The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index; 3 of the 19 sources its claims cite were checked for support.
Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2)
Open accessAbstract
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.
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50 Own result · 13 Own interpretation · 7 No full text of the sources · 6 Sources not found · 6 Own method · 5 No basis given · 2 Partly supported · 1 Supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Supportedcites [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
The Results and Recommendations identify well-matched alternate forms as a way to attenuate practice effects. The statement that forms were used for all the listed tests describes the citing authors’ own methods; the source supports the rationale for that choice, not those study-specific details. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In patients who discontinued from the OP/MAINT phase, the most common (> 20%) new or worsening”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Withdrawal Symptoms
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cognitive performance generally either improved or remained stable postbaseline.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, there was no significant change in the more complex cognitive domains (verbal, visual, working memory, and executive function), suggesting that the slowing in reaction times may be an isolated observation, not implicating attentional deficit.35”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Seventysix patients (9.5%) had TEAEs that led to discontinuation of esketamine.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Safety
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The improvement in MADRS total score appeared to be sustained in patients who were responders (direct and transfer entry) and who continued treatment for up to 1 year of exposure (mean [SD] change from OP/ MAINT baseline to endpoint: 0.3 [8.12])”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Efficacy
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 35
- The quote only partly states this claim. 1
- Probably not a substantial claim. 9
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not matchedcites [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.
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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]).”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Safety
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Withdrawal Symptoms
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most esketamine-related TEAEs were mild or moderate in intensity, occurred shortly after esketamine nasal spray administration, and resolved the same day.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Safety
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Abstract
plainn = 802- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two deaths, assessed as doubtful or unrelated to esketamine by the investigator, were reported”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Safety
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not matchedcites [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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not matchedcites [19] 19. P u b M e d
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not matchedcites [1][2][3][4][5]10
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Abstract
plainn = 779- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The serious TEAEs related to renal and urinary tract disorders were assessed as not related to esketamine and resolved while the treatment was ongoing.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The percentage of responders and remitters at the OP/MAINT phase endpoint was 76.5% and 58.2%, respectively (Table 3).”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Efficacy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plainn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no case of interstitial cystitis or respiratory depression.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Maximum post-dose CADSS total scores generally declined over time, with the steepest decline in the 4-week induction phase.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Responders c at endpoint, n (%) 461 (62.0) d 449 (74.6) e”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainn = 744- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One patient with marked ALT and bilirubin elevations was discontinued due to hepatitis B and ovarian cancer.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The event was not considered related to esketamine treatment by the investigator.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainn = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remitters f at endpoint, n (%) 201 (26.9) b 286 (47.4)”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainn = 286- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“| Remitters j at endpoint, n (%) | 137 (21.1) d | 220 (39.5) g |”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainn = 648- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“| (%) | 310 (47.8) d | 351 (63.0) g |”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainn = 648- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 |”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Additional information · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Delirium occurred 35 minutes after esketamine dosing on day 127 in a patient with prior history of alcohol use.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Additional information
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Clinical Points
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The open-label design did not materially affect the safety findings.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Another study 33 reported that in TRD patients, the life-time risk of suicide attempts is assessed to be close to 30%.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Cognitive deficits, impairments in working memory, and decrements in episodic memory have been documented following acute and repeated recreational abuse of ketamine.8”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“No deaths were reported in the placebo group.”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [113]
In the citing paper
“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].”
In the citing paper
“The safety profile of esketamine, with continuous intermittent dosing for up to 4.5 years in SUSTAIN-3 (2,769 cumulative patient-years), is consistent with its established safety profile in participants with TRD treated for up to 1 year [7, 8, 14].”
In the citing paper
“The incidence of clinically-relevant sedation (MOAA/S score ≤ 3) in SUSTAIN-3 (6.1% in the induction phase and 6.9% in the optimization/maintenance phase) is similar to that observed in the prior long-term SUSTAIN-2 study (8.4% and 7.0% in the respective phases) [14].”
In the citing paper
“Our findings extend those of Wajs et al. [14], who reported a 47.2% remission rate at 12 months.”
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > Cognitive Effects
“no patient manifested impaired reaction time (z score < -1.5 on detection or identification tasks) at study endpoints and follow-up”
§ Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2) > DISCUSSION
“15 71 0.52 -2.01 -1.38 -1.59 -0.43 -2.68 -0.83”
Citations
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“It is reassuring that a long-term study with intranasal esketamine did not identify a significant percentage of individuals experiencing genitourinary symptoms (100, 101).”
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Self-citationKetamine: A tale of two enantiomers
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“A subsequent open-label study has examined the longterm safety of (S)-ketamine nasal spray plus a new oral antidepressant in patients with TRD (Wajs et al., 2020).”
BackgroundSelf-citationEsketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression
Reif, A., Bitter, I., Buyze, J., Cebulla, K., Frey, R., Fu, D.-J., Ito, T., Kambarov, Y., Llorca, P.-M., Oliveira-Maia, A. J., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2304145 · Cited by 222
Self-citationAlnefeesi, Y., Chen-Li, D., Krane, E., Jawad, M. Y., Rodrigues, N. B., Ceban, F., Di Vincenzo, J. D., Meshkat, S., Ho, R. C. M., Gill, H., et al. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.04.037 · Cited by 186
Smith-Apeldoorn, S. Y., Veraart, J. K., Spijker, J., Kamphuis, J., & Schoevers, R. A. (2022) · The Lancet Psychiatry · doi:10.1016/s2215-0366(22)00317-0 · Cited by 169
Martinotti, G., Vita, A., Fagiolini, A., Maina, G., Bertolino, A., Dell'Osso, B., Siracusano, A., Clerici, M., Bellomo, A., Sani, G., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.09.043 · Cited by 146
Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status
Henter, I. D., Park, L. T., & Zarate, C. A. (2021) · CNS Drugs · doi:10.1007/s40263-021-00816-x · Cited by 142
“These issues remain a concern, particularly in the context of long-term (R,S)-ketamine/esketamine use, and suggest that the side effect, safety, and addiction profile of these agents should be explored in larger studies designed to better identify the limitations associated with long-term use [65, 66].”
BackgroundGastaldon, C., Raschi, E., Kane, J. M., Barbui, C., & Schoretsanitis, G. (2021) · Psychotherapy and Psychosomatics · doi:10.1159/000510703 · Cited by 134
Zaki, N., Chen, L., Lane, R., Doherty, T., Drevets, W. C., Morrison, R. L., Sanacora, G., Wilkinson, S. T., Popova, V., & Fu, D.-J. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01577-5 · Cited by 137
“5 years in SUSTAIN-3 (2,769 cumulative patientyears), is consistent with its established safety profile in participants with TRD treated for up to 1 year [7, 8, 14].”
Self-citationLong-term safety of ketamine and esketamine in treatment of depression
Nikayin, S., Murphy, E., Krystal, J. H., & Wilkinson, S. T. (2022) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2022.2066651 · Cited by 128
“older patients (ages 65 or greater), reaction time slowed starting around week 20 of the maintenance phase [10].”
BackgroundSelf-citationThe molecular pathophysiology of depression and the new therapeutics
Tian, H., Hu, Z., Xu, J., & Wang, C. (2022) · MedComm · doi:10.1002/mco2.156 · Cited by 122
Wilkinson, S. T., Rhee, T. G., Joormann, J., Webler, R., Ortiz Lopez, M., Kitay, B., Fasula, M., Elder, C., Fenton, L., & Sanacora, G. (2021) · Psychotherapy and Psychosomatics · doi:10.1159/000517074 · Cited by 108
Self-citationGreenway, K. T., Garel, N., Jerome, L., & Feduccia, A. A. (2020) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2020.1772054 · Cited by 94
“pressants [177], typically administered by repeated 40-minute IV 0.”
BackgroundDodd, S., Bauer, M., Carvalho, A. F., Eyre, H. A., D, M. F. M., Kasper, S. F., Kennedy, S. H., Khoo, J., López‐Jaramillo, C., Malhi, G. S., et al. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2020.1851052 · Cited by 100
Self-citationEsketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis
Fountoulakis, K. N., Saitis, A., & Schatzberg, A. F. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20240515 · Cited by 90
Kasper, S. F., Cubała, W. J., Fagiolini, A. M., Ramos‐Quiroga, J. A., Souery, D., & Young, A. H. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2020.1836399 · Cited by 89
Self-citationEsketamine for Treatment-Resistant Depression: A Review of Clinical Evidence (Review)
Vasiliu, O. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.11810 · Cited by 82
“The duration of moni‑ toring was 48 weeks; MADRS scores decreased during the induction phase (41).”
InfluentialBrain Changes Associated With Long-Term Ketamine Abuse, A Systematic Review
Strous, J. F. M., Weeland, C. J., van der Draai, F. A., Daams, J. G., Denys, D. A. J. P., Lok, A., Schoevers, R. A., & Figee, M. (2022) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2022.795231 · Cited by 85
Novel antidepressant drugs: Beyond monoamine targets
Gonda, X., Döme, P., Neill, J. C., & Tarazi, F. I. (2021) · CNS Spectrums · doi:10.1017/s1092852921000791 · Cited by 83
Martinotti, G., Dell’Osso, B. M., Lorenzo, G. D., Maina, G., Bertolino, A., Clerici, M., Barlati, S., Rosso, G., Nicola, M. D., Marcatili, M., et al. (2023) · Bipolar Disorders · doi:10.1111/bdi.13296 · Cited by 79
Loo, C. K. A., Glozier, N., Barton, D., Baune, B. T., Mills, N. T., Fitzgerald, P. B., Glue, P., Sarma, S., Gálvez, V., Hadži-Pavlović, D., et al. (2023) · The British Journal of Psychiatry · doi:10.1192/bjp.2023.79 · Cited by 86
“4,26 The current results do confirm that if ketamine treat-ment is halted after 4 weeks, the benefits are not sustained for all remitters and that ongoing treatment should be considered.”
Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review
Salahudeen, M. S., Wright, C. M., & Peterson, G. M. (2020) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098620937899 · Cited by 72
Novel Pharmacological Approaches to the Treatment of Depression
Elias, E., Zhang, A. Y., & Manners, M. T. (2022) · Life · doi:10.3390/life12020196 · Cited by 77
“MDD and TRD patients who received esketamine alone or in combination with standard antidepressants had significant improvement in MDD symptoms compared to standard antidepressants [80], with high tolerability and safety [81].”
MethodNikkheslat, N. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100383 · Cited by 72
Glutamatergic Modulators for Major Depression from Theory to Clinical Use
McIntyre, R. S., & Jain, R. (2024) · CNS Drugs · doi:10.1007/s40263-024-01114-y · Cited by 69
Caldiroli, A., Capuzzi, E., Tagliabue, I., Capellazzi, M., Marcatili, M., Mucci, F., Colmegna, F., Clerici, M., Buoli, M., & Dakanalis, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313070 · Cited by 77
Doherty, T., Wajs, E., Melkote, R., Miller, J., Singh, J. B., & Weber, M. A. (2020) · CNS Drugs · doi:10.1007/s40263-020-00699-4 · Cited by 68
“Esketamine, the S-enantiomer of ketamine racemate, was recently approved by the United States (US) Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) as an intranasal formulation for adults with TRD based on efficacy and safety findings from short-term phase II/III studies [4–9] and longer-t…”
BackgroundSelf-citationShen, J., Song, C., Lu, X., Wen, Y., Song, S., Yu, J., & Sun, J. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1038379 · Cited by 72
“During 1 year of esketamine maintenance treatment (30), five patients (0.”
BackgroundTHERAPEUTIC MECHANISMS OF KETAMINE
Mihaljević, S., Pavlović, M., Reine, K., & Čačić, M. (2020) · Psychiatria Danubina · doi:10.24869/psyd.2020.325 · Cited by 83
Ketamine and its metabolites: Potential as novel treatments for depression
Zhang, K., Yao, Y., & Hashimoto, K. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109305 · Cited by 69
Chen, G., Chen, L., Zhang, Y., Li, X., Lane, R., Lim, P., Daly, E. J., Furey, M. L., Fedgchin, M., Popova, V., et al. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyab084 · Cited by 66
Self-citationTakahashi, N., Yamada, A., Shiraishi, A., Shimizu, H., Goto, R., & Tominaga, Y. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03538-y · Cited by 57
Samalin, L., Rothärmel, M., Mekaoui, L., Gaudré-Wattinne, E., Codet, M.-A., Bouju, S., & Sauvaget, A. (2022) · International Journal of Psychiatry in Clinical Practice · doi:10.1080/13651501.2022.2030757 · Cited by 54
“Overall, the safety and tolerability profile of esketamine in this French ATUc programme was acceptable and consistent with the findings described in previous studies (Daly et al. 2019; Fedgchin et al. 2019; Popova et al. 2019; Ochs-Ross et al. 2020; Wajs et al. 2020).”
BackgroundResultInfluentialMcQuaid, J. R., Buelt, A., Capaldi, V., Fuller, M., Issa, F., Lang, A. E., Hoge, C., Oslin, D. W., Sall, J., Wiechers, I. R., et al. (2022) · Annals of Internal Medicine · doi:10.7326/m22-1603 · Cited by 59
“Although there is evidence to support longer-term maintenance use of esketamine, it too has been primarily studied in patients who have previously not responded to trials of antidepressants (37, 38).”
BackgroundEsketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial
Janik, A., Qiu, X., Lane, R., Popova, V., Drevets, W. C., Canuso, C. M., Macaluso, M., Mattingly, G. W., Shelton, R. C., Zajecka, J. M., et al. (2025) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2025.1317 · Cited by 54
Self-citationd’Andrea, G., Pettorruso, M., Lorenzo, G. D., Rhee, T. G., Chiappini, S., Carullo, R., Barlati, S., Zanardi, R., Rosso, G., Nicola, M. D., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.12.038 · Cited by 55
Wang, S., Kim, N.-Y., Na, H.-R., Lim, H. K., Woo, Y. S., Pae, C., & Bahk, W. (2021) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2021.19.2.341 · Cited by 61
“However, number of studies investing long-term safety and tolerability of intranasal esketamine are scarce [35].”
BackgroundChiappini, S., d’Andrea, G., Filippis, S. D., Nicola, M. D., Andriola, I., Bassetti, R., Barlati, S., Pettorruso, M., Sensi, S. L., Clerici, M., et al. (2023) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2023.04.011 · Cited by 52
“…were dissociation and sedation, as previously recorded in both clinical and pharma-covigilance studies ( McIntyre et al., 2021 ; Guo et al., 2022 ; Wajs et al., 2020 ); specifically, side effects monitoring was limited to two hours as requested by the SPC, and they did not require any major…”
Vekhova, K. A., Namiot, E. D., Jonsson, J., & Schiöth, H. B. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3478 · Cited by 61
“42,53 58 In December, 2019, the European Medicines Agency (EMA) approved Spravato® in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) for patients with TRD. 62 A systematic review and meta-analysis by Orhurhu et al .…”
Reporting of harms in clinical trials of esketamine in depression: a systematic review
de Laportalière, T. T., Jullien, A., Yrondi, A., Cestac, P., & Montastruc, F. (2023) · Psychological Medicine · doi:10.1017/s0033291723001058 · Cited by 26
“Psychological Medicine 4307 Ochs-Ross et al., 2020; Popova et al., 2019; Takahashi et al., 2021; Wajs et al., 2020).”
BackgroundPharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression
Vecera, C. M., C. Courtes, A., Jones, G., Soares, J. C., & Machado-Vieira, R. (2023) · Pharmaceuticals · doi:10.3390/ph16111572 · Cited by 48
“Although interpreted by the investigator as unrelated to esketamine, the suicide completer had no history of suicidal behavior or intent [113].”
BackgroundResultInfluentialLi, Y., Wu, H., Jiang, X., Dong, Y.-F., Zheng, J., & Gao, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.04.001 · Cited by 47
Genome-wide association study and polygenic risk score analysis of esketamine treatment response
Li, Q. S., Wajs, E., Ochs-Ross, R., Singh, J. B., & Drevets, W. C. (2020) · Scientific Reports · doi:10.1038/s41598-020-69291-6 · Cited by 49
Self-citationAn, D., Wei, C., Wang, J., & Wu, A. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.648691 · Cited by 45
Ng, J., Rosenblat, J. D., Lui, L. M. W., Teopiz, K. M., Lee, Y. L., Lipsitz, O., Mansur, R. B., Rodrigues, N. B., Nasri, F., Gill, H., et al. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.06.032 · Cited by 47
Sapkota, A., Khurshid, H., Qureshi, I. A., Jahan, N., Went, T. R., Sultan, W., & Alfonso, M. (2021) · Cureus · doi:10.7759/cureus.17352 · Cited by 45
Swainson, J., Klassen, L. J., Brennan, S., Chokka, P. R., Katzman, M. A., Tanguay, R. L., & Khullar, A. (2022) · CNS Drugs · doi:10.1007/s40263-022-00897-2 · Cited by 50
“Further evidence may be gleaned from a 48-week open-label extension phase III esketamine nasal spray trial, where there were no reports of drug seeking, overdose, abuse, or patient requests for dose increases beyond the maximum study dosage of 84 mg once weekly [71].”
BackgroundOchs-Ross, R., Wajs, E., Daly, E., Zhang, Y., Lane, R., Lim, P., Drevets, W. C., Steffens, D. C., Sanacora, G., Jamieson, C., et al. (2021) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2021.09.014 · Cited by 44
Self-citationSafety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review
Moore, T. J., Alami, A., Alexander, G. C., & Mattison, D. R. (2022) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.2707 · Cited by 46
d’Andrea, G., Chiappini, S., McIntyre, R. S., Stefanelli, G., Carullo, R., Andriola, I., Zanardi, R., Martiadis, V., Sensi, S. L., Sani, G., et al. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.06.016 · Cited by 42
Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study
Zaki, N., Chen, L., Lane, R., Doherty, T., Drevets, W. C., Morrison, R. L., Sanacora, G., Wilkinson, S. T., Young, A. H., Lacerda, A. L. T., et al. (2025) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaf027 · Cited by 46
“12 The SUSTAIN-3 trial (NCT02782104) was conducted to assess longer-term safety (including cognitive, hepatic, and renal safety) and sustained efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD. Reported herein are the final results of SUSTAIN-3, which…”
Self-citationAntianhedonic effect of repeated ketamine infusions in patients with treatment resistant depression
Wilkowska, A., Wiglusz, M. S., Gałuszko-Wegielnik, M., Włodarczyk, A., & Cubała, W. J. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.704330 · Cited by 35
“Similar to benzodiazepines, ketamine has abuse potential (32); therefore, it is particularly important to follow-up patients on ketamine treatment, especially on long-term use as this regimen seems to be the most effective (33).”
BackgroundVincenzo, M. D., Martiadis, V., Rocca, B. D., Arsenio, E., D’Arpa, A., Volpicelli, A., Luciano, M., Sampogna, G., & Fiorillo, A. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1394787 · Cited by 39
Benefit–Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment‐Resistant Depression
Katz, E. G., Hough, D. W., Doherty, T., Lane, R., Singh, J. B., & Levitan, B. S. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2024 · Cited by 36
Self-citationIntranasal esketamine: From origins to future implications in treatment-resistant depression
Sanders, B. J., & Brula, A. Q. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.02.020 · Cited by 37
Souza‐Marques, B., Santos‐Lima, C., Araújo-de-Freitas, L., Vieira, F., Jesus‐Nunes, A. P., Quarantini, L. C., & Sampaio, A. S. (2021) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000312 · Cited by 40
Ng, J., Lui, L. M. W., Rosenblat, J. D., Teopiz, K. M., Lipsitz, O., Cha, D. S., Xiong, J., Nasri, F., Lee, Y. L., Kratiuk, K., et al. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05767-1 · Cited by 34
“For IN esketamine, two clinical studies have reported a low occurrence (< 10%) of urological complications at antidepressant doses (28–84 mg) (Daly et al. 2019; Wajs et al. 2020).”
BackgroundInfluentialJones, R., Freeman, M. P., Kornstein, S. G., Cooper, K., Daly, E., Canuso, C. M., & Nicholson, S. (2022) · Archives of Women s Mental Health · doi:10.1007/s00737-021-01185-6 · Cited by 33
Self-citationHavlik, J. L., Wahid, S., Teopiz, K. M., McIntyre, R. S., Krystal, J. H., & Rhee, T. G. (2024) · Current Psychiatry Reports · doi:10.1007/s11920-024-01494-4 · Cited by 35
“Wajs et al. similarly performed an open-label multi-site clinical trial to examine the safety and efficacy of esketamine nasal spray alongside a new oral antidepressant as a treatment for TRD [50].”
McIntyre, R. S., Bitter, I., Buyze, J., Fagiolini, A. M., Godinov, Y., Gorwood, P. A. P. M., Ito, T., Oliveira-Maia, A. J., Vieta, E., Werner‐Kiechle, T., et al. (2024) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2024.05.009 · Cited by 34
“…from long-term studies have repeatedly documented the favourable long-term safety profile of esketamine NS, reporting that treatment ‑ emergent dissociative symptoms were generally transient, with no reported events suggestive of abuse (Wajs et al., 2020; Young et al., 2023; Zaki et al., 2023).”
Self-citationVeraart, J. K. E., Smith-Apeldoorn, S. Y., Spaans, H., Kamphuis, J., & Schoevers, R. A. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.11.123 · Cited by 35
The therapeutic role of ketamine and esketamine in treating psychopathological domains of depression
Jawad, M. Y., Vincenzo, J. D. D., Badulescu, S., Teopiz, K. M., Tabassum, A., Ceban, F., Mckenzie, A., Meshkat, S., Rosenblat, J. D., Ho, R., et al. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109299 · Cited by 32
Guo, H., Wang, B., Yuan, S., Wu, S., Liu, J., He, M., & Wang, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.849758 · Cited by 32
Rothärmel, M., Benosman, C., El‐Hage, W., Berjamin, C., Ribayrol, D., Guillin, O., Gaillard, R., Berkovitch, L., & Moulier, V. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.865466 · Cited by 34
“Phase-3 short-term trials of Esketamine nasal spray (28, 56, or 84 mg) plus an oral antidepressant have demonstrated a statistically significant reduction in depressive symptoms [reduction from baseline Montgomery– Åsberg Depression Rating Scale (MADRS) total score] in patients with TRD compared with an oral antidepre…”
BackgroundVankawala, J., Naples, G., Avila-Quintero, V. J., Ramírez, K. L., Flores, J. M., Bloch, M. H., & Dwyer, J. B. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.549080 · Cited by 30
Capuzzi, E., Caldiroli, A., Capellazzi, M., Tagliabue, I., Marcatili, M., Colmegna, F., Clerici, M., Buoli, M., & Dakanalis, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179338 · Cited by 37
“Some studies may be affected by moderate [28] to high risk of bias [26,30] as well as presenting some concerns in term of risk of bias [31,32].”
BackgroundMethodInfluentialJawad, M. Y., Vincenzo, J. D. D., Ceban, F., Jaberi, S., Lui, L. M. W., Gillissie, E. S., Alnefeesi, Y., Rosenblat, J. D., & McIntyre, R. S. (2022) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2022.2058488 · Cited by 29
“Two long-term SUSTAIN trials (> 4 weeks) included were: (1) A relapse prevention study where patients were treated with IN Esketamine for 16 weeks and then those who achieved remission or response were randomized 1:1 into IN Esketamine and IN placebo along with oral antidepressants [23]; (2) A year long open-label tri…”
InfluentialBoudieu, L., Mennetrier, M., Llorca, P., & Samalin, L. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15122773 · Cited by 31
“The 20-item Physician Withdrawal Checklist was used in four RCTs [32,34,37,42].”
BackgroundMethodInfluentialKetamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression
Borsellino, P., Krider, R. I., Chea, D., Grinnell, R., & Vida, T. A. (2023) · Pharmaceuticals · doi:10.3390/ph16050742 · Cited by 29
“1% of patients in the SUSTAIN-2 trial [88] experienced at least one treatment-emergent adverse event.”
BackgroundResultCastro, M., Wilkinson, S. T., Al Jurdi, R. K., Petrillo, M. P., Zaki, N., Borentain, S., Fu, D. J., Turkoz, I., Sun, L., Brown, B., et al. (2023) · CNS Drugs · doi:10.1007/s40263-023-01026-3 · Cited by 25
“A recent study found that a subset of patients ≥65 years of age, who were nonresponders to ESK treatment after completing the double-blind induction (IND) phase of a randomized 4-week efficacy study and subsequently entered the IND phase of an open-label, long-term, safety and efficacy study of ESK (SUSTAIN-2), receiv…”
BackgroundSelf-citationBaudot, J., Soeiro, T., Tambon, M., Navarro, N., Veyrac, G., Mezaache, S., & Micallef, J. (2021) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12745 · Cited by 25
“Adverse event TRANSFORM-1 (NCT02417064) [31] TRANSFORM-2 (NCT02418585) [32] TRANSFORM-3 (NCT02422186) [33] SUSTAIN-1 (NCT02493868) [34] SUSTAIN-2 (NCT02497287) [35]”
BackgroundJeon, H. J., Ju, P., Sulaiman, A. H., Aziz, S. A., Paik, J., Tan, W., Bai, D., & Li, C. (2022) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2022.20.1.70 · Cited by 25
“The key safety assessments for SUSTAIN-2 included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and “TEAEs of special interest” related to suicidality (assessed by the Columbia Suicide Severity Rating Scale) [33], dissociative symptoms (assessed by the Clinician Administered Dissociative St…”
BackgroundMethodInfluentialSelf-citationMorrens, J., Mathews, M., Popova, V., Borentain, S., Rive, B., Gonzalez Martin Moro, B., Jamieson, C., & Zhang, Q. (2022) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s358367 · Cited by 24
Esketamine combined with SSRI or SNRI for treatment-resistant depression
Del Casale, A., Spirito, S., Arena, J. F., Preissner, S., Borro, M., Gentile, G., Modesti, M. N., Preissner, R., Ferracuti, S., & Simmaco, M. (2025) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2025.0200 · Cited by 23
Ren, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110910 · Cited by 23
“The clinical trials proved that ( S )-ketamine has a more potent and effective rapid antidepressant-like effect than ( R )-ketamine (Daly et al., 2018; Wajs et al., 2020; Leal et al., 2021; Leal et al., 2023).”
BackgroundLiu, Y., Bavato, F., Chung, A.-N., Liu, T., Chen, Y., Huang, M., & Quednow, B. B. (2021) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2021.1907709 · Cited by 24
The antidepressant effect and safety of non-intranasal esketamine: A systematic review
Smith-Apeldoorn, S. Y., Vischjager, M., Veraart, J. K. E., Kamphuis, J., Rot, M. A. H., & Schoevers, R. A. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221084055 · Cited by 25
“These symptoms as well as marked psychomimetic symptoms have, however, also been reported after racemic ketamine and IN esketamine administration (Fedgchin et al., 2019; Short et al., 2018; Wajs et al., 2020).”
BackgroundNikayin, S., & Sanacora, G. (2021) · CNS Drugs · doi:10.1007/s40263-021-00851-8 · Cited by 24
Self-citationBayes, A. J., Short, B. L., Zarate, C. A., Park, L., Murrough, J. W., McLoughlin, D. M., Riva‐Posse, P., Schoevers, R. A., Veraart, J. K. E., Parikh, S. V., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.04.020 · Cited by 22
“, 2019) and also maintenance treatment up to 48 weeks with intranasal esketamine (Wajs et al., 2020).”
BackgroundLan, X., Wang, C., Zhang, F., Liu, H., Li, W., Ye, Y., Hu, Z., Mai, S., Ning, Y., & Zhou, Y. (2023) · Child and Adolescent Psychiatry and Mental Health · doi:10.1186/s13034-023-00647-2 · Cited by 22
“5 years) study of 1148 TRD patients treated with esketamine, indicating that cognitive performances, including attention, visual learning and memory, and executive function, the Hopkins Verbal Learning Test-Revised, generally remained stable from baseline through week 160 after the same maintained therapy phrase (week…”
BackgroundIngrosso, G., Cleare, A. J., & Juruena, M. F. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241303597 · Cited by 21
Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data
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Self-citationOvercoming the myths of esketamine administration: different and not difficult
Buchmayer, F., & Kasper, S. F. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1279657 · Cited by 23
Self-citationSartim, A. G., Marques, J., Silveira, K. M., Gobira, P. H., Guimarães, F. S., Wegener, G., & Joca, S. R. L. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108679 · Cited by 22
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Ketamine and esketamine for crisis management in patients with depression: Why, whom, and how?
Lengvenytė, A., Strumila, R., Olié, É., & Courtet, P. (2022) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2022.02.004 · Cited by 21
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“of recreational ketamine abuse [52]; though the same was initially said about opiate-based medications used for pain”
Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression
Zavaliangos‐Petropulu, A., McClintock, S. M., Khalil, J., Joshi, S. H., Taraku, B., Al‐Sharif, N., Espinoza, R. T., & Narr, K. L. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.04.015 · Cited by 22
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“…on the now established safety pro fi le of ESK after data collected during the previous phase III, IIIb, and long-term clinical trials [12, 13, 14, 15, 16, 17, 18], no new safety signals were observed over patient follow-up in the real-world ESKALE study (median treatment duration of 19.4 weeks).”
InfluentialClinical overview of NMDA-R antagonists and clinical practice
Davoudian, P. A., & Wilkinson, S. T. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.04.004 · Cited by 19
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Self-citationDijkstra, F. M., van de Loo, A. J. A. E., Abdulahad, S., Bosma, E. R., Hartog, M., Huls, H., Kuijper, D. C., de Vries, E., Solanki, B., Singh, J. B., et al. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221078764 · Cited by 17
“The 6-h timepoint for the driving test was chosen as it was expected that most AEs would be resolved by then (Daly et al., 2018; Popova et al., 2019; Wajs et al., 2020).”
BackgroundResultInfluentialSelf-citationLiu, P., Zhang, S., Liang, Y., Gao, Z., Gao, W., & Dong, B. (2022) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s388764 · Cited by 20
Ketamine cystitis following ketamine therapy for treatment-resistant depression – case report
Chang, M., Juruena, M. F., & Young, A. H. (2024) · BMC Psychiatry · doi:10.1186/s12888-023-05468-3 · Cited by 19
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“2% maintained remission at study endpoint.(16) A long-term extension study of SUSTAIN-2 (SUSTAIN-3; NCT02782104) is ongoing, with plans to follow patients for several years.”
BackgroundSelf-citationOraee, S., Alinejadfard, M., Golsorkh, H., Sadeghian, M., Fanaei, M., Centis, R., D’Ambrosio, L., Sotgiu, G., Goudarzi, H., Migliori, G. B., et al. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.11.010 · Cited by 20
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Self-citation
Metadata
- 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
- OpenAlex
- W3017383621
- Cited by
- 308
- References
- 3
- Citations by year
- 2026: 50 · 2025: 61 · 2024: 48 · 2023: 44 · 2022: 47 · 2021: 38 · 2020: 19
- FWCI
- 20.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- The University of Malaya Research Repository (University of Malaya) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0616-10091)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › 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, nasal spray, treatment-resistant depression, major depressive disorder, oral antidepressant, long-term safety, treatment-emergent adverse events, dissociation, cognitive performance, maintenance therapy, induction phase, interstitial cystitis, respiratory depression, antidepressant non-response, elderly patients, mood stabilizers, antipsychotic drugs, antiepileptic drugs
- MeSH terms
- Administration, Intranasal, Administration, Oral, Adolescent, Adult, Aged, Antidepressive Agents, Cognition, Drug Therapy, Combination, Female, Humans, Ketamine, Male, Middle Aged, Young Adult, Nasal Sprays, Depressive Disorder, Treatment-Resistant
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