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Cited by 299Treatment of Major DepressionElectroconvulsive Therapy StudiesPsychedelics and Drug Studies

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression

Open access
Wajs, Ewa, Aluisio, Leah, Holder, Richard, Daly, Ella J., Lane, Rosanne, Lim, Pilar, George, Joyce E., Morrison, Randall L. +13 more·2020·The Journal of Clinical Psychiatry
DOI 10.4088/jcp.19m12891
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Abstract

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Integrity signals

Registry

Crossref · 10.4088/jcp.19m12891

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

3 of 19 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation

    Alternate forms were used for all cognitive tests to attenuate practice effects.

    “Finally, alternate forms (HVLT-R: Forms 1-6; Cogstate: playing-cards-based tests [DET, IDN, OCL, and ONB tasks] and 18 parallel maze forms for the GMLT) were used for all cognitive tests to attenuate practice effects.36”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] 36. Goldberg TE, Harvey PD, Wesnes KA, et al. Practice effects due to serial cognitive assessment: Implications for preclinical Alzheimer's disease randomized controlled trials. Alzheimers Dement (Amst). 2015;1(1):103-111. 36. P u b M e d source
  • Findingcitation

    The incidence of urinary tract infection in this study (8.1%) was analogous to rates in a general adult female population (over 10%) over 1 year.

    “The incidence of UTI (8.1%) in the present study was analogous to rates observed in a general adult female population (over 10%) over a 1-year period.31”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] 31. P u b M e d C r o s s R e f 30. Rowe TA, Juthani-Mehta M. Urinary tract infection in older adults. Aging Health. 2013;9(5):ahe.13.38. P u b M e d C r o s s R e f 31. Foxman B, Barlow R, D'Arcy H, et al. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol. 2000;10(8):509-515. source

      The 'Urinary tract infection' subsection reports that over 10% of women older than 65 had a UTI in the past 12 months. It does not give that rate for the general adult female population. The 8.1% figure is identified as the citing authors' own finding, not a result attributed to this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingown data

    Among patients who discontinued during the OP/MAINT phase, fatigue-lethargy/lack of energy was the most common new or worsening withdrawal symptom at week 1, reported by 25.0%.

    “In patients who discontinued from the OP/MAINT phase, the most common (> 20%) new or worsening”
    Quote in the paperNot a substantial claim
  • Findingown data

    Cognitive performance generally improved or stayed stable after baseline.

    “Cognitive performance generally either improved or remained stable postbaseline.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In this study, preservation or improvement in all clinically significant cognitive domains on the Cogstate and HLVT-R was observed, except in patients aged ≥65 years who had slowing on simple (DET) and choice reaction-time (IDN) tests.

    “In the present study, preservation or improvement in all clinically significant cognitive domains on the Cogstate and HLVT-R was observed, except in patients aged ≥ 65 years, who had slowing of performance only on simple (DET) and choice reaction-time (IDN) tests of the Cogstate.”
    Quote in the paperSubstantial claim
  • May combine two claims. 35
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Study design and conductown data

    High retention rates (75% from IND entered OP/MAINT) and attainment of adequate exposure requirements add to the comprehensiveness of the data.

    “Furthermore, the high retention rates (75% of patients from the IND phase entered the OP/MAINT phase) and attainment of adequate exposure requirements (as outlined in the International Council for Harmonisation [ICH] E1 guideline) 40 adds to the comprehensiveness of the data collected during this longitudinal study.41,42”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [40] 40. P u b M e d C r o s s R e f 40. ICH Harmonised tripartite guideline-The Extent Of Population Exposure To Assess Clinical Safety For Drugs Intended For Long-Term Treatment Of Non-Life-Threatening Conditions E1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 1994.

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

    • cites [41] 41. Abshire M, Dinglas VD, Cajita MI, et al. Participant retention practices in longitudinal clinical research studies with high retention rates. BMC Med Res Methodol. 2017;17(1):30. P u b M e d C r o s s R e f source

      The Background (page unavailable) says participant retention is vital to the power and internal validity of longitudinal research, supporting the general point that retention strengthens the data. The Results (page unavailable) concern studies with at least 80% retention; this paper does not establish the citing study’s 75% transition from IND to OP/MAINT or its exposure requirements. The ICH guideline is cited separately as reference 40. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [42] 42. Simmonds B, Turner N, Thomas L, et al. Patients' experiences of participating in a large-scale trial of cognitive behavioural therapy for depression: a mixed methods study. Fam Pract. 2013;30(6):705-711. 42. P u M e d C r o s s R e f See supplementary material for this article at . source

  • May combine two claims.

    Findingown data

    MADRS total score fell during induction, and the reduction persisted during optimization/maintenance (mean [SD] change: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]).

    “Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The most frequent treatment-emergent adverse events were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%).

    “Dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%) were reported frequently (≥ 20% patients) during the IND and OP/MAINT phases”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean PWC-20 total scores were 8.0 (SD 7.61) at end of treatment and remained similar during follow-up at 7.9 (6.91) at week 1, 8.0 (7.42) at week 2, and 7.7 (7.07) at week 4.

    “The mean (SD) PWC-20 total scores (range 0-60; 0-3-point scale [not present = 0, mild = 1, moderate = 2, severe = 3]) were 8.0 (7.61) (at end of treatment) and 7.9 (6.91) (week 1), 8.0 (7.42) (week 2), and 7.7 (7.07) (week 4) during follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most esketamine-related treatment-emergent adverse events were mild or moderate, began soon after dosing, and resolved the same day.

    “Most esketamine-related TEAEs were mild or moderate in intensity, occurred shortly after esketamine nasal spray administration, and resolved the same day.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Of 802 enrolled patients, 86.2% entered directly and 13.8% were transferred from a short-term study.

    “Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment-emergent adverse events of cystitis were mostly mild, transient, self-limiting, and considered suggestive of an infectious etiology (UTI).

    “No case of interstitial/ ulcerative cystitis was reported, and TEAEs of cystitis were mostly of mild severity, transient and self-limiting, and considered to be suggestive of an infectious etiology (ie, UTI).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two deaths occurred, and neither was judged related to esketamine.

    “Two deaths, assessed as doubtful or unrelated to esketamine by the investigator, were reported”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    This study involved difficult-to-treat patients with a long-term history of TRD, moderate to severe depression at baseline, a mean current episode duration of about 3 years, and about a quarter with prior suicidal ideation.

    “This study involved difficult-to-treat patients with a long-term history of TRD, moderate to severe depression at baseline, and a mean duration of the current depressive episode of about 3 years, and approximately a quarter of the sample had a prior history of suicidal ideation.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] 39. P u b M e d C r o s s R e f 39. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-388.

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

  • May combine two claims.

    Findingcitation

    Mean PWC-20 total score 2 weeks after discontinuation (8.0 [7.42]) was similar to end of treatment (8.0 [7.61]) and approximately 2-3 times lower than scores after successful (17.2 [11.6]) and unsuccessful (24.6 [12.6]) benzodiazepine tapering.

    “The mean (SD) PWC-20 total score 2 weeks after discontinuation of esketamine (8.0 [7.42]) was similar to that observed at end of treatment (8.0 [7.61]) and was approximately 2-to 3-times lower than the total scores reported in patients after successful (17.2 [11.6]) and unsuccessful (24.6 [12.6]) tapering-off of their benzodiazepines.19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 19. P u b M e d

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

  • May combine two claims.

    Findingcitation

    Similar to earlier reports, the severity of dissociative symptoms in this study attenuated over time in most cases, although rare transient reemergence of higher intensity dissociative symptoms at a later dosing session was observed.

    “Similar to that in earlier reports of esketamine, [1][2][3][4][5]10 severity of dissociative symptoms in this study attenuated over time in most cases, although in rare instances transient reemergence of higher intensity dissociative symptoms at a later dosing session was observed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1][2][3][4][5]10

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

  • May combine two claims.

    Findingown data

    Completion rates were 74.5% (580/779) in the induction phase and 24.9% (150/603) in the optimization/maintenance phase.

    “580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Serious treatment-emergent adverse events related to renal and urinary tract disorders were assessed as not related to esketamine and resolved while treatment was ongoing.

    “The serious TEAEs related to renal and urinary tract disorders were assessed as not related to esketamine and resolved while the treatment was ongoing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the OP/MAINT phase endpoint, 76.5% of patients were responders and 58.2% were remitters.

    “The percentage of responders and remitters at the OP/MAINT phase endpoint was 76.5% and 58.2%, respectively (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this study, 6 patients (0.7%) attempted suicide, corresponding to 1.571 attempts per 100 patient years.

    “In the present study, 14.5% of patients who did not have suicidal ideation at baseline reported new suicidal ideation, 6 patients (0.7%) attempted suicide (1.571 per 100 patient years), and 1 patient completed suicide (0.262 per 100 patient years).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No interstitial cystitis or respiratory depression occurred.

    “There was no case of interstitial cystitis or respiratory depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In patients with low cardiovascular risk at baseline, blood pressure increases after esketamine were generally transient and led to discontinuation in 0.7% of patients.

    “In patients with low cardiovascular risk at baseline, increases in BP observed after esketamine administration were generally transient and led to discontinuation in 0.7% of patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Maximum post-dose CADSS total scores generally declined over time, with the steepest decline during the 4-week induction phase.

    “Maximum post-dose CADSS total scores generally declined over time, with the steepest decline in the 4-week induction phase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The PHQ-9 responder rate at endpoint was 461 of 744 patients (62.0%) in the induction phase and 449 of 602 patients (74.6%) in the optimization/maintenance phase.

    “Responders c at endpoint, n (%) 461 (62.0) d 449 (74.6) e”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The anxiety and delusions events were reported together with a serious treatment-emergent adverse event of alcohol abuse, judged not esketamine-related, 5 days after the first esketamine dose.

    “The events of anxiety and delusions were reported together with the serious TEAE of alcohol abuse (not esketaminerelated), 5 days after administration of the first dose of esketamine.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    One patient with marked ALT and bilirubin elevations was discontinued because of hepatitis B and ovarian cancer.

    “One patient with marked ALT and bilirubin elevations was discontinued due to hepatitis B and ovarian cancer.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The investigator did not consider the suicide death to be related to esketamine treatment.

    “The event was not considered related to esketamine treatment by the investigator.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During the induction and optimization/maintenance phases, 13 patients (1.7%) had alanine aminotransferase elevations greater than 3 times the upper limit of normal, and in 11 of these patients the elevations returned to baseline or near baseline while esketamine treatment continued.

    “During the IND and OP/MAINT phases, 13 (1.7%)patients had elevations of alanine aminotransferase (ALT) >3 times the upper limit of normal; in 11 patients these elevations returned to baseline or near baseline levels while treatment with esketamine was ongoing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One of the two deaths in the study was a 60-year-old man with a history of hypertension and right lower limb vein surgery, who died on study day 113 (last esketamine dose day 108) from acute cardiac and respiratory failure, which the investigator assessed as doubtfully related to esketamine.

    “Of the two deaths reported, one patient, a 60-year-old man, with a medical history of hypertension and right lower limb vein surgery, died on day 113 of the study (last dose of esketamine: day 108) due to acute cardiac and respiratory failure that were assessed as doubtfully related to esketamine treatment by the investigator.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The PHQ-9 remission rate at endpoint was 201 patients (26.9%) in the induction phase and 286 patients (47.4%) in the optimization/maintenance phase.

    “Remitters f at endpoint, n (%) 201 (26.9) b 286 (47.4)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The SDS remission rate at endpoint was 137 of 648 patients (21.1%) in the induction phase and 220 of 557 patients (39.5%) in the optimization/maintenance phase.

    “| Remitters j at endpoint, n (%) | 137 (21.1) d | 220 (39.5) g |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The SDS responder rate at endpoint was 310 of 648 patients (47.8%) in the induction phase and 351 of 557 patients (63.0%) in the optimization/maintenance phase.

    “| (%) | 310 (47.8) d | 351 (63.0) g |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean PHQ-9 total scores decreased from induction baseline to endpoint, and this improvement appeared to be maintained from optimization/maintenance baseline to endpoint.

    “The mean (SD) PHQ-9 total scores decreased from IND baseline to endpoint and this improvement appeared to be maintained from OP/MAINT baseline to endpoint”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean SDS total score fell from 22.2 at induction baseline to 12.8 at induction endpoint, and from 11.3 at optimization/maintenance baseline to 9.5 at optimization/maintenance endpoint.

    “Baseline b , mean (SD) | 22.2 (5.45) c | 11.3 (7.27) f |”
    • Also stated in: § Additional information · plain
      “Endpoint, mean (SD) | 12.8 (7.89) d | 9.5 (7.89) g |”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Delirium occurred 35 minutes after esketamine dosing on day 127 in a patient with a prior history of alcohol use.

    “Delirium occurred 35 minutes after esketamine dosing on day 127 in a patient with prior history of alcohol use.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the STAR*D study, remission rates by QIDS-SR ≤5 were 30.6% after 2, 13.7% after 3, and 13.0% after 4 failed antidepressant trials.

    “In the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 38 remission rates assessed by a different instrument and more strict criteria (Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR] ≤ 5) were 30.6% after 2, 13.7% after 3, and 13.0% after 4 failed AD trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] 38. 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. source

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

    Premisecitation

    Suicidal ideation and behavior are associated with treatment-resistant depression, with estimated incidence rates of 0.47 completed and 4.66 attempted suicides per 100 patient years.

    “Suicidal ideation and behavior are associated with TRD with estimated incidence rates of 0.47 completed and 4.66 attempted suicides per 100 patient years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 32. P u b M e d C r o s s R e f 32. Bergfeld IO, Mantione M, Figee M, et al. Treatment-resistant depression and suicidality. J Affect Disord. 2018;235:362-367. source

  • May combine two claims.

    Interpretationown data

    Over up to one year, esketamine nasal spray was acceptably tolerated, and its adverse event profile resembled that seen in shorter studies of patients with treatment-resistant depression.

    “Long-term (up to 1 year) treatment with esketamine nasal spray demonstrated acceptable tolerability and an adverse event profile comparable with that of the shortterm studies in patients with TRD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The open-label design did not materially affect the safety findings.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The definition of remission as MADRS ≤12 was selected because patients had TRD and higher baseline MADRS scores than typically included in general MDD studies.

    “The definition of remission as a MADRS score ≤ 12 was selected taking into account that the patients manifested TRD prior to entry and thus had higher MADRS scores at baseline than those typically included for studies assessing the efficacy of new treatments in the general MDD population.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    This study had limitations including an open-label design, simultaneous initiation of a new oral antidepressant, and absence of a control group.

    “This study had several limitations including its openlabel study design, the simultaneous initiation of a new OAD, and the absence of a control group; however, the high response and remission rates suggest that long-term (up to 1 year) esketamine treatment appears to provide sustained symptom improvement.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Reductions in depressive symptoms were observed during the first 4 weeks of treatment (IND phase) and appeared to be sustained through the 1-year exposure period.

    “Reductions in depressive symptoms were observed during the first 4 weeks of treatment (IND phase) and appeared to be sustained through the 1-year exposure period.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Another study reported that in patients with treatment-resistant depression, the lifetime risk of suicide attempts is assessed to be close to 30%.

    “Another study 33 reported that in TRD patients, the life-time risk of suicide attempts is assessed to be close to 30%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] 33. P u b M e d C r o s s R e f 33. Dunner DL, Rush AJ, Russell JM, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry. 2006;67(5):688-695. source

  • May combine two claims.

    Interpretationown data

    Collectively, the findings and PWC-20 discontinuation symptoms suggest that withdrawal symptoms were infrequent, mild, and generally indistinguishable from early return of MDD symptoms.

    “Collectively, these findings and discontinuation-related symptoms from the PWC-20 assessment suggest that withdrawal symptoms were infrequent, mild, and in quality appeared generally indistinguishable from early return in MDD symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    For most patients, the findings suggested consistent benefits and acceptable tolerability of esketamine nasal spray treatment over up to 1 year.

    “As dosing frequency was based on treatment response together with tolerability, for most patients, the findings suggested consistent benefits and acceptable tolerability of esketamine nasal spray treatment over a period of up to 1 year.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A single subanesthetic dose (0.2 and 0.5 mg/kg) of ketamine showed no cognitive impairment in patients with TRD, but effects of repeated longer-term use remain elusive.

    “Although a single subanesthetic dose (0.2 and 0.5-mg/kg) of ketamine showed no cognitive impairment (working memory and go/no-go tasks on days 3 and 14 postketamine infusion) in patients with TRD, effects on cognitive performance with repeated use of ketamine over longer periods remains elusive.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] 34. P u b M e d C r o s s R e f 34. Chen MH, Li CT, Lin WC, et al. Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion. J Affect Disord. 2018;241:1-7. P u b M e d C r o s s R e f source

  • May combine two claims.

    Premisecitation

    These suicide rates are substantially higher than in the general MDD population and similar to those before and after treatments such as electroconvulsive therapy.

    “These rates are substantially higher than those in the general MDD population and similar to those found before and after treatments such as electroconvulsive therapy.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 32. P u b M e d C r o s s R e f 32. Bergfeld IO, Mantione M, Figee M, et al. Treatment-resistant depression and suicidality. J Affect Disord. 2018;235:362-367. source

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

    Premisecitation

    Cognitive deficits, impairments in working memory, and decrements in episodic memory have been documented following acute and repeated recreational abuse of ketamine.

    “Cognitive deficits, impairments in working memory, and decrements in episodic memory have been documented following acute and repeated recreational abuse of ketamine.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 8. P u b M e d C r o s s R e f 8. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self- administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction. 2010;105(1):121-133. source
42 of 42

  • The paper relies on this without support.

    Long-term safety data for esketamine in treatment-resistant depression were lacking before this study.

    “data on its long-term safety have been lacking prior to the current study.”

  • The paper relies on this without support.

    Esketamine has shown favorable efficacy and tolerability in short-term studies of treatment-resistant depression.

    “Esketamine has shown favorable efficacy and tolerability in short-term studies of patients with treatment-resistant depression (TRD)”

  • The paper relies on this without support.

    The open-label design did not materially affect the safety findings.

    “This open-label (OL), multicenter study was conducted between October 2015 and October 2017 at 114 sites in 21 countries.”

  • The paper relies on this without support.

    Esketamine's rapid plasma clearance, short half-life, and low dosing frequency prevent steady-state accumulation in patients.

    “Notably, the rapid clearance from plasma, short half-life, and low frequency of dosing (weekly or everyother-week) did not allow esketamine to reach steady-state in patients dosed in this study.”
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?

  • Intranasal esketamine spray co-initiated with an antidepressant has demonstrated rapid clinically meaningful efficacy in patients with TRD.

    “Intranasal esketamine spray co-­ initi­ ated with an antidepressant has also demonstrated rapid clinically meaningful efficacy in patients with TRD.”

    From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [195]

    The Efficacy section (page unavailable) reports substantial improvement during the four-week induction phase in patients receiving esketamine nasal spray plus an oral antidepressant. The Discussion says reductions were observed during those four weeks, but does not establish how rapidly clinically meaningful improvement occurred. It also notes that the study was open-label and had no control group, limiting what it can demonstrate about efficacy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • There are data demonstrating long-term (greater than 3-year) safety and tolerability for esketamine.

    “Unlike IV ketamine, there are also data demonstrating long-­ term (i.e., greater than 3-­ year) safety and tolerability for esketamine 194,195 .”

    From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [195]

    The Clinical Points and Discussion (page numbers not supplied) report acceptable safety and tolerability for esketamine nasal spray treatment lasting up to one year. They do not support the attributed duration of greater than three years. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The absence of long-term data with SGAs is a point of differentiation with esketamine, which has long-term multi-year establishment of efficacy and safety.

    “The absence of long-­ term data with SGAs is a point of differentiation with esketamine, which has long-­ term multi-­ year establishment of efficacy and safety 195 .”

    From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [195]

    The Discussion (page unavailable) reports favorable safety and sustained symptom improvement with esketamine plus an oral antidepressant for up to one year. It does not establish efficacy and safety over multiple years, and it does not compare the availability of long-term data for esketamine and SGAs. The study also notes its open-label design and lack of a control group. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • No deaths were reported in the placebo group in the long-term open-label study.

    “No deaths were reported in the placebo group.”

    From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [113]

  • The approvals of esketamine nasal spray were based on efficacy and safety findings from phase 2/3 studies of treatment-resistant depression treatment for 4 weeks to 1 year.

    “The approvals of esketamine nasal spray were based on efficacy and safety findings from phase 2/3 studies of TRD treatment for 4 weeks to 1 year [9–14].”

    From Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study (2023) · cites this paper as [14]

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.

  • Reported absence of impaired reaction time conflicts with patient data

    Major

    The paper says no patient had impaired reaction time at endpoints, using a z-score threshold below −1.5. In the simple-reaction-time table, patient 15 had a baseline score of 0.52 and an OP/MAINT endpoint score of −2.68.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. [7]7. P u b M e d C r o s s R e f 7. Morgan CJ, Curran HV; Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 2012;107(1):27-38.
  2. [9]9. P u M e d C r o s s R e f 9. Sanacora G, Frye MA, McDonald W, et al; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
  3. [28]28. P u b M e d C r o s s R e f 26. Guy W. CGI Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: National Institute of Mental Health; 1976:217-222.
  4. [35]35. Bruce KM, Robinson SR, Smith JA, et al. Validity of a screening tool for detecting subtle cognitive impairment in the middle-aged and elderly. Clin Interv Aging. 2014;9:2165-2176. 35. P u b M e d
  5. [39]39. P u b M e d C r o s s R e f 39. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-388.
  6. [40]40. P u b M e d C r o s s R e f 40. ICH Harmonised tripartite guideline-The Extent Of Population Exposure To Assess Clinical Safety For Drugs Intended For Long-Term Treatment Of Non-Life-Threatening Conditions E1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 1994.

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Related

Authors
Wajs, E., Aluisio, L., Holder, R., Daly, E. J., Lane, R., Lim, P., George, J. E., Morrison, R. L., Sanacora, G., Young, A. H., Kasper, S., Sulaiman, A. H., Li, C.-T., Paik, J.-W., Manji, H., Hough, D., Grunfeld, J., Jeon, H. J., Wilkinson, S. T., Drevets, W. C., & Singh, J. B.
Affiliations
  • Janssen (Belgium) (BE)
  • Janssen Research & Development (United States) (US)
  • Janssen Canada (Canada) (CA)
  • Yale University (US)
  • King's College London (GB)
  • Medical University of Vienna (AT)
  • University of Malaya (MY)
  • Taipei Veterans General Hospital (TW)
  • Kyung Hee University (KR)
  • Peninsula Health (AU)
  • Samsung Medical Center (KR)
Corresponding author
Wajs, Ewa
ORCID
Venue
The Journal of Clinical Psychiatry
Publisher
Physicians Postgraduate Press, Inc
Published
2020-04-28
Volume
81
Issue
3
ISSN
  • 0160-6689 (ISSN-L)
  • 1555-2101
DOI
10.4088/jcp.19m12891
OpenAlex
W3017383621
Cited by
299
References
3
Citations by year
2026: 43 · 2025: 59 · 2024: 47 · 2023: 42 · 2022: 47 · 2021: 39 · 2020: 19 · 2019: 1
FWCI
21.28
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • The University of Malaya Research Repository (University of Malaya) (submittedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
Keywords
esketamine, nasal spray, treatment-resistant depression, major depressive disorder, oral antidepressant, long-term safety, treatment-emergent adverse events, dissociation
MeSH terms
Administration, Intranasal, Administration, Oral, Adolescent, Adult, Aged, Antidepressive Agents, Cognition, Drug Therapy, Combination

About these checks

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.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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