

    “The placebo solution contained a bittering agent (denatonium benzoate) to simulate the taste of esketamine solution and maintain the blinding.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The study was conducted in accordance with ethical principles of the Declaration of Helsinki, Good Clinical Practices, and applicable regulatory requirements.

    “The study was conducted in accordance with ethical principles of the Declaration of Helsinki, 16 Good Clinical Practices, and applicable regulatory requirements.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] 16. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10. 1001/jama.2013.281053

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

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

    Study design and conductown data

    A 2-stage group-sequential design was implemented for the stable remission analysis set, and an independent data-monitoring committee performed a prespecified interim analysis after 31 relapses to assess early efficacy.

    “A 2-stage group-sequential design was implemented for the analysis set of patients who achieved stable remission, and an independent data-monitoring committee performed a prespecified interim analysis after 31 relapses to assess early efficacy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Esketamine has known transient dissociative and sedative effects that are difficult to blind, and these symptoms could have biased the staff who observed treatment administration.

    “Study limitations include the fact that esketamine has known transient dissociative and sedative effects that are difficult to blind; these symptoms could have biased the staff who observed treatment administration.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Institutional review boards and independent ethics committees approved the study protocol and amendments.

    “Institutional review boards and independent ethics committees (eAppendix 1 in Supplement 2) approved the study protocol and amendments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Independent, blinded, remote raters performed MADRS assessments throughout the study.

    “Independent, blinded, remote raters performed MADRS assessments throughout the study (weeks 1, 2, and 4 of the screening and observation phase and weekly during the induction, optimization, maintenance, and follow-up phases).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    On the basis of assumptions about accrual period and rate, maximum study duration, and dropout rate, 211 patients who achieved stable remission needed to be randomized to obtain 84 relapses, providing 90% power to detect a hazard ratio of 0.49 at a 2-sided alpha of .05 for a fixed-sample design.

    “On the basis of assumptions (accrual period and rate, maximum study duration, and dropout rate), 211 patients who achieved stable remission needed to be randomized (1:1 ratio) to obtain 84 relapses, providing 90% power to detect a hazard ratio (HR) of 0.49 at a 2-sided α of .05 for a fixed-sample design to detect superiority of esketamine and antidepressant over antidepressant and placebo in delay”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The interim analysis on patients who achieved stable remission did not show superiority of esketamine and antidepressant over antidepressant and placebo; the study continued, and the number of relapses was reestimated to 59 with an adjusted significance level of .046, ensuring conditional power of 90% or higher after the interim analysis.

    “The interim analysis on patients who achieved stable remission did not show superiority of esketamine and antidepressant over antidepressant and placebo (at a 2-sided significance level of .0097,log-rank test); therefore, the study continued, and the number of relapses in patients who achieved stable remission was reestimated to 59 relapses in total with an adjusted significance level of .046(2-s”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] 24. Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for group sequential trials. Biometrics. 1987;43(1):193-199. doi:10.2307/ 2531959 source

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

    Study design and conductown data

    Most censored patients were considered administrative based on the study having reached its end point; only 13 in the esketamine and antidepressant group and 12 in the antidepressant and placebo group were censored because they discontinued the maintenance phase before having a relapse and before the end of the study.

    “Most censored patients (ie, when participation was ended) were considered as administrative based on the study having reached its end point (ie, based on the target number of relapse events having been achieved and the study stopping).Only 13 (8 patients who achieved stable remission and 5 patients who achieved stable response) in the esketamine nasal spray and oral antidepressant group and 12 (9”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All patients provided written informed consent before entering the study.

    “All patients provided written informed consent before entering the study.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    One patient who achieved stable response was incorrectly randomized as a patient who achieved stable remission, and one patient who did not meet stable remission or stable response criteria was incorrectly randomized as a patient with stable response.

    “One patient who achieved stable response was incorrectly randomized as a patient who achieved stable remission at the end of the optimization phase.One patient did not meet stable remission or stable response criteria and was incorrectly randomized as a patient with stable response.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Relapse was assessed by a relapse adjudication committee.

    “or another clinically relevant event suggestive of relapse (assessed by a relapse adjudication committee).”
    Quote in the paperSubstantial claim
34 of 34

  • The paper relies on this without support.

    Little is known about maintaining antidepressant effects of esketamine and ketamine in the long term.

    “In contrast to available data about short-term antidepressant effects of esketamine and ketamine, 13,14 little is known about maintaining antidepressant effects in the long term.”

  • The paper relies on this without support.

    This is the first controlled maintenance study of esketamine.

    “We report the findings of, to our knowledge, the first controlled maintenance study of esketamine that evaluated whether continued use of intermittently administered esketamine nasal spray plus an oral antidepressant can sustain antidepressant effects among patients with TRD to a greater extent than an oral antidepressant alone.”

  • The paper relies on this without support.

    There is a substantial unmet need for effective treatments that can sustain antidepressant benefits for the population with treatment-resistant depression.

    “There is a substantial unmet need for effective treatments that can sustain antidepressant benefits for the population with TRD.”

  • The paper relies on this without support.

    Esketamine plasma concentrations decrease rapidly for the initial 2 to 4 hours and more gradually thereafter, with a mean terminal half-life of 7-12 hours, and steady state is never reached with intermittent dosing.

    “the decrease in esketamine plasma concentrations is rapid for the initial 2 to 4 hours and more gradual thereafter (mean terminal half-life, 7-12 hours), with steady state never reached with intermittent dosing.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Prolonged esketamine nasal spray 56-84 mg for 16 weeks with an oral antidepressant was well tolerated and produced significant symptom remission.

    “A follow-up report observed that prolonged treatment (weekly or biweekly treatment) with (S)-ketamine nasal spray (56-84 mg; 16 weeks), in conjunction with an oral antidepressant (SSRI or a selective norepinephrine reuptake inhibitor [SNRI]), was well-tolerated with significant remission of symptoms.”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Daly et al., 2019

    The Maintenance Phase section (page unavailable) describes 56–84 mg esketamine with an oral antidepressant over 16 weeks, followed by weekly or biweekly maintenance dosing. The Discussion and Safety Results (pages unavailable) report no new safety concerns and mostly mild-to-moderate maintenance-phase adverse events. However, the Efficacy Results report a significant delay in relapse among patients who had already achieved remission or response—not a significant rate of remission produced by prolonged treatment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Clinical use of esketamine was largely based on four positive Phase 3 efficacy studies that supported FDA approval of intranasal esketamine for treatment-resistant depression and suicidal ideation with intent.

    “With regard to esketamine in particular, clinical use was largely based on four positive Phase 3 efficacy studies [62][63][64][65] that informed the subsequent FDA approval of intranasal esketamine for TRD and suicidal ideation with intent, as described above.”

    From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [62]

    The Discussion (page unavailable) reports that this esketamine nasal-spray trial significantly delayed relapse in patients with treatment-resistant depression, supporting its identification as a positive efficacy study. The Study Population section (page unavailable) says current or recent suicidal ideation or intent was an exclusion criterion. Our copy does not establish that four studies informed FDA approval or that this trial supported approval for suicidal ideation with intent. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Induction trials largely ended at 4 weeks, while maintenance trials relied on designs that include enrichment (randomized withdrawal of responders/remitters).

    “Induction trials largely ended at 4 weeks, while maintenance trials relied on designs that include enrichment (randomized withdrawal of responders/remitters) (22)”

    From Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis (2026) · cites this paper as [22]

    The Discussion describes completed short-term studies as 4-week studies, and the study description in the Conclusions identifies this trial’s 4-week induction phase and randomized-withdrawal maintenance phase. The Maintenance Phase section confirms that only patients with stable remission or response were randomized to continue or discontinue esketamine. This supports the design described, but one maintenance trial does not establish that maintenance trials generally relied on it. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In the continuation trial NCT02493868, the primary outcome of remission remained consistent except when data from all Polish centers were excluded; then the effect size decreased and the analysis was not statistically significant.

    “In the continuation trial (NCT02493868 [12]), the primary outcome of remission remained consistent except when data from all Polish centers were excluded; in this case, the effect size decreased and the analysis was not statistically significant.”

    From Efficacy and safety of esketamine for “treatment resistant depression”: registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials (2025) · cites this paper as [12]

    The Efficacy Results report that excluding one site at a time produced hazard ratios consistent with the overall result. They do not report an analysis excluding all Polish centers or say that such an analysis reduced the effect size and lost statistical significance. The Efficacy End Points and Analyses section defines the primary outcome as time to relapse among patients who had achieved stable remission, rather than remission itself; page numbers were not available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Ketamine and esketamine reliably produce rapid symptom relief, yet responses frequently decay within days to weeks, with high relapse rates following discontinuation.

    “Across clinical trials, ketamine and esketamine reliably produce rapid symptom relief, yet responses frequently decay within days to weeks, with high relapse rates following discontinuation [81,82,83].”

    From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [83]

    The Efficacy Results report relapse after esketamine discontinuation despite continued oral antidepressant treatment, and the Discussion notes many relapses in the first month (page numbers unavailable). The paper also describes short-term efficacy studies of ketamine and esketamine, but these passages do not establish rapid symptom relief or that responses to both drugs frequently decay within days to weeks. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Optimization phase is described as both 12 and 16 weeks long

    Minor

    The methods define the optimization phase as lasting 12 weeks, but later refer to week 16 of that phase. Week 16 appears to refer to the combined induction and optimization period, not the optimization phase itself.

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Authors
Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A. R., Hough, D., Thase, M. E., Zajecka, J., Winokur, A., Divacka, I., Fagiolini, A., Cubala, W. J., Bitter, I., Blier, P., Shelton, R. C., Molero, P., Manji, H., Drevets, W. C., & Singh, J. B.
Affiliations
  • Department of Neuroscience, Janssen Research and Development LLC, Titusville, New Jersey
  • The University of Texas Southwestern Medical Center (US)
  • Department of Neuroscience, Janssen Research and Development LLC, San Diego, California
  • Department of Clinical Biostatistics, Janssen Research and Development LLC, Fremont, California
  • Janssen Research & Development (United States) (US)
  • Department of Clinical Biostatistics, Janssen Research and Development LLC, Titusville, New Jersey
  • University of Pennsylvania (US)
  • Rush University Medical Center (US)
  • UConn Health (US)
  • Private practice, Prague, Czech Republic
  • University of Siena (IT)
  • Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
  • Semmelweis University (HU)
  • University of Ottawa (CA)
  • University of Alabama (US)
  • Clinica Universidad de Navarra (ES)
Corresponding author
Daly, Ella J.
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2019-09-01
Volume
76
Issue
9
Pages
893
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2019.1189
PMC
PMC6551577
OpenAlex
W2948816951
Semantic Scholar
a466e4d3128df9d49edb7484ee67fd7b3ab3d49c
Cited by
795
References
27
Citations by year
2026: 98 · 2025: 110 · 2024: 104 · 2023: 81 · 2022: 69 · 2021: 79 · 2020: 236 · 2019: 16
FWCI
61.98
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Use Siena air (University of Siena) (submittedVersion)
Funders
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Cancer Prevention and Research Institute of Texas
  • Patient-Centered Outcomes Research Institute
  • Sunovion
  • Cerecor
  • Otsuka America
  • University of Oxford
  • H. Lundbeck A/S
  • Gobierno de Navarra
  • Agency for Healthcare Research and Quality
  • Allergan
  • National Institute of Mental Health
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Janssen Research and Development
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
esketamine, treatment-resistant depression, relapse prevention, maintenance therapy, nasal spray, oral antidepressant, sustained remission, long-term efficacy, depression recurrence, ketamine
MeSH terms
Administration, Intranasal, Administration, Oral, Adult, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Ketamine, Male, Middle Aged, Remission Induction, Outcome Assessment, Health Care, Secondary Prevention, Nasal Sprays, Depressive Disorder, Treatment-Resistant

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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